Oral Mucormycosis and Aspergillosis in the Patient with Acute Leukemia.
A 54-year-old male patient with acute lymphoblastic leukemia was referred to the Department of Oral Medicine. He had a primary refractory disease and was treated according to HOVON71 and HAM protocol. Sixteen days after the start of the HAM protocol the patient developed palatal dark red/brownish lesion and maxillary vestibular exophytic lesion. Biopsy specimens from oral lesions were taken and microbiologic evaluation confirmed the presence of Aspergillus fumigatus and Rhizopus genus. The treatment of the patient consisted of the inferior maxillectomy and intravenous posaconazole and amphotericine B for the following 28 days. Since the coinfection with Aspergillus and Rhizopus is extremely rarely seen in the oral cavity, a diagnostic and therapeutic dilemma easily presents itself.


Dual Inhibition of IGF-1R and ErbB3 Enhances the Activity of Gemcitabine and Nab-Paclitaxel in Preclinical Models of Pancreatic Cancer.
Purpose: Insulin-like growth factor receptor 1 (IGF-1R) is critically involved in pancreatic cancer pathophysiology, promoting cancer cell survival and therapeutic resistance. Assessment of IGF-1R inhibitors in combination with standard-of-care chemotherapy, however, failed to demonstrate significant clinical benefit. The aim of this work is to unravel mechanisms of resistance to IGF-1R inhibition in pancreatic cancer and develop novel strategies to improve the activity of standard-of-care therapies.Experimental Design: Growth factor screening in pancreatic cancer cell lines was performed to identify activators of prosurvival PI3K/AKT signaling. The prevalence of activating growth factors and their receptors was assessed in pancreatic cancer patient samples. Effects of a bispecific IGF-1R and ErbB3 targeting antibody on receptor expression, signaling, cancer cell viability and apoptosis, spheroid growth, and in vivo chemotherapy activity in pancreatic cancer xenograft models were determined.Results: Growth factor screening in pancreatic cancer cells revealed insulin-like growth factor 1 (IGF-1) and heregulin (HRG) as the most potent AKT activators. Both growth factors reduced pancreatic cancer cell sensitivity to gemcitabine or paclitaxel in spheroid growth assays. Istiratumab (MM-141), a novel bispecific antibody that blocks IGF-1R and ErbB3, restored the activity of paclitaxel and gemcitabine in the presence of IGF-1 and HRG in vitro Dual IGF-1R/ErbB3 blocking enhanced chemosensitivity through inhibition of AKT phosphorylation and promotion of IGF-1R and ErbB3 degradation. Addition of istiratumab to gemcitabine and nab-paclitaxel improved chemotherapy activity in vivoConclusions: Our findings suggest a critical role for the HRG/ErbB3 axis and support the clinical exploration of dual IGF-1R/ErbB3 blocking in pancreatic cancer. Clin Cancer Res; 24(12); 2873-85. ©2018 AACR.


Patient experience of home and waiting room blood pressure measurement: a qualitative study of patients with recently diagnosed hypertension.
Out-of-office blood pressure (BP) measurement is advocated to confirm hypertension diagnosis. However, little is known about how primary care patients view and use such measurement. To investigate patient experience of out-of-office BP monitoring, particularly home and practice waiting room BP measurement, before, during, and after diagnosis. A cross-sectional, qualitative study with patients from two UK GP surgeries participating in a feasibility study of waiting room BP measurement. Interviewees were identified from recent additions to the practice hypertension register. Interviews were recorded, transcribed, and coded thematically. Of 29 interviewees, 9 (31%) and 22 (76%) had used the waiting room monitor and/or monitored at home respectively. Out-of-office monitoring was used by patients as evidence of control or the lack of need for medication, with the printed results slips from the waiting room monitor perceived to improve 'trustworthiness'. The waiting room monitor enabled those experiencing uncertainty about their equipment or technique to double-check readings. Monitoring at home allowed a more intensive and/or flexible schedule to investigate BP fluctuations and the impact of medication and lifestyle changes. A minority used self-monitoring to inform drug holidays. Reduced intensity of monitoring was reported with both modalities following diagnosis as initial anxiety or patient and GP interest decreased. Home and practice waiting room measurements have overlapping but differing roles for patients. Waiting room BP monitors may be a useful out-of-office measurement modality for patients unwilling and/or unable to measure and record their BP at home.


Influence of sports participation on bone health in the young athlete: a review of the literature.
Peak bone mass is attained during the second and third decades of life. Sports participation during the years that peak bone mass is being acquired may lead to adaptive changes that improve bone architecture through increased density and enhanced geometric properties. A review of the literature evaluating sports participation in young athletes, ages 10-30 years, revealed that sports that involve high-impact loading (eg, gymnastics, hurdling, judo, karate, volleyball, and other jumping sports) or odd-impact loading (eg, soccer, basketball, racquet games, step-aerobics, and speed skating) are associated with higher bone mineral composition, bone mineral density (BMD), and enhanced bone geometry in anatomic regions specific to the loading patterns of each sport. Repetitive low-impact sports (such as distance running) are associated with favorable changes in bone geometry. Nonimpact sports such as swimming, water polo, and cycling are not associated with improvements in bone mineral composition or BMD, and swimming may negatively influence hip geometry. Participating in sports during early puberty may enhance bone mass. Continued participation in sports appears to maintain the full benefits of increased peak bone mass, although former athletes who do not maintain participation in sports may retain some benefits of increased BMD. Long-term elite male cycling was reported to negatively influence bone health, and female adolescent distance running was associated with suppressed bone mineral accrual; confounding factors associated with participation in endurance sports may have contributed to those findings. In summary, young men and women who participate in sports that involve high-impact or odd-impact loading exhibit the greatest associated gains in bone health. Participation in nonimpact sports, such as swimming and cycling, is not associated with an improvement in bone health.


It is not only memory: effects of sensecam on improving well-being in patients with mild alzheimer disease.
Cognitive interventions (either restorative or compensatory) developed for mild Alzheimer's Disease (AD) have been tested widely with cognitive measures, but less is known about how the effects of such interventions are generalizable to daily functioning. In the present study, we looked at affective state and perceived functionality and quality of life indicators, for three different cognitive rehabilitation programs. Fifty-one AD patients in the mild stage of the disease were selected for the study and were randomly assigned to one of three cognitive training groups: (1) Memo+ (a paper and pencil memory training program); (2) SenseCam (wearable camera used as a passive external memory aid); (3) Written diary (a personal journal, used as control condition). All patients attended 11 sessions, twice a week, of 1-hour length. The three outcome indicators were examined with standardized instruments applied before the intervention, one week after and at six months follow-up. After treatment, the SenseCam and Memo+ groups had significantly reduced depressive symptoms compared to the Diary control condition. The same was found for measures of perceived functional capacity. No intervention effects were found for quality of life measures. The immediate effects of the interventions were not maintained at follow-up. Our results suggest that two types of memory rehabilitation can improve depressive symptomology and instrumental activities of daily living, suggesting that these interventions can stimulate not only cognition but also well-being, at least in the short term.


Diagnosed Mental Health Conditions and Risk of Suicide Mortality.
Although mental health conditions are risk factors for suicide, limited data are available on suicide mortality associated with specific mental health conditions in the U.S. population. This study aimed to fill this gap. This study used a case-control design. Patients in the case group were those who died by suicide between 2000 and 2013 and who were patients in eight health care systems in the Mental Health Research Network (N=2,674). Each was matched with 100 general population patients from the same system (N=267,400). Diagnostic codes for five mental health conditions in the year before death were obtained from medical records: anxiety disorders, attention deficit-hyperactivity disorder (ADHD), bipolar disorder, depressive disorders, and schizophrenia spectrum disorder. Among patients in the case group, 51.3% had a recorded psychiatric diagnosis in the year before death, compared with 12.7% of control group patients. Risk of suicide mortality was highest among those with schizophrenia spectrum disorder, after adjustment for age and sociodemographic characteristics (adjusted odds ratio [AOR]=15.0) followed by bipolar disorder (AOR=13.2), depressive disorders (AOR=7.2), anxiety disorders (AOR=5.8), and ADHD (AOR=2.4). The risk of suicide death among those with a diagnosed bipolar disorder was higher in women than men. Half of those who died by suicide had at least one diagnosed mental health condition in the year before death, and most mental health conditions were associated with an increased risk of suicide. Findings suggest the importance of suicide screening and providing an approach to improve awareness of mental health conditions.


Contact dermatitis and atopic dermatitis: two tales, an interwoven story.
Atopic dermatitis is a multifactorial disease that can concomitantly occur with irritant or allergic contact dermatitis. The colloquial use of atopic dermatitis and eczema interchangeably has created confusion among patients and providers alike. Atopic skin is a complex entity that involves a defective barrier and biome, an aberrant immune response, and abnormal neural activation, while eczema is a generalized term denoting a particular appearance common to multiple diagnoses including atopic dermatitis and contact dermatitis. The conventional paradigm that simplifies atopic dermatitis and allergic contact dermatitis into distinct Th2 and Th1 processes, respectively, fails to acknowledge potential immunologic intersection points and contributes to impaired disease management. This article will review the complex interplay of atopic dermatitis and contact dermatitis and discuss treatment strategies for recalcitrant cases.


Review: Current applications and challenges for liquid chromatography coupled to isotope ratio mass spectrometry (LC/IRMS).
High-precision isotope analysis is recognized as an essential research tool in many fields of study. Until recently, continuous flow isotope ratio mass spectrometry (CF-IRMS) was available via an elemental analyzer or a gas chromatography inlet system for compound-specific analysis of light stable isotopes. In 2004, however, an interface that coupled liquid chromatography with IRMS (LC/IRMS) became commercially available for the first time. This brought the capability for new areas of application, in particular enabling compound-specific δ(13)C analysis of non-volatile, aqueous soluble, compounds from complex mixtures. The interface design brought with it several analytical constraints, however, in particular a lack of compatibility with certain types of chromatography as well as limited flow rates and mobile phase compositions. Routine LC/IRMS methods have, however, been established for measuring the δ(13)C isotopic ratios of underivatized individual compounds for application in archeology, nutrition and physiology, geochemistry, hydrology, soil science and food authenticity. Seven years after its introduction, we review the technical advances and constraints, methodological developments and new applications of liquid chromatography coupled to isotope ratio mass spectrometry.


Randomized trial of high-dose chemotherapy with autologous peripheral-blood stem-cell support compared with standard-dose chemotherapy in women with metastatic breast cancer: NCIC MA.16.
We conducted a multicenter, randomized trial to compare progression-free survival (PFS), overall survival (OS), and quality of life in women with metastatic breast cancer (MBC) receiving high-dose chemotherapy plus autologous stem-cell transplantation (ASCT; HDCT) compared with standard-dose therapy. Between April 1997 and December 2000, 386 women with MBC and no prior chemotherapy for metastatic disease were registered. After initial response to anthracycline- or taxane-based induction chemotherapy, 224 patients were randomly assigned: 112 to high-dose cyclophosphamide, mitoxantrone, and carboplatin chemotherapy and ASCT (HDCT), and 112 to standard therapy (ST). Median age was 47 years (range, 25 to 67 years). Thirty two percent of women randomly assigned had estrogen and progesterone receptor-negative breast cancer, 42% had visceral metastases, and 58% had bone metastases. Complete remission rates before random assignment were 11% for those receiving HDCT and 12% for those receiving ST. After a median follow-up of 48 months, 79 deaths were observed in the HDCT arm and 77 deaths were observed in the ST arm; seven patients (6%) in the HDCT arm died as a result of toxicity. The median OS was 24 months for the HDCT arm (95% CI, 21 to 35 months) and 28 months for ST (95% CI, 22 to 33 months; hazard ratio [HR], 0.9; 95% CI, 0.6 to 1.2; P = .43). PFS was 11 months for HDCT and 9 months for ST (HR, 0.6 in favor of HDCT; 95% CI, 0.5 to 0.9; P = .006). HDCT did not improve OS in women with MBC when used as consolidation after response to induction chemotherapy.


Diets, nutrients, genes and the microbiome: recent advances in personalised nutrition.
As individuals seek increasingly individualised nutrition and lifestyle guidance, numerous apps and nutrition programmes have emerged. However, complex individual variations in dietary behaviours, genotypes, gene expression and composition of the microbiome are increasingly recognised. Advances in digital tools and artificial intelligence can help individuals more easily track nutrient intakes and identify nutritional gaps. However, the influence of these nutrients on health outcomes can vary widely among individuals depending upon life stage, genetics and microbial composition. For example, folate may elicit favourable epigenetic effects on brain development during a critical developmental time window of pregnancy. Genes affecting vitamin B12 metabolism may lead to cardiometabolic traits that play an essential role in the context of obesity. Finally, an individual's gut microbial composition can determine their response to dietary fibre interventions during weight loss. These recent advances in understanding can lead to a more complete and integrated approach to promoting optimal health through personalised nutrition, in clinical practice settings and for individuals in their daily lives. The purpose of this review is to summarise presentations made during the DSM Science and Technology Award Symposium at the 13th European Nutrition Conference, which focused on personalised nutrition and novel technologies for health in the modern world.


Computer-based tools for assessing micro-longitudinal patterns of cognitive function in older adults.
Patterns of cognitive change over micro-longitudinal timescales (i.e., ranging from hours to days) are associated with a wide range of age-related health and functional outcomes. However, practical issues of conducting high-frequency assessments make investigations of micro-longitudinal cognition costly and burdensome to run. One way of addressing this is to develop cognitive assessments that can be performed by older adults, in their own homes, without a researcher being present. Here, we address the question of whether reliable and valid cognitive data can be collected over micro-longitudinal timescales using unsupervised cognitive tests.In study 1, 48 older adults completed two touchscreen cognitive tests, on three occasions, in controlled conditions, alongside a battery of standard tests of cognitive functions. In study 2, 40 older adults completed the same two computerized tasks on multiple occasions, over three separate week-long periods, in their own homes, without a researcher present. Here, the tasks were incorporated into a wider touchscreen system (Novel Assessment of Nutrition and Ageing (NANA)) developed to assess multiple domains of health and behavior. Standard tests of cognitive function were also administered prior to participants using the NANA system.Performance on the two "NANA" cognitive tasks showed convergent validity with, and similar levels of reliability to, the standard cognitive battery in both studies. Completion and accuracy rates were also very high. These results show that reliable and valid cognitive data can be collected from older adults using unsupervised computerized tests, thus affording new opportunities for the investigation of cognitive.


Atrial fibrillation and the use of oral bisphosphonates.
Epidemiological studies investigating a possible association between bisphosphonates and atrial fibrillation (AF) have reported conflicting findings. The objective of our study was to determine whether exposure to oral nitrogen-containing bisphosphonates alendronate and risedronate are associated with increased incidence of atrial fibrillation. In a retrospective cohort study we analyzed data from three large independent databases, two from the United States (MarketScan(®) and Ingenix(®)) and one from the United Kingdom (THIN). 144,548 women, age 50-89, bisphosphonate users during 2002-2005 were compared to 668,891 sex- and age-matched controls (1:4). Our primary outcome measure was new incident atrial fibrillation for up to three years; Cox models adjusted for disease and drug history were used to estimated relative risks. We identified a total of 8,001, 1,984, and 817 AF cases in oral bisphosphonate users and nonusers during 744,340 (MarketScan), 243,898 (Ingenix), and 148,779 (THIN) person-years of follow-up, respectively. Compared to nonusers, overall adjusted relative risk (adjRR) (95% confidence interval [CI]) for AF in oral bisphosphonates users was 0.92 (0.85-0.99; MarketScan), 1.00 (0.87-1.16; Ingenix), and 0.97 (0.79-1.20; THIN); overall adjRR (95% CI) for any cardiac dysrrhythmia for MarketScan was 1.01 (0.98-1.05), Ingenix 1.06 (0.99-1.13), and THIN 0.97 (0.79-1.20). In all three databases from the two countries, the risk of AF or cardiac dysrrhythmia was not increased in postmenopausal women treated for up to three years with oral alendronate or risedronate.


The relationship between occupational noise and vibration exposure and headache/eyestrain, based on the fourth Korean Working Condition Survey (KWCS).
The individual and combined effect of occupational noise and vibration exposures, on workers' health has not been thoroughly investigated. In order to find better ways to prevent and manage workers' headache, this study aimed to investigate the effects of occupational noise and vibration exposure on headache/eyestrain. We used data from the fourth Korean Working Condition Survey (2014). After applying inclusion and exclusion criteria, 25,751 workers were included. Occupational noise and vibration exposure and the prevalence of headache/eyestrain were investigated by self-reported survey. Chi-square tests were used to compare differences in baseline characteristics between the group with headache/eyestrain and the group without. Odds ratios and 95% confidence intervals were estimated using a logistic regression model adjusted for several covariates. Area under the receiver operating characteristics curve (AUROC) analysis was used to evaluate the effect of occupational noise and/or vibration exposure. Among the 25,751 study subjects, 4,903 had experienced headache/eyestrain in the preceding year. There were significant differences in age, education level, household income, occupational classification, shift work, occupational vibration exposure, and occupational noise exposure between the two groups (all p<0.05). The odds ratios between each exposure and headache/eyestrain increased proportionally with the level of exposure, increasing from 1.08 to 1.26 with increasing vibration exposure, and from 1.25 to 1.41 with increasing noise exposure. According to the AUROC analysis, the predictive power of each exposure was significant, and increased when the two exposures were considered in combination. The findings of this study show that both occupational noise and vibration exposures are associated with headache/eyestrain; noise exposure more strongly so. However, when the two exposures are considered in combination, the explanatory power for headache/eyestrain is increased. Therefore, efforts aimed at reducing and managing occupational noise and vibration exposure are crucial to maintaining workers' health.


Vagus nerve stimulation induces widespread cortical and behavioral activation.
Vagus nerve stimulation (VNS) is used for management of a variety of neurological conditions, although the therapeutic mechanisms are not fully understood. Accumulating evidence suggests that VNS may modulate cortical state and plasticity through activation of broadly projecting neuromodulatory systems. Using a mouse model, we compared arousal-linked behaviors with dorsal cortical activity obtained with widefield and two-photon GCaMP6s calcium imaging and electrophysiological recordings. We observed robust and reliable cortical and behavioral dose-dependent activation in waking mice to VNS, including pupil dilation and, frequently, whisker movements and locomotion. Widefield calcium imaging and multiunit recording during VNS revealed that this observed increase in arousal state is coupled with a rapid and widespread increase in excitatory activity, including, but not limited to, activation of somatosensory, visual, motor, retrosplenial, and auditory cortical regions. Two-photon GCaMP6s calcium imaging of cholinergic and noradrenergic cortical axons revealed that VNS strongly activates these neuromodulatory systems. Importantly, VNS-evoked activation of neuromodulatory axons and excitatory neurons in the cortex persisted in mice under light anesthesia, in the absence of overt movement. Arousal state changes were abolished by vagus nerve transection, confirming that observed VNS effects were specific to nerve stimulation and triggered widespread activity above that which can be explained by motor activity. Taken together, our results support a model of VNS in which activation of subcortical structures leads to widespread activation of cortex and an increase in arousal state, at least partially due to the activation of cholinergic and noradrenergic modulatory pathways.


Amygdala volumes in childhood absence epilepsy.
Abnormal amygdala volumes in pediatric mood-anxiety disorders and attention deficit hyperactivity disorder (ADHD), as well as high rates of these diagnoses in childhood absence epilepsy (CAE), prompted this study of amygdala volume in CAE. Twenty-six children with CAE and 23 normal children, aged 6.6-15.8 years, underwent MRI at 1.5 T. The tissue imaged with MRI was segmented, and amygdala volumes were obtained by manual tracings. There were no significant amygdala volume differences between the CAE and normal groups. Within the CAE group, however, the children with ADHD had significantly smaller amygdala volumes than the subjects with CAE with no psychopathology and those with mood/anxiety diagnoses. There was also a significant relationship between higher seizure frequency and greater amygdala asymmetry in the epilepsy group. Given ongoing development of the amygdala during late childhood and adolescence, despite the lack of significant group differences in amygdala volumes, the association of amygdala volume abnormalities with ADHD and seizure frequency implies a possible impact of the disorder on amygdala development and CAE-associated comorbidities, such as ADHD.


On the determination of χ(2) in thin films: a comparison of one-beam second-harmonic generation measurement methodologies.
The determination of the second-order susceptibility (χ(2)) of thin film samples can be a delicate matter since well-established χ(2) measurement methodologies such as the Maker fringe technique are best suited for nonlinear materials with large thicknesses typically ranging from tens of microns to several millimeters. Here we compare two different second-harmonic generation setups and the corresponding measurement methodologies that are especially advantageous for thin film χ(2) characterization. This exercise allows for cross-checking the χ(2) obtained for identical samples and identifying the main sources of error for the respective techniques. The development of photonic integrated circuits makes nonlinear thin films of particular interest, since they can be processed into long waveguides to create efficient nonlinear devices. The investigated samples are ABC-type nanolaminates, which were reported recently by two different research groups. However, the subsequent analysis can be useful for all researchers active in the field of thin film χ(2) characterization.


Role of the 2B4 Receptor in CD8+ T-Cell-Dependent Immune Control of Epstein-Barr Virus Infection in Mice With Reconstituted Human Immune System Components.
Patients with X-linked lymphoproliferative (XLP) disease due to deficiency in the adaptor molecule signaling lymphocytic activation molecule-associated protein (SAP) are highly susceptible to one specific viral pathogen, the Epstein-Barr virus (EBV). This susceptibility might result from impaired CD8(+) T-cell and natural killer cell responses to EBV infection in these patients. We demonstrate that antibody blocking of the SAP-dependent 2B4 receptor is sufficient to induce XLP-like aggravation of EBV disease in mice with reconstituted human immune system components. CD8(+) T cells require 2B4 for EBV-specific immune control, because 2B4 blockade after CD8(+) T-cell depletion did not further aggravate symptoms of EBV infection.


The effect of school attendance and school dropout on incident HIV and HSV-2 among young women in rural South Africa enrolled in HPTN 068.
To estimate the association between school attendance, school dropout, and risk of incident HIV and herpes simplex virus type 2 (HSV-2) infection among young women. We used longitudinal data from a randomized controlled trial in rural Mpumalanga province, South Africa, to assess the association between school days attended, school dropout, and incident HIV and HSV-2 in young women aged 13-23 years. We examined inverse probability of exposure weighted survival curves and used them to calculate 1.5, 2.5, and 3.5-year risk differences and risk ratios for the effect of school attendance on incident HIV and HSV-2. A marginal structural Cox model was used to estimate hazard ratios for the effect of school attendance and school dropout on incident infection. Risk of infection increased over time as young women aged, and was higher in young women with low school attendance (<80% school days) compared with high (≥80% school days). Young women with low attendance were more likely to acquire HIV [hazard ratio (HR): 2.97; 95% confidence interval (CI): 1.62, 5.45] and HSV-2 (HR: 2.47; 95% CI: 1.46, 4.17) over the follow-up period than young women with high attendance. Similarly, young women who dropped out of school had a higher weighted hazard of both HIV (HR 3.25 95% CI: 1.67, 6.32) and HSV-2 (HR 2.70; 95% CI 1.59, 4.59). Young women who attend more school days and stay in school have a lower risk of incident HIV and HSV-2 infection. Interventions to increase frequency of school attendance and prevent dropout should be promoted to reduce risk of infection.


The desperate need for good-quality clinical trials to evaluate the optimal source and dose of fibrinogen in managing bleeding.
Recent interest in transfusion management of trauma patients has heightened expectation in the role of blood component therapy in improving patient outcome. Optimal transfusion support in supplementation with fibrinogen has not been defined by high-quality evidence. Current evidence comes mainly from case series and uncontrolled studies and does not support the superiority of one source of fibrinogen over another or the optimal schedule or dose for patient benefit. There are unanswered questions about safety, especially the effects on the risk of hospital-acquired venous thromboembolism, an important consideration in any therapy that alters the hemostatic balance. Studies of cost-effectiveness have not been considered in research. An international move to supplement fibrinogen more 'aggressively' without direct clinical evaluation beforehand represents a failed opportunity to improve our very limited understanding of optimal transfusion practice.


A very long-chain acyl-CoA synthetase-deficient mouse and its relevance to X-linked adrenoleukodystrophy.
X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative and endocrine disorder resulting from mutations in ABCD1 which encodes a peroxisomal membrane protein in the ATP binding cassette superfamily. The biochemical signature of X-ALD is increased levels of saturated very long-chain fatty acids (VLCFA; carbon chains of 22 or more) in tissues and plasma that has been associated with decreased peroxisomal very long-chain acyl-CoA synthetase (VLCS) activity and decreased peroxisomal VLCFA beta-oxidation. It has been hypothesized that ABCD1, which has no demonstrable VLCS activity itself, has an indirect effect on peroxisomal VLCS activity and VLCFA beta-oxidation by transporting fatty acid substrates, VLCS protein or some required co-factor into peroxisomes. Here we report the characterization of a Vlcs knockout mouse that exhibits decreased peroxisomal VLCS activity and VLCFA beta-oxidation but does not accumulate VLCFA. The XALD/Vlcs double knockout mouse has the biochemical abnormalities observed in the individual knockout mice but does not display a more severe X-ALD phenotype. These data lead us to conclude that (1) VLCFA levels are independent of peroxisomal fatty acid beta-oxidation, (2) there is no ABCD1/VLCS interaction and (3) the common severe forms of X-ALD cannot be modeled by decreasing peroxisomal VLCS activity in the XALD mouse.


Direct Characterization of Near-Field Coupling in Gap Plasmon-Based Metasurfaces.
Metasurfaces based on gap surface-plasmon resonators allow one to arbitrarily control the phase, amplitude, and polarization of reflected light with high efficiency. However, the performance of densely packed metasurfaces is reduced, often quite significantly, in comparison with simple analytical predictions. We argue that this reduction is mainly because of the near-field coupling between metasurface elements, which results in response from each element being different from the one anticipated by design simulations, which are commonly conducted for each individual element being placed in an artificial periodic arrangement. In order to study the influence of near-field coupling, we fabricate meta-elements of varying sizes arranged in quasi-periodic arrays so that the immediate environment of same size elements is different for those located in the middle and at the border of the arrays. We study the near-field using a phase-resolved scattering-type scanning near-field optical microscopy (s-SNOM) and conducting numerical simulations. By comparing the near-field maps from elements of the same size but different placements we evaluate the near-field coupling strength, which is found to be significant for large and densely packed elements. This technique is quite generic and can be used practically for any metasurface type in order to precisely measure the near-field response from each individual element and identify malfunctioning ones, providing feedback to their design and fabrication, thereby allowing one to improve the efficiency of the whole metasurface.


Improvements in PM10 exposure and reduced rates of respiratory symptoms in a cohort of Swiss adults (SAPALDIA).
Reductions in mortality following improvements in air quality were documented by several studies, and our group found, in an earlier analysis, that decreasing particulate levels attenuate lung function decline in adults. We investigated whether decreases in particulates with an aerodynamic diameter of less than 10 microm (PM10) were associated with lower rates of reporting respiratory symptoms (i.e., decreased morbidity) on follow-up. The present analysis includes 7,019 subjects who underwent detailed baseline examinations in 1991 and a follow-up interview in 2002. Each subject was assigned model-based estimates of average PM10 during the 12 months preceding each health assessment and the difference was used as the exposure variable of interest (DeltaPM10). Analyses were stratified by symptom status at baseline and associations between DeltaPM10 and change in symptom status during follow-up were adjusted for important baseline characteristics, smoking status at follow-up, and season. We then estimated adjusted odds ratios for symptoms at follow-up and numbers of symptomatic cases prevented due to the observed reductions in PM10. Residential exposure to PM10 was lower in 2002 than in 1991 (mean decline 6.2 microg/m3; SD = 3.9 microg/m3). Estimated benefits (per 10,000 persons) attributable to the observed changes in PM10-levels were: 259 (95% confidence interval [CI]: 102-416) fewer subjects with regular cough, 179 (95% CI, 30-328) fewer subjects with chronic cough or phlegm and 137 (95% CI, 9-266) fewer subjects with wheezing and breathlessness. Reductions in particle levels in Switzerland over the 11-year follow-up period had a beneficial effect on respiratory symptoms among adults.


Validity of visceral adiposity estimates from DXA against MRI in Kuwaiti men and women.
The prevalence of obesity and diabetes in the Middle East is among the highest in the world. Valid measures of abdominal adiposity are essential to understanding the metabolic consequences of obesity. Dual-energy X-ray absorptiometry (DXA) is increasingly being utilised to assess body composition in population studies, and has recently been used to estimate visceral adipose tissue (VAT). The aim of this study was to determine the accuracy of DXA-derived VAT in a Middle Eastern population using magnetic resonance imaging (MRI) as the criterion measure. VAT was estimated from abdominal DXA measures in 237 adult men (n=130) and women (n=107), aged 18-65 years, participating in the Kuwait Wellbeing Study. These estimates were compared with MRI measures of the corresponding anatomical region. The agreement between methods was assessed using Bland-Altman as well as correlation analysis. Median MRI VAT was 1148.5 cm3 (95% confidence interval: 594.2-1734.6) in men and 711.3 cm3 (95% confidence interval: 395.5-1042.8) in women. DXA estimates of VAT showed high correlations with corresponding MRI measures (r=0.94 (P<0.0001) in men; r=0.93 (P<0.0001) in women). DXA overestimated VAT with a mean bias (95% limits of agreement) of 79.7 cm3 (-767 to 963) in men and 46.8 cm3 (-482 to 866) in women. The imprecision of DXA increased with increasing VAT level in both men and women. DXA estimates of VAT are valid for use in Middle Eastern populations, although accuracy decreases with increasing level of visceral adiposity.


Human cytomegalovirus UL29/28 protein interacts with components of the NuRD complex which promote accumulation of immediate-early RNA.
Histone deacetylation plays a pivotal role in regulating human cytomegalovirus gene expression. In this report, we have identified candidate HDAC1-interacting proteins in the context of infection by using a method for rapid immunoisolation of an epitope-tagged protein coupled with mass spectrometry. Putative interactors included multiple human cytomegalovirus-coded proteins. In particular, the interaction of pUL38 and pUL29/28 with HDAC1 was confirmed by reciprocal immunoprecipitations. HDAC1 is present in numerous protein complexes, including the HDAC1-containing nucleosome remodeling and deacetylase protein complex, NuRD. pUL38 and pUL29/28 associated with the MTA2 component of NuRD, and shRNA-mediated knockdown of the RBBP4 and CHD4 constituents of NuRD inhibited HCMV immediate-early RNA and viral DNA accumulation; together this argues that multiple components of the NuRD complex are needed for efficient HCMV replication. Consistent with a positive acting role for the NuRD elements during viral replication, the growth of pUL29/28- or pUL38-deficient viruses could not be rescued by treating infected cells with the deacetylase inhibitor, trichostatin A. Transient expression of pUL29/28 enhanced activity of the HCMV major immediate-early promoter in a reporter assay, regardless of pUL38 expression. Importantly, induction of the major immediate-early reporter activity by pUL29/28 required functional NuRD components, consistent with the inhibition of immediate-early RNA accumulation within infected cells after knockdown of RBBP4 and CHD4. We propose that pUL29/28 modifies the NuRD complex to stimulate the accumulation of immediate-early RNAs.


On anger, shock, fear, and trauma: therapeutic jurisprudence as a response to dignity denials in public policy.
This article asserts that when policymaking processes, outcomes, and implementations stoke fear, anxiety, and trauma, they often lead to denials of human dignity. It cited as prime examples the recent actions of America's current federal government concerning immigration and health care. As a response, I urge that therapeutic jurisprudence should inform both the processes of policymaking and the design of public policy, trained on whether human dignity, psychological health, and well-being are advanced or diminished. I also discuss three methodologies that will help to guide those who want to engage legislation in a TJ-informed manner. Although achieving this fundamental shift will not be easy, we have the raw analytical and intellectual tools to move wisely in this direction.


Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes.
Autoimmune thyroid diseases (AITD) and Type 1 diabetes (T1D) frequently occur in the same individual pointing to a strong shared genetic susceptibility. Indeed, the co-occurrence of T1D and AITD in the same individual is classified as a variant of the autoimmune polyglandular syndrome type 3 (designated APS3v). Our aim was to identify new genes and mechanisms causing the co-occurrence of T1D + AITD (APS3v) in the same individual using a genome-wide approach. For our discovery set we analyzed 346 Caucasian APS3v patients and 727 gender and ethnicity matched healthy controls. Genotyping was performed using the Illumina Human660W-Quad.v1. The replication set included 185 APS3v patients and 340 controls. Association analyses were performed using the PLINK program, and pathway analyses were performed using the MAGENTA software. We identified multiple signals within the HLA region and conditioning studies suggested that a few of them contributed independently to the strong association of the HLA locus with APS3v. Outside the HLA region, variants in GPR103, a gene not suggested by previous studies of APS3v, T1D, or AITD, showed genome-wide significance (p < 5 × 10(-8)). In addition, a locus on 1p13 containing the PTPN22 gene showed genome-wide significant associations. Pathway analysis demonstrated that cell cycle, B-cell development, CD40, and CTLA-4 signaling were the major pathways contributing to the pathogenesis of APS3v. These findings suggest that complex mechanisms involving T-cell and B-cell pathways are involved in the strong genetic association between AITD and T1D.


PTEX is an essential nexus for protein export in malaria parasites.
During the blood stages of malaria, several hundred parasite-encoded proteins are exported beyond the double-membrane barrier that separates the parasite from the host cell cytosol. These proteins have a variety of roles that are essential to virulence or parasite growth. There is keen interest in understanding how proteins are exported and whether common machineries are involved in trafficking the different classes of exported proteins. One potential trafficking machine is a protein complex known as the Plasmodium translocon of exported proteins (PTEX). Although PTEX has been linked to the export of one class of exported proteins, there has been no direct evidence for its role and scope in protein translocation. Here we show, through the generation of two parasite lines defective for essential PTEX components (HSP101 or PTEX150), and analysis of a line lacking the non-essential component TRX2 (ref. 12), greatly reduced trafficking of all classes of exported proteins beyond the double membrane barrier enveloping the parasite. This includes proteins containing the PEXEL motif (RxLxE/Q/D) and PEXEL-negative exported proteins (PNEPs). Moreover, the export of proteins destined for expression on the infected erythrocyte surface, including the major virulence factor PfEMP1 in Plasmodium falciparum, was significantly reduced in PTEX knockdown parasites. PTEX function was also essential for blood-stage growth, because even a modest knockdown of PTEX components had a strong effect on the parasite's capacity to complete the erythrocytic cycle both in vitro and in vivo. Hence, as the only known nexus for protein export in Plasmodium parasites, and an essential enzymic machine, PTEX is a prime drug target.


Evaluation of GFR estimating equations in the general community: implications for screening.
The Kidney Disease Outcomes Quality Initiative has recommended the use of GFR estimating equations to detect silent chronic kidney disease (CKD) in the community. The benefit of general reporting of CKD must be balanced with the harm of mislabeling people who do not have CKD. The popular Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) GFR estimating equations were compared with the recently devised Rule equation in a representative community population sample (2166) divided into subsamples with (385) and without (1781) previous renal impairment. The prevalence of CKD was CG > MDRD >> Rule estimates. The magnitude of difference in prevalence of CKD as detected by the MDRD and CG versus the Rule equation increases markedly when the subsamples with (30.8 and 29.7 versus 17.5%) and without (12 and 11.3 versus 3.0%) previous kidney impairment are compared. General demographic and potential or known risk factors were used in a logistic regression model to assess the association with CKD. The MDRD estimates note female gender (odds ratio 2.19; 95% confidence interval 1.63 to 2.95) and both MDRD and the Rule equations identify hypertension and diabetes as significant CKD risk factors. All estimating equations identify age to be associated with CKD. The annualized serial decline in GFR was CG > MDRD > Rule estimates. Only the Rule GFR estimates detected a greater decline in renal impaired versus unimpaired populations. The calibrated Rule equation seems to perform better than CG and MDRD (CKD 3 versus 11.3 to 12%) but lacks validation against gold standards for community-based screening.


Protein complex prediction via verifying and reconstructing the topology of domain-domain interactions.
High-throughput methods for detecting protein-protein interactions enable us to obtain large interaction networks, and also allow us to computationally identify the associations of proteins as protein complexes. Although there are methods to extract protein complexes as sets of proteins from interaction networks, the extracted complexes may include false positives because they do not account for the structural limitations of the proteins and thus do not check that the proteins in the extracted complex can simultaneously bind to each other. In addition, there have been few searches for deeper insights into the protein complexes, such as of the topology of the protein-protein interactions or into the domain-domain interactions that mediate the protein interactions. Here, we introduce a combinatorial approach for prediction of protein complexes focusing not only on determining member proteins in complexes but also on the DDI/PPI organization of the complexes. Our method analyzes complex candidates predicted by the existing methods. It searches for optimal combinations of domain-domain interactions in the candidates based on an assumption that the proteins in a candidate can form a true protein complex if each of the domains is used by a single protein interaction. This optimization problem was mathematically formulated and solved using binary integer linear programming. By using publicly available sets of yeast protein-protein interactions and domain-domain interactions, we succeeded in extracting protein complex candidates with an accuracy that is twice the average accuracy of the existing methods, MCL, MCODE, or clustering coefficient. Although the configuring parameters for each algorithm resulted in slightly improved precisions, our method always showed better precision for most values of the parameters. Our combinatorial approach can provide better accuracy for prediction of protein complexes and also enables to identify both direct PPIs and DDIs that mediate them in complexes.


Characteristics of functional bowel disorder patients: a cross-sectional survey using the Rome III criteria.
There is some evidence that, despite attempts to classify them separately, functional bowel disorders are not distinct entities and that such divisions are artificial. To examine this issue in a large cohort of secondary care patients. Consecutive, unselected adults with gastrointestinal (GI) symptoms attending out-patient clinics at two hospitals in Hamilton, Ontario were recruited. Demographic data, symptoms and presence of anxiety, depression or somatisation were collected prospectively. We used validated questionnaires, including the Rome III questionnaire, with patients categorised as having irritable bowel syndrome (IBS), functional diarrhoea or chronic idiopathic constipation (CIC). We compared data between these disorders, and measured degree of overlap between them by suspending their mutual exclusivity. Of 3656 patients providing complete lower GI symptom data, 1551 (42.4%) met criteria for a functional bowel disorder. Diarrhoea-predominant IBS (IBS-D) patients were younger, and more were female, met criteria for anxiety, and reported somatisation-type behaviour, compared with functional diarrhoea. Only loose, mushy or watery stools were more common in functional diarrhoea. When mutual exclusivity was suspended, overlap occurred in 27.6%. Constipation-predominant IBS (IBS-C) patients were younger, and more were female, had never married, reported anxiety type symptoms and exhibited somatisation-type behaviour. One in five CIC patients reported abdominal pain or discomfort. All constipation symptoms were more common in IBS-C. When the mutual exclusivity was suspended, overlap occurred in 18.1%. There were significant differences in demographics between individuals with functional bowel disorders. Despite this, the Rome III classification system falls short of describing unique entities.


Prospective comparison of auto and allograft hamstring tendon constructs for ACL reconstruction.
Although allograft use for primary anterior cruciate ligament reconstruction has continued to increase during the last 10 years, concerns remain regarding the long-term function of allografts (primarily that they may stretch with time) and clinical efficacy compared with autograft tendons. We attempted to address these issues by prospectively comparing identical quadrupled hamstring autografts with allograft constructs for primary anterior cruciate ligament reconstruction in patients with a minimum followup of 3 years. Eighty-four patients (37 with autografts and 47 with allografts) were enrolled; the mean followup was 52 +/- 11 months for the autograft group and 48 +/- 8 months for the allograft group. Outcome measurements included objective and subjective International Knee Documentation Committee scores, Lysholm scores, Tegner activity scales, and KT-1000 arthrometer measurements. The two cohorts were similar in average age, acute or chronic nature of the anterior cruciate ligament rupture, and incidence of concomitant meniscal surgeries. At final followup, we found no difference in terms of Tegner, Lysholm, KT-1000, or International Knee Documentation Committee scores. Five anterior cruciate ligament reconstructions failed: three in the autograft group and two in the allograft group. Our data suggest laxity is not increased in allograft tendons compared with autografts and clinical outcome scores 3 to 6 years after surgery are similar. Level II, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.


Single-shot two-dimensional infrared spectroscopy.
Multidimensional infrared spectroscopy is a robust tool for studying the structural dynamics of molecules. In particular, twodimensional infrared (2DIR) spectroscopy can reveal vibrational coupling among the internal modes of molecules, uncovering the transient structure of complex systems. While spectroscopically very powerful, current experimental techniques are time consuming to perform, requiring ~10(6) laser shots for a single 2DIR spectrum. In this work, we demonstrate a new technique that can acquire a full 2DIR correlation spectrum using a single ultrafast laser pulse. This apparatus will allow 2DIR spectroscopy to be extended to systems that were unattainable with previous technology, including, irreversible chemical reactions, rapid flow experiments, or with low repetition rate laser systems.


Putting the genie back in the bottle? Availability and presentation of oral artemisinin compounds at retail pharmacies in urban Dar-es-Salaam.
Recently global health advocates have called for the introduction of artemisinin-containing antimalarial combination therapies to help curb the impact of drug-resistant malaria in Africa. Retail trade in artemisinin monotherapies could undermine efforts to restrict this class of medicines to more theoretically sound combination treatments. This paper describes a systematic search for artemisinin-containing products at a random sample of licensed pharmacies in Dar-es-Salaam, Tanzania in July 2005. Nineteen different artemisinin-containing oral pharmaceutical products, including one co-formulated product, one co-packaged product, and 17 monotherapies were identified. All but one of the products were legally registered and samples of each product were obtained without a prescription. Packaging and labeling of the products seldom included local language or illustrated instructions for low-literate clients. Packaging and inserts compared reasonably well with standards recommended by the national regulatory authority with some important exceptions. Dosing instructions were inconsistent, and most recommended inadequate doses based on international standards. None of the monotherapy products mentioned potential benefits of combining the treatment with another antimalarial drug. The findings confirm the widespread availability of artemisinin monotherapies that led the World Health Organization to call for the voluntary withdrawal of these drugs in malaria-endemic countries. As the global public health community gathers resources to deploy artemisinin-containing combination therapies in Africa, planners should be mindful that these drugs will coexist with artemisinin monotherapies in an already well-established market place. In particular, regulatory authorities should be incorporated urgently into the process of planning for rational deployment of artemisinin-containing antimalarial combination therapies.


Right ventricular remodeling and dysfunction with subsequent annular dilatation and tethering as a mechanism of isolated tricuspid regurgitation.
Secondary tricuspid regurgitation (TR) as a result of pulmonary hypertension and/or left-sided heart disease is caused by tricuspid valve (TV) annular dilatation and tethering of the tricuspid leaflet after right ventricular (RV) dilatation. However, the mechanism of isolated TR without significant pulmonary hypertension remains unknown. The present study investigated the RV function and TV deformations in patients with isolated TR to find out the mechanism and etiology of the disease. Twelve patients with isolated, severe TR were included. RV area, volume, ejection fraction (EF), tenting distance and tenting area were measured. These parameters were compared with 12 age-and gender-matched controls and 12 patients with secondary TR. The cause of isolated TR was incomplete coaptation associated with annular dilatation without other problems. Compared with the controls, RV end-diastolic volumes and annular diameters were significantly larger and RVEF was significantly lower in patients with isolated TR. Tenting area and tenting distance were also significantly higher. However, there were no significant differences in these parameters between patients with isolated and secondary TR. Isolated TR was associated with RV remodeling, systolic dysfunction and resultant annular dilatation and tethering of tricuspid leaflets.


The structure of a glycogen phosphorylase glucopyranose spirohydantoin complex at 1.8 A resolution and 100 K: the role of the water structure and its contribution to binding.
A glucopyranose spirohydantoin (a pyranose analogue of the potent herbicide, hydantocidin) has been identified as the highest affinity glucose analogue inhibitor of glycogen phosphorylase b (GPb). In order to elucidate the structural features that contribute to the binding, the structures of GPb in the native T state conformation and in complex with glucopyranose spirohydantoin have been determined at 100 K to 2.0 A and 1.8 A resolution, respectively, and refined to crystallographic R values of 0.197 (R[free] 0.248) and 0.182 (R[free] 0.229), respectively. The low temperature structure of GPb is almost identical to that of the previously determined room temperature structure, apart from a decrease in overall atomic temperature factors ((B) room temperature GPb = 34.9 A2; (B) 100 K GPb = 23.4 A2). The glucopyranose spirohydantoin inhibitor (Ki = 3.0 microM) binds at the catalytic site and induces small changes in two key regions of the protein: the 280s loop (residues 281-286) that results in a decrease in mobility of this region, and the 380s loop (residues 377-385) that undergoes more significant shifts in order to optimize contact to the ligand. The hydantoin group, that is responsible for increasing the affinity of the glucose compound by a factor of 10(3), makes only one hydrogen bond to the protein, from one of its NH groups to the main chain oxygen of His377. The other polar groups of the hydantoin group form hydrogen bonds to five water molecules. These waters are involved in extensive networks of hydrogen bonds and appear to be an integral part of the protein structure. Analysis of the water structure at the catalytic site of the native enzyme, shows that five waters are displaced by ligand binding and that there is a significant decrease in mobility of the remaining waters on formation of the GPb-hydantoin complex. The ability of the inhibitor to exploit existing waters, to displace waters and to recruit new waters appears to be important for the high affinity of the inhibitor.


Speech-associated labiomandibular movement in Mandarin-speaking children with quadriplegic cerebral palsy: a kinematic study.
The purpose of this study was to investigate the speech-associated labiomandibular movement during articulation production in Mandarin-speaking children with spastic quadriplegic (SQ) cerebral palsy (CP). Twelve children with SQ CP (aged 7-11 years) and 12 age-matched healthy children as controls were enrolled for the study. All children underwent analysis of percentage of consonants correct (PCC) and kinematic analysis of speech tasks using the Vicon Motion 370 system. Kinematic parameters included utterance duration, displacement and velocity of the lip and jaw, coefficient of variation (CV) of lip utterance duration, and spatial and temporal coupling of labiomandibular movement of speech produced in mono-syllable (MS) and poly-syllable (PS) tasks. Children with CP showed lower temporal coupling (MS, p = 0.015; PS, p = 0.007), but not spatial coupling, of labiomandibular movement than healthy children. Children with CP had greater CVs (MS, p = 0.003; PS, p = 0.010) and the peak opening displacement and velocity of lower lip and jaw (p < 0.05) and lower PCC (p < 0.001) than healthy children. Children with SQ CP displayed labiomandibular coupling movement impairment, especially in the aspect of temporal coupling. These children also had high temporal oromotor variability and needed to make more effort to coordinate the labiomandibular movement for speech production.


In vitro activities of and mechanisms of resistance to antifol antimalarial drugs.
Certain drugs that interfere with folate metabolism (sulfones, sulfonamides, and inhibitors of dihydrofolate reductase) play an important role in the chemotherapy and prophylaxis of malaria. The activities and mechanisms of action of these drugs are regarded as similar in most respects to their activities against procaryotic microorganisms. Believed incapable of utilizing intact exogenous folates, plasmodia have been regarded as dependent on de novo synthesis of required folate cofactors. The present investigation, conducted in pursuit of a method for testing the in vitro susceptibility of Plasmodium falciparum to antifol antimalarial drugs, produced evidence that earlier assumptions about the folate metabolism of this organism are not correct. Three of four isolates of P. falciparum were successfully maintained in a culture medium depleted of folic acid and p-aminobenzoic acid. The antimalarial activities of sulfonamides and dihydrofolate reductase inhibitors were, furthermore, variably antagonized by the presence of folic acid and p-aminobenzoic acid in the culture medium. Optimum conditions for assessment of antifol antimalarial activity in vitro therefore require precise control of these factors in the culture medium. Our results suggest that resistance to antifol antimalarial drugs involves a complex of factors related to both the de novo synthesis of active folate cofactors and the ability to utilize exogenous intact folates in various forms.


Improved measles surveillance in Cameroon reveals two major dynamic patterns of incidence.
To characterize the province-specific incidence patterns of measles in Cameroon and determine if an increase in measles incidence during the period January 2000-June 2001 is consistent with coincident epidemics in several regions with different inter-epidemic periods. Periodic behavior of the monthly measles incidence time-series from each province of Cameroon was analyzed using time-series analysis and cluster techniques. Cumulative incidence in each province of Cameroon over a five-year period was associated with birth rates, and vaccination coverage. Distinct patterns of measles incidence were found in two different areas of Cameroon. The three northern-most provinces experience major epidemics every year. Seven southern provinces show evidence of experiencing major epidemics every third year. In January 2000, Cameroon experienced coincident peaks in these two cycles and thus an increase in measles incidence countrywide over the previous year. Higher cumulative province-specific incidence rates were associated with higher birth rates and lower routine vaccination coverage rates. Within one country, two dramatically different dynamic patterns of measles incidence were observed. Long-term surveillance data is crucial to the evaluation of measles immunization campaigns. The availability of a five-year record of measles incidence in Cameroon reveals an interesting dynamic pattern of measles incidence that accounts for the increase in countrywide incidence in 2000-2001.


Dendritic cell deficiency associated with development of BK viremia and nephropathy in renal transplant recipients.
BK virus nephropathy (BKVN) is a significant cause of renal allograft loss. Although overall intensity of immunosuppression is the greatest risk factor, recipient immune factors likely also play a role in the pathogenesis. Dendritic cells (DC) are potent antigen-presenting cells important for the induction of anti-viral cytotoxic T-cell responses. In a previous univariate analysis, we demonstrated a peripheral blood DC (PBDC) deficiency in patients with biopsy-proven BKVN, raising the possibility that reduction in DC predisposed to BK reactivation. In this study, we refined our previous analysis by comparing random posttransplant PBDC levels between an expanded group of patients with BKVN and controls without viremia using a multivariate analysis that accounted for factors known to influence PBDC levels. Next, we compared pretransplant PBDC levels between patients stratified by the presence or absence of posttransplant viremia. Finally, we assessed the predictive value of pretransplant PBDC levels for the development of posttransplant viremia. Analyses revealed a PBDC level deficiency not only posttransplant in patients with BKVN but also pretransplant in patients who subsequently developed posttransplant BK viremia. Furthermore, we identified a pretransplant PBDC level that is a reasonable predictor for the development of posttransplant viremia. Our results identify PBDC deficiency as a previously unrecognized risk factor for BKV reactivation after renal transplantation. Pretransplant PBDC monitoring may prove to be a useful clinical tool in the assessment of patient vulnerability to BKVN posttransplant, which may allow more focused screening.


Exercise in pediatric type 1 diabetes.
The beneficial effects of exercise, including reduction of cardiovascular risk, are especially important in children with type 1 diabetes (T1DM), in whom incidence of lifetime cardiovascular complications remains elevated despite good glycemic control. Being able to exercise safely is therefore a paramount concern. Dysregulated metabolism in T1DM however, causes frequent occurrence of both hypo- and hyperglycemia, the former typically associated with prolonged, moderate exercise, the latter with higher intensity, if shorter, challenges. While very few absolute contraindications to exercising exist in these children, exercise should not be started with glycemia outside the 80-250 mg/dl range. Within this glycemic range, careful adjustments in insulin administration (reduction or infusion rate via insulin pumps, or overall reduction of dosage of multiple injections) should be combined with carbohydrate ingestion before/during exercise, based on prior, individual experience with specific exercise formats. Unfamiliar exercise should always be tackled with exceeding caution, based on known responses to other exercise formats. Finally, gaining a deep understanding of other complex exercise responses, such as the modulation of inflammatory status, which is a major determinant of the cardio-protective effects of exercise, can help determine which exercise formats and which individual metabolic conditions can lead to maximally beneficial health effects.


Exosomal microRNAs in liquid biopsies: future biomarkers for prostate cancer.
Prostate cancer is the second most diagnosed cancer in males in the world. Plasma quantification of prostate-specific antigen substantially improved the early detection of prostate cancer, but still lacks the required specificity. Clinical management of prostate cancer needs advances in the development of new non-invasive biomarkers, ameliorating current diagnosis and prognosis and guiding therapeutic decisions. microRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression at the post-transcriptional level. These miRNAs are expressed in the cells and are also present in cell-derived extracellular vesicles such as exosomes. Exosomes have been shown to act as mediators for cell to cell communication because of the regulatory functions of their content. High levels of exosomes are found in several body fluids from cancer patients and could be a potential source of non-invasive biomarkers. In this review, we summarize the diagnostic and prognostic utility of exosomal miRNAs in prostate cancer.


Modafinil as a Stimulant for Military Aviators.
INTRODUCTION: Modafinil is a wakefulness-promoting stimulant that has been approved by the Republic of Singapore Air Force (RSAF) as a fatigue countermeasure medication since 2011. Each RSAF aircrew member must undergo a ground test to exclude operationally relevant adverse drug effects prior to consuming the medication for operational reasons. This study describes the RSAF's modafinil ground testing outcomes over a 7-yr period.METHODS: This is a retrospective case series of 243 RSAF aircrew members who underwent modafinil 100-mg test dosing over the 7-yr period from September 2011 to September 2018.RESULTS: The median age was 31 yr (range, 21-53 yr) and mean age was 31.7 yr ± 6.19 yr. Of the aircrew members, 234 (96.3%) were men and all were of Asian ethnicity. Of the subjects, 237 (97.5%) were medically cleared for the operational use of modafinil. Among the six (2.47%) who failed modafinil ground testing, headache (cumulative incidence, 1.65%), anxiety (cumulative incidence, 0.41%), diarrhea (cumulative incidence, 0.41%), and insomnia (cumulative incidence, 0.41%) were reported as the side effects experienced. None of the aircrew members experienced major adverse drug events.DISCUSSION: Our findings suggest a low occurrence of adverse drug effects among military aircrew members who undergo modafinil test dosing prior to using the drug operationally. To our knowledge, this is the single largest published case series of modafinil ground testing outcomes among Asian military aviators.Ooi T, Wong SH, See B. Modafinil as a stimulant for military aviators. Aerosp Med Hum Perform. 2019; 90(5):480-483.


Treatment Possibilities for Psychosis in Parkinson's Disease with An Emphasis on the Newly Approved Drug: Pimavanserin.
Parkinson's disease (PD) is a progressive neurodegenerative disorder with prominent motor and non-motor symptoms. Psychosis develops in over 40% of PD patients and it is one of the most distressing symptoms for patients and caregivers alike. Until recently, atypical antipsychotics, clozapine and quetiapine were used to treat psychotic symptoms, but treatment was associated with substantial concerns for side-effects of clozapine and unfounded efficacy for quetiapine. Extensive research has shown that the antipsychotic effect of these drugs could be attributed to serotonin 2a receptor (5-HT2A) triggered mechanisms. A selective 5-HT2A inverse agonist, pimavanserin, has been developed, investigated and has gained approval in April 2016 in the US for the treatment of hallucinations and delusions in PD. In this review we primarily focus on psychosis in PD, the current treatment possibilities and the new, emerging therapy, pimavanserin, a selective 5-HT2A inverse agonist. All articles were reviewed in this topic and indexed in PubMed with keywords: Parkinson's disease psychosis, serotonin 2a receptor inverse agonist, clozapine, quetiapine, pimavanserin.


Procalcitonin in the context of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.
Aneurysmal subarachnoid hemorrhage (aSAH) initiates a deleterious cascade activating multiple inflammatory processes, which can contribute to delayed cerebral ischemia (DCI). Procalcitonin (PCT) is an established marker for sepsis treatment monitoring, and its time course in the context of DCI after aSAH remains unclear. The aim of this trial was to assess the predictive and confirmative value of PCT levels in the context of DCI. All patients admitted to the authors' institution with aSAH between 2014 and 2018 were prospectively screened for eligibility. Daily PCT levels were recorded alongside relevant aSAH characteristics. The predictive and confirmative values of PCT levels were assessed using a receiver operating characteristic and area under the curve (AUC) analysis. The course of PCT levels around the DCI event was evaluated in an infection-free subgroup of patients. A total of 132 patients with aSAH were included. Early PCT levels (first 3 days post-aSAH) had a low predictive value for the development of DCI (AUC 0.661, standard error [SE] 0.050; p = 0.003) and unfavorable long-term outcome (i.e., Glasgow Outcome Scale-Extended scores 1-4; AUC 0.674, SE 0.054; p = 0.003). In a subgroup analysis of infection-free patients (n = 72), PCT levels were higher in patients developing DCI (p = 0.001) and DCI-related cerebral infarction (p = 0.002). PCT concentrations increased gradually after DCI and decreased with successful intervention. In refractory cases progressing to cerebral infarction, PCT levels showed a secondary increase. Early higher PCT levels were associated with the later development of DCI and unfavorable outcome. Analysis of PCT beyond the first couple of days after hemorrhage is hampered by nosocomial infections. In infection-free patients, however, PCT levels rise during DCI and an additional increase develops in patients developing cerebral infarction. Clinical trial registration no.: NCT02142166 (clinicaltrials.gov).


Continuity of care and patient outcomes after hospital discharge.
Patients are often treated in hospital by physicians other than their regular community doctor. After they are discharged, their care is often returned to their regular community doctor and patients may not see the hospital physician. Transfer of information between physicians can be poor. We determined whether early postdischarge outcomes changed when patients were seen after discharge by physicians who treated them in the hospital. This cohort study used population-based administrative databases to follow 938833 adults from Ontario, Canada, after they were discharged alive from a nonelective medical or surgical hospitalization between April 1, 1995, and March 1, 2000. We determined when patients were seen after discharge by physicians who treated them in the hospital, physicians who treated them 3 months prior to admission (community physicians), and specialists. The outcome of interest was 30-day death or nonelective readmission to hospital. Of patients studied, 7.7% died or were readmitted. The adjusted relative risk of death or readmission decreased by 5% (95% confidence interval [CI], 4% to 5%) and 3% (95% CI, 2% to 3%) with each additional visit to a hospital physician rather than a community physician or specialist, respectively. The effect of hospital physician visits was cumulative, with the adjusted risk of 30-day death or nonelective readmission reduced to 7.3%, 7.0%, and 6.7% if patients had 1, 2, or 3 visits, respectively, with a hospital rather than a community physician. The effect was consistent across important subgroups. Patient outcomes could be improved if their early postdischarge visits were with physicians who treated them in hospital rather than with other physicians. Follow-up visits with a hospital physician, rather than another physician, could be a modifiable factor to improve patient outcomes following discharge from hospital.


The importance of optical optimization in whole slide imaging (WSI) and digital pathology imaging.
In the last 10 years, whole slide imaging (WSI) has seen impressive progress not only in image quality and scanning speed but also in the variety of systems available to pathologists. However, we have noticed that most systems have relatively simple optics axes and rely on software to optimize image quality and colour balance. While much can be done in software, this study examines the importance of optics, in particular optical filters, in WSI.Optical resolution is a function of the wavelength of light used and the numerical aperture of the lens system (Resolution = (f) wavelength/2 NA). When illumining light is not conditioned correctly with filters, there is a tendency for the wavelength to shift to longer values (more red) because of the characteristics of the lamps in common use. Most microscopes (but remarkably few WSI devices) correct for this with ND filter for brightness and Blue filter (depends on the light source) for colour correction.Using H&E slides research microscopes (Axiophot, Carl Zeiss MicroImaging, Inc. NY. Eclipse 50i., Nikon Inc. NY) at 20x, an attached digital camera (SPOT RT741 Slider Color, Diagnosis Instruments., MI USA), and a filter set, we examined the effect of filters and software enhancement on digital image quality. The focus value (as evaluated by focus evaluation software developed in house and SPOT imaging Software v4.6) was used as a proxy for image quality. Resolution of tissue features was best with the use of both the Blue and ND filters (in addition to software enhancement). Images without filters but with software enhancement while superficially good, lacked some details of specimen morphology and were unclear compared with the images with filters.The results indicate that the appropriate use of optical filters could measurably improve the appearance and resolution of WSI images.


Safety and cost of stent-assisted coiling of unruptured intracranial aneurysms compared with coiling or clipping.
Stent-assisted coiling (SAC) of unruptured intracranial aneurysms is a treatment alternative to clipping or coiling, although high complication and procedure-related mortality rates have been reported. A retrospective study was conducted of patients undergoing SAC, coiling or clipping of unruptured intracranial aneurysms between 2003 and 2010. Rates of residual aneurysm, recanalization, complications, cost (adjusted to 2010), length of stay (LOS) and outcome were compared between groups. Of 116 subjects, 47 underwent SAC, 33 coiling and 36 clipping. The groups were similar in age, gender and aneurysm location, although the SAC group had significantly larger aneurysms with wider necks (p=0.001). Patients who underwent SAC had more residual aneurysm after initial treatment than those treated with coiling or clipping (75%, 52% and 19%, respectively, p<0.0001), but this difference was smaller at follow-up angiography (50%, 50% and 17% residual, respectively) and was not significant after adjusting for baseline aneurysm and neck size. SAC was not associated with increased recanalization, requirement for additional treatment, mortality or complications after adjusting for aneurysm and neck size. Patients who underwent SAC and those who underwent coiling were more likely to have a good discharge disposition than patients treated with clipping (100% vs 91%, p=0.042). LOS was significantly shorter for patients who underwent SAC or coiling compared with those treated with clipping (p<0.0001). The overall direct cost was higher for patients who underwent SAC than for those treated with coiling or clipping (median $22 544 vs $12 933 vs $14 656, p=0.001), even after adjusting for aneurysm and neck size, LOS and retreatment. SAC is a safe alternative to coiling or clipping of unruptured aneurysms but it is currently more expensive.


The structural and electronic properties of reduced amorphous titania.
Crystalline titania has been extensively studied using experimental and theoretical tools. Amorphous titania, however, has received less attention in the literature, despite its importance for a number of applications, such as photocatalysis, batteries, and electronic devices. In this work we modeled amorphous titania using a combination of molecular dynamics and density functional theory with several stoichiometries (TiOx, 2 ≥ x ≥ 1.75). Our results show that oxygen atom removal from amorphous titania is much easier than from crystalline titania, indicating that reduced amorphous structures are likely common. Ti atoms in amorphous titania exhibit a distribution of coordination numbers (five to seven), but the average coordination number of oxygen increases upon reduction. We also identified that gap states arise in substoichiometric titania due to the formation of Ti3+ centers. Such gap states are highly localized and randomly distributed across different Ti atoms, although we do observe a slight preference for electron localization on seven-coordinated Ti atoms. We observe that band gaps increase with reduction of amorphous titania. We also analyzed a proposed hole hopping mechanism involving oxygen vacancies by calculating hole hopping distances. We found that such distances are large except in very reduced states, indicating likely slow hole diffusion through an oxygen vacancy mechanism. Our work is the first of its kind to thoroughly characterize the structural and electronic properties of amorphous titania in reduced states.


Robust network topologies for generating switch-like cellular responses.
Signaling networks that convert graded stimuli into binary, all-or-none cellular responses are critical in processes ranging from cell-cycle control to lineage commitment. To exhaustively enumerate topologies that exhibit this switch-like behavior, we simulated all possible two- and three-component networks on random parameter sets, and assessed the resulting response profiles for both steepness (ultrasensitivity) and extent of memory (bistability). Simulations were used to study purely enzymatic networks, purely transcriptional networks, and hybrid enzymatic/transcriptional networks, and the topologies in each class were rank ordered by parametric robustness (i.e., the percentage of applied parameter sets exhibiting ultrasensitivity or bistability). Results reveal that the distribution of network robustness is highly skewed, with the most robust topologies clustering into a small number of motifs. Hybrid networks are the most robust in generating ultrasensitivity (up to 28%) and bistability (up to 18%); strikingly, a purely transcriptional framework is the most fragile in generating either ultrasensitive (up to 3%) or bistable (up to 1%) responses. The disparity in robustness among the network classes is due in part to zero-order ultrasensitivity, an enzyme-specific phenomenon, which repeatedly emerges as a particularly robust mechanism for generating nonlinearity and can act as a building block for switch-like responses. We also highlight experimentally studied examples of topologies enabling switching behavior, in both native and synthetic systems, that rank highly in our simulations. This unbiased approach for identifying topologies capable of a given response may be useful in discovering new natural motifs and in designing robust synthetic gene networks.


Challenges in conducting clinical trials in nephrology: conclusions from a Kidney Disease-Improving Global Outcomes (KDIGO) Controversies Conference.
Despite the high costs of treatment of people with kidney disease and associated comorbid conditions, the amount of reliable information available to guide the care of such patients is very limited. Some treatments have been assessed in randomized trials, but most such trials have been too small to detect treatment effects of a magnitude that would be realistic to achieve with a single intervention. Therefore, KDIGO convened an international, multidisciplinary controversies conference titled "Challenges in the Conduct of Clinical Trials in Nephrology" to identify the key barriers to conducting trials in patients with kidney disease. The conference began with plenary talks focusing on the key areas of discussion that included appropriate trial design (covering identification and evaluation of kidney and nonkidney disease outcomes) and sensible trial execution (with particular emphasis on streamlining both design and conduct). Break out group discussions followed in which the key areas of agreement and remaining controversy were identified. Here we summarize the main findings from the conference and set out a range of potential solutions. If followed, these solutions could ensure future trials among people with kidney disease are sufficiently robust to provide reliable answers and are not constrained by inappropriate complexities in design or conduct.


Attenuation of cisplatin nephrotoxicity by inhibition of soluble epoxide hydrolase.
Cisplatin is a highly effective chemotherapeutic agent against many tumors; however, it is also a potent nephrotoxicant. Given that there have been no significant advances in our ability to clinically manage acute renal failure since the advent of dialysis, the development of novel strategies to ablate nephrotoxicity would represent a significant development. In this study, we investigated the ability of an inhibitor of soluble epoxide hydrolase (sEH), n-butyl ester of 12-(3-adamantan-1-yl-ureiido)-dodecanoic acid (nbAUDA), to attenuate cisplatin-induced nephrotoxicity. nbAUDA is quickly converted to AUDA and results in maintenance of high AUDA levels in vivo. Subcutaneous administration of 40 mg/kg of nbAUDA to C3H mice every 24 h resulted in elevated blood levels of AUDA; this protocol was also associated with attenuation of nephrotoxicity induced by cisplatin (intraperitoneal injection) as assessed by BUN levels and histological evaluation of kidneys. This is the first report of the use of sEH inhibitors to protect against acute nephrotoxicity and suggests a therapeutic potential of these compounds.


The spliceosomal autoantigen heterogeneous nuclear ribonucleoprotein A2 (hnRNP-A2) is a major T cell autoantigen in patients with systemic lupus erythematosus.
A hallmark of systemic lupus erythematosus (SLE) is the appearance of autoantibodies to nuclear antigens, including autoantibodies directed to the heterogeneous nuclear ribonucleoprotein A2 (hnRNP-A2), which occur in 20% to 30% of SLE patients as well as in animal models of this disease. To investigate the underlying cellular reactivity and to gain further insight into the nature and potential pathogenic role of this autoimmune response we characterized the T cell reactivity against hnRNP-A2 in patients with SLE in comparison to healthy controls. Cellular proliferation of peripheral blood T cells to hnRNP-A2 was determined by [3H]thymidine incorporation and T cell clones (TCCs) specific for hnRNP-A2 were grown by limiting dilution cloning; IFNgamma, IL-4 and IL-10 in culture supernatants were measured by ELISA. Bioactivity of culture supernatants was determined by incubation of anti-CD3/anti-CD28 stimulated peripheral blood CD4+ T cells with supernatants of TCCs. Stimulation assays performed with peripheral blood mononuclear cells of 35 SLE patients and 21 healthy controls revealed pronounced proliferative responses in 66% of SLE patients and in 24% of the controls, which were significantly higher in SLE patients (p < 0.00002). Furthermore, hnRNP-A2 specific TCCs generated from SLE patients (n = 22) contained a relatively high proportion of CD8+ clones and mostly lacked CD28 expression, in contrast to TCCs derived from healthy controls (n = 12). All CD4+ TCCs of patients and all control TCCs secreted IFNgamma and no IL-4. In contrast, CD8+ TCCs of patients secreted very little IFNgamma, while production of IL-10 did not significantly differ from other T cell subsets. Interestingly, all CD8+ clones producing IL-10 in large excess over IFNgamma lacked expression of CD28. Functional assays showed a stimulatory effect of the supernatants derived from these CD8+ CD28- hnRNP-A2 specific TCCs that was similar to that of CD4+ CD28+ clones. Taken together, the pronounced peripheral T cell reactivity to hnRNP-A2 observed in the majority of SLE patients and the distinct phenotype of patient-derived CD8+ TCCs suggest a role for these T cells in the pathogenesis of SLE.


Decision landscapes: visualizing mouse-tracking data.
Computerized paradigms have enabled gathering rich data on human behaviour, including information on motor execution of a decision, e.g. by tracking mouse cursor trajectories. These trajectories can reveal novel information about ongoing decision processes. As the number and complexity of mouse-tracking studies increase, more sophisticated methods are needed to analyse the decision trajectories. Here, we present a new computational approach to generating decision landscape visualizations based on mouse-tracking data. A decision landscape is an analogue of an energy potential field mathematically derived from the velocity of mouse movement during a decision. Visualized as a three-dimensional surface, it provides a comprehensive overview of decision dynamics. Employing the dynamical systems theory framework, we develop a new method for generating decision landscapes based on arbitrary number of trajectories. This approach not only generates three-dimensional illustration of decision landscapes, but also describes mouse trajectories by a number of interpretable parameters. These parameters characterize dynamics of decisions in more detail compared with conventional measures, and can be compared across experimental conditions, and even across individuals. The decision landscape visualization approach is a novel tool for analysing mouse trajectories during decision execution, which can provide new insights into individual differences in the dynamics of decision making.


First Report of the Natural Infection of Robinia pseudoacacia with Alfalfa mosaic virus.
Robinia pseudoacacia L. (family Fabaceae), commonly known as black locust, is native to the southeastern United States, but has been widely planted and naturalized in temperate regions worldwide. In Europe it is often planted alongside streets and in parks, not only because of the dense canopy and impressive flower clusters in spring, but also because it tolerates air pollution well. In June 2012, several black locust trees exhibiting yellow leaf spots accompanied by mottling and leaf deformation were observed in a park in Backa Topola, North Backa District, Serbia. Numerous aphid colonies were found colonizing symptomatic trees. Leaves collected from nine symptomatic and 10 asymptomatic trees were tested for the presence of three common aphid-transmitted viruses, Alfalfa mosaic virus (AMV), Cucumber mosaic virus, and Potato virus Y, using double-antibody sandwich (DAS)-ELISA with commercial polyclonal antibody (Bioreba AG, Reinach, Switzerland). Commercial positive and negative controls and extracts from healthy black locust leaves were included in each assay. AMV was serologically detected in all symptomatic and also in four of the asymptomatic trees, while no other tested viruses were found. Sap from affected leaves of a ELISA-positive sample (373-12) was mechanically inoculated onto five plants each of Chenopodium quinoa and Nicotiana benthamiana using 0.01 M phosphate buffer (pH 7). Symptoms including local chlorotic leaf lesions followed by mosaic on C. quinoa and a bright yellow mosaic on N. benthamiana were observed on all inoculated plants 5 and 10 days post-inoculation, respectively. The identity of the virus was confirmed using reverse transcription (RT)-PCR analysis. Total RNAs from all naturally and mechanically infected plants were isolated using RNeasy Plant Mini Kit (Qiagen, Hilden, Germany). RT-PCR was carried out using the One-Step RT-PCR Kit (Qiagen) with primer pair CP AMV1 and CP AMV2 specific to the partial CP gene and 3'-UTR of AMV RNA 3 (1). Total RNAs from Serbian AMV isolate from alfalfa (GenBank Accession No. FJ527748) and RNA extract from healthy leaves of R. pseudoacacia were used as positive and negative controls, respectively. All tested plants, as well as the positive control, yielded an amplicon of the correct predicted size (751 bp), while no amplicon was recorded in the healthy control. The amplified product of isolate 373-12 was purified with QIAquick PCR Purification Kit (Qiagen) and sequenced on ABI PRISM 3700 DNA analyzer (Macrogen, South Korea) in both directions (KC288155). Pairwise comparison of the 373-12 isolate CP sequence with those available in GenBank, conducted with MEGA5 software (4), revealed the maximum nucleotide identity of 99% (99% amino acid identity) with the soybean isolate (HQ185569) from Tennessee. AMV has a worldwide distribution and its natural host range includes over 150 plant species, including many herbaceous and several woody plants (2). To our knowledge, this is the first report of R. pseudoacacia as a natural host of AMV worldwide. This finding has potentially significant implications for the successful production of susceptible crops, considering that black locust could act as an important link in the epidemiology of AMV as it may serve as a virus reservoir (3). References: (1) M. M. Finetti-Sialer et al. J. Plant Pathol. 79:115, 1997. (2) R. Hull. Comparative Plant Virology. 2nd ed. Elsevier Academic Press, Burlington, MA, 2009. (3) E. E. Muller et al. Plant Dis. 96:506, 2012. (4) K. Tamura et al. Mol. Biol. Evol. 28:2731, 2011.


Design control for clinical translation of 3D printed modular scaffolds.
The primary thrust of tissue engineering is the clinical translation of scaffolds and/or biologics to reconstruct tissue defects. Despite this thrust, clinical translation of tissue engineering therapies from academic research has been minimal in the 27 year history of tissue engineering. Academic research by its nature focuses on, and rewards, initial discovery of new phenomena and technologies in the basic research model, with a view towards generality. Translation, however, by its nature must be directed at specific clinical targets, also denoted as indications, with associated regulatory requirements. These regulatory requirements, especially design control, require that the clinical indication be precisely defined a priori, unlike most academic basic tissue engineering research where the research target is typically open-ended, and furthermore requires that the tissue engineering therapy be constructed according to design inputs that ensure it treats or mitigates the clinical indication. Finally, regulatory approval dictates that the constructed system be verified, i.e., proven that it meets the design inputs, and validated, i.e., that by meeting the design inputs the therapy will address the clinical indication. Satisfying design control requires (1) a system of integrated technologies (scaffolds, materials, biologics), ideally based on a fundamental platform, as compared to focus on a single technology, (2) testing of design hypotheses to validate system performance as opposed to mechanistic hypotheses of natural phenomena, and (3) sequential testing using in vitro, in vivo, large preclinical and eventually clinical tests against competing therapies, as compared to single experiments to test new technologies or test mechanistic hypotheses. Our goal in this paper is to illustrate how design control may be implemented in academic translation of scaffold based tissue engineering therapies. Specifically, we propose to (1) demonstrate a modular platform approach founded on 3D printing for developing tissue engineering therapies and (2) illustrate the design control process for modular implementation of two scaffold based tissue engineering therapies: airway reconstruction and bone tissue engineering based spine fusion.


Design of in vitro Transcribed mRNA Vectors for Research and Therapy.
The use of in vitro transcribed messenger RNA (ivt mRNA) for vaccination, gene therapy and cell reprograming has become increasingly popular in research and medicine. This method can be used in vitro (transfected in cells) or administered naked or formulated (lipoplexes, polyplexes, and lipopolyplexes that deliver the RNA to specific organs, such as immune structures, the lung or liver) and is designed to be an immunostimulatory or immunosilent agent. This vector contains several functional regions (Cap, 5' untranslated region, open reading frame, 3' untranslated region and poly-A tail) that can all be optimised to generate a highly efficacious ivt mRNA. In this study, we review these aspects and report on the effect of the ivt mRNA purification method on the functionality of this synthetic transient genetic vector.


Actions of nizatidine on the rat uterus, dog stomach and experimentally induced gastric lesions.
Nizatidine is a potent and selective antagonist of histamine. The histamine-induced relaxation of the KCl-treated rat uterus was inhibited dose-dependently by nizatidine. The inhibition was characterized by displacement of the dose-response to histamine to the right, in parallel, without depression of the maximum. The affinity of nizatidine for the histamine H2-receptor of the rat uterus was about 10 times that of cimetidine. The steady-state dose-response acid outputs stimulated by histamine from the Heidenhain pouch and the gastric fistula were also shifted dose-dependently by nizatidine, in parallel, to the right. The inhibition was consistent with a surmountable antagonism of histamine. At high (10(-4) to 10(-3) M) concentrations, nizatidine increased the motility of the guinea pig stomach and duodenum in vitro; this effect was abolished noncompetitively by atropine (10(-8) M) and pyrilamine (10(-4) M). Both nizatidine and cimetidine administered s.c. showed "cytoprotective" action by reducing the gastric lesions induced by 1) aminoguinidine and pylorus ligation and 2) HCl plus aspirin in the rat. On a weight and molar basis, nizatidine was 4 and 5.25 times as effective as cimetidine, respectively. This cytoprotective action of nizatidine was found when acidity and total acid load in the stomach were not affected by the histamine H2-receptor antagonist.


MALDI mass spectrometry imaging analysis of pituitary adenomas for near-real-time tumor delineation.
We present a proof of concept study designed to support the clinical development of mass spectrometry imaging (MSI) for the detection of pituitary tumors during surgery. We analyzed by matrix-assisted laser desorption/ionization (MALDI) MSI six nonpathological (NP) human pituitary glands and 45 hormone secreting and nonsecreting (NS) human pituitary adenomas. We show that the distribution of pituitary hormones such as prolactin (PRL), growth hormone (GH), adrenocorticotropic hormone (ACTH), and thyroid stimulating hormone (TSH) in both normal and tumor tissues can be assessed by using this approach. The presence of most of the pituitary hormones was confirmed by using MS/MS and pseudo-MS/MS methods, and subtyping of pituitary adenomas was performed by using principal component analysis (PCA) and support vector machine (SVM). Our proof of concept study demonstrates that MALDI MSI could be used to directly detect excessive hormonal production from functional pituitary adenomas and generally classify pituitary adenomas by using statistical and machine learning analyses. The tissue characterization can be completed in fewer than 30 min and could therefore be applied for the near-real-time detection and delineation of pituitary tumors for intraoperative surgical decision-making.


Neighbourhood socioeconomic inequality and gender differences in body mass index: The role of unhealthy behaviours.
Reported differences in the severity of the social gradient in body mass index (BMI) by gender may be attributable to differences in behaviour. Self-reported height, weight, socioeconomic and behavioural data were obtained for a sample of 10,281 Australians aged ≥15years in 2009. Multilevel regressions were fitted with BMI as the outcome variable. Two-way interactions between gender and neighbourhood disadvantage were fitted, adjusted for confounders. Models were then adjusted for four behavioural factors ("chips, snacks and confectionary", "smoking, little fruit or veg", "time poor and less physically active" and "alcohol consumption"). Additional models were fitted on a subset with accurate perceptions of weight status (determined by World Health Organization criteria) to control for potential social desirability bias. Although higher BMI was observed for men in most disadvantaged compared with most affluent neighbourhoods (coefficient 0.87, 95% CI 0.35 to 1.40), this pattern was stronger among women (1.80, 95% CI 1.17 to 2.42). Adjusting for differences in behaviours attenuated, but did not fully explain the differences in social gradients observed for men (0.73, 95% CI 0.21 to 1.26) and women (1.73, 1.10 to 2.36). Differences in behaviour did not explain contrasting socioeconomic gradients in adult BMI by gender. Further research on differences in BMI, health and behaviour over time aligned with how heavy a person may perceive themselves to be is warranted.