Biocharts: a visual formalism for complex biological systems.
We address one of the central issues in devising languages, methods and tools for the modelling and analysis of complex biological systems, that of linking high-level (e.g. intercellular) information with lower-level (e.g. intracellular) information. Adequate ways of dealing with this issue are crucial for understanding biological networks and pathways, which typically contain huge amounts of data that continue to grow as our knowledge and understanding of a system increases. Trying to comprehend such data using the standard methods currently in use is often virtually impossible. We propose a two-tier compound visual language, which we call Biocharts, that is geared towards building fully executable models of biological systems. One of the main goals of our approach is to enable biologists to actively participate in the computational modelling effort, in a natural way. The high-level part of our language is a version of statecharts, which have been shown to be extremely successful in software and systems engineering. The statecharts can be combined with any appropriately well-defined language (preferably a diagrammatic one) for specifying the low-level dynamics of the pathways and networks. We illustrate the language and our general modelling approach using the well-studied process of bacterial chemotaxis.


The Oculus Rift: a cost-effective tool for studying visual-vestibular interactions in self-motion perception.
For years now, virtual reality devices have been applied in the field of vision science in an attempt to improve our understanding of perceptual principles underlying the experience of self-motion. Some of this research has been concerned with exploring factors involved in the visually-induced illusory perception of self-motion, known as vection. We examined the usefulness of the cost-effective Oculus Rift in generating vection in seated observers. This device has the capacity to display optic flow in world coordinates by compensating for tracked changes in 3D head orientation. We measured vection strength in three conditions of visual compensation for head movement: compensated, uncompensated, and inversely compensated. During presentation of optic flow, the observer was instructed to make periodic head oscillations (±22° horizontal excursions at approximately 0.53 Hz). We found that vection was best in the compensated condition, and was weakest in the inversely compensated condition. Surprisingly, vection was always better in passive viewing conditions, compared with conditions where active head rotations were performed. These findings suggest that vection is highly dependent on interactions between visual, vestibular and proprioceptive information, and may be highly sensitive to limitations of temporal lag in visual-vestibular coupling using this system.


Knowledge, attitude and practice on diet and physical activity among mothers with young children in the Jhaukhel-Duwakot Health Demographic Surveillance Site, Nepal.
The prevalence of cardiovascular diseases is increasing in low and middle-income countries; Nepal's population shows a high prevalence of behavioral risk factors. Our cross-sectional study in the Jhaukhel-Duwakot Health Demographic Surveillance Site (JD-HDSS), located near the capital Kathmandu, explored knowledge, attitude, and practice (KAP) of mothers with young children regarding diet and physical activity and mothers' perception of their children's attitude and behavior toward the same issues. The purpose of our study was to assess needs of the mothers concerning cardiovascular health in general and more specifically regarding diet and physical activity, and to establish a baseline for future intervention in the community by comparing two villages of JD-HDSS. In August-November 2014, nine trained enumerators interviewed all mothers of children aged 1-7 years (N = 962). We scored responses on dietary and physical activity KAP, then categorized the scores based on the percentage obtained out of the maximum possible scores into "poor," "fair," and "good." More highly educated mothers scored higher for KAP (all p<0.001); the children's behavior score reflected their mother's education level (p = 0.007). Most respondents were unfamiliar with the concept of healthy and unhealthy food. Overall, 57% of respondents in JD-HDSS had "good" knowledge, 44.6% had "good" attitude, and most (90%) had "poor" practice. We observed no significant differences between the villages regarding mothers' knowledge and attitude or children's behavior. Practice score of mothers in Jhaukhel was higher than those in Duwakot regarding diet and physical activity (p<0.001). Mothers' perceived barriers for improving lifestyle were high cost of healthy food, taste preference of other family members, and lack of knowledge regarding healthy food. Barriers for physical activity were lack of leisure time, absence of parks and playgrounds, busy caring for children and old people, feeling lazy, and embarrassed to be physically active in front of others. Our findings suggest that a health education intervention promoting a healthy lifestyle for mothers and children might improve KAP and also improve cardiovascular health. To address mothers' gap between knowledge and practice, a future intervention should consider perceived barriers.


The association between pollutant levels and asthma-related emergency department visits in the Bronx after the World Trade Center attacks.
Objective: To examine the potential impact of the World Trade Center (WTC) attacks on asthma-related emergency department visits (AREDV) in the New York City borough of the Bronx. Methods: We obtained daily nitrogen dioxide (NO2), sulfur dioxide (SO2) and ozone (O3) values from the National Climatic Data Center's collection station in the Bronx from 1999 and 2002, a year before and after the WTC attacks. We compared daily AREDV and pollutant levels between 1999 and 2002 using the Wilcoxon signed rank sum test. We considered each season separately due to seasonal variations of AREDV and pollutants. We then used multiple linear regression models to assess the relationships between the changes in AREDV and the changes in pollutants from 1999 to 2002 in each season. Results: There were statistically significant increases from 1999 to 2002 in the daily NO2 in the summer. Significant increases for daily SO2 and O3 values from 1999 to 2002 occurred in all seasons. Significant increases occurred in daily AREDV values in the spring and fall. Multiple linear regression analyses showed that increases in the daily O3 values were significantly associated with increases in AREDV from 1999 to 2002 in the summer season. Conclusion: We observed a possible association between the WTC attacks and significant increases in O3 and SO2 for all seasons, and NO2 for the summer. AREDV significantly increased following the WTC attacks. Increases in daily O3 values were significantly associated with increases in AREDV in the summer season.


Neurological deficit and cerebral infarction after temporary middle cerebral artery occlusion in unanesthetized cats.
Forty-four unanesthetized cats underwent temporary middle cerebral artery (MCA) occlusion with an implanted, externally controlled balloon cuff occluder. The occlusion was reversed to allow reperfusion of the MCA after 2 min to 24 hr of ischemia. Fourteen cats had temporary occlusions lasting 2 min to 3 hr; their neurological deficits improved or resolved after reperfusion, and brain sections showed only scattered microscopic areas of necrosis. After a 4-hr occlusion, five of nine cats (55%) recovered completely within 24 hr; two had persistent deficit when sacrificed, 10 days later, and each had a circumscribed infarct. All 18 cats undergoing 5-, 6-, 8-, and 24-hr occlusions sustained permanent neurological deficits. Three 3-hr occlusions at 2-day intervals in three cats resulted in permanent deficits and infarcts that were 25% larger than those after single 8-hr occlusions. Ten cats underwent permanent MCA occlusion; three deteriorated neurologically and died, and the survivors showed no improvement. Infarcts after 5-, 6-, and 8-hr occlusions followed by reperfusion were 66% smaller (p less than 0.05) than those after permanent occlusion; reperfusion after 24 hr of occlusion did not reduce infarct size. Hemorrhagic infarction occurred after two permanent occlusions, but after only one 5-hr temporary occlusion. The results obtained with this method of temporary regional ischemia indicate that restoration of flow after 1-8 hr, but not after 24 hr, of MCA occlusion resulted in less severe neurological deficit and smaller infarcts than did permanent occlusion. The infarct size correlated with the duration of MCA occlusion (p less than 0.05) rather than with the degree of deficit during occlusion.


Abnormal magnesium metabolism in two rat models of genetic hypertension.
Magnesium concentrations in erythrocyte ghosts and arterial tissue of male, spontaneously hypertensive rats (SHR) were significantly less than in these tissues of male normotensive controls (Wistar-Kyoto; WKY) of the same age, which were also fed rat chow and tap water. The magnesium concentration in SHR erythrocyte ghosts was increased to the control value by incubating SHR erythrocytes with WKY blood plasma; SHR plasma did not affect the magnesium concentration in WKY erythrocyte ghosts. The magnesium concentrations in erythrocyte ghosts, aortas, and mesenteric arteries from female salt-sensitive (SS/JR) and salt-resistant (SR/JR) Dahl-derived rats, both maintained ad libitum on laboratory rat chow and either tap water or 0.9% NaCl, were not different but were significantly less than those of Sprague-Dawley rats considered as controls. While the ingestion of 0.9% NaCl had no effect on the magnesium concentrations measured in these animals, it caused the salt-sensitive rats to become severely hypertensive. It is evident from these observations that the decreased binding of magnesium to the plasma membrane of cells may be an inheritable metabolic defect that may be associated with the development of hypertension. However, in those instances of hypertension in which this defect occurs, it appears to be a contributing cause of the hypertension; by itself the defect is not a cause of hypertension.


Involvement of the medial pallidum in focal myoclonic dystonia: A clinical and neurophysiological case study.
We successfully treated a patient with familial myoclonic dystonia (FMD), which primarily affected his neck muscles, with bilateral deep brain stimulation (DBS) to the medial pallidum, and investigated the role of the medial pallidum in FMD. A patient with FMD underwent bilateral implantation of DBS electrodes during which field potentials (FPs) in the medial pallidum and electromyograms (EMGs) from the affected neck muscles were recorded. The effects of high-frequency DBS to the medial pallidum on the FMD were also assessed by recording EMGs during and immediately after implantation, as well as 6 days and 8 weeks postoperatively. During spontaneous myoclonic episodes, increased FPs oscillating at 4 and 8 Hz were recorded from the medial pallidum; these correlated strongly with phasic EMG activity at the same frequencies in the contralateral affected muscles. The EMG activity was suppressed by stimulating the contralateral medial pallidum at 100 Hz during the operation and continuous bilateral DBS from an implanted stimulator abolished myoclonic activity even more effectively postoperatively. The phasic pallidal activity correlated with and led the myoclonic muscle activity, and the myoclonus was suppressed by bilateral pallidal DBS, suggesting that the medial pallidum was involved in the generation of the myoclonic activity. High-frequency DBS may suppress the myoclonus by desynchronising abnormal pallidal oscillations. This case study has significant clinical implications, because at present, there is no effective treatment for focal myoclonic dystonia.


Enhanced beetle luciferase for high-resolution bioluminescence imaging.
We developed an enhanced green-emitting luciferase (ELuc) to be used as a bioluminescence imaging (BLI) probe. ELuc exhibits a light signal in mammalian cells that is over 10-fold stronger than that of the firefly luciferase (FLuc), which is the most widely used luciferase reporter gene. We showed that ELuc produces a strong light signal in primary cells and tissues and that it enables the visualization of gene expression with high temporal resolution at the single-cell level. Moreover, we successfully imaged the nucleocytoplasmic shuttling of importin alpha by fusing ELuc at the intracellular level. These results demonstrate that the use of ELuc allows a BLI spatiotemporal resolution far greater than that provided by FLuc.


Orthognathic surgery correction of mandibular hypoplasia accompanying obstructive sleep apnea syndrome.
To examine the surgical correction methods for treating cases of severe mandibular hypoplasia accompanying obstructive sleep apnea syndrome (OSAS). Sixteen cases of severe mandibular hypoplasia were studied in which OSAS was documented by polysomnography (PSG) and cephalometric study. The obstructive site was at the base of the tongue. Surgical procedures such as temporomandibular joint (TMJ) reconstruction and bimaxillary, chin, and hyoid bone advancement were performed to improve each patient's profile, function, and occlusion, and to treat the OSAS. There were great improvements in patient's sleep and daytime quality of life. The pre- and postoperative changes of most PSG values and some cephalometric values (SNB, PAS) were statistically significant. Severe mandibular hypoplasia can cause not only abnormalities in profile and occlusion but also OSAS. The evaluation of OSAS and its treatment effects depend on PSG. It is also very important to confirm the obstructive site in the upper airway by cephalometric study and fiberoptic endoscopy. Orthognathic surgery procedures can advance the maxillary, chin, and hyoid bone, and expand the upper airway simultaneously. These procedures can treat OSAS. Cases of TMJ ankylosis with OSAS should be treated step by step.


Does intraspecific size variation in a predator affect its diet diversity and top-down control of prey?
It has long been known that intraspecific variation impacts evolutionary processes, but only recently have its potential ecological effects received much attention. Theoretical models predict that genetic or phenotypic variance within species can alter interspecific interactions, and experiments have shown that genotypic diversity in clonal species can impact a wide range of ecological processes. To extend these studies to quantitative trait variation within populations, we experimentally manipulated the variance in body size of threespine stickleback in enclosures in a natural lake environment. We found that body size of stickleback in the lake is correlated with prey size and (to a lesser extent) composition, and that stickleback can exert top-down control on their benthic prey in enclosures. However, a six-fold contrast in body size variance had no effect on the degree of diet variation among individuals, or on the abundance or composition of benthic or pelagic prey. Interestingly, post-hoc analyses revealed suggestive correlations between the degree of diet variation and the strength of top-down control by stickleback. Our negative results indicate that, unless the correlation between morphology and diet is very strong, ecological variation among individuals may be largely decoupled from morphological variance. Consequently we should be cautious in our interpretation both of theoretical models that assume perfect correlations between morphology and diet, and of empirical studies that use morphological variation as a proxy for resource use diversity.


The Partnership and Coping Enhancement Programme for couples undergoing in vitro fertilization treatment: the development of a complex intervention in China.
Couples as dyads suffer from the diagnosis of infertility and related treatment. These couples commonly experience emotional and physical pain and tension in their marital lives. The purpose of this study is to report on the process of developing a potentially feasible and effective complex intervention for couples undergoing in vitro fertilization treatment in China. The Medical Research Council (MRC) framework for developing and evaluating the complex intervention was adopted to guide the development of the Partnership and Coping Enhancement Programme (PCEP). In developing the PCEP, three steps were taken, namely, (1) identifying evidence by conducting literature reviews, a concept analysis and a qualitative study; (2) identifying/developing a theory-in this case, a preliminary Endurance with Partnership Conceptual Framework (P-EPCF) was proposed; and (3) modelling the process and outcomes of the PCEP. The PCEP that was developed is targeted mainly at the domains of the partnership mediators of stress in the P-EPCF. It consists of two sections-partnership and coping-and will be delivered to infertile couples on the day of embryo transfer. The main focuses of the programme are to facilitate mutual sharing and support in infertile couples, and to improve their individual and dyadic coping strategies while undergoing IVF treatment, especially in the period when they are waiting for the results of a pregnancy test and after the disclosure of a negative treatment outcome. The programme is couple-based, consisting of experience sharing, psychoeducation, meditation exercise, skill practise and supplemental written materials. The Partnership and Coping Enhancement Programme (PCEP) for couples undergoing in vitro fertilization treatment was developed according to the guideline of the MRC framework. It is recommended that a pilot study be conducted to evaluate its feasibility and to model the process and outcomes of the programme.


Functional characterization of four novel PAX8 mutations causing congenital hypothyroidism: new evidence for haploinsufficiency as a disease mechanism.
Individuals carrying a heterozygous inactivating PAX8 mutation are affected by congenital hypothyroidism (CH), although heterozygous Pax8 knockout mice are not. It has remained unclear whether CH in PAX8 mutation carriers is caused by haploinsufficiency or a dominant negative mechanism. To report clinical and molecular findings of four novel PAX8 mutations, including one early-truncating frameshift mutation. Four probands were CH patients. Two had family history of congenital or childhood hypothyroidism. Three probands were diagnosed in the frame of newborn screening for CH, while one had a negative result in screening but was diagnosed subsequently. Three had thyroid hypoplasia and one had a slightly small thyroid with low echogenicity. For these probands and their family members, we sequenced PAX8 using a standard PCR-based method. Pathogenicity of identified mutations was verified in vitro. We found four novel heterozygous PAX8 mutations in the four probands: L16P, F20S, D46SfsX24, and R133Q. Family studies showed four additional mutation carriers, who were confirmed to have high serum TSH levels. Expression experiments revealed that three mutations (L16P, F20S, and R133Q) had defects in target DNA binding, while D46fs had protein instability that was rescued by the proteasome inhibitor MG132. All four mutations had reduced transactivation on the thyroglobulin promoter, supporting that they were inactivating mutations. D46fs is the first PAX8 mutation with confirmed protein instability. Our clinical and in vitro findings together suggest that pure PAX8 haploinsufficiency can cause CH in humans.


Who has access to counseling and testing and anti-retroviral therapy in Malawi - an equity analysis.
The HIV and AIDS epidemic in Malawi poses multiple challenges from an equity perspective. It is estimated that 12% of Malawians are living with HIV or AIDS among the 15-49 age group. This paper synthesises available information to bring an equity lens on Counselling and Testing (CT) and Antiretroviral Therapy (ART) policy, practice and provision in Malawi. A synthesis of a wide range of published and unpublished reports and studies using a variety of methodological approaches was undertaken. The analysis and recommendations were developed, through consultation with key stakeholders in Malawi. At the policy level Malawi is unique in having an equity in access to ART policy, and equity considerations are also included in key CT documents. The number of people accessing CT has increased considerably from 149,540 in 2002 to 482,364 in 2005. There is urban bias in provision of CT and more women than men access CT. ART has been provided free since June 2004 and scale up of ART provision is gathering pace. By end December 2006, there were 85,168 patients who had ever started on ART in both the public and private health sector, 39% of the patients were male while 61% were female. The majority of patients were adults, and 7% were children, aged 14 years or below. Despite free ART services, patients, especially poor rural patients face significant barriers in access and adherence to services. There are missed opportunities in strengthening integration between CT and ART and TB, Sexually Transmitted Infections (STI) and maternal health services. To promote equitable access for CT and ART in Malawi there is need to further invest in human resources for health, and seize opportunities to integrate CT and ART services with tuberculosis, sexually transmitted infections and maternal health services. This should not only promote access to services but also ensure that resources available for CT and ART strengthen rather than undermine the provision of the essential health package in Malawi. Ongoing equity analysis of services is important in analyzing which groups are unrepresented in services and developing initiatives to address these. Creative models of decentralization, whilst maintaining quality of services are needed to further enhance access of poor rural women, men, girls and boys.


Three-dimensional parallel particle manipulation and tracking by integrating holographic optical tweezers and engineered point spread functions.
We demonstrate an integrated holographic optical tweezers system with double-helix point spread function (DH-PSF) imaging for high precision three-dimensional multi-particle tracking. The tweezers system allows for the creation and control of multiple optical traps in three-dimensions, while the DH-PSF allows for high precision, 3D, multiple-particle tracking in a wide field. The integrated system is suitable for particles emitting/scattering either coherent or incoherent light and is easily adaptable to existing holographic tweezers systems. We demonstrate simultaneous tracking of multiple micro-manipulated particles and perform quantitative estimation of the lateral and axial forces in an optical trap by measuring the fluid drag force exerted on the particles. The system is thus capable of unveiling complex 3D force landscapes that make it suitable for quantitative studies of interactions in colloidal systems, biological materials, and a variety of soft matter systems.


Bioelectrical impedance and strength measurements in patients with heart failure: comparison with functional class.
Patients with chronic heart failure (HF) develop important changes in body composition. Nevertheless, the usual methods of body composition assessment can be misleading in patients with HF because tissue hydration is altered. Bioelectrical impedance vector analysis (BIVA) works without making any assumption about constant soft tissue hydration. In this study, patients with HF and systolic dysfunction (HFS) and preserved systolic function (HFPSF) underwent a body composition evaluation by the BIVA method; the comparison was done between New York Heart Association (NYHA) functional classes I-II and III-IV. We studied 243 patients with HF, 140 (101 in NYHA I-II and 39 in III-IV) with HFS and 103 (67 in NYHA I-II and 36 in II-IV) with HFPSF. Whole-body bioelectrical impedance was measured using BodyStat QuadScan 4000, which is tetrapolar and multiple-frequency equipment. In both HF categories, reactance and phase angle were significantly lower, the impedance ratio of 200 kHz to that at 5 kHz was higher, and had significantly shorter and downsloping impedance vector in the NYHA III-IV group compared with the NYHA I-II group by gender. Bioelectrical impedance analysis allows an easier evaluation of body composition and this might be particularly useful to stratify the severity of HF.


Sleepiness in Parkinson's disease: a controlled study.
Sudden-onset sleep episodes while driving have been reported in Parkinson's disease (PD) patients, and termed sleep attacks because they were reported to be irresistible and to occur without warning. We postulate that these episodes are due to excessive daytime sleepiness secondary to the high frequency of sleep disorders in PD patients and the sedative effects of dopaminergic medications. We assessed the frequency and relationship between excess daytime sleepiness and sleep episodes while driving (SE) in patients with PD. We evaluated 101 consecutive PD patients presenting to the Movement Disorder Center at the Mount Sinai School of Medicine using a questionnaire that incorporated a subjective estimate of sleepiness, the Epworth Sleepiness Scale (ESS) and information on disease severity and dopaminergic medications. One hundred age-matched respondents without PD served as a control population. Excess daytime sleepiness was reported in 76% of PD patients compared to 47% of controls (P < 0.05). The mean ESS scores for PD patients was 9.1 +/- 6.1 versus 5.7 +/- 4.4 in controls (P < 0.001). ESS scores > or =10 were observed in 40.6% of PD patients compared to 19% of controls (P < 0.01) and 24% of PD patients had scores > or =15, compared to 5% of controls (P < 0.001). Sleep episodes while driving were experienced by 20.8% of PD drivers compared to 6% of control drivers (P < 0.05). The mean daily levodopa (L-dopa) dose equivalent was 1,142 +/- 858 mg in PD drivers who experienced a SE while driving compared to 626 +/- 667 mg in those who had not (P < 0.05). Similarly, ESS was significantly greater in drivers with a SE than in those without (11.6 +/- 6.4 vs. 8.4 +/- 4.1; P < 0.05). Logistic regression analysis demonstrated that ESS and mean daily L-dopa dose equivalents were predictors of sleep episodes while driving, whereas age, gender, disease severity, and individual dopaminergic agents were not. These findings support the notion that sleep episodes while driving in PD patients are related to excess daytime sleepiness and dopaminergic load. Physicians should advise and treat patients accordingly.


Who uses firearms as a means of suicide? A population study exploring firearm accessibility and method choice.
The 1996 Australian National Firearms Agreement introduced strict access limitations. However, reports on the effectiveness of the new legislation are conflicting. This study, accessing all cases of suicide 1997-2004, explores factors which may impact on the choice of firearms as a suicide method, including current licence possession and previous history of legal access. Detailed information on all Queensland suicides (1997-2004) was obtained from the Queensland Suicide Register, with additional details of firearm licence history accessed from the Firearm Registry (Queensland Police Service). Cases were compared against licence history and method choice (firearms or other method). Odds ratios (OR) assessed the risk of firearms suicide and suicide by any method against licence history. A logistic regression was undertaken identifying factors significant in those most likely to use firearms in suicide. The rate of suicide using firearms in those with a current license (10.92 per 100,000) far exceeded the rate in those with no license history (1.03 per 100,000). Those with a license history had a far higher rate of suicide (30.41 per 100,000) compared to that of all suicides (15.39 per 100,000). Additionally, a history of firearms licence (current or present) was found to more than double the risk of suicide by any means (OR = 2.09, P < 0.001). The group with the highest risk of selecting firearms to suicide were older males from rural locations. Accessibility and familiarity with firearms represent critical elements in determining the choice of method. Further licensing restrictions and the implementation of more stringent secure storage requirements are likely to reduce the overall familiarity with firearms in the community and contribute to reductions in rates of suicide.


McCleery syndrome: etiology and outcome.
Patients presenting with swelling of the upper extremity without thrombosis have McCleery syndrome or intermittent compression of the subclavian vein. The purpose of this study was to determine outcomes in these patients who underwent first rib resection and scalenectomy (FRRS). Using a prospectively maintained database from 2003 to 2011, patients were retrospectively reviewed for presentation, diagnosis, treatment, and clinical outcomes. Of the patients presenting with venous thoracic outlet syndrome, 19 (11%; 13 F/6 M; mean age 26 [10-44]) presented with intermittent arm swelling, of which 3 were identified as having chronic thrombus. A total of 20 FRRS operations were performed. First rib resection and scalenectomy is effective in relieving symptoms in patients with McCleery syndrome. These patients do not generally need a postoperative venogram unless they experience continuing symptoms. In patients with chronic thrombus, routine postoperative venography at 2 weeks is indicated. Patients can present with intermittent compression if an acute episode of deep vein thrombosis is not aggressively treated.


Potential role of aspirin in the prevention of aneurysmal subarachnoid hemorrhage.
Inflammation is a key element behind the pathophysiology of cerebral aneurysm formation and rupture. Aspirin is a potent inhibitor of cyclooxygenase-2 (COX), which plays a critical role in the expression of immune modulators known to contribute to cerebral aneurysm formation and rupture. Currently, there are no pharmacological therapies for patients with cerebral aneurysms. Both endovascular and microsurgical interventions may be associated with significant morbidity and mortality. Potentially, a medical alternative that prevents aneurysm progression and rupture may be a beneficial therapy for a significant number of patients. In animal models, treatment with aspirin and genetic inactivation of COX-2 decreases aneurysm formation and rupture. Selective inhibition of COX-1 did not decrease aneurysm rupture, suggesting that selection inhibition of COX-2 may be critical in thwarting aneurysm progression. Walls of ruptured human intracranial aneurysms have higher levels of COX-2 and microsomal prostaglandin E2 synthase 1 (mPGES-1), both of which are known to be inhibited by aspirin. In a pilot study, patients undergoing microsurgical clipping had attenuated expression of COX-2, mPGES-1, and macrophages in aneurysm walls after 3 months of aspirin therapy versus those that did not receive aspirin. Additionally, in patients undergoing endovascular therapy, local circulating expression of chemokines and COX-2 were increased in blood samples taken from within aneurysm domes as compared to peripheral blood sample controls. Treatment with aspirin also resulted in decreased expression of COX-2 within leukocytes within aneurysms as compared to peripheral blood samples. Novel molecular imaging with ferumoxytol-enhanced MRI may help in the identification of patients at increased risk for aneurysm rupture and assessment of a response to aspirin therapy. Key Messages: Aspirin has been found to be a safe in patients harboring cerebral aneurysms and clinical studies provide evidence that it may decrease the overall rate of rupture. Furthermore, aspirin is an accessible and inexpensive medicine for patients who may not have access to endovascular or microsurgical treatment or for patients who are deemed low risk of aneurysm rupture, high risk for intervention, or both. Future clinical trials are indicated to determine the overall effect of aspirin on aneurysm progression and rupture. This review provides an update on the potential mechanisms and benefits of aspirin in the treatment of cerebral aneurysms.


Secretory phospholipase A(2)-IIA and cardiovascular disease: a mendelian randomization study.
This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease. Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy. We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable. PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.


Epidemiology of Trichophyton verrucosum infection in Rennes University Hospital, France: A 12-year retrospective study.
Trichophyton verrucosum is a zoophilic dermatophyte, known as a causative agent of inflammatory mycoses of the skin and the scalp in humans. In this study, we reviewed all cases of T. verrucosum infection diagnosed in our laboratory over a 12-year period, to determine epidemiological and clinical characteristics. Among 18,340 samples analyzed, 5,186 cultured positive with dermatophytes (2674 patients), of which 64 samples (41 patients) were positive for T. verrucosum. Our data show that there was a strong influence of age on the type of lesion, with children and adults presenting more frequently with tinea capitis and skin infections, respectively (P < .0001). Infection of children and adults resulted more frequently from indirect and direct exposure to cattle, respectively (P < .01). We observed a marked increase of cases over the last 4 years, with a correlation of the number of cases and the mean annual rainfall (P < .05), suggesting that increasing humidity favors cattle infection, and thereby, human infection. Whether this increase is the consequence of climate changes remains to be determined but should be considered.


Potato Chips, Cookies, and Candy Oh My! Public Commentary on Proposed Rules Regulating Competitive Foods.
The Healthy, Hunger-Free Kids Act of 2010 authorizes the U.S. Department of Agriculture (USDA) to establish nutritional standards for all foods sold in schools participating in federally funded meal programs. These foods, known as competitive foods, are commonly found in school cafeterias, vending machines, fundraisers, and snack bars and are associated with unhealthy dietary patterns. However, little is known about the regulatory process and opportunities for public participation to improve school food. This study investigates public commentary on the USDA's proposed rules governing competitive foods in schools. On February 8, 2013, the USDA's Food and Nutrition Service solicited public comments via Regulations.gov. A corpus of 247,871 public comments was obtained. Duplicate and near-duplicate comments were removed resulting in 3,032 unique comments. Two researchers content analyzed 10% of the sample, removing nonrelevant comments ( n = 249). A majority of commenters are women, and mention their affiliation. Comments tend to be short, and exhibit low levels of complexity. An overwhelming majority of comments expressed concerns about the public health of youth vis-à-vis the new rule, whereas a small but vocal minority opposed the rule for financial and labor reasons and/or opposition to further government regulation. Commentary on proposed rules should be specific, avoiding off-topic remarks. Commenters should be strategic, include their credentials, and provide a rationale for their position. The rules governing competitive foods are poised to reverse the childhood obesity epidemic, and public commentary may shape these rules.


First experimental proof of Proton Boron Capture Therapy (PBCT) to enhance protontherapy effectiveness.
Protontherapy is hadrontherapy's fastest-growing modality and a pillar in the battle against cancer. Hadrontherapy's superiority lies in its inverted depth-dose profile, hence tumour-confined irradiation. Protons, however, lack distinct radiobiological advantages over photons or electrons. Higher LET (Linear Energy Transfer) 12C-ions can overcome cancer radioresistance: DNA lesion complexity increases with LET, resulting in efficient cell killing, i.e. higher Relative Biological Effectiveness (RBE). However, economic and radiobiological issues hamper 12C-ion clinical amenability. Thus, enhancing proton RBE is desirable. To this end, we exploited the p + 11B → 3α reaction to generate high-LET alpha particles with a clinical proton beam. To maximize the reaction rate, we used sodium borocaptate (BSH) with natural boron content. Boron-Neutron Capture Therapy (BNCT) uses 10B-enriched BSH for neutron irradiation-triggered alpha particles. We recorded significantly increased cellular lethality and chromosome aberration complexity. A strategy combining protontherapy's ballistic precision with the higher RBE promised by BNCT and 12C-ion therapy is thus demonstrated.


Protease-activated receptor 2 sensitizes TRPV1 by protein kinase Cepsilon- and A-dependent mechanisms in rats and mice.
Proteases that are released during inflammation and injury cleave protease-activated receptor 2 (PAR2) on primary afferent neurons to cause neurogenic inflammation and hyperalgesia. PAR2-induced thermal hyperalgesia depends on sensitization of transient receptor potential vanilloid receptor 1 (TRPV1), which is gated by capsaicin, protons and noxious heat. However, the signalling mechanisms by which PAR2 sensitizes TRPV1 are not fully characterized. Using immunofluorescence and confocal microscopy, we observed that PAR2 was colocalized with protein kinase (PK) Cepsilon and PKA in a subset of dorsal root ganglia neurons in rats, and that PAR2 agonists promoted translocation of PKCepsilon and PKA catalytic subunits from the cytosol to the plasma membrane of cultured neurons and HEK 293 cells. Subcellular fractionation and Western blotting confirmed this redistribution of kinases, which is indicative of activation. Although PAR2 couples to phospholipase Cbeta, leading to stimulation of PKC, we also observed that PAR2 agonists increased cAMP generation in neurons and HEK 293 cells, which would activate PKA. PAR2 agonists enhanced capsaicin-stimulated increases in [Ca2+]i and whole-cell currents in HEK 293 cells, indicating TRPV1 sensitization. The combined intraplantar injection of non-algesic doses of PAR2 agonist and capsaicin decreased the latency of paw withdrawal to radiant heat in mice, indicative of thermal hyperalgesia. Antagonists of PKCepsilon and PKA prevented sensitization of TRPV1 Ca2+ signals and currents in HEK 293 cells, and suppressed thermal hyperalgesia in mice. Thus, PAR2 activates PKCepsilon and PKA in sensory neurons, and thereby sensitizes TRPV1 to cause thermal hyperalgesia. These mechanisms may underlie inflammatory pain, where multiple proteases are generated and released.


The general anesthetic isoflurane depresses synaptic vesicle exocytosis.
General anesthetics have marked effects on synaptic transmission, but the mechanisms of their presynaptic actions are unclear. We used quantitative laser-scanning fluorescence microscopy to analyze the effects of the volatile anesthetic isoflurane on synaptic vesicle cycling in cultured neonatal rat hippocampal neurons monitored using either transfection of a pH-sensitive form of green fluorescent protein fused to the luminal domain of VAMP (vesicle-associated membrane protein), (synapto-pHluorin) or vesicle loading with the fluorescent dye FM 1-43. Isoflurane reversibly inhibited action potential-evoked exocytosis over a range of concentrations, with little effect on vesicle pool size. In contrast, exocytosis evoked by depolarization in response to an elevated extracellular concentration of KCl, which is insensitive to the selective Na+ channel blocker tetrodotoxin, was relatively insensitive to isoflurane. Inhibition of exocytosis by isoflurane was resistant to bicuculline, indicating that this presynaptic effect is not caused by the well known GABA(A) receptor modulation by volatile anesthetics. Depression of exocytosis was mimicked by a reduction in stimulus frequency, suggesting a reduction in action potential initiation, conduction, or coupling to Ca2+ channel activation. There was no evidence for a direct effect on endocytosis. The effects of isoflurane on synaptic transmission are thus caused primarily by inhibition of action potential-evoked synaptic vesicle exocytosis at a site upstream of Ca2+ entry and exocytosis, possibly as a result of Na+ channel blockade and/or K+ channel activation, with the possibility of lesser contributions from Ca2+ channel blockade and/or soluble N-ethylmaleimide-sensitive factor attachment protein receptor-mediated vesicle fusion.


Comparison of preoperative conference-based diagnosis with histology of cystic tumors of the pancreas.
Diagnostic errors in the evaluation of cystic neoplasms of the pancreas (PCNs) are quite common. Few data are available regarding the impact of these errors on clinical management. The aim of this study was to determine the accuracy of a pancreatic multidisciplinary conference in diagnosing PCNs, to assess the potential risk of misdiagnosis, and to evaluate the clinical impact of these errors. A retrospective consecutive series of patients undergoing surgery for PCNs at Karolinska University Hospital between 2004 and 2012 was analyzed. During the study period, a total of 141 patients had undergone pancreatic resection for PCN. The overall accuracy of the preoperative diagnosis was 60.9 %. The rate of concordance between preoperative diagnosis and histology was similar for asymptomatic and symptomatic lesions (62.8 vs. 59.1 %; p = NS). The rate of correct diagnosis increased over time (54.5 % in 2004-2006, 61.7 % in 2007-2012, 63.5 % in 2010-2012). Univariate analysis identified the location of the lesion (diffuse pancreatic involvement) and a mucinous nature of the lesion as factors conducive to a correct diagnosis. Reevaluation of the original indication for surgery in light of the exact diagnosis showed that a surgical procedure should not have been performed in 12 patients (8.5 %). This study confirms that diagnostic errors are fairly common in the preoperative assessment of PCNs, but the errors are clinically relevant in <10 % of patients.


Congenital psoriasis: case report and literature review.
While childhood psoriasis is fairly common, congenital psoriasis appears to be rare and has not been well characterized. We present a patient with histologically confirmed congenital psoriasis. By reviewing the literature, we aim to both define this disease and compare it to infantile and childhood psoriasis. Electronic searches found articles reporting patients with biopsy-proven congenital psoriasis. We recorded clinical features, such as family history, anatomic involvement, and disease severity. We compared these data with previous descriptions of infantile and childhood psoriasis. We included nine patients with congenital psoriasis in our analysis. No patient had a first-degree family history of psoriasis. While the face, scalp, chest, and trunk were frequently involved, the buttocks generally were spared. Several patients had persistent disease despite therapy. In this series, congenital psoriasis differed from infantile and childhood psoriasis in several respects. Specifically, congenital psoriasis was associated with a lower prevalence of relevant family history, which could increase over time, and a different pattern of anatomic involvement, which may reflect exposure to age-associated environmental factors. Although several patients with congenital psoriasis had severe disease, this likely represents publication bias. Additional reports of congenital psoriasis with extended follow-up are needed to better characterize this condition.


Use of Creatine and Creatinine to Minimize Doxorubicin-Induced Cytotoxicity in Cardiac and Skeletal Muscle Myoblasts.
Doxorubicin (DOX), an effective anticancer agent, can damage cardiac and skeletal muscle tissue via excessive generation of reactive oxygen species (ROS). Supplemental creatine (Cr) has been shown to have a therapeutic role in disease states characterized by increased oxidative stress. To investigate the effects of Cr and creatinine (CrN) on DOX-induced cytotoxicity. Cultured L6 and H9C2 myoblasts were exposed to 25 μM DOX, 10 mM Cr, 10 mM CrN, 25 μM DOX + 10 mM Cr, 25 μM DOX + 10 mM CrN, or control media for 12 h. Viability was assessed using Confocal and Widefield imaging. Immunoblotting was used to determine protein expression. Viability was lowest in the DOX-treated group regardless of cell type; however, when DOX was combined with Cr or CrN, viability was improved. Levels of oxidative stress, as measured by 4-hydroxynonenal (4HNE), were significantly (p < 0.05) higher in the DOX treated cells vs. controls; however, Cr + DOX and CrN + DOX significantly lowered 4HNE levels compared to DOX-treated cells. Creatine kinase (CK), a key marker of cellular damage, was significantly higher in DOX-treated H9c2 cells vs. controls. However, Cr or CrN in combination with DOX, resulted in no significant differences in CK vs. controls. Supplementation with Cr or CrN may preserve cell viability during DOX treatment.


Principal component-based radiative transfer model for hyperspectral sensors: theoretical concept.
Modern infrared satellite sensors such as the Atmospheric Infrared Sounder (AIRS), the Cross-Track Infrared Sounder (CrIS), the Tropospheric Emission Spectrometer (TES), the Geosynchronous Imaging Fourier Transform Spectrometer (GIFTS), and the Infrared Atmospheric Sounding Interferometer (IASI) are capable of providing high spatial and spectral resolution infrared spectra. To fully exploit the vast amount of spectral information from these instruments, superfast radiative transfer models are needed. We present a novel radiative transfer model based on principal component analysis. Instead of predicting channel radiance or transmittance spectra directly, the principal component-based radiative transfer model (PCRTM) predicts the principal component (PC) scores of these quantities. This prediction ability leads to significant savings in computational time. The parameterization of the PCRTM model is derived from the properties of PC scores and instrument line-shape functions. The PCRTM is accurate and flexible. Because of its high speed and compressed spectral information format, it has great potential for superfast one-dimensional physical retrieval and for numerical weather prediction large volume radiance data assimilation applications. The model has been successfully developed for the NAST-I and AIRS instruments. The PCRTM model performs monochromatic radiative transfer calculations and is able to include multiple scattering calculations to account for clouds and aerosols.


[Consensus on the diagnostic and therapeutic approach to pain and stress in the newborn].
Pain and stress experienced by the newborn have not been addressed adequately. Infants in neonatal intensive care units often undergo painful and stressful invasive procedures, and inappropriate treatment increases morbidity and mortality. At the 5th Clinical Consensus of the Ibero-American Society of Neonatology, 32 neonatologists from the region were invited to establish recommendations for the diagnosis and treatment of neonatal pain and stress. Key themes were explored based on the best scientific evidence available in indexed databases. All attendees participated actively in a meeting in Santiago, Chile, with the objective of reaching a consensus on recommendations and conclusions. Pain and neonatal stress affect neurological development and long-term behavior and require timely diagnosis and appropriate management and treatment, including the use of drugs with an appropriate balance between effectiveness and toxicity. The Consensus emphasized the importance of assessing pain in the newborn from a multidimensional viewpoint, and provided recommendations on the indications and limitations for an individualized pharmacological therapy. The use of analgesics has precise indications but also important limitations; there is a lack of randomized studies in newborns, and adverse effects need to be considered. Nonpharmacological measures to mitigate pain were proposed. Stress management should begin in the delivery room, including maternal contact, stimulus reduction and the implementation of intervention reduction protocols. Recommendations for improving clinical practices related to neonatal pain and stress are presented.


Gracilis free muscle transfer for restoration of function after complete brachial plexus avulsion.
The authors report the functional outcomes after functioning free muscle transfer (FFMT) for restoration of the upper-extremity movement after brachial plexus injury (BPI). The authors conducted a retrospective review of 36 gracilis FFMT procedures performed in 27 patients with BPI between 1990 and 2000. Eighteen patients underwent a single gracilis FFMT procedure for restoration of either elbow flexion (17 cases) or finger flexion (one case). Nine patients underwent a double free muscle transfer for simultaneous restoration of elbow flexion and wrist extension (first muscle) and finger flexion (second muscle), combined with direct triceps neurotization. The results obtained in 29 cases of FFMT in which the follow-up period was 1 year are reported. Neurotization of the donor muscle was performed using the musculocutaneous nerve (one case), spinal accessory nerve (12 cases), or multiple intercostal motor nerves (16 cases). Two second-stage muscle flaps failed secondary to vascular insufficiency. Mean electromyography-measured reinnervation time was 5 months. At a minimum follow-up period of 1 year, five muscles achieved less than or equal to Grade M2, eight Grade M3, four Grade M4, and 12 Grade M5. Transfer for combined elbow flexion and wrist extension compared with elbow flexion alone lowered the overall results for elbow flexion strength. Seventy-nine percent of the FFMTs for elbow flexion alone (single transfer) and 63% of similarly innervated muscles transferred for combined motion achieved at least Grade M4 elbow flexion strength. Functioning free muscle transfer is a viable reconstructive option for restoration of upper-extremity function in the setting of severe BPI. It is possible to achieve good to excellent outcomes in terms of muscle grades with the simultaneous reconstruction of two functions by one FFMT, making restoration of basic hand function possible. More reliable results are obtained when a single FFMT is performed for a single function.


Detection of quality visualization of appendiceal orifices using local edge cross-section profile features and near pause detection.
Colonoscopy is an endoscopic technique that allows a physician to inspect the inside of the human colon. The appearance of the appendiceal orifice during colonoscopy indicates a complete traversal of the colon, which is an important quality indicator of the colon examination. In this paper, we present two new algorithms. The first algorithm determines whether an image shows the clearly seen appendiceal orifice. This algorithm uses our new local features based on geometric shape, illumination difference, and intensity changes along the norm direction (cross section) of an edge. The second algorithm determines whether the video is an appendix video (the video showing at least 3 s of the appendiceal orifice inspection). Such a video indicates good visualization of the appendiceal orifice. This algorithm utilizes frame intensity histograms to detect a near camera pause during the apendiceal orifice inspection. We tested our algorithms on 23 videos captured from two types of endoscopy procedures. The average sensitivity and specificity for the detection of appendiceal orifice images with the often seen crescent appendiceal orifice shape are 96.86% and 90.47%, respectively. The average accuracy for the detection of appendix videos is 91.30%.


Mechanisms of lymphatic metastasis in human colorectal adenocarcinoma.
The invasion of lymphatic vessels by colorectal cancer (CRC) and its subsequent spread to draining lymph nodes is a key determinant of prognosis in this common and frequently fatal malignancy. Although tumoural lymphangiogenesis is assumed to contribute to this process, review of the current literature fails to support any notion of a simple correlation between lymphatic vessel density and CRC metastasis. Furthermore, attempts to correlate the expression of various lymphangiogenic growth factors, most notably VEGF-C and VEGF-D, with the lymphatic metastasis of CRC have provided contradictory results. Recent evidence from animal and human models of tumour metastasis suggests that complex functional and biochemical interactions between the microvasculature of tumours and other cell types within the tumour microenvironment may play a pivotal role in the behaviour of commonly metastasizing tumours. Indeed, previous insights into tumoural blood vessels have provided candidate markers of tumoural angiogenesis that are currently the subject of intense investigation as future therapeutic targets. In this review article we survey the current evidence relating lymphangiogenesis and lymphangiogenic growth factor production to metastasis by CRC, and attempt to provide some insight into the apparent discrepancies within the literature. In particular, we also discuss some new and provocative insights into the properties of tumoural lymphatics suggesting that they have specific expression profiles distinct from those of normal lymphatic vessels and that appear to promote metastasis. These findings raise the exciting prospect of future biomarkers of lymphatic metastasis and identify potential targets for new generation anti-tumour therapies.


Clinical and lesion morphologic determinants of coronary angioplasty success and complications: current experience.
This study evaluated the validity of the American College of Cardiology/American Heart Association ABC lesion classification scheme and its modifications. With the continued refinement in angioplasty technique and equipment evolution, the lesion morphologic determinants of immediate angioplasty outcome have changed significantly. Hence, the validity of the classification scheme has been questioned. We assessed the lesion morphologic determinants of immediate angioplasty outcome in 729 consecutive patients who underwent coronary angioplasty of 994 vessels and 1,248 lesions. Angioplasty success was achieved in 91% of lesions, and abrupt closure occurred in 3%. Success was achieved in 96%, 93% and 80% of type A, B and C lesions, respectively (A vs. B, p = NS; B vs. C, p < 0.001; A vs. C, p < 0.001; A vs. B1, p = NS; A vs. B2, p = 0.03; B1 vs. B2, p = 0.02; B2 vs. C, p < 0.001; C1 vs. C2, p = NS). Abrupt closure occurred in 2.1%, 2.6% and 5% of type A, B and C lesions, respectively (A vs. B, B vs. C, A vs. C and A vs. B1, all p = NS; B1 vs. B2, p = 0.01; B2 vs. C1, p = NS; C1 vs. C2, p = 0.04). Type B characteristics had a success rate ranging from 74% to 95% and an abrupt closure rate ranging from 2.2% to 14%. Type C characteristics had a success rate ranging from 57% to 88% and an abrupt closure rate ranging from 0% to 16%. Longer lesions, calcified lesions, diameter stenosis of 80% to 99% and presence of thrombus were predictive of a lower success rate. Longer lesions, angulated lesions, diameter stenosis of 80% to 99% and calcified lesions were predictive of an abrupt closure. The previously proposed classification schemes are outdated and need to be changed for application in current angioplasty practice. Analyzing specific lesion morphologic characteristics rather than applying a simple lesion classification score when evaluating angioplasty outcome may be more useful because it provides a more precise profile of the lesion and allows better patient stratification and selection.


SOM230, a new somatostatin analogue, is highly effective in the therapy of growth hormone/prolactin-secreting pituitary adenomas.
We have previously shown that transgenic mice ubiquitously overexpressing the HMGA2 gene develop growth hormone/prolactin-secreting pituitary adenomas. This animal model has been used to evaluate the therapeutic efficacy of SOM230, a somatostatin analogue with high affinity for the somatostatin receptor subtypes 1, 2, 3, and 5, on the growth of the pituitary adenomas. Four groups of 3- and 9-month-old HMGA2 transgenic mice were treated for 3 months with a continuous s.c. injection of two different dosages of SOM230 (5 or 50 microg/kg/h), one dose of octreotide, corresponding to that used in human therapy, and a placebo, respectively. The development of the tumor before and after therapy was monitored by magnetic resonance imaging of the pituitary region and evaluation of the serum prolactin levels. The highest dose of SOM230 induced a drastic regression of the tumor, whereas octreotide was not able to induce any significant tumor regression, although tumor progression was significantly slowed down. No significant differences were observed between the animals treated with the lowest dose of SOM230 and those receiving placebo. These results clearly support the efficacy of the SOM230 treatment in human pituitary adenomas secreting prolactin based on the dramatic tumor shrinkage and fall in prolactin levels. This beneficial effect could be of crucial clinical usefulness in patients bearing tumors resistant to dopaminergic drugs.


Evaluation of DBPs formation from SMPs exposed to chlorine, chloramine and ozone.
Soluble microbial products (SMPs) are an important group of components in wastewater effluents. In this study, the formation of disinfection by-products (DBPs), including trihalomethanes (THMs), haloacetic acids (HAAs), chlorinated solvents (CSs), haloketones (HKs), haloacetonitriles (HANs) and trichloronitromethane (TCNM) (chloropicrin), from SMPs during chlorination, chloramination and ozonation was investigated. More carbonaceous DBPs (C-DBPs: THMs, HAAs, CSs and HKs) and nitrogenous DBPs (N-DBPs: HANs and TCNM) were formed in chlorination than chloramination. More dichloroacetic and N-DBPs, and higher DBP formation potential were generated by SMPs than by natural organic matter. The results also show that disinfection factors, including temperature, pH, disinfectant dose, reaction time and bromide level significantly affected the formation of DBPs from SMPs. Additionally, the bromine incorporation factor indicates that chloramination may be a good alternative to chlorination in reducing the formation of Br-DBPs from SMPs. Bromide level and pH were the key factors affecting the formation of DBPs in both chlorination and chloramination.


Low-dose caffeine physical dependence in humans.
This study investigated the effects of terminating low dose levels of caffeine (100 mg/day) in 7 normal humans. Substitution of placebo capsules for caffeine capsules occurred under double-blind conditions while subjects rated various dimensions of their mood and behavior. In the first phase of the study, substitution of placebo for 12 consecutive days resulted in an orderly withdrawal syndrome in 4 subjects which peaked on days 1 or 2 and progressively decreased toward prewithdrawal levels over about 1 week. Data from the remaining three subjects provided no evidence of withdrawal. In the second phase of the study, the generality of the withdrawal effect was examined by repeatedly substituting placebo for 100 mg/day of caffeine for 1-day periods separated by an average of 9 days. Despite differences within and across subjects with respect to the presence, nature and magnitude of symptoms, each of the seven subjects demonstrated a statistically significant withdrawal effect. Although the phenomenon of caffeine withdrawal has been described previously, the present report documents that the incidence of caffeine withdrawal is higher (100% of subjects), the daily dose level at which withdrawal occurs is lower (roughly equivalent to the amount of caffeine in a single cup of strong brewed coffee or 3 cans of caffeinated soft drink) and the range of symptoms experienced is broader (including headache, fatigue and other dysphoric mood changes, muscle pain/stiffness, flu-like feelings, nausea/vomiting and craving for caffeine) than heretofore recognized.


Polymer fraction of Aloe vera exhibits a protective activity on ethanol-induced gastric lesions.
For centuries, Aloe has been used as a herbal plant remedy against skin disorders, diabetes, and for its cardiac stimulatory activity. Here, we examined the gastroprotective effects of an Aloe vera polymer fraction (Avpf; molecular weight cut-off ≥50 kDa; 150 mg/kg body weight, p.o.) on an ethanol-induced gastric lesion mouse model. Mice pre-treated with Avpf had significantly fewer gastric lesions than their respective controls. To further examine the potential mechanism underlying this effect, we used reverse transcription-polymerase chain reaction to examine nitric oxide synthase and matrix metalloproteinase (MMP)mRNA expression on tissues from gastric lesions. Our results revealed that the mRNA expressions of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS) were each reduced by ~50% in Avpf-treated mice vs. the controls, whereas, the mRNA expression levels of endothelial nitric oxide synthase remained unchanged. MMP-9, an index for gastric lesions, also alleviated the ethanol-treated gastric ulceration during Avpf treatment. These findings collectively suggest that Avpf significantly protects the gastric mucosa against ethanol-induced gastric damage, at least in part, by decreasing mRNA expression levels of not only iNOS and nNOS, but also MMP-9.


Quantity and source of dietary protein influence metabolite production by gut microbiota and rectal mucosa gene expression: a randomized, parallel, double-blind trial in overweight humans.
Background: Although high-protein diets (HPDs) are frequently consumed for body-weight control, little is known about the consequences for gut microbiota composition and metabolic activity and for large intestine mucosal homeostasis. Moreover, the effects of HPDs according to the source of protein need to be considered in this context.Objective: The objective of this study was to evaluate the effects of the quantity and source of dietary protein on microbiota composition, bacterial metabolite production, and consequences for the large intestinal mucosa in humans.Design: A randomized, double-blind, parallel-design trial was conducted in 38 overweight individuals who received a 3-wk isocaloric supplementation with casein, soy protein, or maltodextrin as a control. Fecal and rectal biopsy-associated microbiota composition was analyzed by 16S ribosomal DNA sequencing. Fecal, urinary, and plasma metabolomes were assessed by 1H-nuclear magnetic resonance. Mucosal transcriptome in rectal biopsies was determined with the use of microarrays.Results: HPDs did not alter the microbiota composition, but induced a shift in bacterial metabolism toward amino acid degradation with different metabolite profiles according to the protein source. Correlation analysis identified new potential bacterial taxa involved in amino acid degradation. Fecal water cytotoxicity was not modified by HPDs, but was associated with a specific microbiota and bacterial metabolite profile. Casein and soy protein HPDs did not induce inflammation, but differentially modified the expression of genes playing key roles in homeostatic processes in rectal mucosa, such as cell cycle or cell death.Conclusions: This human intervention study shows that the quantity and source of dietary proteins act as regulators of gut microbiota metabolite production and host gene expression in the rectal mucosa, raising new questions on the impact of HPDs on the large intestine mucosa homeostasis. This trial was registered at clinicaltrials.gov as NCT02351297.


Resistance of Eucalyptus Clones to Ceratocystis fimbriata.
Ceratocystis fimbriata, the inciting agent of wilt, canker, and dieback in eucalyptus plantations, was first reported in Brazil in 1998. There is no information regarding the resistance of Eucalyptus spp. to this pathogen. We determined the reaction of 18 Brazilian, commercial clones of the hybrid Eucalyptus grandis × E. urophylla to inoculation by two isolates of the pathogen in two experiments. Container-grown, 8-month-old rooted cuttings of each clone were wound-inoculated with a conidial suspension (2.5 × 106/ml). Plants similarly injected with sterile distilled water served as controls. The plants were evaluated after 30 days for length of xylem discoloration. There was a significant isolate by clone interaction, but most clones reacted similarly to the two isolates. Six clones, including one observed to be highly susceptible under field conditions, were highly susceptible (>20 cm discoloration) to one or both isolates of the pathogen. Four clones showed no more discoloration with either isolate than with the control inoculations, and the other eight clones were intermediate in susceptibility. Thus, highly resistant clones are available to manage this disease.


Stigma and social participation in Southern India: differences and commonalities among persons affected by leprosy and persons living with HIV/AIDS.
Stigma is a common phenomenon worldwide and infectious diseases like HIV/AIDS and leprosy are often associated with high levels of stigma. Several studies have been conducted concerning the effects of stigma and the impact on social participation, but comparative studies are rare. The objective of this study was to identify differences and similarities between HIV/AIDS and leprosy-related stigma. From April till July 2009, 190 questionnaire-based interviews were conducted to assess the levels of internalized stigma (Internalized Stigma of Mental Illness scale), perceived stigma (Explanatory Model Interview Catalogue stigma scale) and social participation (Participation scale) in a cross-sectional sample of people affected by leprosy (PL) and people living with HIV/AIDS (PLHA). Respondents were selected from several hospitals, charity projects and during home visits in Vellore district, Tamil Nadu. Our results showed that both PLHA (n = 95) and leprosy-affected respondents (n = 95) faced a substantial burden of internalized and perceived stigma, with the former reporting a significantly higher level of stigma. As a result, PLHA faced more frequent and also more severe participation restrictions than PL. Especially, restrictions in work-related areas were reported by the majority of the respondents. In conclusion, PLHA faced a significantly higher level of stigma and participation restriction than PL. However, the latter also reported a substantial burden of stigma and participation restrictions. The study suggests that it may be possible to develop joint interventions based on the commonalities found. More research is needed to define these more precisely and to test the effectiveness of such joint interventions in reducing stigma and improving social participation.


Recruitment of the de novo DNA methyltransferase Dnmt3a by Kaposi's sarcoma-associated herpesvirus LANA.
The Kaposi's sarcoma-associated herpesvirus LANA protein is expressed in all Kaposi's sarcoma-associated herpesvirus-infected cells, including the tumor cells of endemic and AIDS-associated Kaposi sarcoma, primary effusion lymphoma, and Castleman disease. LANA modulates cell gene expression, but the mechanisms of LANA-mediated transcriptional reprogramming are poorly understood. LANA-repressed cell genes were identified by using retroviral-transduced telomerase-immortalized microvascular endothelial cells. Transciptional repression of targeted genes was relieved by treatment with the methyltransferase inhibitor 5-aza-2'-deoxycytidine, suggesting a role for DNA methylation in repression. We found that LANA coprecipitated with DNA methyltransferases (Dnmts) and recruited endogenous DNA methyltransferase activity from the cell extract. LANA preferentially relocalized Dnmt3a from the nuclear matrix into the chromatin fraction. Further, LANA associated with repressed cellular promoters, recruited Dnmt3a to DNA, and facilitated de novo promoter methylation of a down-regulated gene, cadherin 13 (H-cadherin). The data provide an example of promoter-specific epigenetic DNA modification through viral protein recruitment of de novo Dnmt activity.


Waveguiding in nanoscale metallic apertures.
We study the optical properties of subwavelength metallic waveguides made of nanoscale apertures in a metal. We develop analytical expressions for the fundamental optical modes in apertures. The results are in excellent agreement with finite element calculations. This model provides a physical understanding of the role of non-perfect metallic walls, and of the shape and size of the apertures. They reveal the effect of the skin depth and of the surface plasmon polariton coupling on the waveguide modes. The nanoscopic origin of the increase of the cut-off wavelength due to the electromagnetic penetration depth in the metal is described. Simple expressions and universal curves for the effective index and the cut-off wavelength of the fundamental guided mode of any rectangular metallic waveguide are presented. The results provide an efficient tool for the design of nanoscale waveguides with real metal.


Deiminated proteins in extracellular vesicles and plasma of nurse shark (Ginglymostoma cirratum) - Novel insights into shark immunity.
Peptidylarginine deiminases (PADs) are phylogenetically conserved calcium-dependent enzymes which post-translationally convert arginine into citrulline in target proteins in an irreversible manner, causing functional and structural changes in target proteins. Protein deimination causes generation of neo-epitopes, affects gene regulation and also allows for protein moonlighting. Extracellular vesicles are found in most body fluids and participate in cellular communication via transfer of cargo proteins and genetic material. In this study, post-translationally deiminated proteins and extracellular vesicles (EVs) are described for the first time in shark plasma. We report a poly-dispersed population of shark plasma EVs, positive for phylogenetically conserved EV-specific markers and characterised by TEM. In plasma, 6 deiminated proteins, including complement and immunoglobulin, were identified, whereof 3 proteins were found to be exported in plasma-derived EVs. A PAD homologue was identified in shark plasma by Western blotting and detected an expected 70 kDa size. Deiminated histone H3, a marker of neutrophil extracellular trap formation, was also detected in nurse shark plasma. This is the first report of deiminated proteins in plasma and EVs, highlighting a hitherto unrecognized post-translational modification in key immune proteins of innate and adaptive immunity in shark.


Stability of extemporaneously prepared preservative-free prochlorperazine nasal spray.
The stability of an extemporaneously prepared preservative-free prochlorperazine 5-mg/mL nasal spray was evaluated. The preservative-free prochlorperazine nasal spray was prepared by adding 250 mg of prochlorperazine edisylate to 50 mL of citrate buffer in a low-density polyethylene nasal spray bottle. A stability-indicating high-performance liquid chromatography (HPLC) method was developed and validated using the major degradant prochlorperazine sulfoxide and by performing forced-degradation studies. For chemical stability studies, 3 100-μL samples of the preservative-free prochlorperazine from 5 nasal spray bottles stored at room temperature were collected at days 0, 20, 30, 45, and 60 and were assayed in triplicate using the stability-indicating HPLC method. Microbiological testing involved antimicrobial effectiveness testing based on United States Pharmacopeia (USP) chapter 51 and quantitative microbiological enumeration of aerobic bacteria, yeasts, and mold based on USP chapter 61. Samples for microbiological testing were collected at days 0, 30, and 60. The stability-indicating HPLC method clearly identified the degradation product prochlorperazine sulfoxide without interference from prochlorperazine. All tested solutions retained over 90% of the initial prochlorperazine concentration for the 60-day study period. There were no detectable changes in color, pH, and viscosity in any sample. There was no growth of bacteria, yeast, and mold for 60 days in all samples tested. An extemporaneously prepared preservative-free nasal spray solution of prochlorperazine edisylate 5 mg/mL was physically, chemically, and microbiologically stable for 60 days when stored at room temperature in low-density polyethylene bottles.


Catalysis in solid oxide fuel cells.
Solid oxide fuel cells (SOFCs) and solid oxide electrolyzers (SOEs) hold much promise as highly efficient devices for the direct interconversion of chemical and electrical energy. Commercial application of these devices, however, requires further improvements in their performance and stability. Because the performance of SOFC and SOE electrodes depends on their microstructures, electronic and ionic conductivities, and chemical reactivities, the needed improvements require the expertise of various disciplines, with catalytic science playing an important role. Highly active and thermally stable catalysts are required to limit the internal losses in the devices, increase the range of fuels they can use, and decrease the temperatures at which they operate. In this article we review some of the most important recent advances in catalysis for SOFC and SOE electrodes and highlight additional improvements that are needed.


Randomized, placebo-controlled, double blind study on the clinical efficacy of a cream containing 5% alpha-lipoic acid related to photoageing of facial skin.
alpha-lipoic acid (LA) or the reduced form dihydrolipoate (DHLA) is a potent scavenger with anti-inflammatory properties. Previous uncontrolled studies with topical treatment with 5% LA-containing creams indicate a beneficial effect on photoageing skin. The purpose of this study was to investigate whether a cream containing 5% LA showed any advantages concerning a number of the criteria associated with ageing of the facial skin, compared with an identical cream lacking LA. Thirty-three women, mean age 54.4 years, were included in this controlled study. After randomization half the face was treated twice daily for 12 weeks with the LA cream and the other half with the control cream. The following methods of assessment were used: self-evaluation by the test subjects, clinical evaluation, photographic evaluation and laser profilometry. Profilometry was performed before the start of treatment and at the end. All four methods of assessment showed a statistically significant improvement on the LA-treated half of the face. Laser profilometry, the most objective method used, showed an average decrease in skin roughness of 50.8% (44.9-54.0) on the LA-treated side, compared with 40.7% (32.4-48.7) on the placebo-treated half of the face P < 0.001 (Wilcoxon matched pairs test). It is indicated that 12 weeks of treatment with a cream containing 5% LA improves clinical characteristics related to photoageing of facial skin.


Serum from postmenopausal women directs differentiation of human clonal osteoprogenitor cells from an osteoblastic toward an adipocytic phenotype.
A consistent observation in osteoporosis is bone volume reduction accompanied by increased marrow adipose tissue. No single cause linking the two phenomena has yet been identified. In a human progenitor cell clone (hOP 7) derived from bone marrow, however, we have demonstrated that rabbit serum can direct differentiation away from an osteoblast lineage to one of adipocytes. We now report on whether human serum has a similar effect. Serum was collected from 10 pre- and 10 postmenopausal women and from the 10 postmenopausal women before and following 6-week hormone replacement therapy (HRT). hOP 7 cells were cultured with the various sera, and after 7-14 days adipocytogenesis was determined by oil red O staining and lipoprotein lipase (LPL) and glycerol 3-phosphate dehydrogenase (G3PDH) expression. Incubation with 10% premenopausal serum led to labeling of 10.9% of cells (P < 0.05) with oil red O, whereas application of 10% postmenopausal serum led to a much larger effect, 43.5% labeling (P < 0.001 with respect to premenopausal serum). Oil red O positivity was accompanied by loss of type I collagen expression and increased LPL and G3PDH expression. HRT did not reverse the adipocytogenic effect of postmenopausal serum. In conclusion, serum from postmenopausal women contains factors that steer hOP 7 bone progenitor cells toward an adipocytic phenotype, irrespective of HRT. The study suggests a role for serum factors in the development of fatty marrow in postmenopausal osteoporosis.


Calcification in the ovine intervertebral disc: a model of hydroxyapatite deposition disease.
The study design included a multidisciplinary examination of the mineral phase of ovine intervertebral disc calcifications. The objective of the study was to investigate the mineral phase and its mechanisms of formation/association with degeneration in a naturally occurring animal model of disc calcification. The aetiology of dystrophic disc calcification in adult humans is unknown, but occurs as a well-described clinical disorder with hydroxyapatite as the single mineral phase. Comparable but age-related pathology in the sheep could serve as a model for the human disorder. Lumbar intervertebral discs (n = 134) of adult sheep of age 6 years (n = 4), 8 years (n = 12) and 11 years (n = 2) were evaluated using radiography, morphology, scanning and transmission electron microscopy, energy dispersive X-ray spectroscopy, X-ray powder diffraction, histology, immunohistology and proteoglycan analysis. Half of the 6-year, 84% of the 8-year and 86% of the 11-year-old discs had calcific deposits. These were not well delineated by plain radiography. They were either: (a) punctate deposits in the outer annulus, (b) diffuse deposits in the transitional zone or inner annulus fibrosus with occasional deposits in the nucleus, or (c) large deposits in the transitional zone extending variably into the nucleus. Their maximal incidence was in the lower lumbar discs (L4/5-L6/7) with no calcification seen in the lumbosacral or lower thoracic discs. All deposits were hydroxyapatite with large crystallite sizes (800-1,300 A) compared to cortical bone (300-600 A). No type X-collagen, osteopontin or osteonectin were detected in calcific deposits, although positive staining for bone sialoprotein was evident. Calcified discs had less proteoglycan of smaller hydrodynamic size than non-calcified discs. Disc calcification in ageing sheep is due to hydroxyapatite deposition. The variable, but large, crystal size and lack of protein markers indicate that this does not occur by an endochondral ossification-like process. The decrease in disc proteoglycan content and size suggests that calcification may precede or predispose to disc degeneration in ageing sheep.


Overproduction of delta-endotoxins by sporeless Bacillus thuringiensis mutants obtained by nitrous acid mutagenesis.
Asporogenic and oligosporogenic Bacillus thuringiensis mutants having the ability to overproduce insecticidal crystal protein were generated by using nitrous acid (50 mg/ml), as chemical mutagenic agent. Insecticidal crystal proteins produced by asporogenic mutants remained encapsulated within the cells. Delta-endotoxin production by most of mutants was improved compared to the corresponding wild strains BNS3 and a mutant M26. The overproduction by asporogenic and oligosporogenic mutants was attributed to defect in genes involved in sporulation and to random mutations affecting cell metabolism at different pathways and delta-endotoxin synthesis. Sporeless bioinsecticides could be developed based on stable and environmentally safe Bacillus thuringiensis mutants.


Quantitative trace analysis of complex mixtures using SABRE hyperpolarization.
Signal amplification by reversible exchange (SABRE) is an emerging nuclear spin hyperpolarization technique that strongly enhances NMR signals of small molecules in solution. However, such signal enhancements have never been exploited for concentration determination, as the efficiency of SABRE can strongly vary between different substrates or even between nuclear spins in the same molecule. The first application of SABRE for the quantitative analysis of a complex mixture is now reported. Despite the inherent complexity of the system under investigation, which involves thousands of competing binding equilibria, analytes at concentrations in the low micromolar range could be quantified from single-scan SABRE spectra using a standard-addition approach.


Pharmacotherapeutic options for pancreatic ductal adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy projected to be the 2nd leading cause of cancer related death in the USA by 2030. This manuscript discusses current and evolving treatment approaches in patients with pancreatic cancer. PDAC is classified as: a) resectable, b) borderline resectable, c) unresectable (locally advanced and metastatic). The standard of care for patients who present with resectable pancreatic adenocarcinoma is six months of adjuvant modified (m) FOLFIRINOX, gemcitabine plus capecitabine, or single agent gemcitabine. For many reasons, there has been a paradigm shift to employing neoadjuvant chemotherapy. For resectable and borderline resectable patients, we generally start with systemic therapy and reevaluate resectability with subsequent scans specifically when the tumor is located in the head or body of the pancreas. Combined chemoradiation therapy can be employed in select patients. The standard of care for metastatic PDAC is FOLFIRINOX or gemcitabine and nab-paclitaxel. Germline and somatic genomic profiling should be obtained in all patients. Patients with a germline BRCA mutation can receive upfront gemcitabine and cisplatin. Thorough understanding of molecular pathogenesis in PDAC has opened various therapeutic avenues. We remain optimistic that future treatment modalities such as targeted therapies, cellular therapies and immunotherapy will further improve survival in PDAC.


Profiling property criminals in Turkey.
The main aim of this research is to develop a profile of a thief. Through a comprehensive survey of property crime suspects arrested in the city of Ankara between 2004 and 2005, the authors have attempted to determine the socioeconomic qualities of those involved in these forms of property crimes. Results of the study show that property crimes are a consequence of low education, lack of occupational skills, and alcohol and drug addiction on the part of the offenders. Because of these factors, theft becomes a way of life for offenders after their first act of property crime.


Intravenous immunoglobulin in treatment of Clostridium difficile colitis.
Clostridium difficile infection is the most common infectious cause of healthcare-acquired diarrhoea. Severe infections cause therapeutic challenges for healthcare providers. Various novel treatment modalities are currently being explored for treatment of severe disease. The authors report a 70-year-old female who presented to the emergency room with 1 week history of fever, watery diarrhoea, diffuse abdominal pain and weakness. C difficile toxin was detected in the stool and abdominal CAT scan showed extensive colonic wall thickening. The patient was started on intravenous metronidazole along with oral vancomycin. Due to the severity of the infection the patient was given intravenous immunoglobin for 4 consecutive days. The patient had vast improvement in her clinical symptoms with resolution of the multi-organ system failure. It is currently considered that the predominant intravenous immunoglobin's mechanism of action is through binding and neutralisation of toxin A by IgG antitoxin A antibodies.


[Biochemical mechanisms of chromium action in the human and animal organism].
Modern data concerning biologic characteristics of chromium (Cr3+) its placement in nature, accessibility and metabolic action of its different forms in humans and animals is presented in this survey. Essentiality of chromium for humans is emphasized, data about consumption norms of this microelement and its use for curing different diseases especially diabetes mellitus and atherosclerosis of vessels are presented. The biochemical mechanisms of Cr3+ effect on the metabolism in the human and animal organism are analyzed. It is shown that the organism reacts to chrome additions by the change of some metabolism links. Chrome influences positively growth and development of foetus, stimulates metabolism of glucose and insulin in the humans and animals. However, at the set chromium requirements it is necessary to take into account its low availability in food, high release of Cr3+ from the organism under the influence of stress factors, considerable decline of its level with age, and also in the period of pregnancy and lactation. Therefore experimental researches of introduction of Cr3+ additions to the diet of people and forage of animals taking into account their body mass, age and clinical state, can explain the biochemical mechanisms of biological action of this microelement.


The role of magnesium sulfate in acute asthma: does route of administration make a difference?
The role of magnesium sulfate (MgSO4) in the treatment of acute asthma is not clear. Four recent systematic reviews suggest a limited role of intravenous (i.v.) and inhaled nebulized treatment. The purpose of this review is to summarize the current literature, focus on two recent large multicenter randomized controlled trials, and discuss future research directions. The Magnesium Nebulized Trial In Children (MAGNETIC) trial has shown little benefit to routine use of nebulized MgSO4 in children with acute asthma, but there may be a benefit in those with severe exacerbations and a shorter duration of symptoms. The 3Mg trial has shown no role for nebulized MgSO4 in adults and, at best a limited role for i.v. MgSO4 in only the most severe exacerbations. This is the only study with direct comparison of nebulized and i.v. MgSO4. MgSO4 has a role in severe exacerbations of acute asthma and there is no evidence of benefit outside this clinical situation. Both nebulized and i.v. treatments are well tolerated and inexpensive. In adults, the most effective route of administration is i.v. There are no direct comparison studies in children. Further research should focus on more severe exacerbations.


Seamless tube shape is constrained by endocytosis-dependent regulation of active Moesin.
Most tubes have seams (intercellular or autocellular junctions that seal membranes together into a tube), but "seamless" tubes also exist. In Drosophila, stellate-shaped tracheal terminal cells make seamless tubes, with single branches running through each of dozens of cellular extensions. We find that mutations in braided impair terminal cell branching and cause formation of seamless tube cysts. We show that braided encodes Syntaxin7 and that cysts also form in cells deficient for other genes required either for membrane scission (shibire) or for early endosome formation (Rab5, Vps45, and Rabenosyn-5). These data define a requirement for early endocytosis in shaping seamless tube lumens. Importantly, apical proteins Crumbs and phospho-Moesin accumulate to aberrantly high levels in braided terminal cells. Overexpression of either Crumbs or phosphomimetic Moesin induced lumenal cysts and decreased terminal branching. Conversely, the braided seamless tube cyst phenotype was suppressed by mutations in crumbs or Moesin. Indeed, mutations in Moesin dominantly suppressed seamless tube cyst formation and restored terminal branching. We propose that early endocytosis maintains normal steady-state levels of Crumbs, which recruits apical phosphorylated (active) Moe, which in turn regulates seamless tube shape through modulation of cortical actin filaments.


Calosphaeria Canker of Sweet Cherry Caused by Calosphaeria pulchella in California and South Australia.
California is the second largest sweet cherry producer in the United States with annual revenues up to $200 million. The South Australian cherry industry generates about 10% of Australia's overall production with approximately 1,500 metric tons of cherries produced yearly. In California, perennial canker diseases and subsequent branch dieback are responsible for extensive damage throughout sweet cherry orchards, reducing annual yields and tree longevity. Surveys of cherry orchards and isolation work were conducted in California to identify the main canker-causing agents. Calosphaeria pulchella was the main fungus isolated from cankers, followed by Eutypa lata and Leucostoma persoonii, respectively. Preliminary surveys in cherry orchards in South Australia documented C. pulchella and L. persoonii in cankers. The pathogenicity of C. pulchella in sweet cherry was confirmed following field inoculations of 2- to 3-year-old branches. C. pulchella was able to infect healthy wood and produce cankers with as much virulence as E. lata or L. persoonii. Spore trapping studies were conducted in two sweet cherry orchards in California to investigate the seasonal abundance of C. pulchella spores. Experiments showed that rain and sprinkler irrigation were important factors for aerial dissemination. Finally, this study illustrates the symptoms and signs of the new disease Calosphaeria canker.


Transseptal access and atrial fibrillation ablation guided by intracardiac echocardiography in patients with atrial septal closure devices.
Percutaneous positioning of closure devices is a well-established treatment of atrial septal defects (ASDs). However, patients who have undergone the procedure are at increased risk for developing atrial fibrillation (AF), and treatment by catheter ablation is underutilized due to the perceived difficulty of obtaining transseptal access in the presence of the closure device. The purpose of this study was to report the acute and long-term results of radiofrequency catheter ablation of AF in patients with ASD closure devices. Thirty-nine patients (age 54 ± 6 years, 72% males) with drug-refractory AF (33% paroxysmal, 51% persistent, 16% long-standing persistent) and ASD closure devices (82% Amplatzer, 18% CardioSEAL) underwent radiofrequency catheter ablation. A double transseptal access guided by intracardiac echocardiography was obtained in all patients. In 35 of 39 patients (90%), the transseptal access was obtained in a portion of the native septum, whereas in 4 of 39 patients (10%), a direct access through the device was required. The latter group had a significantly longer time for achieving the double transseptal access (73.6 ± 1.1 minutes vs. 4.3 ± 0.4 minutes, P < .001), longer fluoroscopy time (122 ± 5 minutes vs. 80 ± 8 minutes, P < .001), and total procedural time (4.1 ± 0.2 hours vs. 3.1 ± 0.3 hours, P < .001). At follow-up of 14 ± 4, months the overall success rate was 77% (85% in paroxysmal AF, 73% in nonparoxysmal AF). Transthoracic contrast-enhanced echocardiography with the Valsalva maneuver, performed between 3 and 6 months after the procedure, failed to detect shunt in all patients. Radiofrequency catheter ablation of AF is feasible, safe, and effective in patients with ASD closure devices. Transseptal access can be obtained in portions of the native septum in the majority of cases. Direct transseptal puncture of the device is feasible and safe but requires longer time for each transseptal access.


Long-term administration of the mitochondria-targeted antioxidant mitoquinone mesylate fails to attenuate age-related oxidative damage or rescue the loss of muscle mass and function associated with aging of skeletal muscle.
Age-related skeletal muscle dysfunction is the underlying cause of morbidity that affects up to half the population aged 80 and over. Considerable evidence indicates that oxidative damage and mitochondrial dysfunction contribute to the sarcopenic phenotype that occurs with aging. To examine this, we administered the mitochondria-targeted antioxidant mitoquinone mesylate {[10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)decyl] triphenylphosphonium; 100 μM} to wild-type C57BL/6 mice for 15 wk (from 24 to 28 mo of age) and investigated the effects on age-related loss of muscle mass and function, changes in redox homeostasis, and mitochondrial organelle integrity and function. We found that mitoquinone mesylate treatment failed to prevent age-dependent loss of skeletal muscle mass associated with myofiber atrophy or alter a variety of in situ and ex vivo muscle function analyses, including maximum isometric tetanic force, decline in force after a tetanic fatiguing protocol, and single-fiber-specific force. We also found evidence that long-term mitoquinone mesylate administration did not reduce mitochondrial reactive oxygen species or induce significant changes in muscle redox homeostasis, as assessed by changes in 4-hydroxynonenal protein adducts, protein carbonyl content, protein nitration, and DNA damage determined by the content of 8-hydroxydeoxyguanosine. Mitochondrial membrane potential, abundance, and respiration assessed in permeabilized myofibers were not significantly altered in response to mitoquinone mesylate treatment. Collectively, these findings demonstrate that long-term mitochondria-targeted mitoquinone mesylate administration failed to attenuate age-related oxidative damage in skeletal muscle of old mice or provide any protective effect in the context of muscle aging.-Sakellariou, G. K., Pearson, T., Lightfoot, A. P., Nye, G. A., Wells, N., Giakoumaki, I. I., Griffiths, R. D., McArdle, A., Jackson, M. J. Long-term administration of the mitochondria-targeted antioxidant mitoquinone mesylate fails to attenuate age-related oxidative damage or rescue the loss of muscle mass and function associated with aging of skeletal muscle.


Interprofessional education for the quality use of medicines: designing authentic multimedia learning resources.
It is claimed that health care students who learn together will be better prepared for contemporary practice and more able to work collaboratively and communicate effectively. In Australia, although recognised as important for preparing nursing, pharmacy and medical students for their roles in the medication team, interprofessional education is seldom used for teaching medication safety. This is despite evidence indicating that inadequate communication between health care professionals is the primary issue in the majority of medication errors. It is suggested that the pragmatic constraints inherent in university timetables, curricula and contexts limit opportunities for health professional students to learn collaboratively. Thus, there is a need for innovative approaches that will allow nursing, medical and pharmacy students to learn about and from other disciplines even when they do not have the opportunity to learn with them. This paper describes the development of authentic multimedia resources that allow for participative, interactive and engaging learning experiences based upon sound pedagogical principles. These resources provide opportunities for students to critically examine clinical scenarios where medication safety is, or has the potential to be compromised and to develop skills in interprofessional communication that will prepare them to manage these types of situations in clinical practice.