Healthcare seeking practices and barriers to accessing under-five child health services in urban slums in Malawi: a qualitative study.
Access to child health services is an important determinant of child health. Whereas, child health indicators are generally better in urban than rural areas, some population groups in urban areas, such as children residing in urban slums do not enjoy this urban health advantage. In the context of increasing urbanisation and urban poverty manifesting with proliferation of urban slums, the health of under-five children in slum areas remains a public health imperative in Malawi. This paper explores healthcare-seeking practices for common childhood illnesses focusing on use of biomedical health services and perceived barriers to accessing under-five child health services in urban slums of Lilongwe, Malawi's capital city. Qualitative data from 8 focus group discussions with caregivers and 11 in-depth interviews with key informants conducted from September 2012 to April 2013 were analysed using conventional content analysis. Whereas, caregivers sought care from biomedical health providers, late care-seeking also emerged as a major theme and phenomenon. Home management was actively undertaken for childhood illnesses. Various health system barriers: lack of medicines and supplies; long waiting times; late facility opening times; negative attitude of health workers; suboptimal examination of the sick child; long distance to health facility; and cost of healthcare were cited in this qualitative inquiry as critical health system factors affecting healthcare-seeking for child health services. Interventions to strengthen the health system's responsiveness to expectations are essential to promote utilisation of child health services among urban slum populations, and ultimately improve child health and survival.


Finding the founder of Stockholm - a kinship study based on Y-chromosomal, autosomal and mitochondrial DNA.
Historical records claim that Birger Magnusson (died 1266), famous regent of Sweden and the founder of Stockholm, was buried in Varnhem Abbey in Västergötland. After being lost for centuries, his putative grave was rediscovered during restoration work in the 1920s. Morphological analyses of the three individuals in the grave concluded that the older male, the female and the younger male found in the grave were likely to be Birger, his second wife Mechtild of Holstein and his son Erik from a previous marriage. More recent evaluations of the data from the 1920s seriously questioned these conclusions, ultimately leading to the reopening and reexamination of the grave in 2002. Ancient DNA-analyses were performed to investigate if the relationship between the three individuals matched what we would expect if the individuals were Birger, Erik and Mechtild. We used pyrosequencing of Y-chromosomal and autosomal SNPs and compared the results with haplogroup frequencies of modern Swedes to investigate paternal relations. Possible maternal kinship was investigated by deep FLX-sequencing of overlapping mtDNA amplicons. The authenticity of the sequences was examined using data from independent extractions, massive clonal data, the c-statistics, and real-time quantitative data. We show that the males carry the same Y-chromosomal haplogroup and thus we cannot reject a father-son type of relation. Further, as shown by the mtDNA analyses, none of the individuals are maternally related. We conclude that the graves indeed belong to Birger, Erik and Mechtild, or to three individuals with the exact same kind of biological relatedness.


Simple, sensitive, and specific detection of human immunodeficiency virus type 1 subtype B DNA in dried blood samples for diagnosis in infants in the field.
The detection of virus is used to diagnose human immunodeficiency virus type 1 (HIV-1) infection in infants due to the persistence of maternal antibodies for a year or more. An HIV-1 DNA PCR assay with simple specimen collection and processing was developed and evaluated. Whole blood was collected on filter paper that lysed cells and bound the DNA, eliminating specimen centrifugation and extraction procedures. The DNA remained bound to the filter paper during PCR amplification. Assays of copy number standards showed reproducible detection of 5 to 10 copies of HIV-1 in 5 microl of whole blood. The sensitivity of the assay did not decrease after storage of the standards on filter paper for 3 months at room temperature or after incubation at 37 or 45 degrees C for 20 h. The primers used for nested PCR of the HIV-1 pol gene amplified templates from a reference panel of multiple HIV-1 subtypes but did not amplify a subtype A or a subtype C virus from children living in Seattle. The assay had a sensitivity of 98.4% and a specificity of 98.3% for testing of 122 specimens from 35 HIV-1-infected and 16 uninfected children and 43 seronegative adults living in Washington. The assay had a sensitivity of 99% and a specificity of 100% for testing of 102 HIV-1-positive (as determined by enzyme immunoassay) Peruvian women and 6 seropositive and 34 seronegative infants. This assay, with adsorption of whole blood to filter paper and no specimen processing, provides a practical, economical, sensitive, and specific method for the diagnosis of HIV-1 subtype B infection in infants.


Rescue of the colony-stimulating factor 1 (CSF-1)-nullizygous mouse (Csf1(op)/Csf1(op)) phenotype with a CSF-1 transgene and identification of sites of local CSF-1 synthesis.
Colony-stimulating factor 1 (CSF-1) regulates the survival, proliferation, and differentiation of mononuclear phagocytes. It is expressed as a secreted glycoprotein or proteoglycan found in the circulation or as a biologically active cell-surface glycoprotein. To investigate tissue CSF-1 regulation, CSF-1-null Csf1(op)/Csf1(op) mice expressing transgenes encoding the full-length membrane-spanning CSF-1 precursor driven by 3.13 kilobases of the mouse CSF-1 promoter and first intron were characterized. Transgene expression corrected the gross osteopetrotic, neurologic, weight, tooth, and reproductive defects of Csf1(op)/Csf1(op) mice. Detailed analysis of one transgenic line revealed that circulating CSF-1, tissue macrophage numbers, hematopoietic tissue cellularity, and hematopoietic parameters were normalized. Tissue CSF-1 levels were normal except for elevations in 4 secretory tissues. Skin fibroblasts from the transgenic mice secreted normal amounts of CSF-1 but also expressed some cell-surface CSF-1. Also, lacZ driven by the same promoter/first intron revealed beta-galactosidase expression in hematopoietic, reproductive, and other tissue locations proximal to CSF-1 cellular targets, consistent with local regulation by CSF-1 at these sites. These studies indicate that the 3.13-kilobase promoter/first intron confers essentially normal CSF-1 expression. They also pinpoint new cellular sites of CSF-1 expression, including ovarian granulosa cells, mammary ductal epithelium, testicular Leydig cells, serous acinar cells of salivary gland, Paneth cells of the small intestine, as well as local sites in several other tissues.


Single lung transplantation for lymphangioleiomyomatosis: a single-center experience in Japan.
Lung transplantation is accepted as an effective modality for patients with end-stage pulmonary lymphangioleiomyomatosis (LAM). Generally, bilateral lung transplantation is preferred to single lung transplantation (SLT) for LAM because of native lung-related complications, such as pneumothorax and chylothorax. It remains controversial whether SLT is a suitable surgical option for LAM. The objective of this study was to evaluate the morbidity, mortality and outcome after SLT for LAM in a lung transplant center in Japan. We reviewed the records of 29 patients who underwent SLT for LAM in our hospital between March, 2000 and November, 2017. The data collected included the pre-transplant demographics of recipients, surgical characteristics, complications, morbidity, mortality and survival after SLT for LAM. The most common complication after SLT for LAM was contralateral pneumothorax (n = 7; 24.1%). Six of these recipients were treated successfully with chest-tube placement and none required surgery for the pneumothorax. The second-most common complication was chylous pleural effusion (n = 6; 20.7%) and these recipients were all successfully treated by pleurodesis. The 5-year survival rate after SLT for LAM was 79.5%. LAM-related complications after SLT for this disease can be managed. SLT is a treatment option and may improve access to lung transplantation for patients with end-stage LAM.


Longitudinal sleep EEG trajectories indicate complex patterns of adolescent brain maturation.
New longitudinal sleep data spanning ages 6-10 yr are presented and combined with previous data to analyze maturational trajectories of delta and theta EEG across ages 6-18 yr in non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. NREM delta power (DP) increased from age 6 to age 8 yr and then declined. Its highest rate of decline occurred between ages 12 and 16.5 yr. We attribute the delta EEG trajectories to changes in synaptic density. Whatever their neuronal underpinnings, these age curves can guide research into the molecular-genetic mechanisms that underlie adolescent brain development. The DP trajectories in NREM and REM sleep differed strikingly. DP in REM did not initially increase but declined steadily from age 6 to age 16 yr. We hypothesize that the DP decline in REM reflects maturation of the same brain arousal systems that eliminate delta waves in waking EEG. Whereas the DP age curves differed in NREM and REM sleep, theta age curves were similar in both, roughly paralleling the age trajectory of REM DP. The different maturational curves for NREM delta and theta indicate that they serve different brain functions despite having similar within-sleep dynamics and responses to sleep loss. Period-amplitude analysis of NREM and REM delta waveforms revealed that the age trends in DP were driven more by changes in wave amplitude rather than incidence. These data further document the powerful and complex link between sleep and brain maturation. Understanding this relationship would shed light on both brain development and the function of sleep.


Pharmacogenomic identification of targets for adjuvant therapy with the topoisomerase poison camptothecin.
The response of tumor cells to the unusual form of DNA damage caused by topoisomerase poisons such as camptothecin (CPT) is poorly understood, and knowledge regarding which drugs can be effectively combined with CPT is lacking. To better understand the response of tumor cells to CPT and to identify potential targets for adjuvant therapy, we examined global changes in mRNA abundance in HeLa cells after CPT treatment using Affymetrix U133A GeneChips, which include all annotated human genes (22,283 probe sets). Statistical analysis of the data using a Bayesian/Cyber t test and a modified Benjamini and Hochberg correction for multiple hypotheses testing identified 188 probe sets that are induced and 495 that are repressed 8 h after CPT treatment at a False Discovery Rate of <0.05 and a minimum 3-fold change. This pharmacogenomic approach led us to identify two pathways that are CPT induced: (a) the epidermal growth factor receptor; and (b) nuclear factor-kappaB-regulated antiapoptotic factors. Experiments using HeLa cells in our lab and prior animal model studies performed elsewhere confirm that inhibitors of these respective pathways super-additively enhance CPT's cytotoxicity, suggesting their potential as targets for adjuvant therapy with CPT.


Comparisons of ISO depth of cure for a resin composite in stainless-steel and natural-tooth molds.
The purpose of this study was to compare the depth of cure (DOC) of a resin-based composite (RBC) using the ISO DOC protocol with stainless-steel and molar-tooth molds (4 mm cylindrical cavity). The tooth mold included testing with and without the occlusal surface being covered with black tape around the cavity opening. The RBC was cured with either halogen (HAL) or light-emitting diode (LED) light. The results showed that specimens made in the non-taped tooth mold had DOCs that were significantly greater (28%-35%) than those in the stainless-steel mold. The taped tooth mold also produced significantly greater DOCs, but only by 6%-8%. Knoop hardness (KNH) measurements along the central axis of the RBC specimens showed that depths for 80% of maximum hardness were substantially greater than those determined by the ISO DOC protocol but were limited to the center and quickly dropped below 80% in a lateral direction. The KHN mapping for each of the three molds found that the ISO DOCs could validate a KHN of ≥80% across the RBC to the periphery, only for the non-taped tooth mold. This was due to light incident on the tooth surrounding the RBC being scattered into the RBC.


The impact of role models on health outcomes for lesbian, gay, bisexual, and transgender youth.
There is little research on the impact of role models on health outcomes for lesbian, gay, bisexual, and transgender (LGBT) youth. This exploratory study describes the presence and availability of LGBT-affirming role models, and examines the relationship between the accessibility of role models and health outcomes among a community-based sample of LGBT youth. A convenience sample of 496 ethnically diverse, 16-24-year-old LGBT youth was recruited to complete a computer-assisted interview, using standardized instruments validated with adolescents. The prevalence and characteristics of role models were described. Differences in subgroup distribution were assessed using Pearson χ(2) test (p < .05). Differences in health outcomes for those with and without role models and the nature of those role models were determined using analysis of covariance models, with post hoc Bonferroni tests to probe significant global findings. Sixty percent of the participants reported having a role model, with younger participants significantly more likely to report having a role model. A majority of the participants reported having inaccessible role models, especially among younger participants. The presence and accessibility of a role model did not have a significant relationship to binge drinking, drug use, or sexually transmitted infection diagnoses; however, participants with inaccessible role models showed increased psychological distress versus those with accessible or no role models. Inaccessible role models may not be sufficient for protecting youth from negative outcomes, and formal mechanisms for connecting LGBT youth with caring adults who can serve as role models, such as mentoring programs, are critical.


Clinical utility of HNF1A genotyping for diabetes in aboriginal Canadians.
To determine the diagnostic performance characteristics of HNF1A genotyping for diabetes and impaired glucose tolerance (IGT) in Canadian Oji-Cree Indians. We studied all Oji-Cree subjects > or = 50 years of age (96 subjects) who had participated in a community-wide prevalence survey for type 2 diabetes. Subjects were classified either as having "disease," which included type 2 diabetes and IGT, or not. All subjects were genotyped for the HNF1A G319S mutation. The prevalence of disease in this group was 65.7%, of whom 71.4% had type 2 diabetes. For a carrier of HNF1A S319, the specificity, sensitivity, and positive and negative predictive values were 97.0, 30.1, 95.0, and 42.1%, respectively. When the pretest disease prevalence was accounted for, the probability of disease after a positive test was 97.2%, and the probability of disease after a negative test was 42.2%. The values were very similar for the subgroup of subjects with type 2 diabetes alone. The HNF1A genotype appears to be the most specific genetic test yet reported for the prediction of a common multifactorial disease by applying present-day standards of clinical epidemiology in molecular genetics. A positive test result had particular diagnostic value in the Oji-Cree: a subject with HNF1A S319 was virtually certain of having diabetes or IGT by 50 years of age. In contrast, a subject without HNF1A S319 had a reduced risk compared with the age-specific prevalence but was not totally risk-free. Because HNF1A S319 was not the only predisposing factor for diabetes in the Oji-Cree, subjects without HNF1A S319 were still at some risk for diabetes or IGT.


Prospective gating control for highly efficient cardio-respiratory synchronised short and constant TR MRI in the mouse.
Cardiac and respiratory motion derived image artefacts are reduced when data are acquired with cardiac and respiratory synchronisation. Where steady state imaging techniques are required in small animals, synchronisation is most commonly performed using retrospective gating techniques but these invoke an inherent time penalty. This paper reports the development of prospective gating techniques for cardiac and respiratory motion desensitised MRI with significantly reduced minimum scan time compared to retrospective gating. Prospective gating incorporating the automatic reacquisition of data corrupted by motion at the entry to each breath was implemented in short TR 3D spoiled gradient echo imaging. Motion sensitivity was examined over the whole mouse body for scans performed without gating, with respiratory gating, and with cardio-respiratory gating. The gating methods were performed with and without automatic reacquisition of motion corrupted data immediately after completion of the same breath. Prospective cardio-respiratory gating, with acquisition of 64 k-space lines per cardiac R-wave, was used to enable whole body DCE-MRI in the mouse. Prospective cardio-respiratory gating enabled high fidelity steady state imaging of physiologically mobile organs such as the heart and lung. The automatic reacquisition of data corrupted by motion at the entry to each breath minimised respiratory motion artefact and enabled a highly efficient data capture that was adaptive to changes in the inter-breath interval. Prospective cardio-respiratory gating control enabled DCE-MRI to be performed over the whole mouse body with the acquisition of successive image volumes every 12-15 s at 422 μm isotropic resolution. Highly efficient cardio-respiratory motion desensitised steady state MRI can be performed in small animals with prospective synchronisation, centre-out phase-encode ordering, and the automatic reacquisition of data corrupted by motion at the entry to each breath. The method presented is robust against spontaneous changes in the breathing rate. Steady state imaging with prospective cardio-respiratory gating is much more efficient than with retrospective gating, and enables the examination of rapidly changing systems such as those found when using DCE-MRI.


Safety and performance of diagnostic electrical mapping of renal nerves in hypertensive patients.
The aim of this study was to evaluate the safety and performance of renal nerve stimulation (RNS) for diagnostic mapping of the renal nerves. In this first-in-man study, twenty hypertensive patients underwent RNS using the ConfidenHT system. Bilateral stimulations were performed at three to four sites per artery at 2 and 4 mA. The primary endpoint was change in systolic blood pressure (SBP). Mean office blood pressure was 156/89 mmHg. No periprocedural adverse events occurred. Stimulation with 2 mA resulted in a maximum change of 8.3±6.3 mmHg in SBP (based on 119 stimulations; p<0.001), while stimulating with 4 mA resulted in a maximum change of 10.1±7.8 mmHg (based on 61 stimulations; p<0.001). The mean change in SBP did not vary between mid, distal or branch sites when stimulating at 2 mA but was significantly higher at ostial (23±14 mmHg) than at non-ostial locations (9±7 mmHg) when stimulating at 4 mA (p=0.003). RNS can be performed safely and effectively along the renal artery and results in a large variation in temporary BP changes per patient and per anatomic location. RNS might help in optimising treatment effect and selecting potential responders to renal sympathetic denervation.


L'apport critique de l'évaluation de la communication dans le diagnostic précoce de l'apraxie primaire progressive de la parole.
Primary progressive apraxia of speech (PPAoS) is a neurodegenerative syndrome characterized by speech apraxia at its onset; as it progresses, it often evolves into total mutism. Even though this syndrome is increasingly recognized, its early differential diagnostic is still complex. The objective of this study was to illustrate why a fine evaluation of speech and language is essential for the differential diagnosis of PPAoS. This longitudinal case study presents the progression of a PPAoS patient over a period of 5 years. Periodic neurological and speech-language assessments were carried out to follow the progression of neurological, memory, language and speech symptoms. The different diagnostic labels established over time were also reported. The evolution of the patient's communication profile was characterized by a preservation of language components and episodic memory, in parallel with a progressive deterioration of speech which gradually reduced intelligibility, and was associated with signs of spasticity, resulting in a complete anarthria. This case study sheds light upon the evolution of a patient with PPAoS. A better understanding of the clinical profile and progression of PPAoS is necessary in order to improve early diagnosis and adequate care for these patients.


Influence of noradrenaline denervation on MPTP-induced deficits in mice.
C57/BL6 mice were administered either DSP4 (50 mg/kg, s.c., 30 min after injection of zimeldine, 20 mg/kg, s.c.) or vehicle (saline) at 63 days of age. Three weeks later, one group (n = 10) of DSP4-treated and one group of vehicle-treated mice were administered MPTP (2 x 40 mg/kg, s.c., 24 hours between injections; the High dose groups), one group (n = 10) of DSP4-treated and one group of vehicle-treated mice were administered MPTP (2 x 20 mg/kg, s.c., 24 hours between injections; the Low dose groups), and one group (n = 10) of DSP4-treated and one group of vehicle-treated mice were administered vehicle. Three weeks later, all six groups were tested in motor activity test chambers, followed by injections of L-Dopa (20 mg/kg, s.c.), and then tested over a further 360 min in the activity test chambers. It was found that pretreatment with the selective NA neurotoxin, DSP4, deteriorated markedly the dose-dependent motor activity deficits observed in the vehicle pretreated MPTP treated mice. These 'ultra-deficits' in the spontaneous motor behaviour of MPTP-treated mice were observed over all three parameters: locomotion, rearing and total activity, and were restricted to the 1(st) and 2(nd) 20-min periods. Administration of L-Dopa (20 mg/kg) following the 60-min testing of spontaneous behaviour restored the motor activity of Vehicle + MPTP treated mice (neither the Vehicle + MPTP-Low nor the Vehicle + MPTP-High groups differed from the Vehicle-Vehicle group, here) but failed to do so in the DSP4 pretreated mice. Here, a dose-dependent deficit of L-Dopa-induced motor activity (over all three parameters) was obtained thereby offering further evidence of an 'ultra-deficit' of function due to previous denervation of the NA terminals. The present findings support the notion that severe damage to the locus coeruleus noradrenergic system, through systemic DSP4, disrupts the facilitatory influence on the nigrostriatal DA system, and interferes with the ability of the nigrostriatal pathway to compensate for or recover from marked injury, MPTP treatment.


Self-expanding stent modelling and radial force accuracy.
Computational simulations using finite element analysis are a tool commonly used to analyse stent designs, deployment geometries and interactions between stent struts and arterial tissue. Such studies require large computational models and efforts are often made to simplify models in order to reduce computational time while maintaining reasonable accuracy. The objective of the study is focused on computational modelling and specifically aims to investigate how different methods of modelling stent-artery interactions can affect the results, computational time taken and computational size of the model. Various different models, each with increasing levels of complexity, are used to simulate this analysis, representing the many assumptions and simplifications used in other similar studies in order to determine what level of simplification will still allow for an accurate representation of stent radial force and resulting stress concentrations on the inner lining of the vessel during self-expanding stent deployment. The main conclusions of the study are that methods used in stent crimping impact on the resulting predicted radial force of the stent; that accurate representation of stent-artery interactions can only be made when modelling the full length of the stent due to the incorporation of end effects; and that modelling self-contact of the stent struts greatly impacts on the resulting stress concentrations within the stent, but that the effect of this on the unloading behaviour and resulting radial force of the stent is negligible.


A novel combination treatment for breast cancer cells involving BAPTA-AM and proteasome inhibitor bortezomib.
Glucose-regulated protein 78 kDa/binding immunoglobulin protein (GRP78/BIP) is a well-known endoplasmic reticulum (ER) chaperone protein regulating ER stress by facilitating protein folding, assembly and Ca2+ binding. GRP78 is also a member of the heat shock protein 70 gene family and induces tumor cell survival and resistance to chemotherapeutics. Bortezomib is a highly specific 26S proteasome inhibitor that has been approved as treatment for patients with multiple myeloma. The present study first examined the dose- and time-dependent effects of bortezomib on GRP78 expression levels in the highly metastatic mouse breast cancer 4T1 cell line using western blot analysis. The analysis results revealed that GRP78 levels were significantly increased by bortezomib at a dose as low as 10 nM. Time-dependent experiments indicated that the accumulation of GRP78 was initiated after a 24 h incubation period following the addition of 10 nM bortezomib. Subsequently, the present study determined the half maximal inhibitory concentration of intracellular calcium chelator BAPTA-AM (13.6 µM) on 4T1 cells. The combination effect of BAPTA-AM and bortezomib on the 4T1 cells was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and WST-1 assays and an iCELLigence system. The results revealed that the combination of 10 nM bortezomib + 5 µM BAPTA-AM is more cytotoxic compared with monotherapies, including 10 nM bortezomib, 1 µM BAPTA-AM and 5 µM BAPTA-AM. In addition, the present results revealed that bortezomib + BAPTA-AM combination causes cell death through the induction of apoptosis. The present results also revealed that bortezomib + BAPTA-AM combination-induced apoptosis is associated with a clear increase in the phosphorylation of stress-activated protein kinase/Jun amino-terminal kinase SAPK/JNK. Overall, the present results suggest that bortezomib and BAPTA-AM combination therapy may be a novel therapeutic strategy for breast cancer treatment.


Reclassification of Eubacterium formicigenerans Holdeman and Moore 1974 as Dorea formicigenerans gen. nov., comb. nov., and description of Dorea longicatena sp. nov., isolated from human faeces.
Two strains of a gram-positively staining, obligately anaerobic, non-spore-forming, rod-shaped bacterium, designated strains 111-13A and 111-35T, were isolated from human faeces. Analysis of the 16S rRNA gene sequences indicated that these strains were members of the Clostridium coccoides rRNA group of organisms. The nearest relatives of the unknown bacterium were Eubacterium formicigenerans (having a sequence similarity of 94%) and an uncultured bacterium (similarity > 99%). Characterization studies indicated that the unidentified faecal bacterium was biochemically distinct from Eubacterium formicigenerans, members of the Clostridium coccoides group and all other described Eubacterium species. On the basis of the data from these studies, it is proposed that the hitherto unknown rod-shaped bacterium be designated a species of a novel genus, namely Dorea longicatena gen. nov., sp. nov., and that Eubacterium formicigenerans be transferred to this genus as Dorea formicigenerans gen. nov., comb. nov.


Exploring the Benefits and Value of Public Health Department Internships for Environmental Health Students.
Internships are an essential component of preparing prospective college graduates for entering the practice-based field of environmental health (EH). EH professionals continually encounter events or hazards of high complexity and impact, and many experienced EH professionals are expected to retire within the next several years. Efforts are needed to ensure a supply of highly qualified and prepared graduates is available to sustain and strengthen the EH workforce. The National Environmental Public Health Internship Program (NEPHIP) addresses this need by supporting health department internships for EH students of academic programs accredited by the National Environmental Health Science and Protection Accreditation Council. We conducted an assessment to examine former NEPHIP intern and mentor experiences and perspectives on 1) how well the internships prepared interns for careers in EH and 2) to what extent the internships provided value to the host health department. Overall, the internships appeared to provide EH students with a well-rounded professional and practice-based experience, while health departments benefited from hosting interns with a foundational knowledge and college education in EH. Promoting the value of public health department EH internships could encourage more students and graduates to seek internship or employment opportunities with health departments, ultimately strengthening the EH workforce.


Technical performance during soccer matches of the Italian Serie A league: effect of fatigue and competitive level.
The purpose of this study was to examine the changes in technical and physical performance between the first and second half during official matches of Italian Serie A league. Further aim was to compare the technical and physical performance of the players of the more successful teams (ranked in the first 5 positions) with the players of the less successful teams (ranked in the last 5 positions) from the same league. A total of 416 individual games from 186 soccer players (27+/-4 years, 76+/-5kg, and 181+/-5cm) were analysed using a video match-analysis system. The match performance parameters analysed were: total distance covered (TD), high-intensity running distance (HIR), very high-intensity running distance (VHIR), total distance with the ball (TDB), high-intensity running distance with the ball (HIRB), and very high-intensity running distance with the ball (VHIRB). The number of skill involvements was also measured. The players from the more successful teams covered greater TDB and HIRB and also had more involvements with the ball, completed more short passes, successful short passes, tackles, dribbling, shots and shots on target compared to the less successful teams (P<0.01). A significant decline (P<0.01) between the first and second half was found for both physical performance and some technical scores (involvements with the ball, short passes and successful short passes). This study showed a decline in technical and physical performance between the first and second half, and that both physical performance and technical skills were different between players from more successful and less successful teams.


Augmentation index and central aortic blood pressure in patients with abdominal aortic aneurysms.
Abdominal aortic aneurysm (AAA) is a life-threatening disease as rupture of the aneurysm is associated with high mortality. The likelihood that an AAA will rupture is particularly influenced by the diameter of the aneurysm and the rate of expansion; the reasons for fast expansion are largely unknown. Applanation tonometry (APT) can predict outcome in certain cardiovascular diseases by measuring arterial stiffness (augmentation index, AIx) and central aortic blood pressure (CABP). We tested the hypothesis that AIx and CABP would be higher in patients with fast-progressing AAA. We performed APT and peripheral blood pressure measurements in 114 patients with AAA (11 women) with a mean ± SD age of 67.4±6.1 years. Annual AAA progression rate was determined by ultrasound. Patients were grouped into fast progressors (progression ≥2 mm/year) and slow progressors (progression <2 mm/year). Mean follow-up time after inclusion into the AAA surveillance programme was 22.1 ± 16.3 months. AIx was similar in fast progressors (27.3 ± 13.0%) and slow progressors (26.5 ± 12.6%) (P = 0.73). Fast progressors had a significantly higher CABP during systole (116.0 ± 16.0 mmHg) and diastole (95.7 ± 12.6 mmHg) than slow progressors (109.5 ± 16.3 and 90.0 ± 13.2 mmHg) (P = 0.04 and P = 0.02, respectively). Mean peripheral blood pressure was significantly higher in fast progressors (102.7 ± 12.8 mmHg) than in slow progressors (97.7 ± 12.9 mmHg) (P = 0.04). Augmentation index did not differ in patients with fast and slow-progressing AAA. However, fast progressors had higher central aortic blood pressures suggesting that elevated aortic blood pressure is a risk factor for faster AAA progression, but this needs to be proven in controlled interventional studies.


Probing the Local Generation and Diffusion of Active Oxygen Species on a Pd/Au Bimetallic Surface by Tip-Enhanced Raman Spectroscopy.
Active oxygen species (AOS) play key roles in many important catalytic reactions relevant to clean energy and environment. However, it remains challenging to characterize the active sites for producing AOS and to image the surface properties of AOS, especially on multicomponent metallic catalyst surfaces. Herein, we utilize tip-enhanced Raman spectroscopy (TERS) to probe the local generation and diffusion of OH radicals on a Pd/Au(111) bimetallic catalyst surface. The reactive OH radicals can be catalytically generated from hydrogen peroxide (H2O2) at the metal surface, which then oxidizes the surface adsorbed thiolate, a reactant that is used as the TERS probe. By TERS imaging of the spatial distribution of unreacted thiolate molecules, we demonstrate that the Pd surface is active for generation of OH radicals and the Pd step edge shows much higher activity than the Pd terrace, whereas the Au surface is inactive. Furthermore, we find that the locally generated OH radicals at the Pd step edge could diffuse to both the Au and the Pd surface sites to induce oxidative reactions, with a diffusion length estimated to be about 5.4 nm. Our TERS imaging with few-nanometer spatial resolution not only unravels the active sites but also characterizes in real space the diffusion behavior of OH radicals. The results are highly valuable to understand AOS-triggered catalytic reactions. The strategy of using reactants with large Raman cross sections as TERS probes may broaden the application of TERS for studying catalysis with reactive small molecules.


Influence of sensation seeking on response to alcohol versus placebo: implications for the acquired preparedness model.
Previous research has identified several aspects of behavioral undercontrol that are associated with heavy drinking and problems. Further, research on the acquired preparedness model (Smith and Anderson, 2001) has identified biased learning as a potential mechanism of these effects. Traits like sensation seeking have been linked to stronger positive and weaker negative expectancies, which, in turn, contribute to increased risk for heavy drinking and problems. Although expectancies are thought to represent potentially biased expectations about drinking outcomes, they may also reflect individual differences in alcohol response. The present study examined the strength of associations between sensation seeking and both expectancies (response to placebo) and subjective response under alcohol. Using a between-subjects design, young adult social drinkers (N = 236) were randomly assigned to receive alcohol (target breath alcohol concentration of .08%) or placebo, after which they reported on subjective experiences of stimulation and sedation. Sensation seeking was significantly related to stimulant response, and the strength of this association did not differ by beverage condition (alcohol vs. placebo). The findings argue against a pharmacological explanation for results of prior studies of the acquired preparedness model and support a biased learning interpretation of relations between sensation seeking and positive expectancies. Results also extend the findings on the acquired preparedness model to an implicit measure of positive alcohol expectancies (subjective response to placebo). Future studies using additional measures of implicit expectancies (e.g., Implicit Association Test) would be helpful in determining the relative strength of implicit and explicit expectancies as mediators within the acquired preparedness model.


UN High-Level Meeting on Non-Communicable Diseases: addressing four questions.
Non-communicable diseases (NCDs), principally heart disease, stroke, cancer, diabetes, and chronic respiratory diseases, are a global crisis and require a global response. Despite the threat to human development, and the availability of affordable, cost-effective, and feasible interventions, most countries, development agencies, and foundations neglect the crisis. The UN High-Level Meeting (UN HLM) on NCDs in September, 2011, is an opportunity to stimulate a coordinated global response to NCDs that is commensurate with their health and economic burdens. To achieve the promise of the UN HLM, several questions must be addressed. In this report, we present the realities of the situation by answering four questions: is there really a global crisis of NCDs; how is NCD a development issue; are affordable and cost-effective interventions available; and do we really need high-level leadership and accountability? Action against NCDs will support other global health and development priorities. A successful outcome of the UN HLM depends on the heads of states and governments attending the meeting, and endorsing and implementing the commitments to action. Long-term success requires inspired and committed national and international leadership.


High-power dual-wavelength laser with disordered Nd:CNGG crystals.
We demonstrate the high-power dual-wavelength laser output with disordered Nd:CNGG laser crystals. Continuous-wave output power of 4.03 W was obtained under the incident pump power of 15.62 W. In the passively Q-switched operation, the shortest pulse width, largest pulse energy, and highest peak power were achieved to be 12.9 ns, 173.16 microJ, and 12.3 kW, respectively, with Cr(4+):YAG crystals as the saturable absorbers. By spectral analysis, the output lasers were found to have dual wavelengths. We believed that the passively Q-switched dual-wavelength laser should be possible to be used as a source for the generation of terahertz radiation.


A novel alpha-globin gene arrangement in man.
The human genome has two linked alpha-globin genes on chromosome 16. Deletion of one or more of them, as occurs in alpha-thalassaemia, leads to a reduced output of alpha-globin mRNA in proportion to the number of alpha-globin genes lost. In some racial groups deletion of one of the pair of alpha-globin genes may result from unequal crossing over between the genes on homologous chromosomes by a mechanism resembling that postulated for the formation of the delta beta fusion genes of the Lepore haemoglobins. By analogy, the opposite chromosome in this cross-over should have three alpha-globin genes just as the 'anti-Lepore chromosome has three non-alpha chain genes. We describe here a Welsh family in which three members have five alpha-globn increased alpha mRNA output and it may therefore produce the phenotype of mild beta-thalassaemia.


Infiltrating CD16+ Are Associated with a Reduction in Peripheral CD14+CD16++ Monocytes and Severe Forms of Lupus Nephritis.
Our aim was to characterize glomerular monocytes (Mo) infiltration and to correlate them with peripheral circulating Mo subsets and severity of lupus nephritis (LN). Methods. We evaluated 48 LN biopsy samples from a referral hospital. Recognition of Mo cells was done using microscopic view and immunohistochemistry stain with CD14 and CD16. Based on the number of cells, we classified LN samples as low degree of diffuse infiltration (<5 cells) and high degree of diffuse infiltration (≥5 cells). Immunophenotyping of peripheral Mo subsets was done using flow cytometry. Results. Mean age was 34.0 ± 11.7 years and the mean SLEDAI was 17.5 ± 6.9. The most common SLE manifestations were proteinuria (91%) and hypocomplementemia (75%). Severe LN was found in 70% of patients (Class III, 27%; Class IV, 43%). Severe LN patients and patients with higher grade of CD16+ infiltration had lower levels of nonclassical (CD14+CD16++) Mo in peripheral blood. Conclusions. Our results might suggest that those patients with more severe forms of LN had a higher grade of CD14+CD16+ infiltration and lower peripheral levels of nonclassical (CD14+CD16++) Mo and might reflect a recruitment process in renal tissues. However, given the small sample, our results must be interpreted carefully.


Obesity and cardiovascular risk factors in younger breast cancer survivors: The Cancer and Menopause Study (CAMS).
Breast cancer patients today can expect long-term survival; however, weight gain is a common problem after treatment and increases the risk for recurrence, cardiovascular disease and diabetes. The multi-ethnic cohort from the Cancer and Menopause Study, designed to examine the reproductive and late cardiovascular health effects of treatment in younger female breast cancer survivors (BCS), was used to describe the relationship of behavioral and treatment variables to body mass index (BMI), physical activity (PA), and cardiovascular risk factors. Stage 0, I or II breast cancer survivors who were < or = 50 years at diagnosis and 2-10 years disease-free survivors (mean 5.9 +/- 2.3 years) were recruited from two tumor registries to complete a mail survey that included information on demographics, health-related quality of life, reproductive health, cancer treatment, PA, weight and height. A sub-sample completed an office visit where fasting blood lipids, blood pressure (BP), height and weight were measured. Linear regression analysis was used to model the following outcomes: BMI, PA, blood lipids and BP. Current BMI was positively associated with higher BMI prior to diagnosis, unhappiness with body image and negatively associated with current total PA (model p < 0.001). More work, home and leisure PA were all positively associated with greater physical functioning and higher energy levels (all models, p < 0.001). Total and LDL cholesterol were positively associated with number of years since diagnosis and negatively associated with leisure PA (both models, p < 0.001), while systolic and diastolic BP were both positively associated with age, current use of BP medications and current BMI (models, p < 0.001). Obesity in these BCS is prevalent and associated with premorbid obesity and decreased current physical activity but not with adjuvant treatment. Given the negative health consequences of weight gain and obesity after breast cancer, continued study of the etiology of weight gain, and potential targets for weight gain prevention are required. Interventions that target PA may be important for weight maintenance in BCS.


B-mode ultrasonographic diagnosis in gallbladder wall thickening.
Diseases associated with gallbladder wall thickening include benign entities such as adenomyomatosis of the gallbladder, acute and chronic cholecystitis, and hyperplasia associated with pancreaticobiliary maljunction, and also cancer. Unique conditions such as sclerosing cholecystitis and cholecystitis associated with immune checkpoint inhibitor treatment can also manifest as wall thickening, as in some systemic inflammatory conditions. Gallbladder cancer, the most serious disease that can show wall thickening, can be difficult to diagnose early and to distinguish from benign causes of wall thickening, contributing to a poor prognosis. Differentiating between xanthogranulomatous cholecystitis and gallbladder cancer with wall thickening can be particularly problematic. Cancers that thicken the wall while coexisting with benign lesions that cause wall thickening represent another potential pitfall. In contrast, some benign gallbladder lesions that can cause wall thickening, such as adenomyomatosis and acute cholecystitis, typically show characteristic ultrasonographic features that, together with clinical findings, permit easier diagnosis. In this review of the literature, we describe B-mode abdominal ultrasonographic diagnosis of gallbladder lesions showing wall thickening.


Antimicrobial activity against bacteria with dermatological relevance and skin tolerance of the essential oil from Coriandrum sativum L. fruits.
The aim of this work was to determine the antibacterial activity of essential coriander oil (ECO) on bacteria with dermatological relevance and to assess the skin tolerance of antimicrobial effective ECO concentrations. Essential coriander oil was tested on clinical isolates of different bacteria species, all of which may cause superficial skin infections. Antimicrobial susceptibility testing was performed using a standardized macrodilution test. Essential coriander oil showed good antibacterial activity towards the majority of the bacterial strains tested, including Streptococcus pyogenes (Lancefield group A) and methicillin resistant Staphylococcus aureus (MRSA), with mean minimal inhibitory concentrations of 0.04% v/v and 0.25% v/v, respectively. The skin tolerance of a cream and a lotion containing 0.5% and 1.0% ECO was assessed in 40 healthy volunteers using the occlusive patch test. No skin irritation could be observed by sensitive photometric assessment in any of the volunteers. Because of its activity against Streptococcus pyogenes, Staphylococcus aureus and MRSA combined with excellent skin tolerance, ECO might be useful as an antiseptic for the prevention and treatment of skin infections with Gram-positive bacteria.


Fibroblastic niches prime T cell alloimmunity through Delta-like Notch ligands.
Alloimmune T cell responses induce graft-versus-host disease (GVHD), a serious complication of allogeneic bone marrow transplantation (allo-BMT). Although Notch signaling mediated by Delta-like 1/4 (DLL1/4) Notch ligands has emerged as a major regulator of GVHD pathogenesis, little is known about the timing of essential Notch signals and the cellular source of Notch ligands after allo-BMT. Here, we have shown that critical DLL1/4-mediated Notch signals are delivered to donor T cells during a short 48-hour window after transplantation in a mouse allo-BMT model. Stromal, but not hematopoietic, cells were the essential source of Notch ligands during in vivo priming of alloreactive T cells. GVHD could be prevented by selective inactivation of Dll1 and Dll4 in subsets of fibroblastic stromal cells that were derived from chemokine Ccl19-expressing host cells, including fibroblastic reticular cells and follicular dendritic cells. However, neither T cell recruitment into secondary lymphoid organs nor initial T cell activation was affected by Dll1/4 loss. Thus, we have uncovered a pathogenic function for fibroblastic stromal cells in alloimmune reactivity that can be dissociated from their homeostatic functions. Our results reveal what we believe to be a previously unrecognized Notch-mediated immunopathogenic role for stromal cell niches in secondary lymphoid organs after allo-BMT and define a framework of early cellular and molecular interactions that regulate T cell alloimmunity.


Patterns of surgical care for women with ovarian cancer in New South Wales.
Little is known about the delivery of surgical services and outcomes for women with ovarian cancer across New South Wales (NSW). The study objective was to provide a descriptive analysis of the proportion of women who had surgery for ovarian cancer in NSW in specialist gynaecological oncology hospitals and compare outcomes for women attending specialist and non-specialist services in NSW. This study is a retrospective analysis of women with primary ovarian, fallopian tube or peritoneal cancer from 2009 to 2012. Data were analysed from the NSW Cancer Registry, NSW Admitted Patient Data Collection and Register of Births Deaths and Marriages. Treating hospitals were characterised as public specialist, public non-specialist and private. Morbidity and mortality outcomes are reported. The study included 1106 women. Fifty-seven hospitals performed surgery: seven public specialist, 27 private and 23 public non-specialist hospitals. The highest proportion of surgery was performed in public specialist hospitals (61%). There was considerable variation in the utilisation of public specialist hospitals between local health districts. There was no significant difference in outcomes related to the type of hospital where surgery was performed. Although the majority of women are having surgery in a specialist gynaecological oncology public hospital across NSW, many are not. Women living in regional and remote NSW were less likely to have their surgery in a specialist hospital. This is the first step in understanding where women in NSW are currently receiving their surgical care, as well as the outcomes related to this.


Challenges and Opportunities for Academic Parents During COVID-19.
Parents in academic careers face notable challenges that may go unrecognized by university management and/or policy makers. The COVID-19 pandemic has shed light on some of these challenges, as academic parents shifted to working from home while simultaneously caring for children. On the other hand, many parents found that the shift to working from home offered new opportunities such as working more flexible hours, development of digital skillsets, and increased involvement in the education of their children. In this article we explore the work-related challenges and opportunities experienced by academic parents as a result of the COVID-19 pandemic and offer potential long-term solutions for academic parents and their universities. We use the following methods: (1) a literature review focused on identifying the work-related challenges academic parents faced prior to the pandemic, as well as the impact of the pandemic on scientists and working parents and (2) administer a world-wide survey with the goal of identifying the challenges and opportunities associated with parenting and academic work through the COVID-19 lockdown (304 total responses; 113 complete). Moving forward these findings have enabled conclusions to be drawn in order to shape a new normal. Our aim is to offer university administrators, policy makers, and community service providers with ways to provide additional support for academic parents as well as provide tools for academic parents to learn successful strategies directly from their peers.


cDNA amplification by SMART-PCR and suppression subtractive hybridization (SSH)-PCR.
The comparison of two RNA populations that differ from the effects of a single-independent variable, such as a drug treatment or a specific genetic defect, can identify differences in the abundance of specific transcripts that vary in a population-dependent manner. There are a variety of methods for identifying differentially expressed genes, including microarray, SAGE, qRT-PCR, and DDGE. This protocol describes a potentially less sensitive yet relatively easy and cost-effective alternative that does not require prior knowledge of the transcriptomes under investigation and is particularly applicable when minimal levels of starting material, RNA, are available. RNA input can often be a limiting factor when analyzing RNA from, for example, rigorously purified blood cells. This protocol describes the use of SMART-PCR to amplify cDNA from sub-microgram levels of RNA. The amplified cDNA populations under comparison are then subjected to suppression subtractive hybridization (SSH-PCR), a technique that couples subtractive hybridization with suppression PCR to selectively amplify fragments of differentially expressed genes. The final products are cDNA populations enriched for significantly over-represented transcripts in either of the two input RNA preparations. These cDNA populations may then be cloned to make subtracted cDNA libraries and/or used as probes to screen subtracted cDNA, global cDNA, or genomic DNA libraries.


Mutations conferring resistance to neutralization with monoclonal antibodies in type 1 poliovirus can be located outside or inside the antibody-binding site.
Antigenic variants resistant to eight neutralizing monoclonal antibodies were selected from wild (Mahoney) and attenuated (Sabin) type 1 infectious poliovirions. Cross-immunoprecipitation revealed interrelationships between epitopes which were not detected by cross-neutralization. Operational analysis of antigenic variants showed that seven of eight neutralization epitopes studied were interrelated. Only one neutralization epitope, named Kc, varied independently from all the others. This latter, recognized by C3 neutralizing monoclonal antibody, was present not only on infectious virions but also on heat-denatured (C-antigenic) particles and on isolated capsid protein VP1. Loss of the neutralization function of an epitope did not necessary result from the loss of its antibody-binding capacity. Such potential, but not functional, neutralization epitopes exist naturally on Mahoney and Sabin 1 viruses. Their antibody-binding property could be disrupted by isolating antigenic variants in the presence of the nonneutralizing monoclonal antibody and anti-mouse immunoglobulin antibodies. Single-point mutations responsible for the acquisition of resistance to neutralization in the antigenic variants were located by sequence analyses of their genomes. Mutants selected in the presence of C3 neutralizing monoclonal antibody always had the mutation located inside the antibody-binding site (residues 93 through 103 of VP1) at the amino acid position 100 of VP1. On the contrary, antigenic variants selected in the presence of neutralizing monoclonal antibodies reacting only with D-antigenic particles had mutations situated in VP3, outside the antibody-binding site (residues 93 through 103 of VP1). The complete conversion of the Mahoney to the Sabin 1 epitope map resulted from a threonine-to-lysine substitution at position 60 of VP3.


Glass shape influences drinking behaviours in three laboratory experiments.
Reducing consumption of drinks which contain high levels of sugar and/or alcohol may improve population health. There is increasing interest in health behaviour change approaches which work by changing cues in physical environments ("nudges"). Glassware represents a modifiable cue in the drinking environment that may influence how much we drink. Here, we report three laboratory experiments measuring consumption of soft drinks served in different glasses (straight-sided vs. outward-sloped), using distinct paradigms to measure drinking. In Study 1 (N = 200), though total drinking time was equivalent, participants consumed a soft drink with a more 'decelerated' trajectory from outward-sloped tumblers, characterised by a greater amount consumed in the first half of the drinking episode. In Study 2 (N = 72), during a bogus taste test, participants consumed less from straight-sided wine flutes than outward-sloped martini coupes. In Study 3 (N = 40), using facial electromyography to explore a potential mechanism for decreased consumption, straight-sided glasses elicited more 'pursed' lip embouchures, which may partly explain reduced consumption from these glasses. Using a combination of methods, including objective measures of volume drunk and physiological measures, these findings suggest that switching to straight-sided glasses may be one intervention contributing to the many needed to reduce consumption of health-harming drinks.


CONSISE statement on the reporting of Seroepidemiologic Studies for influenza (ROSES-I statement): an extension of the STROBE statement.
Population-based serologic studies are a vital tool for understanding the epidemiology of influenza and other respiratory viruses, including the early assessment of the transmissibility and severity of the 2009 influenza pandemic, and Middle East respiratory syndrome coronavirus. However, interpretation of the results of serologic studies has been hampered by the diversity of approaches and the lack of standardized methods and reporting. The objective of the CONSISE ROSES-I statement was to improve the quality and transparency of reporting of influenza seroepidemiologic studies and facilitate the assessment of the validity and generalizability of published results. The ROSES-I statement was developed as an expert consensus of the CONSISE epidemiology and laboratory working groups. The recommendations are presented in the familiar format of a reporting guideline. Because seroepidemiologic studies are a specific type of observational epidemiology study, the ROSES-I statement is built upon the STROBE guidelines. As such, the ROSES-I statement should be seen as an extension of the STROBE guidelines. The ROSES-I statement presents 42 items that can be used as a checklist of the information that should be included in the results of published seroepidemiologic studies, and which can also serve as a guide to the items that need to be considered during study design and implementation. We hope that the ROSES-I statement will contribute to improving the quality of reporting of seroepidemiologic studies.


Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine.
Cannabis sativa L. has been utilized for treatment of pain and sleep disorders since ancient times. This review examines modern studies on effects of Delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on sleep. It goes on to report new information on the effects on sleep in the context of medical treatment of neuropathic pain and symptoms of multiple sclerosis, employing standardized oromucosal cannabis-based medicines containing primarily THC, CBD, or a 1 : 1 combination of the two (Sativex). Sleep-laboratory results indicate a mild activating effect of CBD, and slight residual sedation with THC-predominant extracts. Experience to date with Sativex in numerous Phase I-III studies in 2000 subjects with 1000 patient years of exposure demonstrate marked improvement in subjective sleep parameters in patients with a wide variety of pain conditions including multiple sclerosis, peripheral neuropathic pain, intractable cancer pain, and rheumatoid arthritis, with an acceptable adverse event profile. No tolerance to the benefit of Sativex on pain or sleep, nor need for dosage increases have been noted in safety extension studies of up to four years, wherein 40-50% of subjects attained good or very good sleep quality, a key source of disability in chronic pain syndromes that may contribute to patients' quality of life.


Upper spine morphology in hypophosphatemic rickets and healthy controls: a radiographic study.
The aim of this study was to describe upper spine morphology in adult patients with hypophosphatemic rickets (HR) compared with controls to assess differences in spine morphology in terms of severity of skeletal impact and to study associations between spine morphology and craniofacial morphology. The study population comprised 36 HR patients and 49 controls. The atlas and axis dimensions were measured on cephalograms, and the differences between the groups were estimated by regression analysis. The upper spine morphology was visually assessed to estimate the prevalence of cervical vertebral anomalies. The dimensions of the atlas and the axis were larger in HR patients than in controls (P ≤ 0.001), and fusions (FUS) occurred more often in HR patients (39%) than in controls (6%; P ≤ 0.001). In HR patients, the length of the atlas correlated positively (P = 0.008) and the height of the dens correlated negatively (P = 0.043) with the severity of skeletal impact. The height of the posterior arch of the atlas and the length of the axis correlated negatively with the cranial base angle (P ≤ 0.017), and the vertical dimensions of the atlas correlated positively with the thickness of the occipital skull (P ≤ 0.015). The length of the atlas correlated positively with mandibular prognathism (P = 0.042). FUS correlated positively with the frontal and parietal thickness (P = 0.034 and P = 0.003, respectively). The dimension of the atlas and the axis and the prevalence of the FUS were increased in HR patients compared with controls. Upper spine dimensions were associated with craniofacial dimensions, primarily in relation to the posterior cranial fossa.


Urinary isoflavone concentrations are inversely associated with cardiometabolic risk markers in pregnant U.S. women.
Some evidence suggests that phytoestrogens, such as soy-derived isoflavones, may have beneficial effects on cardiovascular health and glycemic control. These data are mainly limited to postmenopausal women or individuals at elevated cardiometabolic risk. There is a lack of data for pregnant women who have elevated estrogen levels and physiologically altered glucose and lipid metabolism. We analyzed data from 299 pregnant women who participated in the NHANES 2001-2008 surveys. Multivariable linear regression analyses were used to examine the association between urinary concentrations of isoflavonoids and cardiometabolic risk markers, adjusted for body mass index, pregnancy trimester, total energy intake, dietary intake of protein, fiber, and cholesterol, and demographic and lifestyle factors. Cardiometabolic risk markers were log-transformed, and geometric means were calculated by quartiles of urinary concentrations of isoflavonoids. Comparing women in the highest vs. lowest quartiles of urine total isoflavone concentrations, we observed significant, inverse associations with circulating concentrations of fasting glucose (79 vs. 88 mg/dL, P-trend = 0.0009), insulin (8.2 vs. 12.8 μU/mL, P-trend = 0.03), and triglyceride (156 vs. 185 mg/dL, P-trend = 0.02), and the homeostasis model assessment of insulin resistance (1.6 vs. 2.8, P-trend = 0.01), but not for total, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. The concentrations of individual isoflavonoids, daidzein, equol, and O-desmethylangolensin were inversely associated with some cardiometabolic risk markers, although no clear pattern emerged. These data suggest that there may be a relation between isoflavone intake and cardiometabolic risk markers in pregnant women.


Anamorphic optical transformation of an amplitude spatial light modulator to a complex spatial light modulator with square pixels [invited].
A method is proposed for the construction of a square pixel complex spatial light modulator (SLM) from a commercial oblong full-high-definition (full-HD) amplitude SLM using an anamorphic optical filter. In the proposed scheme, one half-band of the optical Fourier transform of the amplitude-only spatial light field is rejected in the optical Fourier plane and the other half-band is reformatted to be an effective complex SLM with square pixels. This has an advantage in the viewing window plane since the shape of the viewing window becomes square and more ideal for observers who watch the hologram contents through it. For optimal transformation, the amplitude computer generated hologram encoding scheme was developed. Mathematical modeling of the proposed system is described herein, and it was experimentally demonstrated that the effective complex SLM displays complex holographic three-dimensional images with a clear depth discrimination effect.


The transcriptional regulation of the human angiotensinogen gene after high-fat diet is haplotype-dependent: Novel insights into the gene-regulatory networks and implications for human hypertension.
Single nucleotide polymorphisms (SNPs) in the human angiotensinogen (hAGT) gene may modulate its transcription and affect the regulation of blood pressure via activation of the renin-angiotensin aldosterone system (RAAS). In this regard, we have identified polymorphisms in the 2.5 Kb promoter of the hAGT gene that form two haplotype (Hap) blocks: -6A/G (-1670A/G, -1562C/T, -1561T/C) and -217A/G (-532T/C, -793A/G, -1074T/C & -1178G/A). hAGT gene with Hap -6A/-217A (Hap I) is associated with increased blood pressure whereas, Hap -6G/-217G (Hap II) is associated with normal blood pressure in human subjects. Since RAAS over activity contributes to hypertension in obesity, we have made transgenic mice (TG) containing either Hap I or Hap II of the hAGT gene to understand the role of obesity on its transcriptional regulation. Although, a high-fat diet (60% Kcal from fat, 12 weeks) elevates hAGT and mAGT regardless of haplotype, this effect is significantly (p<0.05) accentuated in Hap I mice, in both adipose and liver tissues. Chromatin Immuno- precipitation (ChIP) assay shows an increased binding of transcription factors including, GR, CEBPβ and STAT3 to the chromatin of the Hap I TG mice after high-fat diet as compared to Hap II TG mice (p<0.05). Differential plasma levels of hAGT in Hap II and I mice, after high-fat diet, further corroborate the variable transcriptional regulation of the hAGT, governed by gene-haplotypes. Taken together, our results show that SNPs in the Hap-I of the hAGT gene promote high-fat diet-induced binding of transcription factors GR, CEBP-β and STAT3, which lead to elevated expression of the hAGT gene in hepatic and adipose tissues.


17q21 gene variation is not associated with asthma in adulthood.
17q21 gene variants are the strongest known genetic determinants for childhood asthma and have been reported to interact with environmental tobacco smoke exposure in childhood. It remains unclear whether individuals with 17q21 risk variants have increased risk of asthma or reduced lung function in adulthood. The aim was to examine the association between the 17q21 region and current adult asthma and lung function, and interaction with active smoking. We investigated the single nucleotide polymorphism rs7216389 at the 17q21 locus in 3471 adults from the Health2006 cross-sectional study and in 7008 adults from The British 1958 Birth Cohort and examined the association with current asthma, spirometry measures, and related atopic traits. Analyses were performed for interaction with active smoking. We found no association between rs7216389[T] and asthma when meta-analyzed (OR = 1.02 [0.92-1.13], P = 0.81). The risk variant was associated with reduced FEV1 as compared to normal FEV1 (OR = 1.10 [1.01-1.12], P = 0.033) and with allergic sensitization (OR = 1.10 [1.03-1.17], P = 0.003). Individuals with rs7216389 risk variants smoked as frequently as individuals without risk variants, and there was no evidence that smoking modified the association between rs7216389 and asthma. Our study suggests that the 17q21 rs7216389 locus variant does not substantially influence asthma risk in adulthood or susceptibility to detrimental effects of active smoking. This contrasts the findings in children and suggests that this locus is associated with a childhood-specific asthma endotype.


Excessive daytime sleepiness and fatigue may indicate accelerated brain aging in cognitively normal late middle-aged and older adults.
Excessive daytime sleepiness (EDS) and fatigue increases with age. The aim of this study was to investigate the association between EDS and fatigue with cortical thickness and hippocampal volume in cognitively normal, late middle-aged and older adults. We performed a cross-sectional observational study of 1374 cognitively-normal subjects aged 50 years and older who had a structural MRI. Regional cortical thickness and hippocampal volume were measured. Multiple linear regression models were fit to explore associations between EDS and fatigue and structural MRI measures in different brain regions, adjusting for multiple covariates. EDS was defined as Epworth Sleepiness Scale ≥10. Fatigue severity was assessed with the Beck Depression Inventory-2. 208 participants had EDS, 27 had significant fatigue, and 11 had both. Participants with EDS or fatigue had significantly lower cognitive scores, more disturbed sleep, and medical comorbidities. The presence of EDS was associated with both global and regional atrophy, whereas fatigue was more associated with frontal and temporal changes. Cortical thinning predicted by EDS and fatigue was maximal in the temporal region with average reduction of 34.2 μm (95% CI, -54.1, -14.3; P = 0.001) and 90.2 μm (95% CI, -142.1, -38.2; P = 0.001), respectively. Fatigue was also associated with hippocampal volume reduction of -374.2 mm3 (95% CI, -670.8, -77.7; P = 0.013). Temporal cortical thinning predicted by presence of EDS and fatigue was equivalent to more than 3.5 and 9 additional years of aging, respectively. EDS and fatigue were associated with cortical thickness reduction primarily in regions with increased age-susceptibility, which may indicate accelerated brain aging.


Epstein-Barr virus-positive follicular lymphoma.
Epstein-Barr virus (EBV) -associated follicular lymphoma is only rarely reported. Herein, we report the largest series analyzing prevalence and clinicopathologic characteristics of EBV-associated follicular lymphoma occurring in unselected cases. Out of 382 analyzed cases, 10 EBV-positive follicular lymphomas were identified (prevalence=2.6%, 95% confidence interval 1.3-4.0%). All EBV-positive follicular lymphomas showed EBV-encoded small RNA-positive lymphoma cells present in a follicular distribution. Of these, eight also had tissue available for testing of expression of latent membrane protein 1 (LMP1), out of which six (75%) were positive. There was a significant association with grades 3A-3B follicular lymphoma (P<0.0001) and CD30 expression (P=0.0002). EBV-positive follicular lymphomas were otherwise morphologically and immunophenotypically indistinguishable from EBV-negative cases of similar grade. Nine of the EBV-positive follicular lymphomas occurred in patients with no known history of immunosuppression, while one patient had a history of hydroxychloroquine administration for Sjögren's syndrome. The mean age in the EBV-positive and -negative follicular lymphomas was 56 (range 31-83 years) and 49 years (range 25-92 years), respectively, with no statistically significant difference. Seven of the patients with EBV-positive follicular lymphoma had additional biopsies from different time points available for review, all of which showed progression of disease in the form of progression of tumor grade. Five of these progressed to diffuse large B-cell lymphoma, one of which had tissue available for testing and was EBV-positive. Our findings suggest that EBV infection may have a role in lymphomagenesis and/or disease progression in a subset of follicular lymphomas, thereby expanding the spectrum of recognized EBV-associated B-cell lymphomas.


Direct interspecies electron transfer via conductive materials: A perspective for anaerobic digestion applications.
Anaerobic digestion (AD) is a microbial process that produces renewable energy in the form of methane by treating organic waste and high-strength wastewater. Recent studies have demonstrated that conductive materials can promote direct interspecies electron transfer (DIET) between exoelectrogenic bacteria and methanogenic archaea. DIET via conductive materials is more effective for methane production than interspecies electron transfer using electron carriers such as hydrogen, a principal route of methane production in conventional AD. This critical review presents the current understanding of DIET via conductive materials for methane production, summarizes the relevant studies published to date, and analyzes these studies with regard to conductive materials, substrates, inocula, performance, and microorganisms. Based on this analysis, possible future directions are suggested for practical DIET applications via conductive materials in AD.


Two sex-chromosome-linked microsatellite loci show geographic variance among North American Ostrinia nubilalis.
PCR-based O. nubilalis population and pedigree analysis indicated female specificity of a (GAAAAT)n microsatellite, and male specificity of a CAYCARCGTCACTAA repeat unit marker. These loci were respectively named Ostrinia nubilalis W-chromosome 1 (ONW1) and O. nubilalis Z-chromosome 1 (ONZ1). Intact repeats of three, four, or five GAAAAT units are present among ONW1 alleles, and biallelic variation exists at the ONZ1 locus. Screening of 493 male at ONZ1 and 448 heterogametic females at ONZ1 and ONW1 loci from eleven North American sample sites was used to construct genotypic data. Analysis of molecular variance (AMOVA) and F-statistics indicated no female haplotype or male ONZ1 allele frequency differentiation between voltinism ecotypes. Four subpopulations from northern latitudes, Minnesota and South Dakota, showed the absence of a single female haplotype, a significant deviation of ONZ1 data from Hardy-Weinberg expectation, and low-level geographic divergence from other subpopulations. Low ONZ1 and ONW1 allele diversity could be attributed either to large repeat unit sizes, low repeat number, reduced effective population (Ne) size of sex chromosomes, or the result of recent O. nubilalis introduction and population expansion, but likely could not be due to inbreeding.


Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans.
We observed a severe autosomal recessive movement disorder in mice used within our laboratory. We pursued a series of experiments to define the genetic lesion underlying this disorder and to identify a cognate disease in humans with mutation at the same locus. Through linkage and sequence analysis we show here that this disorder is caused by a homozygous in-frame 18-bp deletion in Itpr1 (Itpr1(Delta18/Delta18)), encoding inositol 1,4,5-triphosphate receptor 1. A previously reported spontaneous Itpr1 mutation in mice causes a phenotype identical to that observed here. In both models in-frame deletion within Itpr1 leads to a decrease in the normally high level of Itpr1 expression in cerebellar Purkinje cells. Spinocerebellar ataxia 15 (SCA15), a human autosomal dominant disorder, maps to the genomic region containing ITPR1; however, to date no causal mutations had been identified. Because ataxia is a prominent feature in Itpr1 mutant mice, we performed a series of experiments to test the hypothesis that mutation at ITPR1 may be the cause of SCA15. We show here that heterozygous deletion of the 5' part of the ITPR1 gene, encompassing exons 1-10, 1-40, and 1-44 in three studied families, underlies SCA15 in humans.


Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers.
Germline mutations in CDH1 are associated with hereditary diffuse gastric cancer; lobular breast cancer also occurs excessively in families with such condition. To determine if CDH1 is a susceptibility gene for lobular breast cancer in women without a family history of diffuse gastric cancer, germline DNA was analysed for the presence of CDH1 mutations in 318 women with lobular breast cancer who were diagnosed before the age of 45 years or had a family history of breast cancer and were not known, or known not, to be carriers of germline mutations in BRCA1 or BRCA2. Cases were ascertained through breast cancer registries and high-risk cancer genetic clinics (Breast Cancer Family Registry, the kConFab and a consortium of breast cancer genetics clinics in the United States and Spain). Additionally, Multiplex Ligation-dependent Probe Amplification was performed for 134 cases to detect large deletions. No truncating mutations and no large deletions were detected. Six non-synonymous variants were found in seven families. Four (4/318 or 1.3%) are considered to be potentially pathogenic through in vitro and in silico analysis. Potentially pathogenic germline CDH1 mutations in women with early-onset or familial lobular breast cancer are at most infrequent.


Multi fragment melting analysis system (MFMAS) for one-step identification of lactobacilli.
The accurate identification of lactobacilli is essential for the effective management of industrial practices associated with lactobacilli strains, such as the production of fermented foods or probiotic supplements. For this reason, in this study, we proposed the Multi Fragment Melting Analysis System (MFMAS)-lactobacilli based on high resolution melting (HRM) analysis of multiple DNA regions that have high interspecies heterogeneity for fast and reliable identification and characterization of lactobacilli. The MFMAS-lactobacilli is a new and customized version of the MFMAS, which was developed by our research group. MFMAS-lactobacilli is a combined system that consists of i) a ready-to-use plate, which is designed for multiple HRM analysis, and ii) a data analysis software, which is used to characterize lactobacilli species via incorporating machine learning techniques. Simultaneous HRM analysis of multiple DNA fragments yields a fingerprint for each tested strain and the identification is performed by comparing the fingerprints of unknown strains with those of known lactobacilli species registered in the MFMAS. In this study, a total of 254 isolates, which were recovered from fermented foods and probiotic supplements, were subjected to MFMAS analysis, and the results were confirmed by a combination of different molecular techniques. All of the analyzed isolates were exactly differentiated and accurately identified by applying the single-step procedure of MFMAS, and it was determined that all of the tested isolates belonged to 18 different lactobacilli species. The individual analysis of each target DNA region provided identification with an accuracy range from 59% to 90% for all tested isolates. However, when each target DNA region was analyzed simultaneously, perfect discrimination and 100% accurate identification were obtained even in closely related species. As a result, it was concluded that MFMAS-lactobacilli is a multi-purpose method that can be used to differentiate, classify, and identify lactobacilli species. Hence, our proposed system could be a potential alternative to overcome the inconsistencies and difficulties of the current methods.


Cometary science. Subsurface properties and early activity of comet 67P/Churyumov-Gerasimenko.
Heat transport and ice sublimation in comets are interrelated processes reflecting properties acquired at the time of formation and during subsequent evolution. The Microwave Instrument on the Rosetta Orbiter (MIRO) acquired maps of the subsurface temperature of comet 67P/Churyumov-Gerasimenko, at 1.6 mm and 0.5 mm wavelengths, and spectra of water vapor. The total H2O production rate varied from 0.3 kg s(-1) in early June 2014 to 1.2 kg s(-1) in late August and showed periodic variations related to nucleus rotation and shape. Water outgassing was localized to the "neck" region of the comet. Subsurface temperatures showed seasonal and diurnal variations, which indicated that the submillimeter radiation originated at depths comparable to the diurnal thermal skin depth. A low thermal inertia (~10 to 50 J K(-1) m(-2) s(-0.5)), consistent with a thermally insulating powdered surface, is inferred.


Long-Term Follow-Up of Patients After Autologous Bone Marrow Cell Infusion for Decompensated Liver Cirrhosis.
Although several human clinical trials using various bone marrow-derived cell types for cirrhotic or decompensated patients have reported a short-term benefit, long-term follow-up data are limited. We analyzed the long-term clinical outcomes of autologous bone marrow cell infusion (ABMI) for decompensated liver cirrhosis (LC). Patients enrolled in a pilot single-armed ABMI study were followed up more than 5 years. Bone marrow-derived mononuclear cells (BM-MNCs) from decompensated LC were harvested and after processing were infused into a peripheral vein. The laboratory test results and long-term clinical course including liver transplantation (LT), development of cancer, cause of death, and survival after ABMI were analyzed. Nineteen patients were followed up for a median of 66 months after ABMI. Liver function, including serum levels of albumin and Child-Pugh (CP) score, was improved at the 1-year follow-up. Liver volume was significantly greater, cirrhosis was sustained, and collagen content was decreased at the 6-month follow-up. Five years after ABMI, five patients (26.3%) maintained CP class A without LT or death, and five patients (26.3%) had undergone elective LT. Hepatocellular carcinoma (HCC) occurred in five patients (26.3%), and lymphoma and colon cancer occurred in one patient each. Three patients (15.8%) were lost to follow-up at months 22, 31, and 33, respectively, but maintained CP class A until their last follow-up. Five patients expired due to infection. While improved liver function was maintained in some patients for more than 5 years after ABMI, other patients developed HCC. Further studies of long-term follow-up cohorts after cell therapy for LC are warranted.


Deutsch's algorithm with topological charges of optical vortices via non-degenerate four-wave mixing.
We propose a scheme to implement the Deutsch's algorithm through non-degenerate four-wave mixing process. By employing photon topological charges of optical vortices, we demonstrate the ability to realize the necessary four logic gates for all balanced and constant functions. We also analyze the feasibility of the proposed scheme on the single photon level.


The short-term efficacy of a brief motivational intervention designed to increase physical activity among college students.
Research has shown that many college students do not meet recommended national guidelines for physical activity. The objective of this pilot study was to examine the short-term efficacy of a brief motivational intervention (BMI) designed to increase physical activity. Participants were 70 college students who reported low physical activity (83% women, 60% African American). Participants were randomly assigned to either the BMI condition or to an education-only (EO) condition. They completed measures of physical activity at baseline and 1-month follow-up. Those in the BMI condition reported more vigorous-intensity physical activity at a 1-month follow-up than those in the EO condition. The findings from this study provide preliminary support for the efficacy of a BMI designed to increase physical activity among college students. Future studies should continue to examine and refine the intervention in an effort to improve health-related behaviors among this group.


Dynamic acousto-optic control of a strongly coupled photonic molecule.
Strongly confined photonic modes can couple to quantum emitters and mechanical excitations. To harness the full potential in quantum photonic circuits, interactions between different constituents have to be precisely and dynamically controlled. Here, a prototypical coupled element, a photonic molecule defined in a photonic crystal membrane, is controlled by a radio frequency surface acoustic wave. The sound wave is tailored to deliberately switch on and off the bond of the photonic molecule on sub-nanosecond timescales. In time-resolved experiments, the acousto-optically controllable coupling is directly observed as clear anticrossings between the two nanophotonic modes. The coupling strength is determined directly from the experimental data. Both the time dependence of the tuning and the inter-cavity coupling strength are found to be in excellent agreement with numerical calculations. The demonstrated mechanical technique can be directly applied for dynamic quantum gate operations in state-of-the-art-coupled nanophotonic, quantum cavity electrodynamic and optomechanical systems.


Mast cell IL-4 expression is regulated by Ikaros and influences encephalitogenic Th1 responses in EAE.
When exposed to a pathogen, a naive CD4(+) T cell is forced to make a cell fate decision that leads to a polarized population of Th1 IFN-gamma- or Th2 IL-4- producing cells. Although IL-4 has traditionally been considered a factor that promotes Th2 cell differentiation, recent evidence has demonstrated that the site and timing of IL-4 expression in an immune response determines its ultimate effects on CD4(+) T cell fate. Using a mast cell (MC) reconstitution model, we demonstrate that MC-derived IL-4 promoted Th1 responses in vivo. Furthermore, MCs from genetically disparate mouse strains varied in their potential for IL-4 expression. Independent of the activation mode, MCs from Th1-prone C57BL/6 mice exhibited a more robust Il4 response than did the Th2-prone strain Balb/c. The hierarchy of IL-4 expression potential was directly associated with the degree of basal chromatin accessibility at cis-regulatory elements conserved noncoding sequence-1 and V(A) enhancer within the Th2 locus. GATA1/2 and Ikaros, factors with opposing roles in chromatin remodeling, acted at these sites. We propose that GATA and Ikaros proteins coordinately fine-tune accessibility at the Il4 locus during development to variably regulate IL-4 expression. These events likely contribute to the genetically determined heterogeneity in Th1 responses that underlie susceptibility to many diseases.


Illuminating seafloor faults and ocean dynamics with dark fiber distributed acoustic sensing.
Distributed fiber-optic sensing technology coupled to existing subsea cables (dark fiber) allows observation of ocean and solid earth phenomena. We used an optical fiber from the cable supporting the Monterey Accelerated Research System during a 4-day maintenance period with a distributed acoustic sensing (DAS) instrument operating onshore, creating a ~10,000-component, 20-kilometer-long seismic array. Recordings of a minor earthquake wavefield identified multiple submarine fault zones. Ambient noise was dominated by shoaling ocean surface waves but also contained observations of in situ secondary microseism generation, post-low-tide bores, storm-induced sediment transport, infragravity waves, and breaking internal waves. DAS amplitudes in the microseism band tracked sea-state dynamics during a storm cycle in the northern Pacific. These observations highlight this method's potential for marine geophysics.


Cryogen spray cooling in conjunction with pulse dye laser treatment of port wine stains of the head and neck.
When a cryogen spurt is applied to the skin surface for an appropriately short period of time, the spatial distribution of cooling remains localized in the normal overlying epidermis, while leaving the temperature of deeper port wine stain (PWS) blood vessels unchanged. Furthermore, cooling continues after pulsed laser exposure as cryogen remaining on the surface evaporates and removes heat deposited by light absorption in epidermal melanin. The objective of this study was to evaluate the efficacy and advantages of cryogen spray cooling plus flashlamp-pumping in conjunction with dye laser treatment (CSC-LT) of PWS. From 1996 to 2000, a retrospective study was conducted on 63 patients, consisting of 43 women and 20 men, between the ages of 8 and 62 years treated with pulsed dye laser (lambda = 585 nm, tau p = 450 microseconds) over a 4-year period. The duration of cryogen spurts and the delay period between cryogen delivery and laser illumination were controlled. An infrared focal plane array thermodetector measured changes of lesion surface temperature which were recorded. The subject was asked to score discomfort during treatment using a pain scale. The primary efficacy measure was the quantitative assessment of a blanching response score. The ambient skin surface temperature of PWS was 33.31 +/- 1.55 degrees C. The mean pain score for uncooled sites was 39.85 +/- 0.23 compared to 20.18 +/- 0.15 for cooled sites. There was a statistically significant difference in pain elimination between cooled and uncooled sites (p = 0.001). The mean blanching response score of CSC-LT was 3.70. A significant blanching response of PWS when receiving CSC-LT was noted. Our clinical studies demonstrate the feasibility of selective epidermal cooling while achieving photothermolysis of blood vessels during pulsed dye laser treatment of PWS.


End-of-life care discussions among patients with advanced cancer: a cohort study.
National guidelines recommend that physicians discuss end-of-life (EOL) care planning with patients with cancer whose life expectancy is less than 1 year. To evaluate the incidence of EOL care discussions for patients with stage IV lung or colorectal cancer and where, when, and with whom these discussions take place. Prospective cohort study of patients diagnosed with lung or colorectal cancer from 2003 to 2005. Participants lived in Northern California, Los Angeles County, North Carolina, Iowa, or Alabama or received care in 1 of 5 large HMOs or 1 of 15 Veterans Health Administration sites. 2155 patients with stage IV lung or colorectal cancer. End-of-life care discussions reported in patient and surrogate interviews or documented in medical records through 15 months after diagnosis. 73% of patients had EOL care discussions identified by at least 1 source. Among the 1470 patients who died during follow-up, 87% had EOL care discussions, compared with 41% of the 685 patients who were alive at the end of follow-up. Of the 1081 first EOL care discussions documented in records, 55% occurred in the hospital. Oncologists documented EOL care discussions with only 27% of their patients. Among 959 patients with documented EOL care discussions who died during follow-up, discussions took place a median of 33 days before death. The depth and quality of EOL care discussions was not evaluated. Much of the information about discussions came from surrogates of patients who died before baseline interviews could be obtained. Although most patients with stage IV lung or colorectal cancer discuss EOL care planning with physicians before death, many discussions occur during acute hospital care, with providers other than oncologists, and late in the course of illness. National Cancer Institute and Department of Veterans Affairs.


The insert region of Rac1 is essential for membrane ruffling but not cellular transformation.
The Rho family of Ras-related proteins, which includes Rac1, RhoA, and Cdc42, is distinguished from other members of the Ras superfamily of small GTPases in that its members possess additional sequences positioned between beta-strand 5 and alpha-helix 4, designated the insert region. Previous studies have established the importance of an intact insert region for the transforming, but not actin cytoskeletal reorganization, activities of Cdc42 and RhoA. Similarly, the insert region was determined to be essential for Rac1-mediated mitogenesis. Additionally, an intact insert region was also determined to be required for the antiapoptotic activity of Rac1 as well as for Rac1 activation of reactive oxygen species and the NF-kappaB transcription factor. However, it has not been determined whether the insert region is important for Rac1-mediated growth transformation. In this study, we assessed the requirement for the insert region in Rac1 transformation and signaling in NIH 3T3 cells. Unexpectedly, we found that a mutant of constitutively activated Rac1 that lacked the insert region retained potent transforming activity. The insert region of Rac1 was dispensable for Rac1 stimulation of transcription from the cyclin D1 promoter and for activation of the c-Jun, NF-kappaB, and E2F-1 transcription factors but was essential for Rac1 induction of serum response factor activity. While an intact insert region was dispensable for inducing reactive oxygen species production in vivo, it was required for Rac1 induction of lamellipodia. When taken together, these results show that the insert region of Rac1 serves roles in regulating actin organization and cell growth that are distinct from those of the analogous regions of Cdc42 and RhoA and support its involvement in regulating specific downstream effector interactions.


Self-generated surface magnetic fields inhibit laser-driven sheath acceleration of high-energy protons.
High-intensity lasers interacting with solid foils produce copious numbers of relativistic electrons, which in turn create strong sheath electric fields around the target. The proton beams accelerated in such fields have remarkable properties, enabling ultrafast radiography of plasma phenomena or isochoric heating of dense materials. In view of longer-term multidisciplinary purposes (e.g., spallation neutron sources or cancer therapy), the current challenge is to achieve proton energies well in excess of 100 MeV, which is commonly thought to be possible by raising the on-target laser intensity. Here we present experimental and numerical results demonstrating that magnetostatic fields self-generated on the target surface may pose a fundamental limit to sheath-driven ion acceleration for high enough laser intensities. Those fields can be strong enough (~105 T at laser intensities ~1021 W cm-2) to magnetize the sheath electrons and deflect protons off the accelerating region, hence degrading the maximum energy the latter can acquire.


Differential pial and penetrating arterial responses examined by optogenetic activation of astrocytes and neurons.
A variety of brain cells participates in neurovascular coupling by transmitting and modulating vasoactive signals. The present study aimed to probe cell type-dependent cerebrovascular (i.e., pial and penetrating arterial) responses with optogenetics in the cortex of anesthetized mice. Two lines of the transgenic mice expressing a step function type of light-gated cation channel (channelrhodopsine-2; ChR2) in either cortical neurons (muscarinic acetylcholine receptors) or astrocytes (Mlc1-positive) were used in the experiments. Photo-activation of ChR2-expressing astrocytes resulted in a widespread increase in cerebral blood flow (CBF), extending to the nonstimulated periphery. In contrast, photo-activation of ChR2-expressing neurons led to a relatively localized increase in CBF. The differences in the spatial extent of the CBF responses are potentially explained by differences in the involvement of the vascular compartments. In vivo imaging of the cerebrovascular responses revealed that ChR2-expressing astrocyte activation led to the dilation of both pial and penetrating arteries, whereas ChR2-expressing neuron activation predominantly caused dilation of the penetrating arterioles. Pharmacological studies showed that cell type-specific signaling mechanisms participate in the optogenetically induced cerebrovascular responses. In conclusion, pial and penetrating arterial vasodilation were differentially evoked by ChR2-expressing astrocytes and neurons.


Relationship of endothelial cell proliferation to tumor vascularity in human breast cancer.
Current studies of tumor angiogenesis rely on the concept that endothelium proliferates 30-40 times faster in tumors than in normal tissues. This evidence is based on histological autoradiographic data largely from animal studies. To assess endothelial cell proliferation in human cancer we used the more sensitive and specific technique of immunohistochemistry. We measured the frequency and distribution of endothelial cell proliferation and examined their relationship to tumor cell proliferation. For the first time, we also correlated endothelial and tumor cell proliferation with tumor vascularity. Twenty breast carcinomas from patients exposed to bromodeoxyuridine 3-8 h prior to surgery were double immunostained using antibodies to CD31 (as a marker of endothelium) and bromodeoxyuridine (as a marker of proliferation). The labeling index (LI) for both tumor and endothelial cells was determined and tumor vascularity was assessed by counting the number of CD31 positive vessels. Endothelial cell proliferation was predominantly at the tumor periphery while tumor cell proliferation occurred throughout the lesion. The mean LIs for endothelium and tumor were 2.2% (range, 0.8-5.3) and 7.3% (range, 1.3-17.1), respectively. There was no correlation between tumor and endothelial cell LI (P = 0.414) or between the tumor LI or endothelial cell LI and tumor vascularity (P = 0.08 and P = 0.39, respectively). These findings suggest that previous studies in animal tumors have significantly overestimated endothelial cell proliferation and that its importance in tumor angiogenesis may be related more to continual remodeling and migration of vessels than to proliferation alone.


The mouse DXZ4 homolog retains Ctcf binding and proximity to Pls3 despite substantial organizational differences compared to the primate macrosatellite.
The X-linked macrosatellite DXZ4 is a large homogenous tandem repeat that in females adopts an alternative chromatin organization on the primate X chromosome in response to X-chromosome inactivation. It is packaged into heterochromatin on the active X chromosome but into euchromatin and bound by the epigenetic organizer protein CTCF on the inactive X chromosome. Because its DNA sequence diverges rapidly beyond the New World monkeys, the existence of DXZ4 outside the primate lineage is unknown. Here we extend our comparative genome analysis and report the identification and characterization of the mouse homolog of the macrosatellite. Furthermore, we provide evidence of DXZ4 in a conserved location downstream of the PLS3 gene in a diverse group of mammals, and reveal that DNA sequence conservation is restricted to the CTCF binding motif, supporting a central role for this protein at this locus. However, many features that characterize primate DXZ4 differ in mouse, including the overall size of the array, the mode of transcription, the chromatin organization and conservation between adjacent repeat units of DNA sequence and length. Ctcf binds Dxz4 but is not exclusive to the inactive X chromosome, as evidenced by association in some males and equal binding to both X chromosomes in trophoblast stem cells. Characterization of Dxz4 reveals substantial differences in the organization of DNA sequence, chromatin packaging, and the mode of transcription, so the potential roles performed by this sequence in mouse have probably diverged from those on the primate X chromosome.