bluuebunny/crossref_metadata_2025 huggingface dataset:
Titin-based stiffening of muscle fibers in Ehlers-Danlos Syndrome
Authors: Ottenheijm Coen A. C. , Voermans Nicol C. , Hudson Bryan D. , Irving Thomas , Stienen Ger J. M. , van Engelen Baziel G. , Granzier Henk
Published: January 2012

Objective: tenascin-X (TNX) is an extracellular matrix glycoprotein whose absence leads to Ehlers-Danlos Syndrome (EDS). TNX-deficient EDS patients present with joint hypermobility and muscle weakness attributable to increased compliance of the extracellular matrix. We hypothesized that in response to the increased compliance of the extracellular matrix in TNX-deficient EDS patients, intracellular adaptations take place in the elastic properties of the giant muscle protein titin. Methods: we performed extensive single muscle fiber mechanical studies to determine active and passive properties in TNX-deficient EDS patients. Gel-electrophoresis, Western blotting, and microarray studies were used to evaluate titin expression and phosphorylation. X-ray diffraction was used to measure myofilament lattice spacing. Results: passive tension of muscle fibers from TNX-deficient EDS patients was markedly increased. Myofilament extraction experiments indicated that the increased passive tension is attributable to changes in the properties of the sarcomeric protein titin. Transcript and protein data indicated no changes in titin isoform expression. Instead, differences in posttranslational modifications within titin's elastic region were found. In patients, active tension was not different at maximal activation level, but at submaximal activation level it was augmented attributable to increased calcium sensitivity. This increased calcium sensitivity might be attributable to stiffer titin molecules. Conclusion: in response to the increased compliance of the extracellular matrix in muscle of TNX-deficient EDS patients, a marked intracellular stiffening occurs of the giant protein titin. The stiffening of titin partly compensates for the muscle weakness in these patients by augmenting submaximal active tension generation.
Midline thalamic paraventricular nucleus neurons display diurnal variation in resting membrane potentials, conductances, and firing patterns in vitro
Authors: Kolaj Miloslav , Zhang Li , Rønnekleiv Oline K. , Renaud Leo P.
Published: January 2012

Neurons in the rodent midline thalamic paraventricular nucleus (PVT) receive inputs from brain stem and hypothalamic sites known to participate in sleep-wake and circadian rhythms. To evaluate possible diurnal changes in their excitability, we used patch-clamp techniques to record and examine the properties of neurons in anterior PVT (aPVT) in coronal rat brain slices prepared at zeitgeber time (ZT) 2–6 vs. ZT 14–18 and recorded at ZT 8.4 ± 0.2 (day) vs. ZT 21.2 ± 0.2 (night), the subjective quiet vs. aroused states, respectively. Compared with neurons recorded during the day, neurons from the night period were significantly more depolarized and exhibited a lower membrane conductance that in part reflected loss of a potassium-mediated conductance. Furthermore, these neurons were also significantly more active, with tonic and burst firing patterns. Neurons from each ZT period were assessed for amplitudes of two conductances known to contribute to bursting behavior, i.e., low-threshold-activated Ca2+ currents ( IT) and hyperpolarization-activated cation currents ( Ih). Data revealed that amplitudes of both IT and Ih were significantly larger during the night period. In addition, biopsy samples from the night period revealed a significant increase in mRNA for Cav3.1 and Cav3.3 low-threshold Ca2+ channel subtypes. Neurons recorded from the night period also displayed a comparative enhancement in spontaneous bursting at membrane potentials of approximately −60 mV and in burst firing consequent to hyperpolarization-induced low-threshold currents and depolarization-induced current pulses. These novel in vitro observations reveal that midline thalamic neurons undergo diurnal changes in their IT, Ih, and undefined potassium conductances. The underlying mechanisms remain to be characterized.
Probing Local Environments by Time-Resolved Stimulated Emission Spectroscopy
Authors: Rei Ana , Hungerford Graham , Belsley Michael , Ferreira M. Isabel C. , Schellenberg Peter
Published: January 2012

Time-resolved stimulated emission spectroscopy was employed to probe the local environment of DASPMI (4-(4-(dimethylamino)styryl)-N-methyl-pyridinium iodide) in binary solvents of different viscosity and in a sol-gel matrix. DASPMI is one of the molecules of choice to probe local environments, and the dependence of its fluorescence emission decay on viscosity has been previously used for this purpose in biological samples, solid matrices as well as in solution. The results presented in this paper show that time-resolved stimulated emission of DASPMI is a suitable means to probe the viscosity of local environments. Having the advantage of a higher time resolution, stimulated emission can provide information that is complementary to that obtained from fluorescence decay measurements, making it feasible to probe systems with lower viscosity.
Gene Regulation Systems for Gene Therapy Applications in the Central Nervous System
Authors: Naidoo Jerusha , Young Deborah
Published: January 2012

Substantial progress has been made in the development of novel gene therapy strategies for central nervous system (CNS) disorders in recent years. However, unregulated transgene expression is a significant issue limiting human applications due to the potential side effects from excessive levels of transgenic protein that indiscriminately affect both diseased and nondiseased cells. Gene regulation systems are a tool by which tight tissue-specific and temporal regulation of transgene expression may be achieved. This review covers the features of ideal regulatory systems and summarises the mechanics of current exogenous and endogenous gene regulation systems and their utility in the CNS.
In VitroandIn VivoAntitumor Effect of Anti-CD33 Chimeric Receptor-Expressing EBV-CTL againstCD33+Acute Myeloid Leukemia
Authors: Dutour A. , Marin V. , Pizzitola I. , Valsesia-Wittmann S. , Lee D. , Yvon E. , Finney H. , Lawson A. , Brenner M. , Biondi A. , Biagi E. , Rousseau R.
Published: January 2012

Genetic engineering of T cells with chimeric T-cell receptors (CARs) is an attractive strategy to treat malignancies. It extends the range of antigens for adoptive T-cell immunotherapy, and major mechanisms of tumor escape are bypassed. With this strategy we redirected immune responses towards the CD33 antigen to target acute myeloid leukemia. To improvein vivoT-cell persistence, we modified human Epstein Barr Virus-(EBV-) specific cytotoxic T cells with an anti-CD33.CAR. Genetically modified T cells displayed EBV and HLA-unrestricted CD33 bispecificityin vitro. In addition, though showing a myeloablative activity, they did not irreversibly impair the clonogenic potential of normal CD34+hematopoietic progenitors. Moreover, after intravenous administration into CD33+human acute myeloid leukemia-bearing NOD-SCID mice, anti-CD33-EBV-specific T cells reached the tumor sites exerting antitumor activityin vivo. In conclusion, targeting CD33 by CAR-modified EBV-specific T cells may provide additional therapeutic benefit to AML patients as compared to conventional chemotherapy or transplantation regimens alone.
Is the Accuracy of Self-Reported Colorectal Cancer Screening Associated with Social Desirability?
Authors: Vernon Sally W. , Abotchie Peter N. , McQueen Amy , White Arica , Eberth Jan M. , Coan Sharon P.
Published: January 2012

Background: Self-reported cancer screening behaviors are often overreported and may lead to biased estimates of prevalence and of subgroup differences in screening. We examined whether the tendency to give socially desirable responses was associated with concordance between self-reported colorectal cancer (CRC) screening behaviors and medical records.

Methods: Primary care patients (n = 857) age 50 to 74 years completed a mail, face-to-face, or telephone survey that assessed CRC screening and social desirability measured by a short version of the Marlowe–Crowne scale. We used medical records to verify self-reports of fecal occult blood testing (FOBT), sigmoidoscopy, colonoscopy, and barium enema.

Results: Social desirability scores were lower for whites versus African Americans, college graduates, and patients reporting no prior screening tests; they were higher for telephone versus mail or face-to-face survey respondents. In univariable logistic regression analysis, social desirability scores were not associated with concordance for FOBT (OR = 1.03, 95% CI = 0.94–1.13), sigmoidoscopy (OR = 0.95, 95% CI = 0.86–1.04), or colonoscopy (OR = 0.99, 95% CI = 0.88–1.11); however, lower social desirability scores were associated with increased concordance for barium enema (OR = 0.87, 95% CI = 0.77–0.99). In multivariable analyses, no associations were statistically significant.

Conclusion: Social desirability as measured by the Marlowe–Crowne scale was not associated with accuracy of self-reported CRC tests in our sample, suggesting that other explanations for overreporting need to be explored.

Impact: By understanding sources of response bias, we can improve the accuracy of self-report measures. Cancer Epidemiol Biomarkers Prev; 21(1); 61–65. ©2011 AACR.
Chemotherapy and Thyroid Cancer Risk: A Report from the Childhood Cancer Survivor Study
Authors: Veiga Lene H.S. , Bhatti Parveen , Ronckers Cécile M. , Sigurdson Alice J. , Stovall Marilyn , Smith Susan A. , Weathers Rita , Leisenring Wendy , Mertens Ann C. , Hammond Sue , Neglia Joseph P. , Meadows Anna T. , Donaldson Sarah S. , Sklar Charles A. , Friedman Debra L. , Robison Leslie L. , Inskip Peter D.
Published: January 2012

Background: Although ionizing radiation is an established environmental risk factor for thyroid cancer, the effect of chemotherapy drugs on thyroid cancer risk remains unclear. We evaluated the chemotherapy-related risk of thyroid cancer in childhood cancer survivors and the possible joint effects of chemotherapy and radiotherapy.

Methods: The study included 12,547 five-year survivors of childhood cancer diagnosed during 1970 through 1986. Chemotherapy and radiotherapy information was obtained from medical records, and radiation dose was estimated to the thyroid gland. Cumulative incidence and relative risks were calculated with life-table methods and Poisson regression. Chemotherapy-related risks were evaluated separately by categories of radiation dose.

Results: Histologically confirmed thyroid cancer occurred in 119 patients. Thirty years after the first childhood cancer treatment, the cumulative incidence of thyroid cancer was 1.3% (95% CI, 1.0–1.6) for females and 0.6% (0.4–0.8) for males. Among patients with thyroid radiation doses of 20 Gy or less, treatment with alkylating agents was associated with a significant 2.4-fold increased risk of thyroid cancer (95% CI, 1.3–4.5; P = 0.002). Chemotherapy risks decreased as radiation dose increased, with a significant decrease for patients treated with alkylating agents (Ptrend = 0.03). No chemotherapy-related risk was evident for thyroid radiation doses more than 20 Gy.

Conclusions: Treatments with alkylating agents increased thyroid cancer risk, but only in the radiation dose range less than 20 Gy, in which cell sparing likely predominates over cell killing.

Impact: Our study adds to the evidence for chemotherapy agent–specific increased risks of thyroid cancer, which to date, were mainly thought to be related to prior radiotherapy. Cancer Epidemiol Biomarkers Prev; 21(1); 92–101. ©2011 AACR.
Case–control Study of Merkel Cell Polyomavirus Infection and Cutaneous Squamous Cell Carcinoma
Authors: Rollison Dana E. , Giuliano Anna R. , Messina Jane L. , Fenske Neil A. , Cherpelis Basil S. , Sondak Vernon K. , Roetzheim Richard G. , Iannacone Michelle R. , Michael Kristina M. , Gheit Tarik , Waterboer Tim , Tommasino Massimo , Pawlita Michael
Published: January 2012

Background: Merkel cell polyomavirus (MCV) DNA has been reported in 0% to 25% of squamous cell carcinomas (SCC) occurring in immunocompetent individuals. We conducted the first serologic case–control study of MCV and SCC.

Methods: Patients with histologically confirmed cutaneous SCC (n = 173) were recruited from a university dermatology clinic. Controls were individuals who screened negative for and had no history of skin or other cancers (n = 300). Levels of antibodies against capsid antigens for MCV and another polyomavirus, JC virus (JCV), were determined by fluorescent bead-based multiplex serology. Fresh-frozen tumor tissues were obtained from 145 SCC cases and tested for MCV DNA by multiplexed PCR. Associations between MCV seroreactivity and SCC were estimated by ORs and 95% CIs calculated using logistic regression with adjustment for age and sex.

Results: MCV DNA was detected in SCC tumor tissues from 55 (38%) of 145 cases. A statistically significant association was observed between MCV seropositivity and MCV DNA-positive SCC (OR = 2.49, 95% CI = 1.03–6.04), with an almost four-fold association observed when comparing those with MCV antibodies in the fourth versus first quartiles (OR = 3.93, 95% CI = 1.43–10.76, Ptrend = 0.01). No significant associations were observed between MCV seropositivity and MCV DNA-negative SCC (OR = 1.38, 95% CI = 0.76–2.48) or between JCV seropositivity and MCV DNA-positive or DNA-negative SCC.

Conclusion: Past exposure to MCV may be a risk factor for SCC.

Impact: Understanding the role of viral infections in the development of nonmelanoma skin cancer could lead to novel prevention strategies. Cancer Epidemiol Biomarkers Prev; 21(1); 74–81. ©2011 AACR.
Phase I Study of the Combination of Sorafenib and Temsirolimus in Patients with Metastatic Melanoma
Authors: Davies Michael A. , Fox Patricia S. , Papadopoulos Nicholas E. , Bedikian Agop Y. , Hwu Wen-Jen , Lazar Alexander J. , Prieto Victor G. , Culotta Kirk S. , Madden Timothy L. , Xu Quanyun , Huang Sha , Deng Wanleng , Ng Chaan S. , Gupta Sanjay , Liu Wenbin , Dancey Janet E. , Wright John J. , Bassett Roland L. , Hwu Patrick , Kim Kevin B.
Published: January 2012

Purpose: This phase I clinical trial was conducted to determine the safety, efficacy, and molecular effects of sorafenib with temsirolimus in patients with advanced melanoma.

Patients and Methods: Patients with stage IV or unresectable or recurrent stage III melanoma and Eastern Cooperative Oncology Group performance status of 0 to 1 were eligible. Sorafenib was given orally once or twice daily and temsirolimus was given i.v. weekly, both starting on day 1, with a 4-week cycle. Responses were assessed every 2 cycles per Response Evaluation Criteria in Solid Tumors criteria. Consenting patients with accessible tumors underwent optional tumor biopsies before treatment and after the second infusion of temsirolimus. Tumor biopsies were analyzed for activating mutations in BRAF and NRAS, and for expression of P-extracellular signal-regulated kinase (P-ERK) and P-S6 proteins.

Results: A total of 25 patients were accrued to the study. The maximum tolerated doses were sorafenib 400 mg every morning and 200 mg every evening and temsirolimus 25 mg i.v. weekly. Dose-limiting toxicities included thrombocytopenia, hand-foot syndrome, serum transaminase elevation, and hypertriglyceridemia. There were no complete or partial responses with the combination; 10 patients achieved stabilization of disease as their best response. The median progression-free survival was 2.1 months. Matching pretreatment and day 15 tumor biopsies showed marked inhibition of P-S6 with treatment in 3 of 4 evaluable patients, but minimal inhibition of P-ERK.

Conclusions: Combination therapy with sorafenib and temsirolimus resulted in significant toxicity at higher dose levels, failed to achieve any clinical responses in genetically unselected patient population, and did not inhibit P-ERK. Clin Cancer Res; 18(4); 1120–8. ©2012 AACR.
Neural and Personality Correlates of Individual Differences Related to the Effects of Acute Tryptophan Depletion on Future Reward Evaluation
Authors: Demoto Yoshihiko , Okada Go , Okamoto Yasumasa , Kunisato Yoshihiko , Aoyama Shiori , Onoda Keiichi , Munakata Ayumi , Nomura Michio , Tanaka Saori C. , Schweighofer Nicolas , Doya Kenji , Yamawaki Shigeto
Published: January 2012

Background/Aims: In general, humans tend to discount the value of delayed reward. An increase in the rate of discounting leads to an inability to select a delayed reward over a smaller immediate reward (reward-delay impulsivity). Although deficits in the serotonergic system are implicated in this reward-delay impulsivity, there is individual variation in response to serotonin depletion. The aim of the present study was to investigate whether the effects of serotonin depletion on the ability to evaluate future reward are affected by individual personality traits or brain activation. Methods: Personality traits were assessed using the NEO-Five Factor Inventory and Temperament and Character Inventory. The central serotonergic levels of 16 healthy volunteers were manipulated by dietary tryptophan depletion. Subjects performed a delayed reward choice task that required the continuous estimation of reward value during functional magnetic resonance imaging scanning. Results: Discounting rates were increased in 9 participants, but were unchanged or decreased in 7 participants in response to tryptophan depletion. Participants whose discounting rate was increased by tryptophan depletion had significantly higher neuroticism and lower self-directedness. Furthermore, tryptophan depletion differentially affected the groups in terms of hemodynamic responses to the value of predicted future reward in the right insula. Conclusions: These results suggest that individuals who have high neuroticism and low self-directedness as personality traits are particularly vulnerable to the effect of low serotonin on future reward evaluation accompanied by altered brain activation patterns.
Serum Protein Levels of Brain-Derived Neurotrophic Factor and Tropomyosin-Related Kinase B in Bipolar Disorder: Effects of Mood Stabilizers
Authors: Huang Tiao-Lai , Hung Yi-Yung , Lee Chien-Te , Chen Rong-Fu
Published: January 2012

Aim:In this study, we investigated serum protein levels of brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) in patients with bipolar disorder. Methods:Over a 2-year period, 26 patients with bipolar I disorder (manic episode) and 56 healthy controls were recruited. The Young Mania Rating Scale scores of patients with bipolar mania were >26. Serum BDNF and TrkB protein levels were measured with ELISA kits. Results: Using ANCOVA with age adjustment, we found that there were no significant differences in serum BDNF protein levels between patients with bipolar mania and healthy controls (p = 0.582). In contrast, the serum TrkB protein level was significantly higher in bipolar mania patients than in healthy controls (p = 0.001), especially in women (p = 0.001). Of 26 patients with bipolar mania, 21 underwent a second measurement of serum BDNF and TrkB protein levels after a 4-week treatment with mood stabilizers. There were no significant changes in serum BDNF or TrkB protein levels. Conclusion:These findings suggest that serum TrkB protein levels may play an important role in the psychopathology of bipolar mania. However, a larger sample size is needed to confirm these results.
Pancreatic Cystic Lesions without Overt Cytologic Atypia: Proposed Diagnostic Categories for Endoscopic Ultrasound-Guided Fine-Needle Aspiration Cytology with Utilization of Fluid Carcinoembryonic Antigen Level
Authors: Madan Rashna , Khan Emma , Cuka Nathan , Olyaee Mojtaba , Tawfik Ossama , Fan Fang
Published: January 2012

Objectives: It was the aim of this study to examine pancreatic cyst cases that lack markedly atypical or malignant epithelium on endoscopic ultrasound-guided fine-needle aspirations. Study Design: We conducted a retrospective case review study, including 24 cases that were either acellular or lacked cytologic atypia and were subsequently resected. The cases were retrospectively divided into 3 categories: (1) non-diagnostic, (2) cyst contents only, and (3) cyst contents with bland-appearing epithelium. The cyst contents were subdivided into mucinous and non-mucinous types. The cytologic diagnoses were correlated with cyst fluid carcinoembryonic antigen (CEA) levels and subsequent histologic diagnoses. Results: Category 1 comprised 4 cases: 2 cases (CEA >800 ng/ml) with mucin-producing neoplasms and 2 cases (CEA not determined) with microcystic serous cystadenomas. Category 2 included 4 cases with non-mucinous and 4 with mucinous contents. In the first subgroup, 2 cases (CEA >800 ng/ml) showed mucinous cystic neoplasms and 2 cases (CEA negligible or not determined) pseudocysts. In the second subgroup, there were 3 cases with neoplastic mucinous cysts (1 CEA >800 ng/ml, 2 not determined) and 1 case with a lymphoepithelial cyst with mucinous metaplasia (CEA >800 ng/ml). Almost all cases (10/11) in category 3 had neoplastic mucinous cysts regardless of the CEA levels. Conclusions: The proposed 3 cytologic categories of pancreatic cystic lesion combined with cyst fluid CEA levels provide useful clinical information.
Expanding the Multipotent Profile of Huprine-Tacrine Heterodimers as Disease-Modifying Anti-Alzheimer Agents
Authors: Muñoz-Torrero Diego , Pera Marta , Relat Júlia , Ratia Míriam , Galdeano Carles , Viayna Elisabet , Sola Irene , Formosa Xavier , Camps Pelayo , Badia Albert , Clos M. Victòria
Published: January 2012

Background: Multifactorial diseases such as Alzheimer’s disease (AD) should be more efficiently tackled by drugs which hit multiple biological targets involved in their pathogenesis. We have recently developed a new family of huprine-tacrine heterodimers, rationally designed to hit multiple targets involved upstream and downstream in the neurotoxic cascade of AD, namely β-amyloid aggregation and formation as well as acetylcholinesterase catalytic activity. Objective: In this study, the aim was to expand the pharmacological profiling of huprine-tacrine heterodimers investigating their effect on muscarinic M1 receptors as well as their neuroprotective effects against an oxidative insult. Methods: Sprague-Dawley rat hippocampus homogenates were used to assess the specific binding of two selected compounds in competition with 1 nM [3H]pirenzepine (for M1 receptors) or 0.8 nM [3H]quinuclidinyl benzilate (for M2 receptors). For neuroprotection studies, SHSY5Y cell cultures were subjected to 250 µM hydrogen peroxide insult with or without preincubation with some huprine-tacrine heterodimers. Results: A low nanomolar affinity and M1/M2 selectivity has been found for the selected compounds. Huprine-tacrine heterodimers are not neurotoxic to SHSY5Y cells at a range of concentrations from 1 to 0.001 µM, and some of them can protect cells from the oxidative damage produced by hydrogen peroxide at concentrations as low as 0.001 µM. Conclusion: Even though it remains to be determined if these compounds act as agonists at M1 receptors, as it is the case of the parent huprine Y, their low nanomolar M1 affinity and neuroprotective effects expand their multitarget profile and increase their interest as disease-modifying anti-Alzheimer agents.
Effects of Relative Low-Frequency Bilateral Globus Pallidus Internus Stimulation for Treatment of Cervical Dystonia
Authors: Kim Joo Pyung , Chang Won Seok , Park Young Seok , Chang Jin Woo
Published: January 2012

Objective: To assess the effect of relative lower amplitude and frequency for globus pallidus internus (GPi) deep brain stimulation (DBS) of cervical dystonia (CD). Materials and Methods: Between February 2005 and October 2008, 14 patients diagnosed with CD underwent bilateral GPi DBS and all the patients received low-frequency stimulation and were followed for more than 2 years. We activated the implantable pulse generator 3–4 days postoperatively and initial amplitude, pulse width, and frequency were set at 1.5 V, 120 µs, and 70 Hz. The Toronto Western Spasmodic Torticolis Rating Scale (TWSTRS) was applied preoperatively and at 1, 6, 12 and 24 months postoperatively. Results: The overall TWSTRS scores improved 71.2% 2 years postoperatively (p = 0.001). The mean improvement was 78.4% in severity subscores, 68.4% in disability, and 66.8% in pain scores for the 2-year follow-up period. The TWSTRS scores were significantly reduced (p < 0.05), suggesting that the most significant improvement of the TWSTRS scores occurred within 1 month. The final amplitude was 2.9/2.7 V with the pulse width of 147.9/147.9 µs and the frequency of 101.1/100 Hz. Conclusion: According to our results, the initial settings of low amplitude and especially relatively low frequency are safe and effective for treatment of CD.
Towards Erythropoietin Equations That Estimate Oxygen Delivery rather than Static Hemoglobin Targets
Authors: Diskin Charles J.
Published: January 2012

Although we have known since the 19th century that oxygen tension affects erythrocyte production, we have only recently begun to understand many subtleties of erythropoietin physiology. The unanticipated increase in mortality associated with erythropoietin use found in recent randomized studies is prompting a reassessment of static hemoglobin targets. Hemoglobin levels in dialysis patients do not correlate with endogenous erythropoietin production and may be related to differences in oxygen delivery resulting from shifts in the oxygen-hemoglobin dissociation curve. The time may have arrived to develop more physiologic targets such as oxygen delivery that would mimic the natural response to hypoxia. There are several equations that already exist that can compensate for the effects of the concentration of inorganic and organic phosphates as well as pH, carbon dioxide, and temperature on the delivery of oxygen. However, since the shape and dispersion of the oxygen-hemoglobin dissociation curve may actually change in different disease states, more work is needed.
Is There an Association between Advanced Stage of Renal Cell Carcinoma and Paraneoplastic Syndrome?
Authors: Ding Guan-Xiong , Song Ning-Hong , Feng Chen-Chen , Xia Guo-Wei , Jiang Hao-Wen , Hua Li-Xin , Ding Qiang
Published: January 2012

Objective: To investigate any association between renal cell carcinoma (RCC) and paraneoplastic syndromes (PNS). Subjects and Methods: The retrospective analysis included 1,028 patients of Chinese Han nationality with resectable RCC and PNS. The PNS included elevated erythrocyte sedimentation rate (ESR), hypertension, cachexia, anemia, pyrexia, abnormal liver function, hypercalcemia, polycythemia, varicocele and neuromyopathy. Staging was categorized as local (T1–2N0M0) and locally advanced (T3–4NxM0). Results: Among patients with at least one PNS, elevated ESR (p = 0.008), cachexia (p = 0.000), varicocele (p = 0.000) and pyrexia (p = 0.021) were related to advanced stage of RCC. Among patients with only one PNS, hypertension (p = 0.012) and hypercalcemia (p = 0.000) were related to advanced stage. The remaining PNS were not associated with tumor stage. Conclusion: Pyrexia, elevated ESR, cachexia and varicocele were related to advanced RCC. Hypertension and hypercalcemia occurring as single PNS, although also correlated with advanced stage, require further investigation.
Memantine in Everyday Clinical Practice: A Comparison of Studies in Germany and Greece
Authors: Förstl H. , Stamouli S.S. , Janetzky W. , Galanopoulos A. , Karageorgiou C. , Tzanakaki M.
Published: January 2012

Background/Aims: Results from German and Greek non-interventional studies were compared to investigate possible differences concerning efficacy, tolerability and compliance between both countries. Methods: In two open-label, multicentre, non-interventional studies, 4,305 patients with mild to severe Alzheimer’s disease (AD) were treated with daily doses of 20 mg memantine for 6 months. Efficacy was assessed using the Mini-Mental State Examination (MMSE) and instrumental activities of daily living (IADL) scales. Safety and tolerability were recorded. Results: After 6 months, the patients showed an improvement of their cognitive performance by 2 MMSE points compared to baseline (p < 0.001). MMSE values were improved in 67.4% of the patients, while 15.1% remained stable, and MMSE deteriorated in 17.5% only. The ability to perform IADL increased, as is indicated by lower values (baseline: 70.5; after 6 months: 66.6 points). Improvement of cognition and IADL was nearly identical in both countries. Treatment discontinuation was significantly more frequent in the Greek population, mainly due to non-adherence (9.4% of the safety population). 345 adverse events were recorded in 245 patients (6.3%), and they were significantly associated with country and age. Conclusion: The results correspond to those of clinical trials and support the efficacy and good tolerability of memantine in a realistic setting. Differences between the countries were observed regarding the baseline characteristics of patients (more female, older and more severe patients in Germany as well as less pretreatment with cholinesterase inhibitors) and regarding premature discontinuation and reported adverse drug reactions, which were both higher in Greece.
The FDA Outlook of Events Reporting after Ticagrelor or Clopidogrel in the PLATO Trial: Impact of Sponsor Censoring Dates, Drug Discontinuation, and Withdrawal of Consent
Authors: Serebruany Victor L.
Published: January 2012

Background: Censoring by the study sponsor of clinical endpoint events in indication-seeking randomized trials represents a controversial approach since the reported data may be biased in favor of experimental agents due to the obvious conflict of interest. The frequency of drug discontinuation and rates of consent withdrawal may also impact the trial outcomes. Purpose: To assess patterns of event reporting dependent on sponsor censoring dates, drug discontinuation and consent withdrawal in the PLATO trial. Methods: Analysis of theFood and Drug Administration Complete Response Review for ticagrelor. Results: Excluding adjudicated deaths, the distribution for clopidogrel appears more uniform while that for ticagrelor was skewed to the right, suggesting more events were reported after the sponsor censoring end date. PLATO investigators reported 16 unmatched primary endpoint events for ticagrelor immediately following the sponsor censoring date. Twenty-six out of 30 unreported events following early drug discontinuation occurred amongst patients using ticagrelor. More ticagrelor patients withdrew consent (Δ = 47), or were ‘not willing’ to complete the study (Δ = 87) when compared to clopidogrel. Conclusions: Site-reported primary endpoints were unequally distributed for clopidogrel and ticagrelor in the PLATO trial. This pattern suggests the importance of questioning the impact of sponsor-mediated censoring on event reporting by investigators in indication-seeking trials. In PLATO, this pattern seems to have favored the experimental drug and may require further assessment.
Urotensin-II Signaling Mechanism in Rat Coronary Artery
Authors: Domínguez-Rodríguez Alejandro , Díaz Ignacio , Rodríguez-Moyano María , Calderón-Sánchez Eva , Rosado Juan Antonio , Ordóñez Antonio , Smani Tarik
Published: January 2012

Objective—

Human urotensin-II (UII) is considered the most potentendogenous vasoconstrictor discovered to date, although the precise mechanism activated downstream of its receptor UTS2R in blood vessels remains elusive. The aim of this study was to determine the role of the store operated Ca
2+
entry (SOCE) signaling pathway in UII-induced coronary artery vasoconstriction.

Methods and Results—

We used a combination of isometric tension measurement, Ca
2+
imaging, pharmacology, and molecular approaches to study UII-mediated rat coronary artery vasoconstriction and intracellular Ca
2+
mobilization in coronary smooth muscle cells. We found that UII promoted dose-dependent vasoconstriction and elicited Ca
2+
and Mn
2+
influx, which were sensitive to classical SOCE inhibitors. In addition, knockdown of either STIM1 or Orai1 essentially inhibited UII-mediated SOCE and prevented UII but not high-KCL evoked contraction in transfected coronary artery. Moreover, we found that Ca
2+
-independent phospholipase A
2
β was involved in UII effects and that is colocalized with STIM1 in different submembrane compartments. Importantly, STIM1 but not Orai1 downregulation inhibits significantly independent phospholipase A
2
activation. Furthermore, lysophosphatidylcholine, an independent phospholipase A
2
product, activated Orai1 but not STIM1-dependent contraction and SOCE.

Conclusion—

Here, we demonstrated that different critical players of SOCE signaling pathway are required for UII-induced vasoconstriction of rat coronary artery.
Cardiac Complications in Patients With Community-Acquired Pneumonia
Authors: Corrales-Medina Vicente F. , Musher Daniel M. , Wells George A. , Chirinos Julio A. , Chen Li , Fine Michael J.
Published: January 2012

Background—

Community-acquired pneumonia (CAP) affects >5 million adults each year in the United States. Although incident cardiac complications occur in patients with community-acquired pneumonia, their incidence, timing, risk factors, and associations with short-term mortality are not well understood.

Methods and Results—

A total of 1343 inpatients and 944 outpatients with community-acquired pneumonia were followed up prospectively for 30 days after presentation. Incident cardiac complications (new or worsening heart failure, new or worsening arrhythmias, or myocardial infarction) were diagnosed in 358 inpatients (26.7%) and 20 outpatients (2.1%). Although most events (89.1% in inpatients, 75% in outpatients) were diagnosed within the first week, more than half of them were recognized in the first 24 hours. Factors associated with their diagnosis included older age (odds ratio [OR]=1.03; 95% confidence interval [CI], 1.02–1.04), nursing home residence (OR, 1.8; 95% CI, 1.2–2.9), history of heart failure (OR, 4.3; 95% CI, 3.0–6.3), prior cardiac arrhythmias (OR, 1.8; 95% CI, 1.2–2.7), previously diagnosed coronary artery disease (OR, 1.5; 95% CI, 1.04–2.0), arterial hypertension (OR, 1.5; 95% CI, 1.1–2.1), respiratory rate ≥30 breaths per minute (OR, 1.6; 95% CI, 1.1–2.3), blood pH <7.35 (OR, 3.2; 95% CI, 1.8–5.7), blood urea nitrogen ≥30 mg/dL (OR, 1.5; 95% CI, 1.1–2.2), serum sodium <130 mmol/L (OR, 1.8; 95% CI, 1.02–3.1), hematocrit <30% (OR, 2.0; 95% CI, 1.3–3.2), pleural effusion on presenting chest x-ray (OR, 1.6; 95% CI, 1.1–2.4), and inpatient care (OR, 4.8; 95% CI, 2.8–8.3). Incident cardiac complications were associated with increased risk of death at 30 days after adjustment for baseline Pneumonia Severity Index score (OR, 1.6; 95% CI, 1.04–2.5).

Conclusions—

Incident cardiac complications are common in patients with community-acquired pneumonia and are associated with increased short-term mortality. Older age, nursing home residence, preexisting cardiovascular disease, and pneumonia severity are associated with their occurrence. Further studies are required to test risk stratification and prevention and treatment strategies for cardiac complications in this population.
The Argatroban and Tissue-Type Plasminogen Activator Stroke Study
Authors: Barreto Andrew D. , Alexandrov Andrei V. , Lyden Pat , Lee Jessica , Martin-Schild Sheryl , Shen Loren , Wu Tzu-Ching , Sisson April , Pandurengan Renganayaki , Chen Zhongxue , Rahbar Mohammad H. , Balucani Clotilde , Barlinn Kristian , Sugg Rebecca M. , Garami Zsolt , Tsivgoulis Georgios , Gonzales Nicole R. , Savitz Sean I. , Mikulik Robert , Demchuk Andrew M. , Grotta James C.
Published: January 2012

Background and Purpose—

Argatroban is a direct thrombin inhibitor that safely augments recanalization achieved by tissue-type plasminogen activator (tPA) in animal stroke models. The Argatroban tPA Stroke Study was an open-label, pilot safety study of tPA plus Argatroban in patients with ischemic stroke due to proximal intracranial occlusion.

Methods—

During standard-dose intravenous tPA, a 100-μg/kg bolus of Argatroban and infusion for 48 hours was adjusted to a target partial thromboplastin time of 1.75× baseline. The primary outcome was incidence of significant intracerebral hemorrhage defined as either symptomatic intracerebral hemorrhage or Parenchymal Hematoma Type 2. Recanalization was measured at 2 and 24 hours by transcranial Doppler or CT angiography.

Results—

Sixty-five patients were enrolled (45% men, mean age 63±14 years, median National Institutes of Health Stroke Scale=13). The median (interquartile range) time tPA to Argatroban bolus was 51 (38–60) minutes. Target anticoagulation was reached at a median (interquartile range) of 3 (2–7) hours. Significant intracerebral hemorrhage occurred in 4 patients (6.2%; 95% CI, 1.7–15.0). Of these, 3 were symptomatic (4.6%; 95% CI, 0.9–12.9). Seven patients (10%) died in the first 7 days. Within the 2-hour monitoring period, transcranial Doppler recanalization (n=47) occurred in 29 (61%) patients: complete in 19 (40%) and partial in another 10 (21%).

Conclusions—

The combination of Argatroban and intravenous tPA is potentially safe in patients with moderate neurological deficits due to proximal intracranial arterial occlusions and may produce more complete recanalization than tPA alone. Continued evaluation of this treatment combination is warranted.

Clinical Trial Registration—

URL:
www.clinicaltrials.gov
. Unique identifier: NCT00268762.
Ezetimibe and Regression of Carotid Atherosclerosis
Authors: Bogiatzi Chrysi , Spence J. David
Published: January 2012

Background and Purpose—

There has been recent controversy over failure of ezetimibe to reduce carotid intima-media thickness. Much of this is based on failure to understand important differences among ultrasound phenotypes of atherosclerosis.

Methods—

We analyzed the effect of adding ezetimibe to the regimen of patients being followed in vascular prevention clinics where measurement of carotid plaque burden (total plaque area) is used to guide therapy.

Results—

There were complete data in 231 patients with total plaque area for 2 years before and 2 years after initiation of ezetimibe. In the 2 years before and after initiation of ezetimibe, total cholesterol decreased significantly before (
P
<0.0001) and after initiation of ezetimibe (
P
<0.0001); low-density lipoprotein cholesterol declined significantly before (
P
<0.0001) and after (
P
=0.003) initiation of ezetimibe. Triglycerides declined significantly before ezetimibe (
P
<0.0001) but did not change after addition of ezetimibe (
P
=0.48). High-density lipoprotein cholesterol did not change significantly before (
P
=0.87) but declined significantly after ezetimibe (
P
=0.03). Despite the decline in low-density lipoprotein cholesterol before addition of ezetimibe, there was a significant mean increase in within-individual total plaque area in the 2 years before addition of ezetimibe by 6.89±39.57 mm
2
(SD); after addition of ezetimibe, despite the decline in high-density lipoprotein, plaque area decreased by −3.05±SD 38.18 mm
2
SD (
P
<0.01).

Conclusions—

Ezetimibe appears to regress carotid plaque burden. To assess effects of antiatherosclerotic therapies, it is important to measure plaque burden. These findings should be tested in a clinical trial.
Age structure and growth in a population of Pelobates varaldii (Anura, Pelobatidae) from northwestern Morocco
Authors: Mezzasalma Marcello , Maria Guarino Fabio , Crottini Angelica , Andreone Franco , de Pous Philip
Published: January 2012

Age structure and growth in the Moroccan spadefoot toad, Pelobates varaldii were estimated by skeletochronology and reported for the first time for a population living in NW Morocco. Snout vent length and body mass did not significantly differ between the sexes, although females appeared larger and heavier than males. Age ranged 2-7 years in males (mean age±SD: 4.5±1.2, n = 66) and 2-10 years in females (4.7±2.4, n = 20). The difference in age was not significant between the sexes. The modal age was 5 years for males and 3 years for females. The age distributions significantly differed between the sexes. Von Bertalanffy growth curves showed a similar profile between the sexes although growth coefficient was higher in males than in females. Longevity and growth rates of P. varaldii were compared with those of other species of the genus Pelobates.
The Origin and Aim of Posterior Analytics II.19
Authors: Bronstein David
Published: January 2012

Abstract

In Posterior Analytics II.19 Aristotle raises and answers the question, how do first principles become known? The usual view is that the question asks about the process or method by which we learn principles and that his answer is induction. I argue that the question asks about the original prior knowledge from which principles become known and that his answer is perception. Hence the aim of II.19 is not to explain how we get all the way to principles but to defend the claim that our knowledge of them originates in perception. Aristotle explains how we learn principles earlier in book II, in his account of definitional inquiry. In II.19 he explains how we reach by induction the preliminary accounts necessary for such inquiries.
Status of the Asiatic Sea Snakes of the Hydrophis nigrocinctus group (H. nigrocinctus, H. hendersoni, and H. walli; Elapidae, Hydrophiinae)
Authors: Elmberg Johan , Ineich Ivan , McCarthy Colin , Rasmussen Arne R.
Published: January 2012

The literature of the Hydrophis nigrocinctus group, including Hydrophis nigrocinctus, H. hendersoni and H. walli, is reviewed. Based on internal and external morphological data from the literature and own examination of museum specimens, we recognize two valid species in the complex: Hydrophis nigrocinctus and H. hendersoni. Hydrophis walli is synonymised with H. nigrocinctus.
The Origin and Development of the Johannine Egō Eimi Sayings in Cognitive-Critical Perspective
Authors: Anderson Paul N.
Published: January 2012

The long-held critical judgment that the I-am sayings of Jesus in the Fourth
Gospel have no connection at all with the teachings of Jesus of Nazareth is
based primarily on the inference that they are entirely missing from the
Synoptics. As a result, John has been expunged from Jesus research, assuming
its patent ahistoricity; yet critical analyses have largely overlooked
Johannine- Synoptic similarities. While the Johannine presentation of Jesus’
I-am sayings is indeed distinctive and highly theological, it cannot be
claimed that either the I-am convention of speech or its predicate metaphors
and themes are absent from the Synoptics. Indeed, some absolute I-am sayings
are present in Mark, and each of the nine terms used with the predicate
nominative in John are also present in the Synoptics. Therefore, it cannot
be claimed that such terms, on the basis of the Synoptics alone, were never
used by the historical Jesus or present within early traditional material.
As a means of discerning a plausible understanding of how the Johannine
presentation of the I-am sayings of Jesus may have emerged,
cognitive-critical analysis poses a way forward. Within the developing
memory of the Johannine tradition, earlier words of Jesus likely became
crafted into the evangelist’s apologetic presentation of Jesus’ ministry as
a means of convincing later audiences that he was indeed the
Messiah/Christ.
Diplomatic Training and the Challenges Facing the EEAS
Authors: Duke Simon
Published: January 2012

Summary

Following a difficult birth, the European External Action Service (EEAS) is now a much scrutinized reality. Much of the analysis has concentrated on its quasi-institutional nature, its relations with the principal external action actors in the European Union and beyond, as well as the question of its legal capacity. Relatively little attention, however, has been paid to the important training dimensions, which are critical to the smooth development of the Service, especially considering the disparate backgrounds of EEAS constituents. This article argues that there is no ‘one-size-fits-all’ solution to the training dilemma. Differentiation rather than standardization, within the constraints of a programme (rather than a full-blown European Diplomatic Academy), will be the salient features of the first years of training in the EEAS. It is also argued that training can be a key strategic tool for the Service’s development and, more generally, the external relations of the EU itself.
How do dentists understand evidence and adopt it in practice?
Authors: Sbaraini Alexandra , Carter Stacy M , Evans R Wendell
Published: January 2012

Although there is now a large evidence-based dentistry literature, previous investigators have shown that dentists often consider research evidence irrelevant to their practice. To understand why this is the case, we conducted a qualitative study.

Objective: Our aim was to identify how dentists define evidence and how they adopt it in practice.

Methods: A qualitative study using grounded theory methodology was conducted. Ten dentists working in eight dental practices were interviewed about their experience and work processes while adopting evidence-based preventive care. Analysis involved transcript coding, detailed memo writing, and data interpretation.

Results: Findings revealed that dentists’ direct observations – referred to as clinical evidence – provided the most tangible and trusted evidence in practice and during discussions with colleagues. Dentists described a detailed process used to gather, compare and implement clinical evidence. This process began when they were exposed to novelty in daily practice and proceeded through self-driven testing, producing clinical or tangible evidence that clinicians could use in practice.

Conclusion: Based on these findings, we propose an alternative to the linear form of knowledge transfer commonly represented in the literature.
Coercion in psychiatric care: Can paternalism justify coercion?
Authors: Seo Mi Kyung , Kim Seung Hyun , Rhee MinKyu
Published: January 2012

Background:

It has long been debated whether coercion can be justified as paternalism in the field of mental health and it is still a continuing issue of controversy today.

Aims:

This study analyses whether coercive intervention in mental health can be justified by the basic assumptions of paternalists: the assumption of incompetence, the assumption of dangerousness and the assumption of impairment.

Method:

This study involved 248 patients: 158 (63.7%) were diagnosed with schizophrenia and 90 (36.3%) were diagnosed with mood disorder. In this study, experiences of coercion were divided into legal status, subjective (perceived coercion) and objective experiences (experienced coercion).

Results:

The assumption of incompetence was justified in all three categories of coercion whereas the assumption of dangerousness was not justified in any. The assumption of impairment was not justified in legal status and perceived coercion, but provided a partial explanation to serve as a basis for justifying experienced coercive measures.

Conclusions:

It can be noted that mental health experts who support paternalism without question must reconsider their previous methods. Above all, the reason why the assumption of dangerousness was not justified in any of the categories of coercion was because coercive intervention used to prevent harm to oneself and others must be very carefully carried out.