Targeted therapies for non-small cell lung cancer: an evolving landscape.
Over the past decade, a multitude of targeted agents have been explored in the treatment of advanced non-small cell lung cancer (NSCLC). Thus far, two broad classes of agents have been implemented in clinical practice: (a) vascular endothelial growth factor (VEGF)-directed therapies and (b) antagonists of the epidermal growth factor receptor (EGFR). In the former category, the agent bevacizumab (a monoclonal antibody) has shown landmark improvements in survival when added to cytotoxic therapy. Small molecule tyrosine kinase inhibitors (TKI) targeting the VEGF receptor (i.e., sunitinib, sorafenib, and vandetanib) show activity in phase II clinical studies. With respect to EGFR-directed therapies, the TKIs gefitinib and erlotinib have shown significant benefit, and have uncovered valuable information about the biology of lung cancer. Outside of therapies directed specifically at VEGF- and EGFR-mediated signaling, trials evaluating insulin-like growth factor-1 receptor (IGF-IR)-targeting agents, cyclooxygenase-2 (COX-2) inhibitors, c-met inhibitors, irreversible pan-HER inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and histone deacetylase (HDAC) inhibitors are ongoing. Inhibitors of ALK show great promise in patients with the relevant gene translocation. Herein, the clinical development of novel therapies for NSCLC is described, including some discussion of relevant biomarkers and determination of synergy with both cytotoxic therapy and other targeted agents.


The relationship of anxiety and smoking behaviors to medication adherence among cigarette smokers living with HIV.
People living with HIV/AIDS [PLWH] who smoke cigarettes report lower medication adherence. The purpose of the current study was to examine the relationship between anxiety and smoking behaviors (e.g., smoking quantity and frequency) and medication adherence in a sample of PLWH who smoke. PLWH who reported current cigarette smoking and use of antiretroviral medication were recruited from Center for Positive Living at Montefiore Medical Center (New York, US). Participants completed questions about their current smoking behavior, anxiety symptoms, and medication adherence. The analytic sample included sixty-eight PLWH who smoked cigarettes (female 48.5%, mean age = 49.1 ± 8.8 years, 52.2% Latino/a). The participants smoked an average of 10.53 (SD = 8.6) cigarettes daily and just over half of participants (55.9%) reported high medication adherence. There was a significant association between greater anxiety symptoms and poorer medication adherence (OR = 1.09, CI = 1.04-1.15, p = .001). Participants with higher anxiety symptoms were more likely to report forgetting to take their medication, forgetting to take medication when leaving on a trip, stopping medication when feeling symptoms are under control, and when feeling hassled about sticking to the treatment plan. Within this sample of current smokers, there were no significant associations between smoking quantity or frequency and medication adherence and no interactive effects of these smoking behaviors and anxiety on medication adherence. Current cigarette smoking PLWH who reported greater anxiety symptoms were less likely to adhere to their medication than current smoking PLWH who reported fewer anxiety symptoms. PLWH who smoke may benefit from assessment and management of anxiety.


Intramedullary spinal cord metastases, mainly of nonneurogenic origin.
The clinical data and imaging studies of 12 patients with intramedullary metastases were reviewed retrospectively to see if these lesions had a typical radiographic appearance and to determine the sensitivity of the various radiologic examinations. The lesions were identified antemortem by either myelography, CT, MR, and/or intraoperative spinal sonography (IOSS). Final diagnosis was based on biopsy material from either the spinal cord lesion, another metastatic site, and/or the primary tumor. Ten patients had primary tumors located outside the central nervous system, while only two patients had primary brain tumors. Metrizamide myelography and CT demonstrated a definite intramedullary mass in nine of 11 patients. In five patients the mass was relatively small, well-defined, single, and resembled a primary spinal cord neoplasm. In the other four patients, longer and sometimes several segments of the cord were involved. These appeared irregular and nodular and were often associated with intradural lesions at separate sites. MR detected not only enlargement and abnormal signal in the cord but also clinically unsuspected brain lesions. IOSS localized lesions for biopsy and monitored tumor resection. These various imaging procedures showed that cord metastases were often more extensive than anticipated clinically. Spread of tumor into the spinal and intracranial subarachnoid space was common. Imaging of the entire spinal canal and brain, preferably with MR, is therefore recommended to aid in diagnosis, prognosis, and treatment.


Reduced growth, abnormal kidney structure, and type 2 (AT2) angiotensin receptor-mediated blood pressure regulation in mice lacking both AT1A and AT1B receptors for angiotensin II.
The classically recognized functions of the renin-angiotensin system are mediated by type 1 (AT1) angiotensin receptors. Whereas man possesses a single AT1 receptor, there are two AT1 receptor isoforms in rodents (AT1A and AT1B) that are products of separate genes (Agtr1a and Agtr1b). We have generated mice lacking AT1B (Agtr1b -/-) and both AT1A and AT1B receptors (Agtr1a -/-Agtr1b -/-). Agtr1b -/- mice are healthy, without an abnormal phenotype. In contrast, Agtr1a -/-Agtr1b -/- mice have diminished growth, vascular thickening within the kidney, and atrophy of the inner renal medulla. This phenotype is virtually identical to that seen in angiotensinogen-deficient (Agt-/-) and angiotensin-converting enzyme-deficient (Ace -/-) mice that are unable to synthesize angiotensin II. Agtr1a -/-Agtr1b -/- mice have no systemic pressor response to infusions of angiotensin II, but they respond normally to another vasoconstrictor, epinephrine. Blood pressure is reduced substantially in the Agtr1a -/- Agtr1b -/- mice and following administration of an angiotensin converting enzyme inhibitor, their blood pressure increases paradoxically. We suggest that this is a result of interruption of AT2-receptor signaling. In summary, our studies suggest that both AT1 receptors promote somatic growth and maintenance of normal kidney structure. The absence of either of the AT1 receptor isoforms alone can be compensated in varying degrees by the other isoform. These studies reaffirm and extend the importance of AT1 receptors to mediate physiological functions of the renin-angiotensin system.


Resuscitation from severe hemorrhage.
The potential to be successfully resuscitation from severe traumatic hemorrhagic shock is not only limited by the "golden 1 hr", but also by the "brass (or platinum) 10 mins" for combat casualties and civilian trauma victims with traumatic exsanguination. One research challenge is to determine how best to prevent cardiac arrest during severe hemorrhage, before control of bleeding is possible. Another research challenge is to determine the critical limits of, and optimal treatments for, protracted hemorrhagic hypotension, in order to prevent "delayed" multiple organ failure after hemostasis and all-out resuscitation. Animal research is shifting from the use of unrealistic, pressure-controlled, hemorrhagic shock models and partially realistic, volume-controlled hemorrhagic shock models to more realistic, uncontrolled hemorrhagic shock outcome models. Animal outcome models of combined trauma and shock are needed; a challenge is to find a humane and clinically realistic long-term method for analgesia that does not interfere with cardiovascular responses. Clinical potentials in need of research are shifting from normotensive to hypotensive (limited) fluid resuscitation with plasma substitutes. Topics include optimal temperature, fluid composition, analgesia, and pharmacotherapy. Hypotensive fluid resuscitation in uncontrolled hemorrhagic shock with the addition of moderate resuscitative (28 degrees to 32 degrees C) hypothermia looks promising in the laboratory. Regarding the composition of the resuscitation fluid, despite encouraging results with new preparations of stroma-free hemoglobin and hypertonic salt solutions with colloid, searches for the optimal combination of oxygen-carrying blood substitute, colloid, and electrolyte solution for limited fluid resuscitation with the smallest volume should continue. For titrating treatment of shock, blood lactate concentrations are of questionable value although metabolic acidemia seems helpful for prognostication. Development of devices for early noninvasive monitoring of multiple parameters in the field is indicated. Molecular research applies more to protracted hypovolemic shock followed by the systemic inflammatory response syndrome or septic shock, which were not the major topics of this discussion.


DUPAN-2 as a Risk Factor of Early Recurrence After Curative Pancreatectomy for Patients With Pancreatic Ductal Adenocarcinoma.
Several patients with pancreatic ductal adenocarcinoma (PDAC) experience postoperative early recurrence (ER). We evaluated PDAC patients to identify the risk factors for postoperative ER (≤6 months), including preoperative serum DUPAN-2 level. We retrospectively evaluated 74 PDAC patients who underwent pancreatectomy with curative intent. Clinicopathological factors including age, sex, body mass index, postoperative complications, pathological factors, preoperative C-reactive protein/albumin ratio, neutrophil/lymphocyte ratio, modified Glasgow prognostic score, preoperative tumor markers (carcinoembryonic antigen, carbohydrate antigen 19-9, SPAN-1, and DUPAN-2), and history of adjuvant chemotherapy were investigated. Early recurrence risk factors were determined using multivariate logistic regression analysis. Recurrence and ER occurred in 52 (70.3%) and 23 (31.1%) patients, respectively. Univariate analysis revealed that postoperative complications, C-reactive protein/albumin ratio ≥0.02, neutrophil/lymphocyte ratio ≥3.01, carbohydrate antigen 19-9 ≥ 92.3 U/mL, SPAN-1 ≥ 69 U/mL, DUPAN-2 ≥ 200 U/mL, and absence of adjuvant chemotherapy were significant risk factors for ER. In multivariate analysis, DUPAN-2 ≥ 200 U/mL (P = 0.04) and absence of adjuvant chemotherapy (P = 0.02) were identified as independent risk factors for ER. A higher level of preoperative DUPAN-2 was an independent risk factor for ER. For patients with high DUPAN-2 level, neoadjuvant therapies might be required to avoid ER.


Altered nitric oxide mechanism within the paraventricular nucleus contributes to the augmented carotid body chemoreflex in heart failure.
Our previous study demonstrated a contribution of the paraventricular nucleus (PVN) of the hypothalamus in the processing of the carotid body (CB) chemoreflex. Nitric oxide (NO) (within the PVN), known to modulate autonomic function, is altered in rats with heart failure (HF). Therefore, the goal of the present study was to examine the influence of endogenous and exogenous NO within the PVN on the sympathoexcitatory component of the peripheral chemoreflex in normal and HF states. We measured mean arterial blood pressure, heart rate, renal sympathetic nerve activity (RSNA), and phrenic nerve activity (PNA) in sham-operated and HF rats (6-8 wk after coronary artery ligation) after incremental doses of potassium cyanide (25-100 mug/kg iv). There was potentiation of the reflex responses in HF compared with sham-operated rats. Bilateral microinjection of an inhibitor of NO synthase, N(G)-monomethyl-l-arginine (50 pmol), into the PVN augmented the RSNA and PNA response to peripheral chemoreceptor stimulation in sham-operated rats but had no effect in HF rats. Conversely, bilateral microinjection of a NO donor, sodium nitroprusside (50 nmol), into the PVN attenuated the RSNA response of the peripheral chemoreflex in sham-operated rats but to a smaller extent in HF rats. These data indicate that 1) NO within the PVN plays an important role in the processing of the CB chemoreflex and 2) there is an impairment of the NO function within the PVN of HF rats, which contributes to an augmented peripheral chemoreflex and subsequent elevation of sympathetic activity in HF.


Pathological diagnosis of general rules for the description of thyroid cancer by Japanese Society of Thyroid Pathology and Japan Association of Endocrine Surgery.
The Japanese Society of Thyroid Pathology and the Japan Association of Endocrine Surgeons developed the eighth edition of the General Rules for the Description of Thyroid Cancer (GRDTC) in December 2019. This article describes the pathological diagnosis of the GRDTC, which has been improved through repeated revisions based on the experience of Japanese pathologists and translated into English to introduce the Japanese diagnostic standard to foreign countries. In this edition of the GRDTC, the histopathological classification and descriptions differ in some respects from those of the fourth edition of the World Health Organization (WHO) classification as revised in 2017. For example, the GRDTC does not adopt the concept of borderline lesions (FT-UMP, WDT-UMP, and NIFTP) of the WHO, taking into consideration the popular histological criteria accepted by Japanese pathologists. The cytological reporting system of the GRDTC was partly modified from the Bethesda system in 2015. It has an additional cyst fluid category separated from the unsatisfactory category that has been demonstrated to be useful in Japan. This translated edition makes it easy to submit Japanese clinicopathological studies of thyroid tumors in an international journal. We also wish to contribute to the improvement, standardization, and globalization of the pathological diagnosis of thyroid tumors.


Thyrotropin releasing hormone biosynthesis in neonatal rat pancreas.
We studied the in vitro synthesis of thyrotropin releasing hormone (TRH) by pancreatic cells, using [14C]histidine incorporation and radioimmunoassay. Neonatal pancreases were incubated in Krebs-Ringer-bicarbonate buffer, pH 7.4, at 37 degrees C, under 95% O2-5% CO2. [14C]histidine was added and its incorporation into the tissue proteins was followed up to 4 hours. The methanolic pancreatic extracts obtained were subjected to Sephadex G-200 chromatography. Two peaks of [14C] radioactivity were eluted, one small (20% of total radioactivity) with the void volume and one large in a position identical to synthetic TRH. Both radioactive peaks corresponded to immunoreactive TRH peaks present in the same samples. In pulse-chase experiments, excess cold histidine was used and samples taken showed again similar radioactive peaks with an initial increase and a later decrease in the size of the small peak. We conclude that the neonatal rat pancreas actively synthesizes TRH and/or a higher molecular weight TRH-like protein, which may represent a TRH precursor.


Diet and skin disease in dogs and cats.
Dietary factors have a major role in the maintenance of healthy coat and skin, and are significant in the etiology and therapy of certain skin diseases. Nutritional deficiencies are now uncommon as a result of the widespread feeding of complete and balanced pet foods. Deficiencies of (n-6) polyunsaturated fatty acids, zinc and vitamins, however, do arise in certain animal- or product-related instances. Supraphysiologic doses of vitamin A have been used in the management of vitamin A-responsive dermatosis in Cocker spaniels; other keratinization defects and seborrheic conditions may respond to retinoid therapy. Much interest has been paid to the therapeutic value of polyunsaturated fatty acid supplements in the management of dermatologic conditions associated with hypersensitivity reactions or keratinization defects. These studies have generally yielded disappointing results, which may reflect shortcomings in the design of some trials. Nevertheless, a placebo-controlled, double-blind, cross-over study has demonstrated a clear benefit of high dose (n-3) fatty acids in the management of pruritic skin disease. There is also preliminary experimental evidence that specific dietary (n-6):(n-3) fatty ratios are useful in the dietary management of inflammatory diseases. Although results of controlled clinical trials are awaited, the argument exists that it is the absolute amount of (n-3) fatty acid intake rather than ratio that is responsible for potential health benefits.


Monotonically convergent optimization in quantum control using Krotov's method.
The non-linear optimization method developed by A. Konnov and V. Krotov [Autom. Remote Cont. (Engl. Transl.) 60, 1427 (1999)] has been used previously to extend the capabilities of optimal control theory from the linear to the non-linear Schrödinger equation [S. E. Sklarz and D. J. Tannor, Phys. Rev. A 66, 053619 (2002)]. Here we show that based on the Konnov-Krotov method, monotonically convergent algorithms are obtained for a large class of quantum control problems. It includes, in addition to nonlinear equations of motion, control problems that are characterized by non-unitary time evolution, nonlinear dependencies of the Hamiltonian on the control, time-dependent targets, and optimization functionals that depend to higher than second order on the time-evolving states. We furthermore show that the nonlinear (second order) contribution can be estimated either analytically or numerically, yielding readily applicable optimization algorithms. We demonstrate monotonic convergence for an optimization functional that is an eighth-degree polynomial in the states. For the "standard" quantum control problem of a convex final-time functional, linear equations of motion and linear dependency of the Hamiltonian on the field, the second-order contribution is not required for monotonic convergence but can be used to speed up convergence. We demonstrate this by comparing the performance of first- and second-order algorithms for two examples.


The effect of dietary sainfoin ( Onobrychis viciifolia) on local cellular responses to Trichostrongylus colubriformis in sheep.
The effect of sainfoin (Onobrychis viciifolia) hay consumption on the pathophysiology and local cellular responses of growing lambs during infection with Trichostrongylus colubriformis was investigated. Thirty-two lambs, 16 weeks of age, were allocated to 1 of 4 treatment groups (n=8) that were offered either grass (G) or sainfoin (S) hay while concurrently either infected (+), or not (-) with 12,000 L3 T. colubriformis larvae per week for 6 weeks. Liveweight gains were affected by diet (P=0.002) and reduced by infection (P<0.05). Faecal egg count was reduced in S+compared to G+ from days 35 to 42 (P=0.001); however, total egg output, worm burdens at day 42 and worm fecundity were similar between diets (P>0.05).Feeding sainfoin appeared to enhance immune cell development with tissue eosinophils, mast cells and pan T cells present in greater concentrations in S+ than in G+ animals. However, further studies are required to determine if the enhanced immune cell development is a consequence of a greater nutrient supply or a direct influence of sainfoin metabolites on local inflammatory responses to the gastrointestinal nematode T. colubriformis.


Nifedipine-induced changes in the electrohysterogram of preterm contractions: feasibility in clinical practice.
Objective. Evaluating changes in the power spectral density (PSD) peak frequency of the electrohysterogram (EHG) caused by nifedipine in women with preterm contractions. Methods. Calculation of the PSD peak frequency in EHG contraction bursts at different times of nifedipine treatment in women in gestational age 24 to 32 weeks with contractions. Results. A significant (P < .05) decrease of PSD peak frequency between EHG signals measured before and 15 minutes after administration of nifedipine. A significant (P < .05) decrease in PSD peak frequency comparing signals recorded within 24 hours after administration of nifedipine to signals 1 day after tocolytic treatment. A higher average PSD peak frequency for patients delivering within 1 week than that for patients delivering after 1 week from nifedipine treatment (P > .05). Conclusions. EHG signal analysis has great potential for quantitative monitoring of uterine contractions. Treatment with nifedipine leads to a shift to lower PSD peak frequency in the EHG signal.


Comparison of Stereotactic Radiosurgery (SRS) and Hypo-fractionated Radiosurgery (hSRS) for Vestibular Schwannomas: A Meta-Analysis of available literature.
Stereotactic Radiosurgery (SRS) and recently, hypo-fractionated Radiosurgery (hSRS) are increasingly utilized as treatment for Vestibular Schwannomas (VS). We performed a meta-analysis of literature comparing these modalities. The PubMed database of articles was searched for studies that compared SRS and hSRS in patients with VS. Variables analyzed include tumor control, hearing preservation, facial nerve preservation, trigeminal nerve preservation, and total complications. Heterogeneity across the studies was gauged using Higgins's inconsistency index (I2). Funnel plots and Egger's regression intercept test were used to address the publication bias. Thirteen studies that satisfied the search criteria were selected for meta-analysis. The studies identified in our study included 353 SRS and 511 hSRS-treated patients. Analysis of heterogeneity showed that hSRS is employed for relatively larger tumor sizes in comparison to SRS. Pooled meta-analysis estimates showed no significant differences between SRS and hSRS in terms of tumor control (odds ratio [OR], 0.620; 95% CI, 0.21-1.86, P = 0.39), hearing preservation (OR, 1.07; 95% CI, 0.59-1.93, P = 0.83), facial nerve preservation (OR, 0.53; 5% CI, 0.23-1.21, P = 0.13), or trigeminal nerve preservation (OR, 0.67; 95% CI, 0.24-1.89, P = 0.49) at a mean follow-up of 39 months. Statistically significant heterogeneity was found across the studies only for tumor diameter (I2 = 65.69%, P = 0.003) but not for other variables. Meta-analysis of thirteen studies comparing SRS and hSRS as treatment for VS showed comparable tumor control, hearing preservation, facial nerve preservation, and trigeminal nerve preservation.


Incidence and impact of adverse effects to antibiotics in hospitalized adults with pneumonia.
This study sought to define the incidence, economic impact, and nature of adverse drug effects (ADEs) related to antibiotics in pneumonia hospitalizations in the US. Adult pneumonia hospitalizations were tabulated in statewide (New York) and national databases, respectively, from 2000 through 2005. The incidences of antibiotic related ADEs were determined by identifying antibiotic specific e-codes (external cause of injury codes). The modeled effect of the presence of antibiotic ADEs on length of stay (LOS) and total charges were also calculated. ADEs due to specific antibiotic classes, and the presence of certain cutaneous allergic and gastro-intestinal manifestations commonly attributable to ADEs, were tabulated. ADEs related to antibiotics were reported in a small but consistent proportion (0.45-0.6%) of pneumonia hospitalizations in both cohorts. The most common identifiable antibiotics class associated with ADEs was the cephalosporins followed by penicillins and quinolones. Over 60% of the ADEs were associated with reported dermal/allergic and gastro-intestinal manifestations. Multivariate analysis adjusting for co-morbid conditions and demographic factors showed that the presence of an antibiotic adverse drug effect was a significant independent predictor of greater LOS and higher total hospital charges. ADEs related to antibiotics can be identified by analyzing administrative hospitalization databases. For pneumonia, a common hospitalization diagnosis, there is a defined calculable impact and incidence of antibiotic associated adverse effects. This should be considered in planning hospitalization resource allocation and in developing equitable hospitalization reimbursements. Identifying the nature of antibiotic associated adverse effects may facilitate the development of strategies for reducing these adverse effects.


Observed mechanisms activating the recent subpolar North Atlantic Warming since 2016.
The overturning circulation of the subpolar North Atlantic (SPNA) plays a fundamental role in Earth's climate variability and change. Here, we show from observations that the recent warming period since about 2016 in the eastern SPNA involves increased western boundary density at the intergyre boundary, likely due to enhanced buoyancy forcing as a response to the strong increase in the North Atlantic Oscillation since the early 2010s. As these deep positive density anomalies spread southward along the western boundary, they enhance the North Atlantic Current and associated meridional heat transport at the intergyre region, leading to increased influx of subtropical heat into the eastern SPNA. Based on the timing of this chain of events, we conclude that this recent warming phase since about 2016 is primarily associated with this observed mechanism of changes in deep western boundary density, an essential element in these interactions. This article is part of a discussion meeting issue 'Atlantic overturning: new observations and challenges'.


Cholesteric Flakes in Motion Driven by the Elastic Force from Nematic Liquid Crystals.
The paper presents a methodology to control the motion and orientation of suspended reflective cholesteric flakes in a nematic liquid crystal (LC) matrix. The flakes exhibit a dielectric anisotropy which controls their alignment with their in-plane axes parallel to an external electrical dc field. The elastic forces imposed by the LC host affect the switching behavior of the flakes and take care of the realignment to the planar state as soon as the dc field is switched off. When the LC host has a positive dielectric anisotropy, the switching voltage of the flakes is reduced by a factor of 2 in comparison with a LC host with negative dielectric anisotropy or in comparison with an isotropic host. We discovered that the LC host further regulates the back relaxation of cholesteric to return to the planar state upon retrieving the electric field. Whereas, in the isotropic fluid, flakes do not exhibit a preferred orientation when relaxed. Based on this newly proposed principle, we demonstrated its application as an optical switch for smart windows. Depending on the pitch of the cholesteric helix of the flakes, the light of a preset wavelength is reflected. Upon application of an electric field, the embedded flakes rotate their planes perpendicular to the substrate and consequently the incident light becomes fully transmitted without reflection or scattering of light.


Atrial natriuretic factor can increase renal solute excretion primarily by raising glomerular filtration.
Controversy persists on whether atrial natriuretic factor (ANF) raises renal solute excretion simply by increasing glomerular filtration rate (GFR) or whether it directly inhibits tubular transport (independent of changes in flow rate). Free-flow micropuncture techniques were used in 10 Munich-Wistar rats. ANF caused a significant increase in single-nephron and whole-kidney GFR (41.6 +/- 1.4 to 52.7 +/- 2.3 nl/min and 0.95 +/- 0.05 to 1.24 +/- 0.09 ml/min, respectively). Although absolute proximal sodium, bicarbonate, and chloride reabsorption increased, the increment in reabsorption was less than the increase in load; therefore solute delivery out of the proximal tubule increased by approximately 30-35%. Whole-kidney electrolyte excretion also rose markedly. When single-nephron and whole-kidney GFR were reduced back to a control level by aortic constriction (40.2 +/- 1.8 nl/min and 0.93 +/- 0.05 ml/min, respectively), proximal transport reverted to normal values despite persistent ANF administration. Ninety percent of the ANF-induced natriuresis and chloruresis were simultaneously abolished when GFR was normalized. In conclusion, ANF has no direct effect on reabsorption in the superficial proximal convoluted tubule independent of changes in filtration rate. Although direct effects on more distal or deeper nephron segments are not precluded, the present data suggest that ANF can increase renal solute excretion predominantly by acutely augmenting GFR.


Relative value of ZAP-70, CD38, and immunoglobulin mutation status in predicting aggressive disease in chronic lymphocytic leukemia.
Leukemia-cell expression of ZAP-70, CD38, or unmutated immunoglobulin heavy chain variable region genes (U-IGHV) each is associated with aggressive disease in patients with chronic lymphocytic leukemia (CLL). To assess the relative strength of each marker, we defined thresholds for designating a case as positive for CD38 or ZAP-70 in a test cohort of 307 patients and used these data-defined criteria to stratify patients in an independent cohort of 705 patients. Multivariable analysis revealed that ZAP-70 was the strongest risk factor. Knowledge of the IGHV mutation status or CD38 did not improve our ability to predict the time to first treatment except for ZAP-70-negative cases, which could be segregated into 2 groups of intermediate-risk or low-risk disease based on whether they expressed unmutated or mutated IGHV. ZAP-70 maintained its high relative prognostic value for the subset of patients with early-stage, asymptomatic disease, including patients evaluated within 1 year of diagnosis. Although it is premature to recommend therapy based on these risk factors, patients with ZAP-70-positive CLL cells should be monitored closely for disease progression as they have a median time from diagnosis to requiring initial therapy by standard criteria of approximately 3 years.


Short- and long-term implicit memory in aging and Alzheimer's disease.
Implicit memory processes were investigated via picture naming in healthy young and older adults and in persons with mild Alzheimer's disease (AD). Repetition priming in picture-naming was intact in all groups over the course of a short retention interval (seconds), and only the AD group revealed a deficit over a longer interval (72 hours). In addition, the AD group showed impaired procedural memory, with no benefit of practice on picture-naming. Impaired long-term priming was related to severity of AD. Both theoretical and methodological implications are discussed.


Does Preadmission Cutaneous Chlorhexidine Preparation Reduce Surgical Site Infections After Total Hip Arthroplasty?
Periprosthetic hip infections are among the most catastrophic complications after total hip arthroplasty (THA). We had previously proven that the use of chlorhexidine cloths before surgery may help decrease these infections; hence, we increased the size of the previously reported cohort. (1) Does a preadmission chlorhexidine cloth skin preparation protocol decrease the risk of surgical site infection in patients undergoing THA? (2) When stratified using the National Healthcare Safety Network (NHSN) risk categories, which categories are associated with risk reduction from the preadmission chlorhexidine preparation protocol? Between 2007 and 2013, a group of 998 patients used chlorhexidine cloths before surgery, whereas a group of 2846 patients did not use them and underwent standard perioperative disinfection only. Patient records were reviewed to determine the development of periprosthetic infection in both groups of patients. Patients without the preoperative chlorhexidine gluconate disinfection protocol had a higher risk of infections (infections with protocol: six of 995 [0.6%]; infections in control: 46 of 2846 [1.62%]; relative risk: 2.68 [95% confidence interval {CI}, 1.15-0.26]; p = 0.0226). When stratified based on risk category, no differences were detected; preadmission chlorhexidine preparation was not associated with reduced infection risk for low, medium, and high NHSN risk categories (p = 0.386, 0.153, and 0.196, respectively). The results of our study suggest that this cloth application appears to reduce the risk of infection in patients undergoing THA. When stratified by risk categories, we found no difference in the infection rate, but these findings were underpowered. Although future multicenter randomized trials will need to confirm these preliminary findings, the intervention is inexpensive and is unlikely to be risky and so might be considered on the basis of this retrospective, comparative study. Level III, therapeutic study.


Rapid extraction of genomic DNA from medically important yeasts and filamentous fungi by high-speed cell disruption.
Current methods of DNA extraction from different fungal pathogens are often time-consuming and require the use of toxic chemicals. DNA isolation from some fungal organisms is difficult due to cell walls or capsules that are not readily susceptible to lysis. We therefore investigated a new and rapid DNA isolation method using high-speed cell disruption (HSCD) incorporating chaotropic reagents and lysing matrices in comparison to standard phenol-chloroform (PC) extraction protocols for isolation of DNA from three medically important yeasts (Candida albicans, Cryptococcus neoformans, and Trichosporon beigelii) and two filamentous fungi (Aspergillus fumigatus and Fusarium solani). Additional extractions by HSCD were performed on Saccharomyces cerevisiae, Pseudallescheria boydii, and Rhizopus arrhizus. Two different inocula (10(8) and 10(7) CFU) were compared for optimization of obtained yields. The entire extraction procedure was performed on as many as 12 samples within 1 h compared to 6 h for PC extraction. In comparison to the PC procedure, HSCD DNA extraction demonstrated significantly greater yields for 10(8) CFU of C. albicans, T. beigelii, A. fumigatus, and F. solani (P < or = 0.005), 10(7) CFU of C. neoformans (P < or = 0.05), and 10(7) CFU of A. fumigatus (P < or = 0.01). Yields were within the same range for 10(8) CFU of C. neoformans and l0(7) CFU of C. albicans for both HSCD extraction and PC extraction. For 10(7) CFU of T. beigelii, PC extraction resulted in a greater yield than did HSCD (P < or = 0.05). Yields obtained from 10(8) and 10(7) CFU were significantly greater for filamentous fungi than for yeasts by the HSCD extraction procedure (P < 0.0001). By the PC extraction procedure, differences were not significant. For all eight organisms, the rapid extraction procedure resulted in good yield, integrity, and quality of DNA as demonstrated by restriction fragment length polymorphism, PCR, and random amplified polymorphic DNA. We conclude that mechanical disruption of fungal cells by HSCD is a safe, rapid, and efficient procedure for extracting genomic DNA from medically important yeasts and especially from filamentous fungi.


Novel type of staphylococcal cassette chromosome mec in a methicillin-resistant Staphylococcus aureus strain isolated in Sweden.
We identified a novel type of staphylococcal cassette chromosome mec (SCCmec) element carried by methicillin-resistant Staphylococcus aureus (MRSA) strain JCSC6082 isolated in Sweden. The SCCmec element was demarcated by characteristic nucleotide sequences at both ends and was integrated at the 3' end of orfX. The element carried a novel combination of a type 5 ccr gene complex and class C1 mec gene complex. The J regions of the element were homologous to those of the SCCmercury element of S. aureus strain 85/2082, with nucleotide identity greater than 99%. However, the novel SCCmec element from JCSC6082 did not carry the mer operon nor Tn554, suggesting that evolution to SCCmec could have been from a common ancestor by acquisition of the class C1 mec gene complex. The novel SCCmec element from JCSC6082 was flanked by a novel SCC-like chromosome cassette (CC6082), which was demarcated by two direct repeats and could be excised from the chromosome independently of the SCCmec element. Our data suggest that novel SCCmec elements can be generated on the staphylococcal chromosome through the recombination between extant SCC elements and mec gene complexes.


Complement Component 3 Negatively Regulates Antibody Response by Modulation of Red Blood Cell Antigen.
Red blood cell (RBC) alloimmunization can make it difficult to procure compatible RBCs for future transfusion, directly leading to increased morbidity and mortality in transfusion-dependent patients. However, the factors that regulate RBC alloimmunization remain incompletely understood. As complement has been shown to serve as a key adjuvant in the development of antibody (Ab) responses against microbes, we examined the impact of complement on RBC alloimmunization. In contrast to the impact of complement component 3 (C3) in the development of an immune response following microbial exposure, transfusion of C3 knockout (C3 KO) recipients with RBCs expressing KEL (KEL RBCs) actually resulted in an enhanced anti-KEL Ab response. The impact of C3 appeared to be specific to KEL, as transfusion of RBCs bearing another model antigen, the chimeric HOD antigen (hen egg lysozyme, ovalbumin and Duffy), into C3 KO recipients failed to result in a similar increase in Ab formation. KEL RBCs experienced enhanced C3 deposition and loss of detectable target antigen over time when compared to HOD RBCs, suggesting that C3 may inhibit Ab formation by impacting the accessibility of the target KEL antigen. Loss of detectable KEL on the RBC surface did not reflect antigen masking by C3, but instead appeared to result from actual removal of the KEL antigen, as western blot analysis demonstrated complete loss of detectable KEL protein. Consistent with this, exposure of wild-type B6 or C3 KO recipients to KEL RBCs with reduced levels of detectable KEL antigen resulted in a significantly reduced anti-KEL Ab response. These results suggest that C3 possesses a unique ability to actually suppress Ab formation following transfusion by reducing the availability of the target antigen on the RBC surface.


Lung transplantation in advanced COPD: is it worth it?
Chronic obstructive pulmonary disease (COPD) is a condition of progressive airflow obstruction occurring primarily as a result of tobacco use that accounts for substantial worldwide morbidity and mortality. Medical therapy, with the exception of oxygen and smoking cessation, does not appreciably alter the natural progression of the disease. In contrast, when performed in carefully selected candidates, lung transplantation can provide substantial benefits in physiology, function, quality of life, and survival. Strict selection criteria limit transplant to highly compliant candidates with advanced disease but preserved functional status who are capable of successfully undergoing the operation. Although either single or bilateral lung transplant may be offered in COPD, recent evidence suggests that bilateral transplant is the preferred operation due to superior long-term outcomes. Regardless of the type of transplant operation, however, all lung transplant recipients are susceptible to numerous complications, including posttransplant infection and rejection. Despite these and other potential complications, advances in medical and surgical management now make lung transplantation a worthwhile therapeutic option in appropriately selected patients. In fact, lung transplant represents the only intervention that can substantially improve long-term outcomes in COPD patients with very advanced disease. Further work to refine recipient selection, improve lung allocation algorithms, and develop better treatments of chronic allograft dysfunction will lead to an even greater benefit to lung transplantation in this ill patient population.


Application of Rasch analysis in the development and psychometric evaluation of dental undergraduates preparedness assessment scale.
The aim of this study was to develop a valid and reliable scale to measure preparedness of new dental graduates. The scale development and validation was carried out using the Rasch measurement model. Following a pilot and pre-testing of the scale, a national study was undertaken with undergraduate students from all dental schools as well as foundation dentists in UK. To examine the internal validity of the scale, we conducted a Rasch analysis. External validity of the scale was checked through validation with a range of stakeholders. An excellent fit to the Rasch model provided evidence of internal construct validity. The scale demonstrated invariance, ordered thresholds and lack of differential item functioning. Unidimensionality of the scale was confirmed by independent t-tests. The PSI value was 0.877, indicating a good degree of person separation and internal consistency. Test-retest reliability of the scale was also established. The preparedness scale developed in this project reflects innovative research using a systematic approach and employment of modern psychometric methods. The scale can be used for assessment of the preparedness of undergraduate students by dental educators and potential employers as well as by the student for self-assessment.


Cognitive impairment in spontaneously hypertensive rats: role of central nicotinic receptors. Part II.
The adult spontaneously hypertensive rat (SHR) has been shown to exhibit a decrease in the expression and nicotine-stimulated function of brain nicotinic acetylcholine receptors, factors that could play a role in the impaired ability of this strain in the performance of learning and memory-related tasks. The purpose of this study was to determine whether either or both the impaired task performance and the loss of nicotinic receptors is directly related to the presence of the hypertensive state. To address this issue, two experimental approaches were taken. In the first series, 4-week-old pre-hypertensive SHR were tested in two phases of a water maze (spatial memory) task, and their performance was compared with that of two age-matched normotensive strains, Wistar Kyoto (WKY) and Wistar rats. During phase 1, SHR and WKY rats were not different in their ability to learn the task. In contrast, during phase 2 (subsequent series of trials after a 4 day inter-phase period), where rats were required to find a new platform location, SHR exhibited significantly impaired performance compared to both WKY and Wistar normotensive controls. In a single trial passive avoidance paradigm, SHR again displayed significantly reduced avoidance behavior as compared with both WKY and Wistar rats. In consecutive coronal sections the density of [3H]cytisine binding sites was decreased in pre-hypertensive SHR by up to 18% in about 40% of the brain regions examined, with the deficits particularly apparent in frontal cortex (layers 4-6), posterior subiculum, several thalamic regions, and the interpeduncular nucleus. In the second series, age-matched SHR and WKY were treated with the antihypertensive agent hydralazine administered in the drinking water beginning at 4 weeks of age. Hydralazine prevented the development of hypertension in adult SHR, but did not forestall the reduced expression of brain nicotinic receptors, nor the impairment in learning- and memory-related tasks normally observed in untreated adults with established hypertension. Moreover, the magnitude of nicotine-stimulated rubidium efflux from cortical and striatal synaptosomes in vitro was significantly reduced in samples derived from hydralazine-treated SHR as compared with those from hydralazine-treated, or untreated WKY. These results support the contention that the hypertensive state does not directly contribute to the reduced expression of nicotinic receptors in SHR. Therefore, the SHR may provide an important genetic model for the study of the role of central nicotinic receptors in cognitive and learning abnormalities.


Vitamin C-mediated Maillard reaction in the lens probed in a transgenic-mouse model.
Aging human lens crystallins are progressively modified by yellow glycation, oxidation, and cross-linked carbonyl compounds that have deleterious properties on protein structure and stability. In order to test the hypothesis that some of these compounds originate from oxidized vitamin C, we have overexpressed the human vitamin C transporter 2 (hSCVT2) in the mouse lens. We find that levels of ascorbic and dehydroascorbic acid are highly elevated compared to the wild type and that the lenses have accumulated yellow color and advanced Maillard reaction products identical with those of the human lens. Treatment of the mice with nucleophilic inhibitors can slow down the process, opening new avenues for the pharmacological prevention of senile cataractogenesis.


Assessment of cell line models of primary human cells by Raman spectral phenotyping.
Researchers have previously questioned the suitability of cell lines as models for primary cells. In this study, we used Raman microspectroscopy to characterize live A549 cells from a unique molecular biochemical perspective to shed light on their suitability as a model for primary human pulmonary alveolar type II (ATII) cells. We also investigated a recently developed transduced type I (TT1) cell line as a model for alveolar type I (ATI) cells. Single-cell Raman spectra provide unique biomolecular fingerprints that can be used to characterize cellular phenotypes. A multivariate statistical analysis of Raman spectra indicated that the spectra of A549 and TT1 cells are characterized by significantly lower phospholipid content compared to ATII and ATI spectra because their cytoplasm contains fewer surfactant lamellar bodies. Furthermore, we found that A549 spectra are statistically more similar to ATI spectra than to ATII spectra. The spectral variation permitted phenotypic classification of cells based on Raman spectral signatures with >99% accuracy. These results suggest that A549 cells are not a good model for ATII cells, but TT1 cells do provide a reasonable model for ATI cells. The findings have far-reaching implications for the assessment of cell lines as suitable primary cellular models in live cultures.


Impact of Agroecological Infrastructures on the Dynamics of Dysaphis plantaginea (Hemiptera: Aphididae) and Its Natural Enemies in Apple Orchards in Northwestern France.
Apple orchard production is facing new environmental and societal challenges, resulting, in particular, in strong pressure to reduce pesticide use. Cider-apple production, for which the perfect visual aspect of fruits is not a marketability imperative, offers good opportunities to study production systems that are developing new agronomic strategies, which could be subsequently extended to all apple-production types. Agroecological infrastructures play an important role in providing shelter, food resources, or reproduction habitats to many arthropods. Consequently, setting-up agroecological infrastructures in the vicinity of or within orchards could increase natural enemy presence and thus improve the biological control of pests. In this study, we focused on Dysaphis plantaginea (Passerini), one of the major pests in apple orchards in Europe, which causes important economic production losses. During two years (2014 and 2015), we monitored the population dynamics of D. plantaginea, its natural enemies, and mutualistic ants in commercial production cider-apple orchards. The influences of the cider-apple cultivar, insecticide use, and distance to agroecological infrastructures (hedgerows and flower strips) were assessed. Our results suggest that flower strips favor an increase in natural enemy abundance in the vicinity of the orchards and could thus play an important role in the production system by improving the biological control of D. plantaginea.


The relationship of temperature rise to specific absorption rate and current in the human leg for exposure to electromagnetic radiation in the high frequency band.
Of the biological effects of human exposure to radiofrequency and microwave radiation, the best-established are those due to elevation of tissue temperature. To prevent harmful levels of heating, restrictions have been proposed on the specific absorption rate (SAR). However, the relationship between SAR and temperature rise is not an invariant, since not only the heat capacity but also the efficiency of heat dissipation varies between different tissues and exposure scenarios. For small enough SAR, the relationship is linear and may be characterized by a 'heating factor' deltaT/SAR. Under whole-body irradiation the SAR may be particularly high in the ankles due to the concentration of current flowing through a relatively small cross-sectional area. In a previous paper, the author has presented calculations of the SAR distribution in a human leg in the high frequency (HF) band. In this paper, the heating factor for this situation is derived using a finite element approximation of the Pennes bioheat equation. The sensitivity of the results to different blood perfusion rates is investigated, and a simple local thermoregulatory model is applied. Both time-dependent and steady-state solutions are considered. Results confirm the appropriateness of the ICNIRP reference level of 100 mA on current through the leg, but suggest that at higher currents significant thermoregulatory adjustments to muscle blood flow will occur.


[Effects of 1,2,4-trichlorobenzene stress on active oxygen in germinated soybean seeds].
Pot culture experiment on the effects of 1,2,4-trichlorobenzene (TCB) stress on active oxygen metabolism of germinated soybean seeds indicated that during the beginning (1st-3rd day) of 100-300 micrograms.g-1 TCB treatment, the respiratory peak appeared earlier, and the respiratory rate, the accumulation of superoxide radical (O2-.) and H2O2, as well as the malondialdehyde (MDA) content were all enhanced. During 1-6 days of TCB stress, peroxidase (POD) activity gradually increased, and superoxide dismutase (SOD) activity increased firstly, and decreased afterward. These results suggested that the injury effects of TCB stress on germinated soybean seeds were achieved by excessive accumulation of active oxygen resulted from the degradation of active oxygen scavenging enzyme system.


Pilot study of enhanced tobacco-cessation services coverage for low-income smokers.
This study explored the feasibility of covering nicotine replacement therapy (NRT) and paying for pharmacist-delivered smoking cessation counseling at the time of NRT pick-up for low-income, managed Medicaid and Basic Health Plan (a state insurance program) enrollees. A prospective pilot intervention was used at two community health centers (CHCs) and two community pharmacies. Participants were adult managed-Medicaid or Basic Health Plan enrollees who attended the pilot CHCs and smoked. An innovative insurance benefit that included coverage for NRT and $15 payment to the pharmacist to deliver cessation counseling with each prescription fill. Proportion of eligible patients who used the cessation benefit and patient and pharmacist satisfaction with the intervention. During the 9-month intervention, 32 patients at the pilot clinics were referred for NRT and pharmacist-delivered counseling. This number represented roughly 5% of eligible smokers. Of these, 26 received NRT with concomitant pharmacist-delivered cessation counseling at least once. Recipients reported a high level of satisfaction with this intervention. Pharmacists indicated they would continue providing counseling if reimbursement remained adequate and if counseling lasted no longer than 5-10 min. However, 12 (38%) who were referred were no longer insured by the sponsoring plan by the end of the 9-month pilot period. Pharmacist-delivered cessation counseling may be feasible and merits further study. More importantly, this pilot reveals two key obstacles in our low-income, culturally diverse setting: low participation and rapid turnover of insureds. Future interventions will need to address these barriers.


Associated differences in response to alcohol in rats and mice: biochemical and behavioral review.
The purpose of this review was an examination of the biochemical and behavioral literature on alcohol and aging. The biochemical literature indicated that older animals show differences in response to alcohol using metabolic measures such as: alcohol dehydrogenase, blood alcohol concentration, and acetaldehyde. However, these differences were not always in the predicted direction (i.e, a reduction with increasing age), suggesting that changes in these metabolic factors do not fully explain differences among age groups in response to alcohol. Behavioral data demonstrated that preference for alcohol was affected by the age of the animal and/or previous experience with the drug. Generally, alcohol preference decreases with advancing age, but this was dependent in a large part on the genotype of the animal and the concentration of alcohol used. Several methodological problems are apparent in the literature on age-related changes in response to alcohol (e.g., narrow range of ages used, inadequate dose-response curves and an absence of proper control groups). Ways of reducing these problems and directions for future research were discussed.


Information Processing at Successive Stages of Decision Making: Need for Cognition and Inclusion-Exclusion Effects.
Levin and Jasper's (1995) phased narrowing technique for tracking changes in information usage across successive stages of the decision-making process was combined with Huneke's (1996) "pull-down menu" extension of Payne, Bettman, and Johnson's (1988) software package for generating measures of information processing. Because this technique provided considerable data for each individual subject at each stage, we were able to focus on individual differences in information processing across stages, most notably differences related to need for cognition (NC; Cacioppo & Petty, 1982). In a computerized information search and decision task, 60 college students were first asked to narrow their options for purchasing a notebook computer to form a consideration set and were then asked to make a final choice from this set. At the consideration set formation stage, half the subjects were instructed to adopt a mindset to include options while the other half were asked to exclude options. Especially in the inclusion condition where subjects showed greater narrowing of options, high NC subjects processed information in a more focused manner with greater depth and breadth than did low NC subjects, and the quality of their selections tended to be higher. There was no evidence of widespread shifts in strategy as individuals moved from set formation to final choice but, as a group, high NC subjects were more successful at adaptive decision making. Copyright 2000 Academic Press.


Linezolid Induced Twice Pure Red Cell Aplasia in a Patient with Central Nervous System Infection after Allogeneic Stem Cell Transplantation.
Linezolid (LZD), severed as the first oxazolidinone antibiotic, was active against multidrug-resistant gram-positive strains. LZD can induce thrombocytopenia, anemia and leukocytopenia. Currently, reports on pure red cell aplasia (PRCA) cases induced by LZD are relatively rare (4-7). In this paper, we reported a patient with PRCA twice induced by LZD. A 37-year-old man was diagnosed with myelodysplatic syndrome (MDS) and underwent allo-HSCT from an unrelated donor with ABO blood type and leukocyte antigen (HLA)-matching. After HSCT for 2 years, the patient suffered from refractory fever and headache. He was first treated with empirical antifungal agent and antibiotics for central nervous system (CNS) infection, but then changed to LZD therapy for little effect. Twenty-eight days after LZD treatment, the symptom improved significantly but the hemoglobin declined to 70 g/L and the reticulocyte level was only 0.23%. The LZD therapy was stopped and the fever and headache symptoms reoccurred 1 week latter. Then, erythropoietin (EPO) and halved dosage of LZD were used for treatment. The CNS infection and the anemia symptom relieved gradually and the level of hemoglobin and reticulocyte declined again. After blood transfusion, the half dose of LZD was sustained without anaemia recovery. In summary, patients with anemia, myelosuppressants history or potential abnormal proliferation of T cells may suffer PRCA with long term LZD treatment. The monitoring of complete blood count and reticulocyte count were necessary during LZD therapy. If the clinical condition permits, LZD dosage reduction and blood transfusion should be considered.


[A methodology for the diagnosis of craniocerebral trauma].
New functions of neurosurgical diagnosis--examination and control--have been disclosed from analysis of methods of noninvasive visualization of the brain. The effect of computed tomography and magnetic resonance tomography on the surgical concept in craniocerebral trauma is shown. Adequate application of the principle of visualization of the damage for establishing the diagnosis of craniocerebral trauma is substantiated.


The transforming potential of the c-erbB-2 protein is regulated by its autophosphorylation at the carboxyl-terminal domain.
The mutant c-erbB-2 protein with Glu instead of Val-659 exhibited transforming activity in NIH 3T3 cells. This protein showed enhanced tyrosine kinase activity in vitro and enhanced autophosphorylation at Tyr-1248 located proximal to the carboxyl terminus. Enhanced tyrosine phosphorylation of several cellular proteins was detected in cells expressing the Glu-659 c-erbB-2 protein. Introduction of an additional mutation at the ATP-binding site (Lys-753 to Met) of this protein resulted in abolition of its transforming ability. These data indicate that the transforming potential of c-erbB-2 is closely correlated with elevated tyrosine kinase activity of the gene product. To investigate the role of autophosphorylation in cell transformation, we introduced an additional mutation at the autophosphorylation site of the Glu-659 c-erbB-2 protein (Tyr-1248 to Phe). This mutant protein exhibited lower tyrosine kinase activity and lower transforming activity. On the other hand, when the carboxyl-terminal 230 amino acid residues were deleted from the c-erbB-2 protein, the tyrosine kinase activity and cell-transforming activity of the protein were enhanced. Thus, the carboxyl-terminal domain, which contains the major autophosphorylation site, Tyr-1248, may regulate cellular transformation negatively and autophosphorylation may eliminate this negative regulation.


Clinical implications of cardiac magnetic resonance imaging fibrosis.
Cardiac magnetic resonance (CMR) is a non-invasive imaging method that allows to characterize myocardial tissue. In particular, using the late gadolinium enhancement technique, it is possible to identify areas of focal fibrosis. Specific distribution patterns of this fibrosis allow us to distinguish ischaemic cardiomyopathy (iCMP) from non-ischaemic cardiomyopathy (nCMP) and sometimes to identify the aetiology of the latter. Diffuse fibrosis can also be identified using the parametric T1 mapping sequences. For this purpose, the native T1 of the tissue is measured before the administration of the contrast agent (c.a.) or the extracellular volume is calculated after c.a. Both focal and diffuse fibrosis evaluated with CMR appear to be strong prognostic predictors for the identification of threatening ventricular arrhythmias and sudden cardiac death. These evidence open the doors to a possible role of CMR in the selection of the patient to be sent to a defibrillator implant in primary prevention. In this review, we will briefly review the techniques used in CMR for the evaluation of fibrosis. We will then focus on the clinical role of myocardial tissue fibrosis detection in iCMP and nCMP.


Molecular Mechanisms of Luteolin Against Atopic Dermatitis Based on Network Pharmacology and in vivo Experimental Validation.
To undercover the underlying mechanisms of luteolin against atopic dermatitis (AD), clinically characterized by recurrent eczematous lesions and intense itching, based on network pharmacology, molecular docking and in vivo experimental validation. TCMSP, STITCH and SwissTargetPrediction databases were utilized to screen the corresponding targets of luteolin. Targets related to AD were collected from DisGeNET, GeneCards and TTD databases. PPI network of intersection targets was constructed through STRING 11.0 database and Cytoscape 3.9.0 software. GO and KEGG enrichment analysis were performed to investigate the critical pathways of luteolin against AD. Further, the therapeutic effects and candidate targets/signaling pathways predicted from network pharmacology analysis were experimentally validated in a mouse model of AD induced by 2, 4-dinitrofluorobenzene (DNFB). A total of 31 intersection targets were obtained by matching 151 targets of luteolin with 553 targets of AD. Among all, 20 core targets were identified by PPI network topology analysis, including IL-6, TNF, IL-10, VEGFA, IL-4, etc., and molecular docking indicated that luteolin binds strongly to these core targets. KEGG pathway enrichment analysis suggested that the intersected targets were significantly enriched in IL-17 signaling pathway, Th17 cell differentiation, Th1 and Th2 cell differentiation, JAK/STAT signaling pathway, etc. The in vivo experiment validated that luteolin could alleviate AD-like skin symptoms, as evidenced by the lower SCORAD score, the reduced infiltration of mast cells and the recovery of skin barrier function. Furthermore, luteolin restored immune balance by regulating the production of Th1/Th2/Th17-mediated cytokines, which were both the predicted core targets. Moreover, luteolin inhibited the phosphorylation of JAK2 and STAT3 in the lesional skin. Together, the present study systematically clarifies the ameliorative effects and possible molecular mechanisms of luteolin against AD through the combination of network pharmacology and experimental validation, shedding light on the future development and clinical application of luteolin.


Ehrlichia chaffeensis and Anaplasma phagocytophilum lack genes for lipid A biosynthesis and incorporate cholesterol for their survival.
Ehrlichia chaffeensis and Anaplasma phagocytophilum are agents of human monocytic and granulocytic ehrlichioses, respectively. They are extremely sensitive to mechanical stress and are pleomorphic gram-negative bacteria. Membrane incorporation of cholesterol from the eukaryotic host is known to be essential for other fragile and pleomorphic bacteria and mycoplasmas that lack a cell wall. Thus, we tested whether cholesterol is required for E. chaffeensis and A. phagocytophilum. Using a freeze fracture technique and biochemical analysis, these bacteria were found to contain significant levels of membrane cholesterol. These bacteria lack genes for cholesterol biosynthesis or modification. However, host cell-free bacteria had the ability to take up directly exogenous cholesterol or NBD-cholesterol, a fluorescent cholesterol derivative. Treatment of the bacteria with cholesterol extraction reagent methyl-beta-cyclodextrin caused their ultrastructural changes. Furthermore, pretreatment of the bacteria with methyl-beta-cyclodextrin or NBD-cholesterol deprived these bacteria of the ability to infect leukocytes, thus killing these obligate intracellular bacteria. Analysis of E. chaffeensis and A. phagocytophilum genome sequences revealed that these bacteria lack all genes for the biosynthesis of lipid A and most genes for the biosynthesis of peptidoglycan, which confer structural strength to gram-negative bacteria. Taken together, these results suggest that human ehrlichiosis agents became cholesterol dependent due to the loss of these genes. As the first report of gram-negative bacteria incorporating cholesterol for survival, these findings offer insight into the unique nature of their parasitism and imply that cholesterol is important in the control of human ehrlichioses.


Integrated photonics interferometric interrogator for a ring-resonator ultrasound sensor.
We present a compact integrated photonics interrogator for a ring-resonator (RR) ultrasound sensor, the so-called MediGator. The MediGator consists of a special light source and an InP Mach-Zehnder interferometer (MZI) with a 3 ×3 multi-mode interferometer. Miniaturization of the MZI to chip size enables high temperature stability and negligible signal drift. The light source has a -3 dB bandwidth of 1.5 nm, a power density of 9 dBm/nm and a tuning range of 5.7 nm, providing sufficient signal level and robust alignment for the RR sensor. The mathematical procedure of interrogation is presented, leading to the optimum MZI design. We measure the frequency response of the sensor using the MediGator, giving a resonance frequency of 0.995MHz. Further, high interrogation performance is demonstrated at the RR resonance frequency for an ultrasound pressure range of 1.47 - 442.4 Pa, which yields very good linearity between the pressure and the resulting modulation amplitude of the RR resonance wavelength. The measured signal time traces match well with calculated results. Linear fitting of the pressure data gives a sensor sensitivity of 77.2 fm/Pa. The MediGator provides a low detection limit, temperature robustness and a large measurement range for interrogating the RR ultrasound sensor.


3D LnIII-MOFs: slow magnetic relaxation and highly sensitive luminescence detection of Fe3+ and ketones.
Five new 3D isostructural lanthanide metal organic frameworks (Ln-MOFs), [Ln(HL)1.5(H2O)(DMF)]·2H2O (Ln = GdIII (1), SmIII (2), DyIII (3), EuIII (4) and TbIII (5), H3L = 5-(3',5'-dicarboxylphenyl) nicotinic acid) were synthesized by solvothermal methods and studied by structural analyses, magnetic analyses and luminescence sensing. Crystallographic studies revealed that these compounds are 3D frameworks in which the LnIII-COO chains with alternating four and two carboxylate bridges are interlinked by the organic ligands L, and contain microporous channels with accessible Lewis-base sites, coordinated water molecules and uncoordinated carboxyl groups, which are easy to combine and recognise various analytes. Magnetic studies demonstrated that the carboxylate bridges transmit interchain dominant ferromagnetic interactions in Gd-MOF (1) and Dy-MOF (3), while the decrease of the χT value in Sm-MOF (2) is due to the thermal depopulation effect of the excited levels. Furthermore, Dy-MOF (3) also shows slow magnetic relaxation behaviour under a zero dc field. The luminescence selective sensing experiments showed that Eu-MOF (4) and Tb-MOF (5) can act as recyclable sensors towards Fe3+ ions in water and the simulated biological fluids, and towards ketones in a water system with high sensitivity, selectivity and relatively low detection limits.


A Content Analysis of Health and Safety Communications Among Internet-Based Sex Work Advertisements: Important Information for Public Health.
The capacity to advertise via the Internet continues to contribute to the shifting dynamics in adult commercial sex work. eHealth interventions have shown promise to promote Internet-based sex workers' health and safety internationally, yet minimal attention has been paid in Canada to developing such interventions. Understanding the information communicated in Internet-based sex work advertisements is a critical step in knowledge development to inform such interventions. The purpose of this content analysis was to increase our understanding of the health and safety information within the Internet advertisements among women, men, and transgender sex workers and to describe how this information may be utilized to inform eHealth service development for this population. A total of 75 Internet-based sex worker advertisements (45 women, 24 men, and 6 transgender persons) were purposefully selected from 226 advertisements collected as part of a larger study in Western Canada. Content analysis was employed to guide data extraction about demographic characteristics, sexual services provided, service restrictions, health practices and concerns, safety and security, and business practices. Frequencies for each variable were calculated and further classified by gender. Thematic analysis was then undertaken to situate the communications within the social and commercialized contexts of the sex industry. Four communications themes were identified: (1) demographic characteristics; (2) sexual services; (3) health; and (4) safety and security. White was the most common ethnicity (46/75, 61%) of advertisements. It was found that 20-29 years of age accounted for 32 of the 51 advertisements that provided age. Escort, the only legal business title, was the most common role title used (48/75, 64%). In total, 85% (64/75) of advertisements detailed lists of sexual services provided and 41% (31/75) of advertisements noted never offering uncovered services (ie, no condom). Gender and the type of Web-based platform mattered for information communicated. It was found that 35 of the 45 women's advertisements were situated in personal websites and hosted details about nonsexual aspects of an appointment. Men and transworkers used Internet classified advertisement platforms with predetermined categories. Communications about sexually transmitted infections (STIs) occurred in only 16% (12/75) of advertisements with men accounting for 7. Women's advertisements accounted for 26 of the 37 advertisements noting safety restrictions. Zero men or transpersons restricted alcohol or drug use. In total, 75% (56/75) of advertisements offered out-call services and the average minimal hourly rate ranged from Can $140/h to Can $200/h. The study findings contribute to understandings about the diverse platforms used in commercial sex advertisements, and how sex workers frame information for potential clients. This information affords health care providers and policy makers insights to how they might assist with promoting the health of Internet-based sex workers and their clients.


Novel Clinical Toxicology and Pharmacology of Organophosphorus Insecticide Self-Poisoning.
Organophosphorus insecticide self-poisoning is a major global health problem, killing over 100,000 people annually. It is a complex multi-organ condition, involving the inhibition of cholinesterases, and perhaps other enzymes, and the effects of large doses of ingested solvents. Variability between organophosphorus insecticides-in lipophilicity, speed of activation, speed and potency of acetylcholinesterase inhibition, and in the chemical groups attached to the phosphorus-results in variable speed of poisoning onset, severity, clinical toxidrome, and case fatality. Current treatment is modestly effective, aiming only to reactivate acetylcholinesterase and counter the effects of excess acetylcholine at muscarinic receptors. Rapid titration of atropine during resuscitation is lifesaving and can be performed in the absence of oxygen. The role of oximes in therapy remains unclear. Novel antidotes have been tested in small trials, but the great variability in poisoning makes interpretation of such trials difficult. More effort is required to test treatments in adequately powered studies.


Effect of gaze-stabilization exercises on vestibular function during postural control.
Gaze-stabilization exercise (GSE) is often conducted in vestibular rehabilitation, but its effect on vestibular function in postural control is not clear. We investigated whether GSE affects vestibular function during static upright standing and vestibulospinal reflex (VSR) in healthy young adults. First, the center of pressure of the total trajectory length (CoP-L) was measured before each GSE task or control (only standing) task (pre), immediately after (post), and 10 min after (post10) in the static standing position on foam rubber with the eyes open or closed (EC). Second, the H-reflex on the soleus muscle was measured after the onset of ipsilateral anodal galvanic vestibular stimulation before and after a GSE or a control task to estimate the amount of VSR induced by electrical vestibular input. CoP-L for the pre, post, and post10 control tasks and the GSE in EC did not differ significantly; the CoP-L for the post and post10 tasks in EC were significantly lower than that for the pretask. The H-reflex was inhibited by galvanic vestibular stimulation in the pre-GSE tasks. The inhibition increased after GSE, but not during control tasks. These findings suggest that GSE immediately improves the postural stability required for vestibular function and can be mediated by VSR improvements.


Gene Editing in Human Lymphoid Cells: Role for Donor DNA, Type of Genomic Nuclease and Cell Selection Method.
Programmable endonucleases introduce DNA breaks at specific sites, which are repaired by non-homologous end joining (NHEJ) or homology recombination (HDR). Genome editing in human lymphoid cells is challenging as these difficult-to-transfect cells may also inefficiently repair DNA by HDR. Here, we estimated efficiencies and dynamics of knockout (KO) and knockin (KI) generation in human T and B cell lines depending on repair template, target loci and types of genomic endonucleases. Using zinc finger nuclease (ZFN), we have engineered Jurkat and CEM cells with the 8.2 kb human immunodeficiency virus type 1 (HIV-1) ∆Env genome integrated at the adeno-associated virus integration site 1 (AAVS1) locus that stably produce virus particles and mediate infection upon transfection with helper vectors. Knockouts generated by ZFN or clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) double nicking techniques were comparably efficient in lymphoid cells. However, unlike polyclonal sorted cells, gene-edited cells selected by cloning exerted tremendous deviations in functionality as estimated by replication of HIV-1 and human T cell leukemia virus type 1 (HTLV-1) in these cells. Notably, the recently reported high-fidelity eCas9 1.1 when combined to the nickase mutation displayed gene-dependent decrease in on-target activity. Thus, the balance between off-target effects and on-target efficiency of nucleases, as well as choice of the optimal method of edited cell selection should be taken into account for proper gene function validation in lymphoid cells.


Sampling Asian minorities to assess health and welfare.
The aims were (1) to sample a specified subgroup of the Asian minority; (2) to give proper representation to those outside the areas of concentration; and (3) to evaluate the costs and benefits of the method. Glasgow postcodes with varying concentrations of Asians were sampled, and 173 Asians aged 30-40 were interviewed after household screening of 1439 Asian names identified on the electoral roll or valuation roll. Areas with few Asians, and households with two or more members aged 30-40, were undersampled, and then reweighted. Nurse measures of blood pressure, lung function, and body mass were taken, and selected interview measures of health and social background are reported. Substantial differences in blood pressure, reported health, and social background were revealed between Asians in areas of concentration and those in areas of dispersion. Loss in effective sample size due to undersampling and reweighting was 4-5% in the case of the area sampling, 13% in the case of the household sampling. Losses of potential sample members through under registration were probably less than 6%. The present sampling method targets subgroups successfully, and improves on sampling in areas of concentration, in that it enables dispersed members of the minority, who differ in crucial indices of health and social position, to be represented. The costs of the method are acceptable.


Genotoxicity assessment in two Amazonian estuaries using the Plagioscion squamosissimus as a biomonitor.
Genotoxicity studies in coastal ecosystems have been a priority in Environmental Risk Assessment (ERA). This research aimed to study the genotoxicity by the micronucleus test and comet assay in two Brazilian Amazon estuaries (anthropized and control) using Plagioscion squamosissimus as a biomonitor. Blood samples were collected from 54 specimens. No significant genotoxic effects were detected in the cells analyzed, although the highest occurrence (MN and DNA damages) was observed in anthropized site. The percentage of genomic damage differed between the sites studied, being always higher in anthropizes site as well. Of the nucleoids analyzed in this site, on average, 28 ± 14.42% of the cells were classified in the highest damage class. The fish analyzed in the present study are direct influenced of xenobiont agents capable of producing damage to the genetic material of aquatic organisms in both sites and, consequently, may bring consequences still little reported in studies of morphophysiological alterations in humans.


Expression of apoptosis-related markers and clinical outcome in patients with advanced colorectal cancer.
The clinical relevance of bax and bcl-2 protein expression has been investigated in 84 patients with recurrent or metastatic colorectal cancer submitted to a chemotherapy regimen including methotrexate and fluorouracil/leucovorin. Cytoplasmic immunostaining of bax and bcl-2 was present in 65.5% and 38%, respectively, of the tumours. No association was found between bax and bcl-2 or between p53 and bax or bcl-2 protein expression. Moreover, the biomarkers were unrelated to patient and tumour characteristics known to affect the clinical outcome of colorectal cancer patients. In general, the apoptosis-related markers did not appear indicative of short- and long-term clinical response nor of prognosis. Bcl-2-negative lesions were more frequent among patients who reached an objective clinical response, which is in agreement with previously reported data regarding other tumour types. When the interrelationship between p53 and bax expression was examined, a better response rate (40%) was found for patients whose tumours did not express p53 and bax, and a better prognosis (2-year probability of overall survival 75%) for patients with p53-positive and bax-negative tumours. In the present series of patients with advanced colorectal cancer submitted to systemic chemotherapy we did not find a clear association between expression of apoptosis-related markers and clinical outcome, even in the subset of patients in which the apoptotic index as determined by the TUNEL approach was investigated.


A fluid dynamics study in a 50 cc pulsatile ventricular assist device: influence of heart rate variability.
Although left ventricular assist devices (LVADs) have had success in supporting severe heart failure patients, thrombus formation within these devices still limits their long term use. Research has shown that thrombosis in the Penn State pulsatile LVAD, on a polyurethane blood sac, is largely a function of the underlying fluid mechanics and may be correlated to wall shear rates below 500 s(-1). Given the large range of heart rate and systolic durations employed, in vivo it is useful to study the fluid mechanics of pulsatile LVADs under these conditions. Particle image velocimetry (PIV) was used to capture planar flow in the pump body of a Penn State 50 cubic centimeters (cc) LVAD for heart rates of 75-150 bpm and respective systolic durations of 38-50%. Shear rates were calculated along the lower device wall with attention given to the uncertainty of the shear rate measurement as a function of pixel magnification. Spatial and temporal shear rate changes associated with data collection frequency were also investigated. The accuracy of the shear rate calculation improved by approximately 40% as the resolution increased from 35 to 12 μm/pixel. In addition, data collection in 10 ms, rather than 50 ms, intervals was found to be preferable. Increasing heart rate and systolic duration showed little change in wall shear rate patterns, with wall shear rate magnitude scaling by approximately the kinematic viscosity divided by the square of the average inlet velocity, which is essentially half the friction coefficient. Changes in in vivo operating conditions strongly influence wall shear rates within our device, and likely play a significant role in thrombus deposition. Refinement of PIV techniques at higher magnifications can be useful in moving towards better prediction of thrombosis in LVADs.


Pain reduction induced by tapentadol in patients with musculoskeletal chronic pain fosters better sleep quality.
Poor sleep may predict the increase and intensification of pain over time with increased insomnia symptoms being both a predictor and an indicator of worse pain outcomes and physical functioning status over time. However, the impact of different analgesic therapies on quality of life, functional recovery and sleep has been poorly assessed to date, whereas these evaluations may greatly help clinicians in the selection of treatment when dealing with patients with chronic pain (CP). To explore whether tapentadol-induced pain relief may drive improved sleep quality, we carried out a pooled analysis of real-world data collected from 487 patients with CP (mean age, 68.3 years; 57.7% women) suffering from a wide range of chronic musculoskeletal pain conditions and treated with tapentadol. Following tapentadol treatment, patients experienced an 80% reduction in the frequency of very disturbed sleep as well as a 50% reduction in the predominant sleep complaint reported by patients with CP - that is, nocturnal awakenings. A significantly greater proportion of patients reported good/restful sleep at the end of the study period compared to baseline (72.4% versus 25.3%; p<0.01). This benefit was observed regardless of the clinical setting, treatment duration, posology or patient age and was associated with a higher proportion of patients reporting an improved global health status and good tolerability. The reduction in pain intensity provided by tapentadol fosters sleep quality and favours a better quality of life. Therefore, our findings provide the rationale for addressing sleep quality as a relevant outcome, complementary to pain relief in CP management.


Attitudes to routine HIV counselling and testing, and knowledge about prevention of mother to child transmission of HIV in eastern Uganda: a cross-sectional survey among antenatal attendees.
HIV testing rates have exceeded 90% among the pregnant women at Mbale Regional Referral Hospital in Mbale District, eastern Uganda, since the introduction of routine antenatal counselling and testing for HIV in June 2006. However, no documented information was available about opinions of pregnant women in eastern Uganda about this HIV testing approach. We therefore conducted a study to assess attitudes of antenatal attendees towards routine HIV counselling and testing at Mbale Hospital. We also assessed their knowledge about mother to child transmission of HIV and infant feeding options for HIV-infected mothers. The study was a cross-sectional survey of 388 women, who were attending the antenatal clinic for the first time with their current pregnancy at Mbale Regional Referral Hospital from August to October 2009. Data were collected using a pre-tested questionnaire and analysed using descriptive statistics and logistic regression. Permission to conduct the study was obtained from the Makerere University College of Health Sciences, the Uganda National Council of Science and Technology, and Mbale Hospital. The majority of the antenatal attendees (98.5%, 382/388) had positive attitudes towards routine HIV counselling and testing, and many of them (more than 60%) had correct knowledge of how mother to child transmission of HIV could occur during pregnancy, labour and through breastfeeding, and ways of preventing it. After adjusting for independent variables, having completed secondary school (odds ratio: 2.5, 95% confidence interval: 1.3-4.9), having three or more pregnancies (OR: 2.5, 95% CI: 1.4-4.5) and belonging to a non-Bagisu ethnic group (OR: 1.7, 95% CI: 1.0-2.7) were associated with more knowledge of exclusive breastfeeding as one of the measures for prevention of mother to child transmission of HIV. Out of 388 antenatal attendees, 386 (99.5%) tested for HIV and 382 (98.5%) received same-day HIV test results. Routine offer of antenatal HIV counselling and testing is largely acceptable to the pregnant women in eastern Uganda and has enabled most of them to know their HIV status as part of the prevention of mother to child transmission of HIV package of services. Our findings call for further strengthening and scaling up of this HIV testing approach in many more antenatal clinics countrywide in order to maximize its potential benefits to the population.


The Drosophila caspase Ice is important for many apoptotic cell deaths and for spermatid individualization, a nonapoptotic process.
Caspase family proteases play important roles in the regulation of apoptotic cell death. Initiator caspases are activated in response to death stimuli, and they transduce and amplify these signals by cleaving and thereby activating effector caspases. In Drosophila, the initiator caspase Nc (previously Dronc) cleaves and activates two short-prodomain caspases, Dcp-1 and Ice (previously Drice), suggesting these as candidate effectors of Nc killing activity. dcp-1-null mutants are healthy and possess few defects in normally occurring cell death. To explore roles for Ice in cell death, we generated and characterized an Ice null mutant. Animals lacking Ice show a number of defects in cell death, including those that occur during embryonic development, as well as during formation of adult eyes, arista and wings. Ice mutants exhibit subtle defects in the destruction of larval tissues, and do not prevent destruction of salivary glands during metamorphosis. Cells from Ice animals are also markedly resistant to several stresses, including X-irradiation and inhibition of protein synthesis. Mutations in Ice also suppress cell death that is induced by expression of Rpr, Wrinkled (previously Hid) and Grim. These observations demonstrate that Ice plays an important non-redundant role as a cell death effector. Finally, we demonstrate that Ice participates in, but is not absolutely required for, the non-apoptotic process of spermatid differentiation.


Engineering graphene with red phosphorus quantum dots for superior hybrid anodes of sodium-ion batteries.
Red phosphorus (P) has been considered to be one of the most promising anode materials for sodium-ion batteries (SIBs) because of its highest theoretical capacity (∼2600 mA h g-1). For the first time, we report a reliable hydrothermal method for the preparation of red phosphorus quantum dots (RPQDs) with commercial red P as a source. Moreover, an effective strategy was designed to fabricate RPQDs/rGO nanohybrids for addressing the intrinsic issues of red P as anode materials for SIBs. Benefiting from the nanostructuring of red P and the coupling of RPQDs with rGO, the obtained nanohybrids not only promote electron and ion transfer, but also effectively enhance the electronic conductivity, restrain the aggregation of RPQDs and buffer the large volume changes of red phosphorus during the charge-discharge process. The nanohybrids deliver an initial specific capacity of 1161 mA h g-1 and a low capacity deterioration rate of less than 0.12% per cycle even after 250 cycles at a current density of 200 mA g-1. The feasibility of large-scale production of the RPQDs/rGO nanohybrid, associated with its outstanding Na-ion storage properties and low cost, demonstrates that the RPQDs/rGO hybrid is a very promising anode material for SIBs.


Local ciliate communities associated with aquatic macrophytes.
This study, based within the catchment area of the River Frome, an important chalk stream in the south of England, compared ciliated protozoan communities associated with three species of aquatic macrophyte common to lotic habitats: Ranunculus penicillatus subsp. pseudofluitans, Nasturtium officinale and Sparganium emersum. A total of 77 ciliate species were counted. No species-specific ciliate assemblage was found to be typical of any one plant species. Ciliate abundance between plant species was determined to be significantly different. The ciliate communities from each plant species were unique in that the number of species increased with ciliate abundance. The community associated with R. penicillatus subsp. pseudofluitans showed the highest consistency and species richness whereas S. emersum ciliate communities were unstable. Most notably, N. officinale was associated with low ciliate abundances and an apparent reduction in biofilm formation, discussed herein in relation to the plant's production of the microbial toxin phenethyl isothiocyanate. We propose that the results reflect differences in the quantity and quality of biofilm present on the plants, which could be determined by the different plant morphologies, patterns of plant decay and herbivore defense systems, all of which suppress or promote the various conditions for biofilm growth.


Prevalence of thymidylate synthase gene 5'-untranslated region variants in an Argentinean sample.
Thymidylate synthase (TYMS) is a key enzyme in nucleotide synthesis and therefore, an important target of many chemotherapeutic agents. Expression of TYMS mRNA is thought to be modulated by a 28-bp tandem repeat polymorphism within its 5'-untranslated region, raising the question of this variant's utility in predicting the efficacy and toxicity of cancer treatment regimens. The aim of the present research was to describe the distribution of this TYMS polymorphism in the Argentinean population. A total of 199 randomly selected DNA samples from healthy volunteers were analyzed using polymerase chain reaction and polyacrylamide gel electrophoresis. The 2R and 3R alleles were present in 47.74 and 52.26% of samples, respectively, with frequencies of 21.6 (43), 52.3 (104), and 26.1% (52) recorded for the 2R/2R, 2R/3R, and 3R/3R genotypes, respectively. No significant difference regarding gender was observed. Our prevalence data are similar to those reported for other Caucasian populations. This opens a discussion concerning the reference population valid for comparisons and the clinical importance of this genotyping test as an additional tool in personalized medicine.


A selective, nontoxic, OFF-ON fluorescent molecular sensor based on 8-hydroxyquinoline for probing Cd(2+) in living cells.
In spite of the fact that cadmium(II) has been recognized as a highly toxic element and that excessive exposure to this metal ion has been reported to have many adverse effects on human health, very few selective and specific fluorescent probes are available for imaging Cd(2+) in living cells. Herein, we report the spectroscopic and photochemical characterization of 5-(5-chloro-8-hydroxyquinolinylmethyl)-2,8-dithia-5-aza-2,6-pyridinophane (L) as a fluorescent sensor for the selective imaging of Cd(2+) in living cells. In particular, the response of L to Cd(2+) was first assessed in aqueous solutions, sodium dodecyl sulfate micelles, and liposomes, and subsequently in living cells by fluorescence microscopy techniques. Cytofluorimetric analyses of leukemic HL-60 cells loaded with L also allowed evaluation of the toxicity of the probe and the selective analysis of its intracellular fluorescence in the presence of Cd(2+). Furthermore, the 1:1 complex species [Cd(L)H(2)O](2+) responsible for the OFF-ON chelation enhancement of fluorescence (CHEF) effect on L was structurally characterized; time-dependent DFT calculations allowed the prediction of theoretical excitations, which were comparable with the experimental ones.


Oxygen concentration modulates the differentiation of muscle stem cells toward myogenic and adipogenic fates.
The physiological oxygen concentration of many tissues is far lower than that in which cells are typically cultured in vitro and this may inadvertently influence the proliferation and differentiation potential of many cell types. Muscle derived stem cells, known as satellite cells are responsible for the maintenance and repair of muscle tissue post-natally and in vivo would be exposed to oxygen concentrations of ∼2-5%. Relatively few studies describe the function of these cells in large animal models and here we investigate the influence oxygen concentration has on modulating porcine muscle derived stem cell fate. We compared cells derived from two metabolically distinct muscles, the diaphragm and the hind limb semi-membranosus (SM) muscle. The two sub-populations responded differently to culture at atmospheric (∼20%) and physiological (∼5%) oxygen concentration. While myogenesis was enhanced in both populations at low oxygen, noticeably diaphragm derived cells exhibited greater myotube formation, than those from SM. The trans-differentiation of cells derived from these two sources was similarly affected, with considerable differences seen in adipogenic and neuronal tendencies. In addition to the effect of oxygen on cell phenotype, the expression of key signalling proteins varied between the two sub-populations during early time-points of induced differentiation, suggesting altered regulation of muscle specific stem cells under these conditions. While differences in muscle stem cell potential requires further investigation, the culture of cells in physiological oxygen concentration appears as fundamental to recreating the micro-environmental niche as routinely used factors such as cytokines, substrata and matrices.


Ion flow through a membrane: effect of chemical reaction on time dependence.
The membrane model previously described [Hays, T.R., Buckwalter, C.Q., Lin S.H. & Eyring, H. (1978) Proc. Natl. Acad. Sci. USA 75, 1612-1615] for ion flow through a membrane is expanded to include the effect of binding of the mobile ion at the occupiable sites in the membrane. Two different effects were investigated: alteration of the association-dissociation rates at constant equilibrium constant and alteration of the equilibrium constant at constant dissociation constant. Increasing the rates of association and dissociation initially causes an increased slowing of the relaxation to the final steady state, though ultimately the curves for the faster rates cross those for the slower states. Increasing the equilibrium constant causes a greater delay in the relaxation curve, with the curves for different equilibrium constants not crossing. Overall, the effect of binding is not very great unless the equilibrium constant for binding is quite large.


Clinics in diagnostic imaging (45). Osmotic myelinolysis ( central potine myelinolysis).
A 65-year-old woman developed progressive neurological deterioration following rapid correction of hyponatremia. Magnetic resonance imaging showed T2 hyperintense areas in the central pons, basal ganglia and deep white matter, typical of osmotic myelinolysis (OM). Previously thought to be uniformly fatal, there are increasing reports of non-fatal cases of OM. The recognition and understanding of this entity is important to prevent or reduce the incidence of its occurrence, as there is no specific treatment once it develops. The clinical and radiological features of OM are reviewed.


Auditory processing following sequential bilateral cochlear implantation: a pediatric case study using event-related potentials.
Past studies using event-related potentials (ERPs) elicited to single syllable stimuli in unilateral and bilateral cochlear implant users have suggested reorganization of the auditory cortex within the first 6-8 mo postimplantation (Sharma et al, 2002a, 2002b, 2006; Bauer et al, 2006). Better behavioral performance with bilateral implants is expected when bilateral cochlear implantation is performed simultaneously or when a second implant is provided after a short interval of auditory deprivation at a younger age (Murphy and O'Donoghue, 2007; Wolfe et al, 2007; Steffens et al, 2008). The purpose of this case study was to examine changes in various levels of auditory processing using single syllable and word-level stimuli in a child who received bilateral cochlear implants sequentially. Brain responses were recorded at pre-activation and 2, 4, and 6 mo postactivation of a second cochlear implant using passive paradigms involving two types of auditory perception (speech and word level). Auditory stimuli were presented at 75 dB SPL(A) through a speaker above the participant's head with the cochlear implant(s) at typical user settings. Cortical responses were recorded from 128 electrodes. The participant was a 6-yr-old female with the diagnosis of bilateral profound sensorineural hearing loss. She received her first cochlear implant in her right ear (2 yr, 4 mo of age), underwent revision surgery (3 yr, 6 mo of age), and later received a bilateral cochlear implant (6 yr, 8 mo of age). For the purposes of the case study, the waveforms were visually examined for morphology and amplitude or latency differences between conditions. The ERPs of the cochlear implant user were compared to those from a group of five children with normal hearing. The results suggest that sequential bilateral cochlear implantation contributes to improved auditory processing beyond the benefits of the single implant even in users with an extended period of deafness in the later-implanted ear.


Psychological aspects of breast cancer.
This paper reviews the common psychological concerns expressed by women with breast cancer. It also reviews the epidemiology of psychiatric diagnoses in this population. The special diagnostic problems and available pharmacological and psychotherapeutic interventions are discussed. The aim of psychiatric treatment in breast cancer patients is to relieve major psychological symptoms as well as to address underlying intrapsychic conflicts that become prominent during treatment.


Anti-high mobility group box 1 monoclonal antibody ameliorates experimental autoimmune encephalomyelitis.
High mobility group box 1 (HMGB1) is an established inflammatory mediator when released from cells. Recent studies have implicated extracellular HMGB1 in the pathogenesis of various autoimmune diseases. The objective of this study was to determine whether HMGB1 could be a therapeutic target for experimental autoimmune encephalomyelitis (EAE). In this study, an anti-HMGB1 monoclonal antibody was injected intraperitoneally into a mouse model of EAE. We also measured serum cytokines levels in EAE and anti-HMGB1 monoclonal antibody-treated EAE. As a result, intraperitoneal injection of an anti-HMGB1 monoclonal antibody ameliorated the clinical and pathological severity of EAE and attenuated interleukin-17 up-regulation in serum. In conclusion, HMGB1 is involved in EAE pathogenesis and could trigger inflammation in the central nervous system. The novel aspect of this study is the demonstration that anti-HMGB1 ameliorates EAE. HMGB1 may be a novel therapeutic strategy for multiple sclerosis.