Acute Aortic Dissection Following Treatment for Castration-Resistant Prostate Cancer.
A 65-year-old man presents to the emergency department with increasing back pain. His history includes hypertension, peripheral neuropathy, duodenal ulcer, superior mesenteric vein thrombus, stage IIB colon cancer treated with surgery and adjuvant chemotherapy, renal cell carcinoma treated with surgery, and prostate cancer treated with surgery and radiation. He is otherwise healthy. His family history is positive for colon cancer. Physical examination found significantly elevated blood pressure and a computed tomography scan of the thoracic and lumbar spine was performed, with findings of a type B aortic dissection extending from the aberrant right subclavian artery down to the abdominal aorta. .


BDNF contributes to IBS-like colonic hypersensitivity via activating the enteroglia-nerve unit.
The over-expressed colonic brain-derived neurotrophic factor (BDNF) has been reported to be associated with abdominal pain in patients with irritable bowel syndrome (IBS). However, the neuropathological mechanism is unclear. We here investigated the involvement of enteroglial cells (EGCs) and enteric nerves in IBS-like visceral hypersensitivity. We showed that glial fibrillary acidic protein (GFAP), tyrosine receptor kinase B (TrkB) and substance P (SP) were significantly increased in the colonic mucosa of IBS patients. The upregulation of those proteins was also observed in the colon of mice with visceral hypersensitivity, but not in the colon of BDNF(+/-) mice. Functionally, TrkB or EGC inhibitors, or BDNF knockdown significantly suppressed visceral hypersensitivity in mice. Using the EGC cell line, we found that recombinant human BDNF (r-HuBDNF) could directly activate EGCs via the TrkB-phospholipase Cγ1 pathway, thereby inducing a significant upregulation of SP. Moreover, supernatants from r-HuBDNF-activated EGC culture medium, rather than r-HuBDNF alone, triggered markedly augmented discharges in isolated intestinal mesenteric afferent nerves. r-HuBDNF alone could cause mesenteric afferent mechanical hypersensitivity independently, and this effect was synergistically enhanced by activated EGCs. We conclude that EGC-enteric nerve unit may be involved in IBS-like visceral hypersensitivity, and this process is likely initiated by BDNF-TrkB pathway activation.


The Thai-Burmese border: drug studies of Plasmodium falciparum in pregnancy.
Plasmodium falciparum malaria is increasing world-wide, as is resistance to the available antimalarials. On the Thai-Burmese border this problem is most acute in pregnant women, as options for their treatment are even more restricted because of the unknown effects of antimalarials on the foetus. Presented here are the results of descriptive, clinical, drug studies on quinine, mefloquine and artemisinin derivatives for P. falciparum in pregnant women. Mefloquine and quinine have high failure rates for primary and recrudescent infections. Artemisinin-based treatments in pregnant women have proved safe, tolerable and efficacious. However, randomized drug studies with these drugs and other new antimalarials are required to define the true safety and efficacy of these drugs in pregnant women.


Height-diameter allometry and above ground biomass in tropical montane forests: Insights from the Albertine Rift in Africa.
Tropical montane forests provide an important natural laboratory to test ecological theory. While it is well-known that some aspects of forest structure change with altitude, little is known on the effects of altitude on above ground biomass (AGB), particularly with regard to changing height-diameter allometry. To address this we investigate (1) the effects of altitude on height-diameter allometry, (2) how different height-diameter allometric models affect above ground biomass estimates; and (3) how other forest structural, taxonomic and environmental attributes affect above ground biomass using 30 permanent sample plots (1-ha; all trees ≥ 10 cm diameter measured) established between 1250 and 2600 m asl in Kahuzi Biega National Park in eastern Democratic Republic of Congo. Forest structure and species composition differed with increasing altitude, with four forest types identified. Different height-diameter allometric models performed better with the different forest types, as trees got smaller with increasing altitude. Above ground biomass ranged from 168 to 290 Mg ha-1, but there were no significant differences in AGB between forests types, as tree size decreased but stem density increased with increasing altitude. Forest structure had greater effects on above ground biomass than forest diversity. Soil attributes (K and acidity, pH) also significantly affected above ground biomass. Results show how forest structural, taxonomic and environmental attributes affect above ground biomass in African tropical montane forests. They particularly highlight that the use of regional height-diameter models introduces significant biases in above ground biomass estimates, and that different height-diameter models might be preferred for different forest types, and these should be considered in future studies.


Radicals Generated in Tetramolecular Guanine Quadruplexes by Photoionization: Spectral and Dynamical Features.
G-quadruplexes are four-stranded DNA structures playing a key role in many biological functions and are promising for applications in the field of nanoelectronics. Characterizing the generation and fate of radical cations (electron holes) within these systems is important in relation to the DNA oxidative damage and/or conductivity issues. This study focuses on guanine radicals in G-quadruplexes formed by association of four TGGGGT strands in the presence of Na+ cations, (TG4T)4/Na+. Using nanosecond transient spectroscopy with 266 nm excitation, we quantitatively characterize hydrated ejected electrons and three types of guanine radicals. We show that, at an energy lower by 2.7 eV than the guanine ionization potential, one-photon ionization occurs with quantum yield of (3.5 ± 0.5) × 10-3. Deprotonation of the radical cations is completed within 20 μs, leading to the formation of (G-H2)• radicals, following a strongly nonexponential decay pattern. Within 10 ms, the latter undergoes tautomerization to deprotonated (G-H1)• radicals. The dynamics of the various radicals determined for (TG4T)4/Na+, in connection to those reported previously for telomeric G-quadruplexes TEL21/Na+, is correlated with energetic factors computed by quantum chemical methods. The faster deprotonation of radical cations in (TG4T)4/Na+ compared to TEL21/Na+ explains that irradiation of the former does not generate 8-oxodGuo, which is readily detected by high-performance liquid chromatography/mass spectrometry in the case of TEL21/Na+.


The Role of the Immune Response in the Pathogenesis of Thyroid Eye Disease: A Reassessment.
Although thyroid eye disease is a common complication of Graves' disease, the pathogenesis of the orbital disease is poorly understood. Most authorities implicate the immune response as an important causal factor. We sought to clarify pathogenesis by using gene expression microarray. An international consortium of ocular pathologists and orbital surgeons contributed formalin fixed orbital biopsies. RNA was extracted from orbital tissue from 20 healthy controls, 25 patients with thyroid eye disease (TED), 25 patients with nonspecific orbital inflammation (NSOI), 7 patients with sarcoidosis and 6 patients with granulomatosis with polyangiitis (GPA). Tissue was divided into a discovery set and a validation set. Gene expression was quantified using Affymetrix U133 Plus 2.0 microarrays which include 54,000 probe sets. Principal component analysis showed that gene expression from tissue from patients with TED more closely resembled gene expression from healthy control tissue in comparison to gene expression characteristic of sarcoidosis, NSOI, or granulomatosis with polyangiitis. Unsupervised cluster dendrograms further indicated the similarity between TED and healthy controls. Heat maps based on gene expression for cytokines, chemokines, or their receptors showed that these inflammatory markers were associated with NSOI, sarcoidosis, or GPA much more frequently than with TED. This is the first study to compare gene expression in TED to gene expression associated with other causes of exophthalmos. The juxtaposition shows that inflammatory markers are far less characteristic of TED relative to other orbital inflammatory diseases.


[Pregnancy during dialysis: experience in six patients].
The frequency of pregnancies during dialysis is increasing. This condition requires changes in the dialysis schedule and nutritional approach. To report the experience in six patients with terminal kidney disease who became pregnant. Retrospective review of medical records of women with terminal kidney disease in dialysis who became pregnant in a period of 27 years. We recorded six successful pregnancies among women in hemodialysis treatment aged 32 ± 4 years. The mean dialysis-time per week was 19.5 ± 2.7 hours and Kt/V was 1.55 ± 0.17. The mean systolic blood pressure was 130 ± 13.3 mmHg. The mean packed cell volume of the group increased from 22.7% during pre-gestational stage to 30.2% during third trimester of pregnancy. All patients received an intensive treatment for anemia. The most common symptom of pregnancy was hyperemesis. The mean gestational age (GA) at diagnosis was 13.4 ± 4.7 weeks. All patients had preterm deliveries at a GA of 33 ± 1.7 weeks, and 66% of offspring were appropriate for gestational age. A multidisciplinary approach allows high rate of successful pregnancies during hemodialysis.


An evaluation of a therapeutic garden's influence on the quality of life of aged care residents with dementia.
To evaluate whether a therapeutic garden can improve the quality of life of aged care residents with dementia and their carers, objective instruments as well as interviews with residents, staff, and family members were employed. Residents' mean quality of life scores increased by just over 10%, mean depression scores decreased similarly and mean agitation scores decreased by almost half. Resident, staff and family member interviews elicited positive feedback including observations that it had improved the quality of life for residents and decreased staff and family stress levels. In sum, qualitative and quantitative pre and post findings indicate that an environmental change such as a therapeutic garden can improve the lives of aged care residents with dementia, and their formal and informal carers.


Comparison of denitrification performances using PLA/starch with different mass ratios as carbon source.
A suitable carbon source is significant for biological nitrate removal from groundwater. In this study, slow-release carbon sources containing polylactic acid (PLA) and starch at 8:2, 7:3, 6:4, 5:5, 4:6, and 3:7 ratios were prepared using a blending and fusing technique. The PLA/starch blend was then used as a solid carbon source for biological nitrate removal. The carbon release rate of PLA/starch was found to increase with increased starch content in leaching experiments. PLA/starch at 5:5 mass ratio was found to have the highest denitrification performance and organic carbon consumption efficiency in semi-continuous denitrification experiments, and was also revealed to support complete denitrification at 50 mg-N/L influent nitrate concentration in continuous experiments. The effluent nitrate concentration was <2 mg NO(3)(-)-N/L, which met the national standard (GB 14848-93) for groundwater. Scanning electron microscopy results further showed that the surface roughness of PLA/starch increased with prolonged experimental time, which may be conducive to microorganism attachment. Therefore, PLA/starch was a suitable carbon source and biofilm carrier for groundwater remediation.


A cross-sectional study to assess the intelligence quotient (IQ) of school going children aged 10-12 years in villages of Mysore district, India with different fluoride levels.
Besides dental and skeletal fluorosis, excessive fluoride intake can also affect the central nervous system without first causing the physical deformities associated with skeletal fluorosis. With the existence of widespread endemic fluorosis in India, the possible adverse effect of elevated fluoride in drinking water on the Intelligence Quotient (IQ) level of children is a potentially serious public health problem. This study assessed the Intelligence Quotient (IQ) of school going children aged 10-12 years in villages of Mysore district with different fluoride levels. In this cross-sectional study, 405 school children aged 10-12 years were selected from three villages in Mysore district with normal fluoride (1.20 mg F/l), low fluoride (0.40 mg F/l) and high fluoride (2.20 mg F/l) in their water supplies. A pre designed questionnaire was used to collect the required data for the survey which included socio demographic details, oral hygiene practices, diet history, body mass index and dental fluorosis. Intelligence Quotient was assessed using Raven's colored Progressive Matrices Test. In bivariate analysis, significant relationships were found between water fluoride levels and Intelligence Quotient of school children (P < 0.05). In the high fluoride village, the proportion of children with IQ below 90, i.e. below average IQ was larger compared to normal and low fluoride village. Age, gender, parent education level and family income had no significant association with IQ. School children residing in area with higher than normal water fluoride level demonstrated more impaired development of intelligence when compared to school children residing in areas with normal and low water fluoride levels. Thus, children's intelligence can be affected by high water fluoride levels.


Discovery and Preclinical Development of Netarsudil, a Novel Ocular Hypotensive Agent for the Treatment of Glaucoma.
Rho-associated protein kinase (ROCK) inhibitors lower intraocular pressure (IOP) by increasing aqueous outflow through the trabecular meshwork (TM). The preclinical characterization of netarsudil, a new ROCK/norepinephrine transporter (NET) inhibitor currently in clinical development, is presented herein. The kinase inhibitory activity of netarsudil was compared to its esterase metabolite, netarsudil-M1, and 3 other ROCK inhibitors using a commercially available kinase assay kit. Disruption of actin stress fibers was measured in primary porcine TM cells and disruption of focal adhesions in transformed human TM (HTM) cells. Induction of fibrosis markers after exposure to transforming growth factor-β2 (TGF-β2) was conducted in primary HTM cells. Ocular hypotensive activity and tolerability of topical formulations were evaluated in normotensive Dutch Belted rabbits and Formosan Rock monkeys. In vitro corneal metabolism assays were conducted using dog, pig, rabbit, monkey, and human corneas. In vivo ocular pharmacokinetics was studied in Dutch Belted rabbits. Netarsudil inhibited kinases ROCK1 and ROCK2 with a Ki of 1 nM each, disrupted actin stress fibers and focal adhesions in TM cells with IC50s of 79 and 16 nM, respectively, and blocked the profibrotic effects of TGF-β2 in HTM cells. Netarsudil produced large reductions in IOP in rabbits and monkeys that were sustained for at least 24 h after once daily dosing, with transient, mild hyperemia observed as the only adverse effect. Netarsudil is a novel ROCK/NET inhibitor with high potency in biochemical and cell-based assays, an ability to produce large and durable IOP reductions in animal models, and favorable pharmacokinetic and ocular tolerability profiles.


The Survey of the Health of Wisconsin (SHOW), a novel infrastructure for population health research: rationale and methods.
Evidence-based public health requires the existence of reliable information systems for priority setting and evaluation of interventions. Existing data systems in the United States are either too crude (e.g., vital statistics), rely on administrative data (e.g., Medicare) or, because of their national scope (e.g., NHANES), lack the discriminatory power to assess specific needs and to evaluate community health activities at the state and local level. This manuscript describes the rationale and methods of the Survey of the Health of Wisconsin (SHOW), a novel infrastructure for population health research. The program consists of a series of independent annual surveys gathering health-related data on representative samples of state residents and communities. Two-stage cluster sampling is used to select households and recruit approximately 800-1,000 adult participants (21-74 years old) each year. Recruitment and initial interviews are done at the household; additional interviews and physical exams are conducted at permanent or mobile examination centers. Individual survey data include physical, mental, and oral health history, health literacy, demographics, behavioral, lifestyle, occupational, and household characteristics as well as health care access and utilization. The physical exam includes blood pressure, anthropometry, bioimpedance, spirometry, urine collection and blood draws. Serum, plasma, and buffy coats (for DNA extraction) are stored in a biorepository for future studies. Every household is geocoded for linkage with existing contextual data including community level measures of the social and physical environment; local neighborhood characteristics are also recorded using an audit tool. Participants are re-contacted bi-annually by phone for health history updates. SHOW generates data to assess health disparities across state communities as well as trends on prevalence of health outcomes and determinants. SHOW also serves as a platform for ancillary epidemiologic studies and for studies to evaluate the effect of community-specific interventions. It addresses key gaps in our current data resources and increases capacity for etiologic, applied and translational population health research. It is hoped that this program will serve as a model to better support evidence-based public health, facilitate intervention evaluation research, and ultimately help improve health throughout the state and nation.


Long Noncoding RNA MALAT1 and Regulation of the Antioxidant Defense System in Diabetic Retinopathy.
The retina experiences increased oxidative stress in diabetes, and the transcriptional activity of Nrf2, which is critical in regulating many antioxidant genes, is decreased. The nuclear movement/transcriptional activity of Nrf2 is mediated by its intracellular inhibitor Keap1, and retinal Keap1 levels are increased in diabetes. Gene expression is also regulated by long noncoding RNAs (LncRNAs). Our aim was to investigate the role of LncRNA MALAT1 in the regulation of Keap1-Nrf2-antioxidant defense in diabetic retinopathy. LncRNA MALAT1 expression (quantitative real-time PCR, immunofluorescence, and RNA sequencing), its interactions with Keap1 (FACS), Keap1-Nrf2 interactions, and transcription of the antioxidant response genes (immunofluorescence and nuclear RNA sequencing) were investigated in retinal endothelial cells exposed to high glucose. Glucose increased LncRNA MALAT1 levels by increasing Sp1 transcription factor binding at its promoter. Downregulation of LncRNA MALAT1 by its siRNA prevented glucose-induced increase in Keap1 and facilitated Nrf2 nuclear translocation and antioxidant gene transcription. Retinal microvessels from streptozotocin-induced diabetic mice and human donors with diabetic retinopathy also presented similar increases in LncRNA MALAT1 and its interactions with Keap1 and decreases in Nrf2-mediated antioxidant defense genes. Thus, LncRNA MALAT1, via Keap1-Nrf2, regulates antioxidant defense in diabetic retinopathy. Inhibition of LncRNA MALAT1 has potential to protect the retina from oxidative damage and to prevent or slow down diabetic retinopathy.


Self-organized formation of a Blazed-grating-like structure on Si(100) induced by focused ion-beam.
A new one-step method, which has been named self-organized formation, for microfabrication of blazed-grating-like structures after bombardment with a focused ion beam (FIB) with an ion energy of 50 keV and a beam current of 0.5 nA is presented. The structure is fabricated by the FIB by raster scanning (not by patterned scanning) upon a substrate of a silicon wafer, Si(100), with total scanning time of 14 min. With this method the parameters are unchanged during the whole process, unlike for the point-by-point direct writing technique, in which the exposure intensity or the electron- or ion-beam dose is changed for each point. The surface roughness of the structure, Ra, is 2.5 nm over an area of 1 mum X 1 mum. To evaluate the performance of this method we carried out a simulation, using the PCGrate program. The simulated diffraction efficiency, of diffraction order -3 working in the reflection mode, can be as much as 79.1% for the violet wavelength of 400 nm. Using a He-Ne laser as the light source produced a measured diffraction efficiency of the order of -2 of 70.4%, which is near the simulated value of 76.9% at a wavelength of 600 nm. The depth and the period of the structure can be controlled by process parameters of the FIB, such as ion energy and ion flux.


Trends in Micropollutant Biotransformation along a Solids Retention Time Gradient.
For many polar organic micropollutants, biotransformation by activated sludge microorganisms is a major removal process during wastewater treatment. However, our current understanding of how wastewater treatment operations influence microbial communities and their micropollutant biotransformation potential is limited, leaving major parts of observed variability in biotransformation rates across treatment facilities unexplained. Here, we present biotransformation rate constants for 42 micropollutants belonging to different chemical classes along a gradient of solids retention time (SRT). The geometric mean of biomass-normalized first-order rate constants shows a clear increase between 3 and 15 d SRT by 160% and 87%, respectively, in two experiments. However, individual micropollutants show a variety of trends. Rate constants of oxidative biotransformation reactions mostly increased with SRT. Yet, nitrifying activity could be excluded as primary driver. For substances undergoing other than oxidative reactions, i.e., mostly substitution-type reactions, more diverse dependencies on SRT were observed. Most remarkably, characteristic trends were observed for groups of substances undergoing similar types of initial transformation reaction, suggesting that shared enzymes or enzyme systems that are conjointly regulated catalyze biotransformation reactions within such groups. These findings open up opportunities for correlating rate constants with measures of enzyme abundance such as genes or gene products, which in turn should help to identify enzymes associated with the respective biotransformation reactions.


Influence of smoking cessation after diagnosis of early stage lung cancer on prognosis: systematic review of observational studies with meta-analysis.
To systematically review the evidence that smoking cessation after diagnosis of a primary lung tumour affects prognosis. Systematic review with meta-analysis. CINAHL (from 1981), Embase (from 1980), Medline (from 1966), Web of Science (from 1966), CENTRAL (from 1977) to December 2008, and reference lists of included studies. Randomised controlled trials or observational longitudinal studies that measured the effect of quitting smoking after diagnosis of lung cancer on prognostic outcomes, regardless of stage at presentation or tumour histology, were included. Two researchers independently identified studies for inclusion and extracted data. Estimates were combined by using a random effects model, and the I(2) statistic was used to examine heterogeneity. Life tables were used to model five year survival for early stage non-small cell lung cancer and limited stage small cell lung cancer, using death rates for continuing smokers and quitters obtained from this review. In 9/10 included studies, most patients studied were diagnosed as having an early stage lung tumour. Continued smoking was associated with a significantly increased risk of all cause mortality (hazard ratio 2.94, 95% confidence interval 1.15 to 7.54) and recurrence (1.86, 1.01 to 3.41) in early stage non-small cell lung cancer and of all cause mortality (1.86, 1.33 to 2.59), development of a second primary tumour (4.31, 1.09 to 16.98), and recurrence (1.26, 1.06 to 1.50) in limited stage small cell lung cancer. No study contained data on the effect of quitting smoking on cancer specific mortality or on development of a second primary tumour in non-small cell lung cancer. Life table modelling on the basis of these data estimated 33% five year survival in 65 year old patients with early stage non-small cell lung cancer who continued to smoke compared with 70% in those who quit smoking. In limited stage small cell lung cancer, an estimated 29% of continuing smokers would survive for five years compared with 63% of quitters on the basis of the data from this review. This review provides preliminary evidence that smoking cessation after diagnosis of early stage lung cancer improves prognostic outcomes. From life table modelling, the estimated number of deaths prevented is larger than would be expected from reduction of cardiorespiratory deaths after smoking cessation, so most of the mortality gain is likely to be due to reduced cancer progression. These findings indicate that offering smoking cessation treatment to patients presenting with early stage lung cancer may be beneficial.


Nebulised heparin as a treatment for COVID-19: scientific rationale and a call for randomised evidence.
Nebulised unfractionated heparin (UFH) has a strong scientific and biological rationale and warrants urgent investigation of its therapeutic potential, for COVID-19-induced acute respiratory distress syndrome (ARDS). COVID-19 ARDS displays the typical features of diffuse alveolar damage with extensive pulmonary coagulation activation resulting in fibrin deposition in the microvasculature and formation of hyaline membranes in the air sacs. Patients infected with SARS-CoV-2 who manifest severe disease have high levels of inflammatory cytokines in plasma and bronchoalveolar lavage fluid and significant coagulopathy. There is a strong association between the extent of the coagulopathy and poor clinical outcomes.The anti-coagulant actions of nebulised UFH limit fibrin deposition and microvascular thrombosis. Trials in patients with acute lung injury and related conditions found inhaled UFH reduced pulmonary dead space, coagulation activation, microvascular thrombosis and clinical deterioration, resulting in increased time free of ventilatory support. In addition, UFH has anti-inflammatory, mucolytic and anti-viral properties and, specifically, has been shown to inactivate the SARS-CoV-2 virus and prevent its entry into mammalian cells, thereby inhibiting pulmonary infection by SARS-CoV-2. Furthermore, clinical studies have shown that inhaled UFH safely improves outcomes in other inflammatory respiratory diseases and also acts as an effective mucolytic in sputum-producing respiratory patients. UFH is widely available and inexpensive, which may make this treatment also accessible for low- and middle-income countries.These potentially important therapeutic properties of nebulised UFH underline the need for expedited large-scale clinical trials to test its potential to reduce mortality in COVID-19 patients.


The role of the applied epidemiologist in armed conflict.
BACKGROUND: Applied epidemiologists are increasingly working in areas of insecurity and active conflict to define the health risks, suggest feasible means to reduce these risks and, monitor the capacity and reconstruction of the public health system. In 2001, The Carter Center and the United States Institute for Peace sponsored a conference within which "Violence and Health" was discussed and a working group on applied epidemiology formed. The group was tasked to describe the skills that are essential to effective functioning in these settings and thereby provide guidance to the applied epidemiology training programs. METHODS: We conducted a literature review and consultation of a convenience sample of practitioners of applied epidemiology with experience in conflict areas. RESULTS AND CONCLUSIONS: The health programs designed to prevent and mitigate conflict are in their early stages of implementation and the evaluation measures for success are still being defined. The practice of epidemiology in conflict must occur within a larger humanitarian and political context to be effective. The skills required extend beyond the normal epidemiological training that focuses on the valid collection and interpretation of data and fall into two general categories: (1) Conducting a thorough assessment of the conflict setting in order to design more effective public health action in conflict settings, and (2) Communicating effectively to guide health program implementation, to advocate for needed policy changes and to facilitate interagency coordination. These are described and illustrated using examples from different countries.


Identifying ERBB2 Activating Mutations in HER2-Negative Breast Cancer: Clinical Impact of Institute-Wide Genomic Testing and Enrollment in Matched Therapy Trials.
The yield of comprehensive genomic profiling in recruiting patients to molecular-based trials designed for small subgroups has not been fully evaluated. We evaluated the likelihood of enrollment in a clinical trial that required the identification of a specific genomic change based on our institute-wide genomic tumor profiling. Using genomic profiling from archived tissue samples derived from patients with metastatic breast cancer treated between 2011 and 2017, we assessed the impact of systematic genomic characterization on enrollment in an ongoing phase II trial (ClinicalTrials.gov identifier: NCT01670877). Our primary aim was to describe the proportion of patients with a qualifying ERBB2 mutation identified by our institutional genomic panel (OncoMap or OncoPanel) who enrolled in the trial. Secondary objectives included median time from testing result to trial registration, description of the spectrum of ERBB2 mutations, and survival. Associations were calculated using Fisher's exact test. We identified a total of 1,045 patients with metastatic breast cancer without ERBB2 amplification who had available genomic testing results. Of these, 42 patients were found to have ERBB2 mutation and 19 patients (1.8%) were eligible for the trial on the basis of the presence of an activating mutation, 18 of which were identified by OncoPanel testing. Fifty-eight percent of potentially eligible patients were approached, and 33.3% of eligible patients enrolled in the trial guided exclusively by OncoPanel testing. More than one half of eligible patients were approached for trial participation and, significantly, one third of those were enrolled in NCT01670877. Our data illustrate the ability to enroll patients in trials of rare subsets in routine clinical practice and highlight the need for these broadly based approaches to effectively support the success of these studies.


Human babesiosis on Nantucket Island: transmission by nymphal Ixodes ticks.
In order to identify potential vectors of human babesiosis (Babesia microli) in southern Massachusetts, I attempted to transmit the infection via nymphal ticks of that species found to be most abundant on reservoir hosts (Peromyscus leucopus) in nature. Mice were collected at frequent intervals throughout a year in a known enzootic focus on Nantucket Island, and ticks were removed by hand. Ticks of only two species were present; larvae and nymphs of Ixodes scapularis were about 10 times as numerous as were those of Dermacentor variabilis. Accordingly, I. scapularis were used in attempts to transmit a strain of Babesia derived from a human infection recently acquired near the study site. Larvae were permitted to feed on an infected hamster and nymphs derived from these larvae were placed on each of 11 non-infected hamsters. All but one hamster became infected. Nymphs reared from larvae that had attached to a non-infected hamster did not transmit babesiosis to other hamsters. These results suggest that I. scapularis serves as a vector of babesios-s on Nantucket hamsters. These results suggest that I. scapularis serves as a vector of babesiosis on Nantucket Island.


Patient-centered documentation: an effective and efficient use of clinical information systems.
After 2 years of experience with a basic computerized system for documenting care, the nursing leaders in an inner city hospital undertook a redesign process to create an effective and efficient system for documentation that also provided data for monitoring care processes, patient outcomes, and staff performance. The basic system was a source of frustration and dissatisfaction for nurses, physicians, and managers. The redesigned system has exceeded the expectations of staff and physicians and delighted managers. Managers can now access the clinical data collected by the staff to create meaningful reports describing the patient population, identifying patients needs, monitoring staff compliance with care standards, and tracking improvements in care processes.


Zero-n gap soliton.
Periodic structures consisting of alternating layers of positive-index and negative-index materials have a novel bandgap at the frequency at which the average refractive index is zero. We show that, in the presence of a Kerr nonlinearity, this zero-n gap can switch from low transmission to a perfectly transmitting state, forming a nonlinear resonance or gap soliton in the process. This zero-n gap soliton is omnidirectional, in contrast to the usual Bragg gap soliton of positive-index periodic structures.


Early prefrontal brain responses to the Hedonic quality of emotional words--a simultaneous EEG and MEG study.
The hedonic meaning of words affects word recognition, as shown by behavioral, functional imaging, and event-related potential (ERP) studies. However, the spatiotemporal dynamics and cognitive functions behind are elusive, partly due to methodological limitations of previous studies. Here, we account for these difficulties by computing combined electro-magnetoencephalographic (EEG/MEG) source localization techniques. Participants covertly read emotionally high-arousing positive and negative nouns, while EEG and MEG were recorded simultaneously. Combined EEG/MEG current-density reconstructions for the P1 (80-120 ms), P2 (150-190 ms) and EPN component (200-300 ms) were computed using realistic individual head models, with a cortical constraint. Relative to negative words, the P1 to positive words predominantly involved language-related structures (left middle temporal and inferior frontal regions), and posterior structures related to directed attention (occipital and parietal regions). Effects shifted to the right hemisphere in the P2 component. By contrast, negative words received more activation in the P1 time-range only, recruiting prefrontal regions, including the anterior cingulate cortex (ACC). Effects in the EPN were not statistically significant. These findings show that different neuronal networks are active when positive versus negative words are processed. We account for these effects in terms of an "emotional tagging" of word forms during language acquisition. These tags then give rise to different processing strategies, including enhanced lexical processing of positive words and a very fast language-independent alert response to negative words. The valence-specific recruitment of different networks might underlie fast adaptive responses to both approach- and withdrawal-related stimuli, be they acquired or biological.


Development and validation of a bespoke phantom to test accuracy of Cobb angle measurements.
Adolescent idiopathic scoliosis (AIS) is a spinal deformity that causes the spine to bend laterally. Patients with AIS undergo frequent X-ray examinations to monitor the progression of the disorder by through the measurement of the Cobb angle. Frequent exposure of adolescents poses the risk of radiation-induced cancer. The aim of this research was to design and build a bespoke phantom representing a 10-year-old child with AIS to allow optimisation of imaging protocols for AIS assessment through the accuracy of Cobb angle measurements. Poly-methyl methacrylate (PMMA) and plaster of Paris (PoP) were used to represent human soft tissue and bone tissue, respectively, to construct a phantom exhibiting a 15° lateral curve of the spine. The phantom was validated by comparing the Hounsfield unit (HU) of its vertebrae with that of human and sheep. Additionally, comparisons of signal-to-noise ratio (SNR) to those from a commercially available phantom. An assessment of the accuracy of the radiographic assessment of the Cobb angle measurement was performed. The HU of the PoP vertebrae was 628 (SD = 56), human vertebrae was 598 (SD = 79) and sheep vertebra was 605 (SD = 83). The SNR values of the two phantoms correlated strongly (r = 0.93 (p = 0.00)). The measured scoliosis angle was 14°. The phantom has physical characteristics (in terms of spinal deformity) and radiological characteristics (in terms of HU and SNR values) of the spine of a 10-year-old child with AIS. This phantom has utility for the optimisation of x-ray imaging techniques in 10 year old children. A phantom to investigate new x-ray imaging techniques and technology in the assessment of scoliosis and to optimise currently used protocols.


Focus grid generation by in-line holography.
We describe a simple way to generate a wide-area high-resolution focus grid by in-line holography and study the factors that impacts its quality. In our holographic recording setup, the reference beam was the direct transmission of the incoming collimated laser beam through a mask coating with thin metal film, and the sample beam was the transmission of the laser through small apertures fabricated on the mask. The interference of the two beams was then recorded by a holographic plate positioned behind the mask. Compared with other recording schemes, the in-line holography scheme has many distinct advantages and is more suitable for generating a wide-area focus grid. We explored the dependence of diffraction quality, including reconstructed focus spot intensity and spot size, on different parameters for recording, such as optical density of the metal film, size of the apertures, and focal lengths. A wide-area focus grid (170 x 138 spots with area 5.1 mm x 4.1 mm) was recorded using the in-line holography scheme for a demonstration.


Prediction of neonatal metabolic acidosis in women with a singleton term pregnancy in cephalic presentation.
We sought to predict neonatal metabolic acidosis at birth using antepartum obstetric characteristics (model 1) and additional characteristics available during labor (model 2). In 5667 laboring women from a multicenter randomized trial that had a high-risk singleton pregnancy in cephalic presentation beyond 36 weeks of gestation, we predicted neonatal metabolic acidosis. Based on literature and clinical reasoning, we selected both antepartum characteristics and characteristics that became available during labor. After univariable analyses, the predictors of the multivariable models were identified by backward stepwise selection in a logistic regression analysis. Model performance was assessed by discrimination and calibration. To correct for potential overfitting, we (internally) validated the models with bootstrapping techniques. Of 5667 neonates born alive, 107 (1.9%) had metabolic acidosis. Antepartum predictors of metabolic acidosis were gestational age, nulliparity, previous cesarean delivery, and maternal diabetes. Additional intrapartum predictors were spontaneous onset of labor and meconium-stained amniotic fluid. Calibration and discrimination were acceptable for both models (c-statistic 0.64 and 0.66, respectively). In women with a high-risk singleton term pregnancy in cephalic presentation, we identified antepartum and intrapartum factors that predict neonatal metabolic acidosis at birth.


New Combination/Application of Polymer-Based Nanoparticles for Biomedical Engineering.
Polymer-based nanoparticles (PNPs) are attractive in part due to their ultra-small size, versatility and target specificity. Therefore, PNPs have been increasingly used in a variety of biomedical applications including diagnoses and therapeutic treatment. In this chapter, we focus on the recent studies (within 5 years) with some new ideas/agent's application in biomedical field and roughly divide applications of PNPs into four categories: (1) Delivery, (2) In vivo imaging, (3) Therapies, and (4) Other applications. First, we introduce how PNPs can enhance the treatment and delivery efficiency of therapeutic agent. Second, how PNPs can be used to help in vivo imaging system for disease tracking and monitor. Then, we reveal some novel PNPs which is able to function as an agent in photodynamic, photothermal, sonodynamic and neuron capture therapy. Furthermore, we also mention some interesting applications of PNPs for biomedical field in individual form or cluster employment, such as immunoswitch particles, surface fabrication. Finally, the challenges and future development of PNPs are also discussed. In delivery section, we focus on how polymer "can be used" as vehicles in delivery application. But, in the section of imaging and therapies, we carried on how polymer as an "adjuvant" for functional enhancement. The biodegradable property of PNPs is the feature that they can be controllable for itself degradation and drug release as a chief actor. Besides, in imaging and therapies application, PNPs can be the support role for helping contrast agent or photo/sonosensitizer to enlarge their imaging or therapeutic effect.


Use of self-reported psychopathy assessments with older adults: An update on evaluation of their psychometrics for people over 60 years.
Psychometric properties of self-report psychopathy scales have generally been established in samples of people under the age of 40. Personality traits are, however, likely to persist into old age, so it is important to understand the performance of user-friendly self-report psychopathy measures among older people. The aims of this study were to find out the extent to which self-reported scales developed for rating psychopathy have been used with people of 60 years or older and the extent of any evidence that the psychometric properties of the scales vary with age. A systematic literature review, with searching limited to PubMed, EBSCOhost, and Google Scholar for the years 1990-2017, of studies of the psychometric properties of five prominent self-report psychopathy scales: the Self-Report Psychopathy Scale, Levenson Self-Report Psychopathy Scale, Psychopathic Personality Inventory, Triarchic Psychopathy Measure, and the Elemental Psychopathy Assessment according to age of participants. Fourteen studies were found for the years 1990-2017. Age ranges in these samples are wide, with a typical mean age of approximately 30 years. None of these studies focused solely on adults of 60 years or older or attempted to isolate findings by specific age group. Studies of the use of self-rated psychopathy tools remain inconclusive about their psychometrics in older people. Further investigations should follow three main paths: first, deriving samples solely of older adults from the general population-to improve the generalisability of their results; second, item response theory methods should be used to detect differential item functioning between younger and older adults; finally, modifications of extant measures with and without items with potential age-bias should be tested.


Safety of active implantable devices during MRI examinations: a finite element analysis of an implantable pump.
The goal of this study was to propose a general numerical analysis methodology to evaluate the magnetic resonance imaging (MRI)-safety of active implants. Numerical models based on the finite element (FE) technique were used to estimate if the normal operation of an active device was altered during MRI imaging. An active implanted pump was chosen to illustrate the method. A set of controlled experiments were proposed and performed to validate the numerical model. The calculated induced voltages in the important electronic components of the device showed dependence with the MRI field strength. For the MRI radiofrequency fields, significant induced voltages of up to 20 V were calculated for a 0.3T field-strength MRI. For the 1.5 and 3.0OT MRIs, the calculated voltages were insignificant. On the other hand, induced voltages up to 11 V were calculated in the critical electronic components for the 3.0T MRI due to the gradient fields. Values obtained in this work reflect to the worst case situation which is virtually impossible to achieve in normal scanning situations. Since the calculated voltages may be removed by appropriate protection circuits, no critical problems affecting the normal operation of the pump were identified. This study showed that the proposed methodology helps the identification of the possible incompatibilities between active implants and MR imaging, and can be used to aid the design of critical electronic systems to ensure MRI-safety.


Microbial spectrum and outcome of peritoneal dialysis related peritonitis in Qatar.
Peritoneal dialysis therapy rapidly expanded in Qatar during the last decade. Peritoneal dialysis related peritonitis remains the leading cause of morbidity and technique failure. The objective of this study was to determine the incidence of peritoneal dialysis related peritonitis in Qatar, during a five year study period. The records of all patients on maintenance peritoneal dialysis from January 1, 2003 to December 31, 2007 were reviewed. Episodes of peritonitis, microbial profile, clinical course and outcome were analyzed. A total of 241 patients were included, males represented 74%, the mean age was 53 + or - 13 years, and 48% of patients were diabetics. During the study period 118 episode of peritonitis were observed, with a mean incidence of 0.24 + or - 0.1 episodes per patient year. Gram-positive organisms were isolated in 40% of episodes, with Staphylococcus epidermidis and Staphylococcus hemolyticus being the commonest organisms, isolated in 21% and 9% of infections, respectively. Escherichia coli was the commonest Gram-negative organism and was isolated in 9% of peritonitis episodes, whereas culture-negative peritonitis represented 28% of all diagnosed infections. Seventy nine percent of peritonitis episodes completely resolved with the use of intraperitoneal antimicrobial therapy. Peritoneal dialysis catheters were removed in 19% of episodes. Peritonitis related mortality rate was 3%, and it was due to Candida spp. and Pseudomonas aeruginosa. Despite its low incidence, peritonitis remained the leading cause of patient dropout. Prompt diagnosis and prudent management as well as psychological support to the patients remained essential to reduce the incidence of technique failure following peritonitis episodes.


Emotional breakthrough and psychedelics: Validation of the Emotional Breakthrough Inventory.
Psychedelic therapy is gaining recognition and the nature of the psychedelic experience itself has been found to mediate subsequent long-term psychological changes. Much emphasis has been placed on the occurrence of mystical-type experiences in determining long-term responses to psychedelics yet here we demonstrate the importance of another component, namely: emotional breakthrough. Three hundred and seventy-nine participants completed online surveys before and after a planned psychedelic experience. Items pertaining to emotional breakthrough were completed one day after the psychedelic experience, as were items comprising the already validated Mystical Experience Questionnaire and the Challenging Experience Questionnaire. Emotional breakthrough, Mystical Experience Questionnaire and Challenging Experience Questionnaire scores were used to predict changes in well-being (Warwick-Edinburgh Mental Wellbeing Scale) in a subsample of 75 participants with low well-being baseline scores (⩽45). Factor analyses revealed six emotional breakthrough items with high internal consistency (Cronbach's alpha=0.932) and supported our prior hypothesis that emotional breakthrough is a distinct component of the psychedelic experience. Emotional breakthrough scores behaved dose-dependently, and were higher if the psychedelic was taken with therapeutic planning and intent. Emotional breakthrough, Mystical Experience Questionnaire and Challenging Experience Questionnaire scores combined, significantly predicted subsequent changes in well-being (r=0.45, p=0.0005, n=75), with each scale contributing significant predictive value. Emotional breakthrough and Mystical Experience Questionnaire scores predicted increases in well-being and Challenging Experience Questionnaire scores predicted less increases. Here we validate a six-item 'Emotional Breakthrough Inventory'. Emotional breakthrough is an important and distinct component of the acute psychedelic experience that appears to be a key mediator of subsequent longer-term psychological changes. Implications for psychedelic therapy are discussed.


Lymphocyte Invasion in IC10/Basal-Like Breast Tumors Is Associated with Wild-Type TP53.
Lymphocytic infiltration is associated with better prognosis in several epithelial malignancies including breast cancer. The tumor suppressor TP53 is mutated in approximately 30% of breast adenocarcinomas, with varying frequency across molecular subtypes. In this study of 1,420 breast tumors, we tested for interaction between TP53 mutation status and tumor subtype determined by PAM50 and integrative cluster analysis. In integrative cluster 10 (IC10)/basal-like breast cancer, we identify an association between lymphocytic infiltration, determined by an expression score, and retention of wild-type TP53. The expression-derived score agreed with the degree of lymphocytic infiltration assessed by pathologic review, and application of the Nanodissect algorithm was suggestive of this infiltration being primarily of cytotoxic T lymphocytes (CTL). Elevated expression of this CTL signature was associated with longer survival in IC10/Basal-like tumors. These findings identify a new link between the TP53 pathway and the adaptive immune response in estrogen receptor (ER)-negative breast tumors, suggesting a connection between TP53 inactivation and failure of tumor immunosurveillance. The association of lymphocytic invasion of ER-negative breast tumors with the retention of wild-type TP53 implies a novel protective connection between TP53 function and tumor immunosurveillance.


Milk Fat Globule-EGF Factor 8, Secreted by Mesenchymal Stem Cells, Protects Against Liver Fibrosis in Mice.
Mesenchymal stem cells (MSCs) mediate tissue repair and might be used to prevent or reduce liver fibrosis. However, little is known about the anti-fibrotic factors secreted from MSCs or their mechanisms. Umbilical cord-derived MSCs (UCMSCs) were differentiated into hepatocyte-like cells (hpUCMSCs), medium was collected, and secretome proteins were identified and quantified using nanochip-liquid chromatography/quadrupole time-of-flight mass spectrometry. Liver fibrosis was induced in mice by intraperitoneal injection of thioacetamide or CCl4; some mice were then given injections of secretomes or proteins. Liver tissues were collected and analyzed by histology or polymerase chain reaction array to analyze changes in gene expression patterns. We analyzed the effects of MSC secretomes and potential anti-fibrotic proteins on transforming growth factor β 1 (TGFβ1)-mediated activation of human hepatic stellate cell (HSC) lines (hTert-HSC and LX2) and human primary HSCs. Liver tissues were collected from 16 patients with liver cirrhosis and 16 individuals without cirrhosis (controls) in Korea and analyzed by immunohistochemistry and immunoblots. In mice with fibrosis, accumulation of extracellular matrix proteins was significantly reduced 3 days after injecting secretomes from UCMSCs, and to a greater extent from hpUCMSCs; numbers of activated HSCs that expressed the myogenic marker α-smooth muscle actin (α-SMA, encoded by ACTA2 [actin, alpha 2, smooth muscle]) were also reduced. Secretomes from UCMSCs, and to a greater extent from hpUCMSCs, reduced liver expression of multiple fibrotic factors, collagens, metalloproteinases, TGFβ, and Smad proteins in the TGFβ signaling pathways. In HSC cell lines and primary HSCs, TGFβ1-stimulated upregulation of α-SMA was significantly inhibited (and SMAD2 phosphorylation reduced) by secretomes from UCMSCs, and to a greater extent from hpUCMSCs. We identified 32 proteins in secretomes of UCMSCs that were more highly concentrated in secretomes from hpUCMSCs and inhibited TGFβ-mediated activation of HSCs. One of these, milk fat globule-EGF factor 8 (MFGE8), was a strong inhibitor of activation of human primary HSCs. We found MFGE8 to down-regulate expression of TGFβ type I receptor by binding to αvβ3 integrin on HSCs and to be secreted by MSCs from umbilical cord, teeth, and bone marrow. In mice, injection of recombinant human MFGE8 had anti-fibrotic effects comparable to those of the hpUCMSC secretome, reducing extracellular matrix deposition and HSC activation. Co-injection of an antibody against MFGE8 reduced the anti-fibrotic effects of the hpUCMSC secretome in mice. Levels of MFGE8 were reduced in cirrhotic liver tissue from patients compared with controls. MFGE8 is an anti-fibrotic protein in MSC secretomes that strongly inhibits TGFβ signaling and reduces extracellular matrix deposition and liver fibrosis in mice.


SpySwitch enables pH- or heat-responsive capture and release for plug-and-display nanoassembly.
Proteins can be empowered via SpyTag for anchoring and nanoassembly, through covalent bonding to SpyCatcher partners. Here we generate a switchable version of SpyCatcher, allowing gentle purification of SpyTagged proteins. We introduce numerous histidines adjacent to SpyTag's binding site, giving moderate pH-dependent release. After phage-based selection, our final SpySwitch allows purification of SpyTag- and SpyTag003-fusions from bacterial or mammalian culture by capture at neutral pH and release at pH 5, with purity far beyond His-tag methods. SpySwitch is also thermosensitive, capturing at 4 °C and releasing at 37 °C. With flexible choice of eluent, SpySwitch-purified proteins can directly assemble onto multimeric scaffolds. 60-mer multimerization enhances immunogenicity and we use SpySwitch to purify receptor-binding domains from SARS-CoV-2 and 11 other sarbecoviruses. For these receptor-binding domains we determine thermal resilience (for mosaic vaccine development) and cross-recognition by antibodies. Antibody EY6A reacts across all tested sarbecoviruses, towards potential application against new coronavirus pandemic threats.


Metaphorical language processing and amygdala activation in L1 and L2.
The present study aims to investigate the neural correlates of processing conventional figurative language in non-native speakers in a comparison with native speakers. Italian proficient L2 learners of German and German native speakers read conventional metaphorical statements as well as literal paraphrases that were comparable on a range of psycholinguistic variables. Results confirm previous findings that native speakers show increased activity for metaphorical processing, and left amygdala activation increases with increasing Metaphoricity. At the whole-brain level, L2 learners showed the expected overall differences in activation when compared to native speakers (in the fronto-temporal network). But L2 speakers did not show any distinctive activation outside the caudate nucleus as Metaphoricity increased, suggesting that the L2 speakers were less affected by increasing Metaphoricity than native speakers were. With small volume correction, only a single peak in the amygdala reached threshold for L2 speakers as Metaphoricity increased. The findings are consistent with the view that metaphorical language is more engaging for native speakers but not necessarily for L2 speakers.


Defectiveness of interferon production and of rubella virus interference in a line of African green monkey kidney cells (Vero).
Vero cells, a line of African green monkey kidney cells, failed to produce interferon when infected with Newcastle disease, Sendai, Sindbis, and rubella viruses, although the cells were sensitive to interferon. Further, infection of Vero cells with rubella virus did not result in interference with the replication of echovirus 11, Newcastle disease virus, or vesicular stomatitis virus, even in cultures where virtually every cell was infected with rubella virus. Under the same conditions, BSC-1 cells and other cells of primate origin produced interferon and showed rubella virus interference. The results indicate that the presence of rubella virus in the cell does not in itself exclude multiplication of other viruses and that rubella virus interference appears to be linked to the capability of the cell to produce interferon.


An exploration of men's experiences of learning intermittent self-catheterisation with a silicone catheter.
Intermittent self-catheterisation (ISC) is the method of choice for men with lower urinary tract symptoms who need to drain retained urine from the bladder. It is preferred to using an indwelling urinary catheter as it has lower risks of complications and catheter-associated urinary tract infection. Learning ISC can be challenging for men initially but, with the support of knowledgeable nurses experienced in teaching ISC, the technique can be learned, accepted and normalised, improving symptom control and quality of life. This paper discusses the results of a survey exploring men's experiences of learning ISC with the Hydrosil Go™ (C.R. Bard Inc-now part of Becton, Dickinson and Company) silicone catheter and to highlight issues important to men when learning and living with ISC. The survey collected data from four countries: UK, France, Netherlands and Italy. It aims to help nurses who teach ISC and inform them to discuss what matters to men when learning and living with ISC.


Attitudes and practices among internists concerning genetic testing.
Many questions remain concerning whether, when, and how physicians order genetic tests, and what factors are involved in their decisions. We surveyed 220 internists from two academic medical centers about their utilization of genetic testing. Rates of genetic utilizations varied widely by disease. Respondents were most likely to have ordered tests for Factor V Leiden (16.8 %), followed by Breast/Ovarian Cancer (15.0 %). In the past 6 months, 65 % had counseled patients on genetic issues, 44 % had ordered genetic tests, 38.5 % had referred patients to a genetic counselor or geneticist, and 27.5 % had received ads from commercial labs for genetic testing. Only 4.5 % had tried to hide or disguise genetic information, and <2 % have had patients report genetic discrimination. Only 53.4 % knew of a geneticist/genetic counselor to whom to refer patients. Most rated their knowledge as very/somewhat poor concerning genetics (73.7 %) and guidelines for genetic testing (87.1 %). Most felt needs for more training on when to order tests (79 %), and how to counsel patients (82 %), interpret results (77.3 %), and maintain privacy (80.6 %). Physicians were more likely to have ordered a genetic test if patients inquired about genetic testing (p < .001), and if physicians had a geneticist/genetic counselor to whom to refer patients (p < .002), had referred patients to a geneticist/genetic counselor in the past 6 months, had more comfort counseling patients about testing (p < .019), counseled patients about genetics, larger practices (p < .032), fewer African-American patients (p < .027), and patients who had reported genetic discrimination (p < .044). In a multiple logistic regression, ordering a genetic test was associated with patients inquiring about testing, having referred patients to a geneticist/genetic counselor and knowing how to order tests. These data suggest that physicians recognize their knowledge deficits, and are interested in training. These findings have important implications for future medical practice, research, and education.


The localization of target antigens and autoantibodies in linear IgA disease is variable: correlation of immunogold electron microscopy and immunoblotting.
Linear IgA disease (LAD) of adults and children is a dapsone-responsive, autoimmune subepidermal blistering disease characterized by linear IgA deposits at the basement membrane zone (BMZ) of the skin and mucosa. Circulating IgA antibodies to BMZ components are often present. In this study we investigated the ultrastructural localization of the antigens and autoantibodies in six patients with LAD (five adults and one child). Using a direct postembedding immunogold electron microscopy (EM) technique, three different patterns of IgA antibody deposition were seen in the skin of four patients with LAD. The IgA deposits localized within the uppermost part of the lamina lucida and to the basal surface of the hemidesmosome in two patients, to the lamina lucida in one, and to the lamina densa in the fourth patient. Using an indirect immunogold EM technique and serum or purified blister fluid from two additional LAD patients, we showed that the serum autoantibodies of one patient bound to the hemidesmosome of the BMZ, while the autoantibodies in the blister fluid of the other patient bound to the lamina densa and sublamina densa including the anchoring fibrils in a labelling pattern similar to that of the monoclonal antibody (LH7.2) to collagen VII. All the autoantibodies binding to the hemidesmosome or lamina lucida recognized a protein in epidermal extracts of molecular weight 180 kDa or its breakdown product of 97 kDa, 200 kDa or 230 kDa. The antibodies binding to the lamina densa recognized proteins of 180 and 285 kDa. The antibodies that bound to the lamina densa and anchoring fibrils recognized collagen VII. In this immunogold EM study we have shown four patterns of IgA labelling in six patients with LAD, associated with five different antigens as recognized by immunoblotting. These results, together with our previous immunofluorescence and immunoblotting findings add support to the contention that LAD is a heterogeneous disease as regards both the target antigens and epitopes.


Characterization of opioid, sigma, and phencyclidine receptors in the neuroblastoma-brain hybrid cell line NCB-20.
Opioid, sigma, and phencyclidine (PCP) receptors were characterized in the mouse neuroblastoma--Chinese hamster brain hybrid cell line NCB-20. Quantitative receptor assays under equilibrium binding conditions with highly specific radioligands demonstrated the presence of delta, but not mu or kappa, opioid receptors on NCB-20 cell membranes. NCB-20 cells were shown to possess two distinct sites specific for sigma opioids and PCP derivatives. One site was labeled by (+)-[3H]N-allylnormetazocine [(+)-[3H]SKF-10,047] (Kd = 69 nM; Bmax = 4100 fmol/mg of protein). The rank order of potency of drugs at this site was (+)-3-(3-hydroxy-phenyl)-N-(1-propyl)piperidine [(+)-3-PPP] greater than haloperidol greater than (+)-SKF-10,047 greater than (+/-)-ethylketocyclazocine greater than (+/-)-bremazocine greater than N-[1-(2-thienyl) cyclohexyl]piperidine (TCP) greater than dexoxadrol. This site is similar in its ligand selectivity to the haloperidol-sensitive sigma receptor of rat brain. The other site was labeled by the potent phencyclidine derivative [3H]TCP (Kd = 335 nM; Bmax = 9300 fmol/mg of protein). This density is equivalent to approximately 60,000 sites/cell. The rank order of potency of drugs at this site was TCP greater than (+)-3-PPP greater than PCP greater than dexoxadrol greater than haloperidol greater than cyclazocine greater than levoxadrol greater than (+)-SKF-10,047; mu and delta ligands were inactive. This site is similar to the rat brain PCP receptor. The NCB-20 cell line is the only cultured cell line that has been demonstrated to have PCP receptors.


Anaesthesia management for bronchoscopic and surgical lung volume reduction.
Optimizing the patient's condition before the lung volume reduction (LVR) according to recommendations by American College of Cardiology/American Heart Association (ACC/AHA) guideline on perioperative cardiovascular evaluation is mandatory. Implementation of a multimodal analgesia concept and the use short-acting anaesthetics enhances recovery and avoids postoperative pulmonary complications. Normovolemia, normothermia, lung protective ventilation and an evidence-based concept of airway management (i.e., double-lumen tube, bronchus blocker) are suggested for intraoperative management of surgical lung volume reduction (SLVR). General anaesthesia (using remifentanil, propofol and mivacurium) with an i-gel® supraglottic airway device should be used for bronchoscopic lung volume reduction (BLVR). Jet ventilation through rigid bronchoscopy or with a jet catheter may be an alternative concept. Experienced consultants should perform anaesthesia for LVR.


Cytokine enhancement of in vitro antibody-dependent cellular cytotoxicity mediated by chimeric anti-GD3 monoclonal antibody KM871.
The chimeric KM871 monoclonal antibody targets the GD3 disialoganglioside antigen and is under investigation for its immunotherapeutic potential in melanoma. Preclinical and phase I studies have demonstrated the biodistribution and specific tumour targeting of KM871 to metastatic melanoma in vivo, with a long half-life and lack of immunogenicity making it an attractive candidate for further clinical trials. In vitro studies have demonstrated KM871 induces high levels of cytotoxicity in both antibody-dependent cellular-cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) assays. In order to investigate the potential for cytokine upregulation of KM871-mediated ADCC, freshly isolated healthy donor PBMC effector cells were cultured in the presence or absence of the cytokines interleukin-2, interleukin-12 and granulocyte/macrophage-colony stimulating factor and the ADCC determined over a 10-day period. In the absence of these cytokines, ADCC activity of 1 micro g/ml KM871 on (51) Cr-labeled SK-MEL-28 target cells could not be detected after 72 hrs of culture of PBMC effector cells in media. In contrast, ADCC mediated by KM871 was significantly enhanced and maintained for the 10-day study period upon culturing PBMCs with media containing IL-2 and/or IL-12, but not with GM-CSF. FACS analysis of the effector cell population indicated CD3-/CD16+56+ NK cells were primarily responsible for the KM871-mediated ADCC activity and a direct correlation was observed between the percentage of NK cells and the level of cytotoxicity mediated by the PBMCs. Furthermore, ADCC was significantly reduced using NK-depleted PBMCs. These results suggest combining IL-2 or IL-12 with KM871 may enhance KM871 immune-mediated cell killing in patients with metastatic melanoma.


Ovarian cancer mortality among immigrants in Australia and Canada.
This study examined the impact of changing environments on ovarian cancer by comparing age-standardized mortality rates of numerous immigrants groups in Australia and Canada to those in the origin countries for the period 1984-1988. Mortality rates by length of residence in Australia (0-29 and 30+ years) were also calculated. In Australia, the mortality rates for all four immigrant groups from low-risk countries and 53.8% from high-risk countries (n = 13) shifted toward the rate of the native-born Australians. In Canada, rates for 88.9% of immigrant groups from low-risk countries (n = 9) and 30.0% from high-risk countries (n = 10) converged to the rate of native-born Canadians. Among individual immigrant groups there was not a consistent pattern of convergence with length of residence in Australia. There was evidence of convergence among the long-term residents of some of the groups and in the aggregate analysis. The increased mortality among the majority of immigrant groups is consistent with the reported inverse relationship between parity and ovarian cancer and the generally lower parity of immigrant women compared to those in their home country. The period of residence and analyses suggests that long-term environmental and lifestyle factors in the new place of residence may also influence ovarian cancer mortality.


The Kidney-Related Effects of Polystyrene Microplastics on Human Kidney Proximal Tubular Epithelial Cells HK-2 and Male C57BL/6 Mice.
Understanding the epidemic of chronic kidney disease of uncertain etiology may be critical for health policies and public health responses. Recent studies have shown that microplastics (MPs) contaminate our food chain and accumulate in the gut, liver, kidney, muscle, and so on. Humans manufacture many plastics-related products. Previous studies have indicated that particles of these products have several effects on the gut and liver. Polystyrene (PS)-MPs (PS-MPs) induce several responses, such as oxidative stress, and affect living organisms. The aim of this study was to investigate the effects of PS-MPs in kidney cells in vitro and in vivo. PS-MPs were evaluated in human kidney proximal tubular epithelial cells (HK-2 cells) and male C57BL/6 mice. Mitochondrial reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, inflammation, and autophagy were analyzed in kidney cells. In vivo, we evaluated biomarkers of kidney function, kidney ultrastructure, muscle mass, and grip strength, and urine protein levels, as well as the accumulation of PS-MPs in the kidney tissue. Uptake of PS-MPs at different concentrations by HK-2 cells resulted in higher levels of mitochondrial ROS and the mitochondrial protein Bad. Cells exposed to PS-MPs had higher ER stress and markers of inflammation. MitoTEMPO, which is a mitochondrial ROS antioxidant, mitigated the higher levels of mitochondrial ROS, Bad, ER stress, and specific autophagy-related proteins seen with PS-MP exposure. Furthermore, cells exposed to PS-MPs had higher protein levels of LC3 and Beclin 1. PS-MPs also had changes in phosphorylation of mitogen-activated protein kinase (MAPK) and protein kinase B (AKT)/mitogen-activated protein kinase (mTOR) signaling pathways. In an in vivo study, PS-MPs accumulated and the treated mice had more histopathological lesions in the kidneys and higher levels of ER stress, inflammatory markers, and autophagy-related proteins in the kidneys after PS-MPs treatment by oral gavage. The results suggest that PS-MPs caused mitochondrial dysfunction, ER stress, inflammation, and autophagy in kidney cells and accumulated in HK-2 cells and in the kidneys of mice. These results suggest that long-term PS-MPs exposure may be a risk factor for kidney health. https://doi.org/10.1289/EHP7612.


The rectosigmoid junction: are limits important?
The rectosigmoid junction (RSJ) is the limit between the sigmoid colon and the rectum. The limits of this transition zone have been a source of controversy. There are multiple definitions that aim to establish the beginning of the rectum. Some organizations propose the use of more than one definition. Generally, these definitions use either radiological markings, endoscopic measurements or anatomical landmarks. However, no consensus exists currently.


Effects of chronic prednisone therapy on mood and memory.
In animals, stress and corticosteroids can be associated with both reversible and irreversible changes in the hippocampus. Changes in memory and hippocampal structure, perhaps in part due to cortisol elevations, are reported in some patients with mood disorders. Minimal data are available on the effects of long-term exposure to corticosteroids on the human hippocampus. We previously reported greater depressive symptom severity, poorer memory and smaller hippocampal volumes in patients with asthma or rheumatic diseases receiving long-term prednisone therapy than in controls. In this report, patients and controls were assessed a mean of 4 years after the first assessment to determine if depressive and manic symptoms and cognition remained stable, improved or worsened. Seven prednisone-treated patients and six controls were identified and agreed to reassessment with psychiatric symptom and neurocognitive measures. Follow-up MRIs for hippocampal volume analysis were available for two prednisone-treated participants. With the exception of an increase in depressive symptoms in those receiving prednisone, participants and controls did not show significant change in mood or cognition from the initial assessment. One participant discontinued prednisone and showed improvement in psychiatric symptoms and cognition. Hippocampal volumes were available in two prednisone-treated participants and showed inconsistent findings. A limitation is the small sample size. Our findings, although preliminary in nature, suggest that long-term prednisone therapy is associated with initial changes in mood, memory and hippocampal volume that appear to stabilize over time.


Multiple colonizations lead to cryptic biodiversity in an island ecosystem: comparative phylogeography of anchialine shrimp species in the Ryukyu Archipelago, Japan.
Archipelagos of the Indo-West Pacific are considered to be among the richest in the world in biodiversity, and phylogeographic studies generally support either the center of origin or the center of accumulation hypothesis to explain this pattern. To differentiate between these competing hypotheses for organisms from the Indo-West Pacific anchialine ecosystem, defined as coastal bodies of mixohaline water fluctuating with the tides but having no direct oceanic connections, we investigated the genetic variation, population structure, and evolutionary history of three caridean shrimp species (Antecaridina lauensis, Halocaridinides trigonophthalma, and Metabetaeus minutus) in the Ryukyu Archipelago, Japan. We used two mitochondrial genes--cytochrome c oxidase subunit I (COI) and large ribosomal subunit (16S-rDNA)--complemented with genetic examination of available specimens from the same or closely related species from the Indian and Pacific Oceans. In the Ryukyus, each species encompassed 2-3 divergent (9.52%-19.2% COI p-distance) lineages, each having significant population structure and varying geographic distributions. Phylogenetically, the A. lauensis and M. minutus lineages in the Ryukyus were more closely related to ones from outside the archipelago than to one another. These results, when interpreted in the context of Pacific oceanographic currents and geologic history of the Ryukyus, imply multiple colonizations of the archipelago by the three species, consistent with the center of accumulation hypothesis. While this study contributes toward understanding the biodiversity, ecology, and evolution of organisms in the Ryukyus and the Indo-West Pacific, it also has potential utility in establishing conservation strategies for anchialine fauna of the Pacific Basin in general.


Physiological response to water immersion: a method for sport recovery?
Recovery from exercise can be an important factor in performance during repeated bouts of exercise. In a tournament situation, where athletes may compete numerous times over a few days, enhancing recovery may provide a competitive advantage. One method that is gaining popularity as a means to enhance post-game or post-training recovery is immersion in water. Much of the literature on the ability of water immersion as a means to improve athletic recovery appears to be based on anecdotal information, with limited research on actual performance change. Water immersion may cause physiological changes within the body that could improve recovery from exercise. These physiological changes include intracellular-intravascular fluid shifts, reduction of muscle oedema and increased cardiac output (without increasing energy expenditure), which increases blood flow and possible nutrient and waste transportation through the body. Also, there may be a psychological benefit to athletes with a reduced cessation of fatigue during immersion. Water temperature alters the physiological response to immersion and cool to thermoneutral temperatures may provide the best range for recovery. Further performance-orientated research is required to determine whether water immersion is beneficial to athletes.


Molecular markers implicating early malignant events in cervical carcinogenesis.
Human papillomavirus can induce a stepwise progression of precursor lesions to carcinoma. Sensitive and specific molecular markers are needed to identify the cervical lesions (CIN) at risk for this progression. hTERT activation could be one indicator of a point of no return in malignant progression. The UT-DEC-1 cell line is an in vitro model for the study of human papillomavirus-induced progression. Using molecular mining, nine potential genes interlinking hTERT and viral oncogene expression with the phenotypical features of CIN2 were identified. After preliminary testing with real-time PCR, five genes were selected for further analysis: hTERT, DKC1, Bcl-2, S100A8, and S100A9. These proteins were also tested in a series of 120 CIN lesions using immunohistochemistry. Analysis of the mRNA expression of these genes at different cell passages revealed three time points with significant changes. hTERT, Bcl-2, and S100A9 were also overexpressed in CIN lesions, and the expression pattern changed during the progression toward CIN3 lesions. These identified time points that were combined with the mRNA overexpression of target genes matched events previously shown to be important in the progression toward malignancy: (a) the viral integration into the cell genome and episome loss; (b) the selection of cells with an acquired growth advantage and ability to maintain telomerase activity; and (c) the final stage of malignancy with permanently upregulated telomerase. hTERT, Bcl-2, and S100A9 together might compose a potential prognostic marker panel for the assessment of CIN lesions. These results, however, need further validation in prospective clinical settings. (c)2010 AACR.


Cardiac troponin in patients hospitalized with acute decompensated heart failure: A systematic review and meta-analysis.
Elevated cardiac troponin (cTn) is often observed in patients with acute decompensated heart failure (ADHF). We assessed the magnitude of association and quality of supporting evidence between cTn and clinically important outcomes in persons hospitalized for ADHF. We searched MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus from inception through February 28, 2015. The outcomes analyzed included hospital length of stay (LOS), readmissions, and mortality. Random effects meta-analysis was used to combine outcomes across studies. We included 26 clinical studies. A detectable or elevated cTn was associated with increased LOS (odds ratio [OR]: 1.05; 95% confidence interval [CI]: 1.01-1.10), increased in-hospital mortality (OR: 2.57; 95% CI: 2.27-2.91), and a composite of mortality and major adverse events (OR: 1.33; 95% CI: 1.03-1.71) during hospitalization. ADHF patients with a detectable or elevated cTn were at increased risk for mortality and composite of mortality and readmission over the short term (mortality OR: 2.11; 95% CI: 1.43-3.12; composite OR: 2.81; 95% CI: 1.60-4.92), intermediate term (mortality OR: 2.21; 95% CI: 1.46-3.35; composite OR: 2.30; 95% CI: 1.78-2.99), and long term (mortality OR: 3.69; 95% CI: 2.64-5.18; composite OR: 3.49; 95% CI: 2.08-5.84). The overall confidence in estimates was moderate. Among ADHF patients, a detectable or elevated cTn identifies subjects at increased risk for adverse clinical outcomes during acute hospitalization and those at higher risk for postdischarge mortality and composite of readmission and mortality. Journal of Hospital Medicine 2016;11:446-454. 2016 Society of Hospital Medicine.


Terrestrial feeding in aquatic turtles: environment-dependent feeding behavior modulation and the evolution of terrestrial feeding in Emydidae.
Evolutionary transitions between aquatic and terrestrial environments are common in vertebrate evolution. These transitions require major changes in most physiological functions, including feeding. Emydid turtles are ancestrally aquatic, with most species naturally feeding only in water, but some terrestrial species can modulate their feeding behavior appropriately for both media. In addition, many aquatic species can be induced to feed terrestrially. A comparison of feeding in both aquatic and terrestrial environments presents an excellent opportunity to investigate the evolution of terrestrial feeding from aquatic feeding, as well as a system within which to develop methods for studying major evolutionary transitions between environments. Individuals from eight species of emydid turtles (six aquatic, two terrestrial) were filmed while feeding underwater and on land. Bite kinematics were analyzed to determine whether aquatic turtles modulated their feeding behavior in a consistent and appropriate manner between environments. Aquatic turtles showed consistent changes between environments, taking longer bites and using more extensive motions of the jaw and hyoid when feeding on land. However, these motions differ from those shown by species that naturally feed in both environments and mostly do not seem to be appropriate for terrestrial feeding. For example, more extensive motions of the hyoid are only effective during underwater suction feeding. Emydids evolving to feed on land probably would have needed to evolve or learn to overcome many, but not all, aspects of the intrinsic emydid response to terrestrial feeding. Studies that investigate major evolutionary transitions must determine what responses to the new environment are shown by naïve individuals in order to fully understand the evolutionary patterns and processes associated with these transitions.


Comparison of Local Recurrence Among Early Breast Cancer Patients Treated With Electron Intraoperative Radiotherapy vs Hypofractionated Photon Radiotherapy an Observational Study.
To evaluate local recurrence (LR) in women with early breast cancer (BC) who underwent intraoperative radiation therapy with electrons particles (IORT-E) or adjuvant hypofractionated external radiotherapy (HYPOFX). We retrospectively analyzed 470 patients with early BC treated at our center from September 2009 to December 2012. 235 women were treated with breast-conserving surgery and immediate IORT-E (21 Gy/1 fraction) while 235 patients underwent wide excision followed by hypofractionated whole-breast irradiation. Radiotherapy modality was chosen according to an individualized decision based on tumor features, stage, technical feasibility, age, and acceptance to be enrolled in the IORT-E group. After a median follow-up of 6 years, we observed 8 (3.4%) and 1 (0.42%) LR in the IORT-E and in the HYPOFX group (p = 0.02), respectively. The two groups differed in the prevalence of clinical characteristics (p < 0.05): age, tumor size, surgical margins, receptors, ki67, and histology. 4 and 1 woman in the IORT-E and HYPOFX group died of BC, respectively (p = 0.167). OS and DFS hazard ratio [HR] were 2.14 (95% IC, 1.10-4.15) and 2.09 (95% IC, 1.17-3.73), respectively. Our comparison showed that IORT-E and HYPOFX are two effective radiotherapy modalities after conservative surgery in early BC. However, at 6 years a significant higher rate of LR occurred in patients submitted to IORT-E with respect to HYPOFX. This finding may be correlated to some subsets of patients who, depending on the biological characteristics of the BC, may be less suitable to IORT-E.


A molecular theory of nematic-nematic phase transitions in mesogenic dimers.
We study theoretically the molecular origins of the fascinating, and still debated, nematic-nematic phase transition exhibited by symmetric, statistically achiral, mesogenic dimers. A simple molecular model that mimics the key features and symmetry (C2V) of this class of mesogens is presented. In the mean-field approximation, the model yields up to three positionally disordered phases, one isotropic and two nematic. The low temperature nematic phase (NX) has a local two-fold symmetry axis, which is also a direction of molecular polar ordering and is tightly twisted about a macroscopic phase axis. The onset of polar ordering generates spontaneous chiral symmetry breaking and the formation of chiral domains of opposite handedness, manifested primarily by the twisting of the polar director. Within these domains the statistical balance between the enantiomer conformations is slightly shifted and the principal axes of the ordering tensors of the molecular segments twist at constant tilt angles with the helical axis. Key experimental results on the NX phase of liquid crystalline dimers are discussed in the light of the theoretical predictions of the model, which are also contrasted with the predictions of the twist-bend nematic model.


Peripheral Membrane Proteins Facilitate Nanoparticle Binding at Lipid Bilayer Interfaces.
Molecular understanding of the impact of nanomaterials on cell membranes is critical for the prediction of effects that span environmental exposures to nanoenabled therapies. Experimental and computational studies employing phospholipid bilayers as model systems for membranes have yielded important insights but lack the biomolecular complexity of actual membranes. Here, we increase model membrane complexity by incorporating the peripheral membrane protein cytochrome c and studying the interactions of the resulting membrane systems with two types of anionic nanoparticles. Experimental and computational studies reveal that the extent of cytochrome c binding to supported lipid bilayers depends on anionic phospholipid number density and headgroup chemistry. Gold nanoparticles functionalized with short, anionic ligands or wrapped with an anionic polymer do not interact with silica-supported bilayers composed solely of phospholipids. Strikingly, when cytochrome c was bound to these bilayers, nanoparticles functionalized with short anionic ligands attached to model biomembranes in amounts proportional to the number of bound cytochrome c molecules. In contrast, anionic polymer-wrapped gold nanoparticles appeared to remove cytochrome c from supported lipid bilayers in a manner inversely proportional to the strength of cytochrome c binding to the bilayer; this reflects the removal of a weakly bound pool of cytochrome c, as suggested by molecular dynamics simulations. These results highlight the importance of the surface chemistry of both the nanoparticle and the membrane in predicting nano-bio interactions.


The prevention and management of chronic disease in primary care: recommendations from a knowledge translation meeting.
Seven chronic disease prevention and management programs were implemented across Quebec with funding support from a provincial-private industry funding initiative. Given the complexity of implementing integrated primary care chronic disease management programs, a knowledge transfer meeting was held to share experiences across programs and synthesize common challenges and success factors for implementation. The knowledge translation meeting was held in February 2014 in Montreal, Canada. Seventy-five participants consisting of 15 clinicians, 14 researchers, 31 knowledge users, and 15 representatives from the funding agencies were broken up into groups of 10 or 11 and conducted a strengths, weaknesses, opportunities, and threats analysis on either the implementation or the evaluation of these chronic disease management programs. Results were reported back to the larger group during a plenary and recorded. Audiotapes were transcribed and summarized using pragmatic thematic analysis. Strengths to leverage for the implementation of the seven programs include: (1) synergy between clinical and research teams; (2) stakeholders working together; (3) motivation of clinicians; and (4) the fact that the programs are evidence-based. Weaknesses to address include: (1) insufficient resources; (2) organizational change within the clinical sites; (3) lack of referrals from primary care physicians; and (4) lack of access to programs. Strengths to leverage for the evaluation of these programs include: (1) engagement of stakeholders and (2) sharing of knowledge between clinical sites. Weaknesses to address include: (1) lack of referrals; (2) difficulties with data collection; and (3) difficulties in identifying indicators and control groups. Opportunities for both themes include: (1) fostering new and existing partnerships and stakeholder relations; (2) seizing funding opportunities; (3) knowledge transfer; (4) supporting the transformation of professional roles; (5) expand the use of health information technology; and (6) conduct cost evaluations. Fifteen recommendations related to mobilisation of primary care physicians, support for the transformation of professional roles, and strategies aimed at facilitating the implementation and evaluation of chronic disease management programs were formulated based on the discussions at this knowledge translation event. The results from this knowledge translation day will help inform the sustainability of these seven chronic disease management programs in Quebec and the implementation and evaluation of similar programs elsewhere.


Depression in Asthma: Prevalence and Clinical Implications.
BACKGROUND: Asthma and depression are both common illnesses. Data suggest that the prevalence of asthma and asthma-related morbidity and mortality has increased in the past 2 decades. Asthma has long been considered an illness in which mood and emotions contribute to symptom exacerbation. Therefore, we reviewed the recent literature on depression in persons with asthma. DATA SOURCES: The MEDLINE (1966-1999) and PSYCHINFO (1967-1999) databases were used to find English-language articles on asthma and depression. Search terms included asthma, depression, dysthymia, and mood. DATA SYNTHESIS: This literature suggests depressive symptoms are more common in asthma patients than in the general population and perhaps even more common than in some other general medical conditions. Depression may be associated with asthma morbidity and mortality. Limited data suggest the older tricyclic antidepressants may improve both depression and asthma symptoms. However, no studies have examined the use of second-generation antidepressants in asthma patients. CONCLUSION: Depressive symptoms are common in asthma patients. However, the prevalence of depressive disorders in this population is not well determined. Future studies should focus on determining the prevalence of major depressive disorder in this population and the effect of antidepressants on mood and asthma symptoms.


Dietary and other risk factors in women having fibrocystic breast conditions with and without concurrent breast cancer: a nested case-control study in Shanghai, China.
Risk of breast cancer is increased in women with proliferative benign breast conditions. Most of these conditions, however, do not progress to breast cancer. The purpose of our study was to identify factors possibly associated with this progression. Women with proliferative fibrocystic breast conditions alone (214), and women with proliferative fibrocystic breast conditions and concurrent breast cancer (130), were compared to each other, and each of these groups of women were also compared to 1,070 controls; and 176 women with non-proliferative benign breast conditions alone, and 155 also with breast cancer, were similarly compared. All study subjects were selected from a cohort of women enrolled in a trial of breast self-examination in Shanghai. Women were interviewed to ascertain information on suspected risk factors for breast cancer and dietary habits. Conditional logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Increased risks of both proliferative fibrocystic breast conditions alone, and with breast cancer, were associated with low parity, a prior benign breast lump and breast cancer in a first-degree relative. Decreasing trends in the risk of both conditions with increasing intake of fruits and vegetables were observed. No factors were significantly associated with risk of breast cancer relative to risk of proliferative changes. Similar, but in some instances weaker, associations were observed for non-proliferative fibrocystic conditions with and without breast cancer. The possible risk or protective factors that were observed in our study most likely alter the risk of breast cancer at an early stage in the carcinogenic process, and probably do not alter risk of progression from proliferative fibrocystic breast conditions to breast cancer.


Invasion of Phytophthora infestans at the landscape level: how do spatial scale and weather modulate the consequences of spatial heterogeneity in host resistance?
Strategic spatial patterning of crop species and cultivars could make agricultural landscapes less vulnerable to plant disease epidemics, but experimentation to explore effective disease-suppressive landscape designs is problematic. Here, we present a realistic, multiscale, spatiotemporal, integrodifference equation model of potato late blight epidemics to determine the relationship between spatial heterogeneity and disease spread, and determine the effectiveness of mixing resistant and susceptible cultivars at different spatial scales under the influence of weather. The model framework comprised a landscape generator, a potato late blight model that includes host and pathogen life cycles and fungicide management at the field scale, and an atmospheric dispersion model that calculates spore dispersal at the landscape scale. Landscapes consisted of one or two distinct potato-growing regions (6.4-by-6.4-km) embedded within a nonhost matrix. The characteristics of fields and growing regions and the separation distance between two growing regions were investigated for their effects on disease incidence, measured as the proportion of fields with ≥1% severity, after inoculation of a single potato grid cell with a low initial level of disease. The most effective spatial strategies for suppressing disease spread in a region were those that reduced the acreage of potato or increased the proportion of a resistant potato cultivar. Clustering potato cultivation in some parts of a region, either by planting in large fields or clustering small fields, enhanced the spread within such a cluster while it delayed spread from one cluster to another; however, the net effect of clustering was an increase in disease at the landscape scale. The planting of mixtures of a resistant and susceptible cultivar was a consistently effective option for creating potato-growing regions that suppressed disease spread. It was more effective to mix susceptible and resistant cultivars within fields than plant some fields entirely with a susceptible cultivar and other fields with a resistant cultivar, at the same ratio of susceptible to resistant potato plants at the landscape level. Separation distances of at least 16 km were needed to completely prevent epidemic spread from one potato-growing region to another. Effects of spatial placement of resistant and susceptible potato cultivars depended strongly on meteorological conditions, indicating that landscape connectivity for the spread of plant disease depends on the particular coincidence between direction of spread, location of fields, distance between the fields, and survival of the spores depending on the weather. Therefore, in the simulation of (airborne) pathogen invasions, it is important to consider the large variability of atmospheric dispersion conditions.


A glimpse into the future - Personalized medicine for smoking cessation.
The devastating consequences of tobacco smoking for individuals and societies motivate studies to identify and understand the biological pathways that drive smoking behaviors, so that more effective preventions and treatments can be developed. Cigarette smokers respond to nicotine in different ways, with a small number of smokers remaining lifelong low-level smokers who never exhibit any symptoms of dependence, and a larger group becoming nicotine dependent. Whether or not a smoker transitions to nicotine dependence has clear genetic contributions, and variants in the genes encoding the α5-α3-β4 nicotinic receptor subunits most strongly contribute to differences in the risk for developing nicotine dependence among smokers. More recent work reveals a differential response to pharmacologic treatment for smoking cessation based on these same genetic variants in the α5-α3-β4 nicotinic receptor gene cluster. We anticipate a continuing acceleration of the translation of genetic discoveries into more successful treatment for smoking cessation. Given that over 400,000 people in the United States and over 5 million people world-wide die each year from smoking related illnesses, an improved understanding of the mechanisms underlying smoking behavior and smoking cessation must be a high public health priority so we can best intervene at both the public health level and the individual level. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.