The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alpha-1-Beta glycine receptor function.
Loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the development of chronic pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine. Cannabidiol is a nonpsychotropic plant constituent of Cannabis sativa. As we hypothesized that non-CB receptor mechanisms of cannabidiol might contribute to its anti-inflammatory and neuroprotective effects, we investigated the interaction of cannabidiol with strychnine-sensitive alpha(1 )and alpha(1)beta glycine receptors by using the whole-cell patch clamp technique. Cannabidiol showed a positive allosteric modulating effect in a low micromolar concentration range (EC(50) values: alpha(1) = 12.3 +/- 3.8 micromol/l and alpha(1)beta = 18.1 +/- 6.2 micromol/l). Direct activation of glycine receptors was observed at higher concentrations above 100 micromol/l (EC(50) values: alpha(1) = 132.4 +/- 12.3 micromol/l and alpha(1)beta = 144.3 +/- 22.7 micromol/l). These in vitro results suggest that strychnine-sensitive glycine receptors may be a target for cannabidiol mediating some of its anti-inflammatory and neuroprotective properties.


Deoxynivalenol and zearalenone in Fusarium-contaminated wheat in Mexico City.
Fusarium spp. invasion causes head blight, a destructive disease in the world's main wheat-growing areas, and deoxynivalenol (DON) and zearalenone (ZEA) contamination in cereal-based products. No data are available on the relationship between Fusarium spp. on commercial wheat samples in Mexico City and the presence of mycotoxins. A total of 30 wheat samples were subject to a PCR method involving genes of the trichothecene and zearalenone biosynthesis pathways to detect the presence of Fusarium. Detection and quantification of DON and ZEA was performed using liquid chromatography coupled to UV detection. PCR indicated the presence of the Tri5 and PKS4 genes in 16.7 and 23.3% of samples, respectively. DON and ZEA contamination was found in 51.2 and 71.4% of samples, respectively, where a positive amplification was obtained. This work presents up-to-date information on mycotoxin contamination in Mexico, where improved contamination/exposure data and firm control/monitoring measures are needed.


Clear cell renal cell carcinoma induces fibroblast-mediated production of stromal periostin.
Increase in periostin (PN) was reported in clear cell renal cell carcinoma (ccRCC). But how PN contributes to ccRCC pathogenesis remains unclear. This research will investigate the underlying mechanism. The PN protein in 37 adjacent non-tumour kidney (ANK) tissues, their respective ccRCCs, 16 cases of metastasised ccRCC and xenograft tumours was analysed by immunohistochemistry. PN expression in ccRCC cells and NIH3T3 fibroblasts was examined by real time PCR (polymerase chain reaction) and western blot. PN was detected at low levels in the tubular epithelial cells of ANKs. PN was robustly increased in the ccRCC-associated stroma of both organ-confined and metastasised ccRCCs. Furthermore, despite A498 ccRCC cells and their-derived xenograft tumour cells expressing a low level of PN, a strong presence of stromal PN was observed especially in the boundary region between xenograft tumour mass and non-tumour tissue. Collectively, these results suggest that the ccRCC-associated PN was derived from stroma instead of tumours. This notion was supported by the co-existence of PN with α-smooth muscle actin (αSMA), a marker of activated fibroblasts, in both local and metastasised ccRCC. Furthermore, co-culture of NIH3T3 mouse fibroblasts with either human A498 or 786-0 ccRCC cells dramatically enhanced PN transcription only in NIH3T3 cells as well as NIH3T3 cell-mediated accumulation of extracellular PN. In return, extracellular PN significantly enhanced A498 cell attachment. Elevation of PN promotes NIH3T3 cell proliferation and enhanced AKT activation. ccRCC induces fibroblast-mediated accumulation of stromal PN; stromal PN enhances ccRCC cell attachment and fibroblast proliferation.


Surgical sequence of reduction in double mandibular fractures treatment.
This study aims to clarify, according to our experience, the correct surgical sequence which should be followed in order to treat double mandibular fractures. From January 2007 to January 2010, we have conducted a retrospective study on a sample of patients operated on in our department. We include only those cases in which the jaw was fractured in 2 places, in particular patients who suffer a fracture in tooth-bearing areas (symphysis, parasymphysis, and anterior body) and also contralaterally in non tooth-bearing areas (posterior body, angle, ramus, and condyle). The sample was divided into 2 groups based on the fracture sequence of reduction. At 1-year follow-up, the group of patients who received first the tooth-bearing fractured areas treatment, followed by treatment of non tooth-bearing fractured area on bifocal mandibular fracture (Group A), showed less postoperative complications and reduced surgical time and costs. In patients of group B, the non-execution of rigid IMF for the non tooth-bearing fractures made bone segments more free to move. Thus, reduction and fixation of non tooth-bearing fractures is facilitated, but poses a greater risk of complications. The surgeon in this case does not have the occlusal help guide; thus, the tooth-bearing fracture reduction and the subsequent fixation may be imperfect. It is recommended from this study that reduction of the tooth-bearing fragment be prior to that of the tooth-free fragment for the double mandibular fracture. Double mandibular fractures, Toothbearing area, Multiple mandibular fracture, Non-toothbearing area.


Adaptation of coronavirus JHM to persistent infection of murine sac(-) cells.
Coronaviruses can establish persistent infections in the central nervous system of rodents, and these are associated with demyelinating encephalomyelitis. The effects of persistence on the virus are difficult to study in vivo but may have a crucial influence on the course of infection. We therefore produced a persistent infection in vitro using the neurotropic coronavirus JHM, in order to investigate the events underlying the establishment of such an infection and the adaptation of the virus to persistence. The persistent infection was maintained for over 115 passages and continued to release high levels of infectious virus. During the 18 months of culture the number of cells expressing virus antigen detected by indirect immune fluorescence decreased to 40%. Analysis showed that the carried virus contained a significant proportion of heterogeneous temperature-sensitive mutants. All virus clones isolated possessed the capacity to induce a more productive growth cycle, a less pronounced cytopathic effect and showed a much reduced neurovirulence when inoculated into newborn and weanling rats. Evidence for structural changes involving the surface peplomer protein (E2) was obtained using hybridoma antibodies, which neutralized the parental JHM virus but not the JHM-Pi virus. Defective interfering particles and interferon activities have been excluded as possible agents instrumental in the establishment and maintenance of the chronic infection, and we suggest that the emergence of virus variants of lowered virulence is central to these processes.


Stress, support, psychological states and sleep.
A stress-support model incorporating indicators of life events, social support and SCL-90 measures of psychological distress was hypothesized to affect both reported and objective (somnographic) sleep. To determine the effects of these antecedents on sleep among 69 mid-life women, two models were tested, using both partial correlations and path analysis. Of all the measures of life events and social support examined in this study only negative LEs and contacts with non-supportive persons were associated (positively) with psychological distress, differentially explaining between 9% and 19% of the variance in each of five SCL-90 subscales. Both negative life events and contacts with non-supportive persons influenced depression and the SCL-90 PST index, whereas only negative life events affected anxiety, phobic anxiety and paranoid ideation. Anxiety, depression and the PST index, as indicators of psychological distress, had direct inverse effects on reported sleep with significant adjusted R2 values ranging from 10% to 16%. The model did not hold for somnographic sleep. The factors which are likely to contribute to the absence of an observed relationship between psychological distress and somnographic sleep are discussed.


Multiple paternity in Belding's ground squirrel litters.
Sexually receptive female Spermophilus beldingi (Rodentia: Sciuridae) usually mate with several different males. The paternity of 27 litters born in 1977 and 1978 was ascertained by combining field observations of mating with laboratory paternity exclusion analyses. Most of the litters (78 percent) were multiply sired, usually by two or three males. This may be the highest frequency of multiple paternity ever directly demonstrated in a natural population.


Frankenstein: Learning Deep Face Representations Using Small Data.
Deep convolutional neural networks have recently proven extremely effective for difficult face recognition problems in uncontrolled settings. To train such networks, very large training sets are needed with millions of labeled images. For some applications, such as near-infrared (NIR) face recognition, such large training data sets are not publicly available and difficult to collect. In this paper, we propose a method to generate very large training data sets of synthetic images by compositing real face images in a given data set. We show that this method enables to learn models from as few as 10 000 training images, which perform on par with models trained from 500 000 images. Using our approach, we also obtain state-of-the-art results on the CASIA NIR-VIS2.0 heterogeneous face recognition data set.


Long-term Outcomes Associated With Total Arterial Revascularization vs Non-Total Arterial Revascularization.
The optimal conduits for coronary artery bypass grafting (CABG) remain controversial in multivessel coronary artery disease. To compare the long-term clinical outcomes of total arterial revascularization (TAR) vs non-TAR (CABG with at least 1 arterial and 1 saphenous vein graft) in a multicenter population-based study. This multicenter population-based cohort study using propensity score matching took place from October 2008 to March 2017 in Ontario, Canada, with a mean and maximum follow-up of 4.6 and 9.0 years, respectively. Individuals with primary isolated CABG were identified, with at least 1 arterial graft. Exclusion criteria were individuals from out of province and younger than 18 years. Patients undergoing a cardiac reoperation or those in cardiogenic shock were also excluded because these conditions would potentially bias the surgeon toward not performing TAR. Analysis began April 2019. Total arterial revascularization. Primary outcome was time to first event of a composite of death, myocardial infarction, stroke, or repeated revascularization (major adverse cardiac and cerebrovascular events). Secondary outcomes included the individual components of the primary outcome. Of 49 404 individuals with primary isolated CABG, 2433 (4.9%) received TAR, with the total number of bypasses being 2, 3, and 4 or more vessels in 1521 (62.5%), 865 (35.6%), and 47 individuals (1.9%), respectively. The mean (SD) age was 61.2 (10.4) years and 1983 (81.5%) were men. After propensity score matching, 2132 patient pairs were formed, with equal total number of bypasses (mean [SD], 2.4 [0.5]) but with more arterial grafts in the TAR group (mean [SD], 2.4 [0.5] vs 1.2 [0.4]; P < .01). In-hospital death (15 [0.7%] vs 21 [1.0%]; P = .32) did not differ between TAR vs non-TAR groups after propensity score matching. Throughout 8 years, TAR was associated with improved freedom from major adverse cardiac and cerebrovascular events (hazard ratio, 0.78; 95% CI, 0.68-0.89), death (hazard ratio, 0.80; 95% CI, 0.66-0.97), and myocardial infarction (hazard ratio, 0.69; 95% CI, 0.51-0.92). There was no difference in stroke and repeated revascularization. Total arterial revascularization was associated with improved long-term freedom from major adverse cardiac and cerebrovascular events, death, and myocardial infarction and may be the procedure of choice for patients with reasonable life expectancy requiring CABG.


The "ultra-free" ultrafiltration technique compared with equilibrium dialysis for determination of unbound thiopental concentrations in serum.
We compare a new ultrafiltration technique, involving a unique Millipore membrane, with the classical method of equilibrium dialysis for determining the fraction of thiopental not bound to serum proteins. This fraction, as determined by equilibrium dialysis at 37 degrees C, ranged between 12 and 16% for total concentrations at 50 microgram/L to 10 mg/L of serum. In contrast, ultrafiltration at 37 degrees C yielded a 49% higher value for unbound thiopental: 26.3 (SD 2.6)%. Determined at room temperature (24 degrees C), there was no statistically significant difference for results by the two methods: 14.2 and 15.9%, respectively. The discrepancy between results at 37 degrees C may partly be explained by serum proteins penetrating the Ultra-Free filter. For the routine clinical measurement of unbound drug concentrations, the ultrafiltration membrane at room temperature appears to be sufficiently accurate and less time-consuming than equilibrium dialysis.


Promoting evidence-based practice through peer teaching: Practical tips to run a departmental teaching program in a healthcare setting.
This article was migrated. The article was marked as recommended. In the face of knowledge explosion with new scientific evidence being published at an accelerated pace, doctors are faced with the challenge of keeping abreast with the relevant evidence to bring it to their patient. Evidence-based practice is core to providing the best care for patients and unawareness of new evidence against a certain practice in medicine can see the perpetuation of practices that are not evidence-based. Peer teaching through departmental teaching programs is a useful tool to conceptualise evidence by bringing the patient into the classroom to consider the relevant evidence surrounding their care. Running a successful departmental teaching program which matches the intrinsic self-concept of clinicians who have multiple demands on their time is faced with multiple barriers. This article provides tips drawn from experience and supported by evidence from the literature that can be used in various healthcare settings to coordinate a departmental teaching program.


Controlled evaluation of BACTEC PLUS 27 and Roche Septi-Chek anaerobic blood culture bottles.
Becton Dickinson Diagnostic Instrument Systems (Sparks, Md.) recently introduced BACTEC high-volume aerobic and anaerobic bottles that accept up to 10 ml of blood for use on their nonradiometric blood culture instruments. Both bottles contain 25 ml of tryptic soy broth, 0.05% sodium polyanetholesulfonate, and mixed resins. We compared the anaerobic bottle, designated BACTEC PLUS 27 (BP27), with the Roche Septi-Chek (RSC) Columbia broth anaerobic bottle in a collaborative evaluation at three university hospitals. A total of 5,152 adequately filled blood cultures were obtained from adult patients with suspected bacteremia or fungemia. Staphylococcus aureus was recovered significantly more often (P less than 0.03) from BP27 bottles alone; there were no other significant differences in yield. When microorganisms were recovered from both anaerobic bottles, growth was detected earlier in BP27 than it was in RSC (P less than 0.001), especially for S. aureus (P less than 0.001) and Staphylococcus epidermidis (P less than 0.02). We conclude that the yield from BP27 bottles is equivalent to or better (S. aureus) than that from RSC anaerobic bottles with Columbia broth and that speed of detection is superior with BP27 bottles.


Diffuse Exfoliative Rash with Sepsis and Eosinophilia: A Case of Erythroderma?
BACKGROUND Erythroderma is an exfoliative dermatitis that manifests as generalized erythema and scaling that involves 90% of the body surface. If untreated, erythroderma can be fatal because of its metabolic burden and risk of secondary infections. CASE REPORT The patient was a 56-year-old male with prior rash attributed to group A Streptococcal cellulitis and discharged on Augmentin, Clindamycin with hydrocortisone cream, and Bactrim, but he had been noncompliant. He was admitted again for rash involving the face, torso, and extremities characterized by diffuse, desquamative, dry scales in morbilliform pattern. The patient was septic with Staphylococcus aureus bacteremia and compromised skin barrier. He was started on vancomycin and switched to Cefazolin IV due to concern for drug reaction. Autoimmune workup included antibodies for anti-Jo-1, anti-dsDNA, anti-centromere, and ANCA. However, only antinuclear antibody and scleroderma antibody were positive. Given the unclear workup results and lack of response to antibiotics, the patient was started on prednisone 60 mg PO and topical Triamcinolone 0.1% cream. A skin biopsy revealed psoriasiform hyperplasia with atypical T cell infiltrate and eosinophils, but negative for T cell gene rearrangement. The rash resolved after day 12 of application of topical Triamcinolone. CONCLUSIONS This case is unique in terms of the rarity of erythroderma and the diagnostic challenge given confounding factors such as noncompliance and drug reaction. Serious causes, such as SLE and cutaneous T cell lymphoma, were ruled out. Fortunately, the rash responded well to steroids; however, given the adverse effects of long-term use of topical steroids, the patient will need follow up with Dermatology.


Cooperation as a signal of time preferences.
Many evolutionary models explain why we cooperate with non-kin, but few explain why cooperative behaviour and trust vary. Here, we introduce a model of cooperation as a signal of time preferences, which addresses this variability. At equilibrium in our model (i) future-oriented individuals are more motivated to cooperate, (ii) future-oriented populations have access to a wider range of cooperative opportunities, and (iii) spontaneous and inconspicuous cooperation reveal stronger preference for the future, and therefore inspire more trust. Our theory sheds light on the variability of cooperative behaviour and trust. Since affluence tends to align with time preferences, results (i) and (ii) explain why cooperation is often associated with affluence, in surveys and field studies. Time preferences also explain why we trust others based on proxies for impulsivity, and, following result (iii), why uncalculating, subtle and one-shot cooperators are deemed particularly trustworthy. Time preferences provide a powerful and parsimonious explanatory lens, through which we can better understand the variability of trust and cooperation.


CB1 and LPA1 Receptors Relationship in the Mouse Central Nervous System.
Neurolipids are a class of bioactive lipids that are produced locally through specific biosynthetic pathways in response to extracellular stimuli. Neurolipids are important endogenous regulators of neural cell proliferation, differentiation, oxidative stress, inflammation and apoptosis. Endocannabinoids (eCBs) and lysophosphatidic acid (LPA) are examples of this type of molecule and are involved in neuroprotection. The present study analyzes a possible relationship of the main receptor subtypes for both neurolipid systems that are present in the central nervous system, the CB1 and LPA1 receptors, by using brain slices from CB1 KO mice and LPA1-null mice. Receptor-mediated G protein activation and glycerophospholipid regulation of potential precursors of their endogenous neurotransmitters were measured by two different in vitro imaging techniques, functional autoradiography and imaging mass spectrometry (IMS), respectively. Possible crosstalk between CB1 and LPA1 receptors was identified in specific areas of the brain, such as the amygdala, where LPA1 receptor activity is upregulated in CB1 KO mice. More evidence of an interaction between both systems was that the CB1-mediated activity was clearly increased in the prefrontal cortex and cerebellum of LPA1-null mice. The eCB system was specifically over-activated in regions where LPA1 has an important signaling role during embryonic development. The modifications on phospholipids (PLs) observed in these genetically modified mice by using the IMS technique indicated the regulation of some of the PL precursors of both LPA and eCBs in specific brain areas. For example, phosphatidylcholine (PC) (36:1) was detected as a potential LPA precursor, and phosphatidylethanolamine (PE) (40:6) and PE (p18:0/22:6) as potential eCB precursors. The absence of the main cerebral receptors for LPA or eCB systems is able to induce modulation on the other at the levels of both signaling and synthesis of endogenous neurotransmitters, indicating adaptive responses between both systems during prenatal and/or postnatal development.


[Time trends of digestive system tumor mortality in Italy, 1970-89].
Time trends of mortality from digestive cancers in Italy during the period 1970-1989 were here studied either at the national level and for wide geographical areas (North, Center and South). Cancers of oral cavity and pharynx, of colon and rectum, of gallbladder and of the pancreas presented, during the considered period a generalized increasing trend. Stomach cancer mortality was decreasing in both sexes and in all areas, but a less marked rate of decrease appeared for younger cohorts, particularly for women. Trends almost stable, or contrasting across sexes and age classes, were observed for malignant tumours of the oesophagus and of the liver.


Is there an outcome benefit? Patient engagement technology in addition to the electronic medical record patient portal following elective colorectal surgery.
Patient engagement technologies (PET) are an area of growing innovation and investment, but whether PET use in the setting of electronic medical record (EMR) supported patient portals are associated with improved outcomes is unknown. Therefore, we assessed PET and EMR activation among patients undergoing elective colorectal surgery on an enhanced recovery pathway. We identified adults undergoing elective colorectal surgery between 1/2017 and 7/2021. EMR activations were assessed and patients were considered PET users if they used a proprietary PET application. Multivariable logistic regression was used to identify factors associated with PET use and determine whether the level of engagement (percentage of messages read by the patient) was associated with 30-day outcomes. 484 patients (53.5% PET users, 81.6% with an activated EMR patient portal, 30.8% ≥ 70 years of age) were included. PET users were younger, more likely to have their EMR portal activated and had decreased odds of prolonged length of stay [odds ratio (OR) 0.5, 95% confidence interval (CI) 0.4-0.8]. Among patients ≥ 70 years, PET users had reduced odds of readmissions (OR 0.2, 95% CI 0.1-0.9) compared to PET non-users. The most engaged PET users had decreased morbidity (OR 0.2, 95% CI 0.1-0.8) and readmissions (OR 0.3, 95% CI 0.1-0.8) compared to the least engaged PET users. When controlling for EMR activation, patients who use PET, specifically those with higher levels of engagement or aged ≥ 70, have improved outcomes following elective colorectal surgery. Interventions aimed at increasing the adoption of PET among older adults may be warranted.


A genetic variant of MDM4 influences regulation by multiple microRNAs in prostate cancer.
The oncogene MDM4, also known as MDMX or HDMX, contributes to cancer susceptibility and progression through its capacity to negatively regulate a range of genes with tumour-suppressive functions. As part of a recent genome-wide association study it was determined that the A-allele of the rs4245739 SNP (A>C), located in the 3'-UTR of MDM4, is associated with an increased risk of prostate cancer. Computational predictions revealed that the rs4245739 SNP is located within a predicted binding site for three microRNAs (miRNAs): miR-191-5p, miR-887 and miR-3669. Herein, we show using reporter gene assays and endogenous MDM4 expression analyses that miR-191-5p and miR-887 have a specific affinity for the rs4245739 SNP C-allele in prostate cancer. These miRNAs do not affect MDM4 mRNA levels, rather they inhibit its translation in C-allele-containing PC3 cells but not in LNCaP cells homozygous for the A-allele. By analysing gene expression datasets from patient cohorts, we found that MDM4 is associated with metastasis and prostate cancer progression and that targeting this gene with miR-191-5p or miR-887 decreases in PC3 cell viability. This study is the first, to our knowledge, to demonstrate regulation of the MDM4 rs4245739 SNP C-allele by two miRNAs in prostate cancer, and thereby to identify a mechanism by which the MDM4 rs4245739 SNP A-allele may be associated with an increased risk for prostate cancer.


[Epidemiology of pressure ulcers: interpreting data epidemiological as an indicator of quality].
The incidence of pressure ulcers (PU) is still a current problem in our society and a constant challenge for all professionals and health institutions. Health professionals worry increasingly about the safety of their patients in the hospital environment. However, pressure ulcers continue to be one of the most common types of injuries acquired during hospitalization. The objective of this study is to compare the incidence and prevalence of pressure ulcers in community settings and care differentiated and interpret these values as indicators of quality of care. A review of literture reporting incidence and prevalence of pressure ulcer as an outcome measure and is relation with quality indicators. Electronic databases (CINAHL, MEDLINE and EBSCO) were searched from 1 January 1999 to 31 Dezembro 2012 in the English, Spanish and Portuguese language. The MESH descriptors data were Pressure ulcer, epidemiology, Quality indicator, incidence and prevalence. The 17 papers reported studiest conducted in nine countries. Diderent measurement instruments were utilised to measure theincidence and prevalence of pressure ulcers. Four themes emerged from the thematic analysis, the importance of prevention and treatment, diferential diagnosis and summary minimum data set for epidemiological studies. Prevalence varies in Europe between 3 and 28%, and the locations with the highest incidences services and intensive care medicine. A system of classification of pressure ulcers in their different categories and the differential diagnosis with injuries humidity reduces the misclassification of UP. Different instruments of data collection does not allow us to compare results between different countries but identifies different contexts.


Exercise-induced GH secretion in the assessment of GH deficiency in adult individuals.
The role of exercise testing in the assessment of GH deficiency (GHD) in adult patients is currently unclear. This study aimed at evaluating the diagnostic value of exercise-induced GH levels in the detection of severe GHD in adult patients. Fourteen patients confirmed to have severe GHD according to current guidelines and 20 healthy control individuals (CI) exercised for 120 min at 50-60% of their individual VO2(max). GH was measured before and every 30 min throughout exercise. The diagnostic value of predicting GHD was assessed by performing receiver operating characteristics (ROC) analysis for each time point of GH assessment. To optimise comparability within the study population a sub-analysis with ten individuals specifically matched for gender, age, body mass index and waist was performed. Exercise-induced GH secretion was significantly lower in patients with GHD than in CI (P<0.001). Area under the ROC curve (AUC(ROC)) was 0.954±0.033, 0.993±0.009, 0.989±0.012 and 0.992±0.009 for the overall population and 0.870±0.086, 0.980±0.024, 0.970±0.034 and 0.978±0.027 for the matched individuals at 30, 60, 90 and 120 min of exercise respectively. At 60 min of exercise a cut off GH value of 2.4 ng/ml translates into a sensitivity of 100% and a specificity of 95 and 90% in the diagnosis of GHD for the overall population and matched individuals respectively. GH assessment during a standardised aerobic exercise of moderate intensity is a reliable test with high diagnostic accuracy in predicting severe GHD in adult individuals. Based on the current findings exercise duration of 60 min appears to be sufficient for diagnostic purposes.


Neighborhood immigrant density and population health among native-born Americans.
The healthy immigrant effect-whereby immigrants are on average healthier than the native-born-have been well studied. However, little is known about the relationship between immigration and the health of the native-born. This study fills this important research gap by examining the association between neighborhood immigrant density and several population health measures among native-born Americans. We used data from the Los Angeles County Health Survey to analyze four individual-level health behaviors and outcomes, including regular fast food consumption, fruit and vegetable consumption, body mass index, and hypertension. We conducted multilevel logistic regressions to assess the association between neighborhood immigrant density and the four health behaviors and outcomes. The results showed that neighborhood immigrant density was negatively associated with regular fast food consumption (OR = 0.33; 95% CI, 0.18-0.59), BMI (β = -2.16, 95% CI, -3.13 to -1.19), and hypertension (OR = 0.58; 95% CI, 0.38-0.89), and positively associated with fruit/vegetable consumption (OR = 1.64; 95% CI, 1.01-2.66) among native-born Americans. In conclusion, native-born Americans who lived in a neighborhood with a high density of immigrants had healthier behaviors and better health outcomes compared to those who lived in a neighborhood with a low density of immigrants.


Category and letter verbal fluency across the adult lifespan: relationship to EEG theta power.
The purpose of this study was to examine the impact of age, sex, and education on category and letter verbal fluency task performance. A secondary goal was to examine whether resting EEG theta power in bilateral frontal and temporal lobes impacts age-associated decline in verbal fluency task performance. A large sample (N = 471) of healthy, normal participants, age 21-82, was assessed for letter fluency (i.e., FAS), and for category fluency (i.e., Animal Naming), and with a 32-channel EEG system for 'eyes-open' resting theta power. The effects of age, sex, and education were examined using analyses of variance. Correlation analyses were used to test the impact of theta power on age and fluency performance by controlling for the effects of theta when examining the relationship between the other two variables. The results indicated that performance on both fluency tests declined linearly with age, but that the rate of decline was greater for category fluency. These age changes were not associated with education level, and there were no sex differences. While theta power was negatively associated with age and positively associated with Animal Naming performance, it did not moderate the relationship between the two. The differential age-associated decline between category and letter fluency suggests separate neurobiological substrates underlying the two domains of performance, which is not related to theta activity.


Overexpression of HuD, but not of its truncated form HuD I+II, promotes GAP-43 gene expression and neurite outgrowth in PC12 cells in the absence of nerve growth factor.
We have previously shown that the RNA-binding protein HuD binds to a regulatory element in the growth-associated protein (GAP)-43 mRNA and that this interaction involves its first two RNA recognition motifs (RRMs). In this study, we investigated the functional significance of this interaction by overexpression of human HuD protein (pcHuD) or its truncated form lacking the third RRM (pcHuD I+II) in PC12 cells. Morphological analysis revealed that pcHuD cells extended short neurites containing GAP-43-positive growth cones in the absence of nerve growth factor (NGF). These processes also contained tubulin and F-actin filaments but were not stained with antibodies against neurofilament M protein. In correlation with this phenotype, pcHuD cells contained higher levels of GAP-43 without changes in levels of other NGF-induced proteins, such as SNAP-25 and tau. In mRNA decay studies, HuD stabilized the GAP-43 mRNA, whereas HuD I+II did not have any effect either on GAP-43 mRNA stability or on the levels of GAP-43 protein. Likewise, pcHuD I+II cells showed no spontaneous neurite outgrowth and deficient outgrowth in response to NGF. Our results indicate that HuD is sufficient to increase GAP-43 gene expression and neurite outgrowth in the absence of NGF and that the third RRM in the protein is critical for this function.


Comparison of Whitening Dentifrices on the Effectiveness of In-office Tooth Bleaching: A Double-blind Randomized Controlled Clinical Trial.
To investigate the effect of whitening dentifrices on the effectiveness of in-office tooth bleaching. A double-blind randomized controlled clinical trial was performed. The participants were randomly allocated into three groups according to the different dentifrices used during this clinical trial: regular dentifrice (group C), conventional whitening dentifrice (group CW), and whitening dentifrice containing blue covarine (group CU). All participants received in-office tooth bleaching for the maxillary anterior teeth (two sessions conducted at a one-week interval). Tooth color was measured with a spectrophotometer at baseline (T1), after the first bleaching session (T2), after the second bleaching session (T3); one week after the completion of in-office bleaching (T4); and three weeks after the completion of in-office bleaching (T5). The data were statistically analyzed through repeated analysis of variance and the Tukey test (α=0.05). Sixty participants completed the study (n=20 per group). At T3, group CU exhibited the lowest ΔE values ( p=0.008). The ΔE values increased from T4 to T5 in the CW and CU groups, whereas a decrease in ΔE values was observed for group C. The use of a whitening dentifrice containing blue covarine during in-office bleaching reduced color changes. After tooth bleaching, brighter tooth colors were observed in the participants who brushed with whitening dentifrices compared to those who brushed with a regular dentifrice.


Time Spent in Lateral Sleep Position and Asymmetry in Glaucoma.
To explore sleep position in asymmetric primary open-angle glaucoma (POAG) with a focus on low pressure glaucoma (LPG). Sleep laboratory videos of 54 POAG patients were examined for lateral sleep. Then, 29 LPG patients (intraocular pressure [IOP] < 22 mm Hg) with an intereye visual field index (VFI) asymmetry of more than 5% continuously recorded their sleep position at home for 2 nights by using a portable device. Correlations were sought between sleep position, visual field (VF), and retinal nerve fiber layer (RNFL) symmetry as well as ocular biometric data and positional IOP changes. Finally, an expanded data set of 178 POAG patients (63 LPG and 115 high pressure glaucoma [HPG; IOP ≥ 22 mm Hg]) was used to correlate VF and the RNFL symmetry to the self-assessed sleep position collected in a survey. In the video analysis, patients spent 19% ± 2% (mean ± SEM) more time sleeping on one side than on the other. Right-sided sleep was preferred. Right-sided sleep was 1.6 times more common in continuously recorded home data and correlated to an asymmetric VF that was worse in the left eye (b = -0.422, P = 0.002). Pulse amplitude of left eyes was lower in the right decubitus position (P = 0.02). In the expanded survey, 73% of LPG and 58% of HPG patients slept asymmetrically. Right-sided sleepers had a worse RNFL symmetry score. Asymmetric sleep behavior is common. Right-sided sleep was preferred and correlated with a lower VFI on the left.


Pulsed Electric Field Processing of Orange Juice: A Review on Microbial, Enzymatic, Nutritional, and Sensory Quality and Stability.
During the last decades pulsed electric field (PEF) processing received considerable attention due to its potential to enhance food products or create alternatives to conventional methods in food processing. It is generally acknowledged that PEF processing can deliver safe and chill-stable fruit juices with fresh-like sensory and nutritional properties. Relatively low-processing temperature and short residence times can achieve highly effective inactivation of microorganisms while retaining product quality. A first commercial application of PEF for preservation of fruit juices was launched in 2006 in the United States. Since then, industrial-scale processing equipment for liquid and solid products were developed and, in Europe in 2009, an industrial juice preservation line was installed using 20 kV/cm pulses at 40 to 50 °C to extend the chill-stability of fruit juices, including citrus juices and smoothies, from 6 to 21 d. The related PEF processing costs are in the range of US $0.02 to 0.03 per liter and are justified due to access to new markets and reduced return of spoiled product. However, despite its commercial success there are still many unknown factors associated with PEF processing of fruit and citrus juices and many conflicting reports in the literature. This literature review, therefore, aims to provide a comprehensive overview of the current scientific knowledge of PEF effects on microbial, enzymatic, nutritional, and sensory quality and stability of orange juices.


Understanding ring-closing and racemization to prepare α-amino acid NCA and NTA monomers: a DFT study.
Polypeptides and polypeptoids are promising materials in biomedical applications bearing α-amino acid repeating units, which are prepared from ring-opening polymerizations of α-amino acid N-carboxyanhydride (NCA) or N-thiocarboxyanydride (NTA) monomers. Detailed studies on monomer synthetic routes are essential to explore new α-amino acid NCA and NTA monomers as well as the corresponding poly(α-amino acid) materials. In this contribution, density functional theory (DFT) is applied to investigate the mechanism of the Leuchs approach including two possible pathways, precursor structure and racemization in the ring-closing reaction. According to DFT calculations, pathway 2 is preferred with lower ΔG than pathway 1, and the rate-determining step is recognized as an SN2 substitution with releasing equivalent halogenated hydrocarbon, which explains our experimental observations. Racemization results from the reaction between the NTA monomer and a strong protonic acid, which can be suppressed by low temperature and short reaction time. Racemization is inhibited by steric hindrance in those NTAs of α-amino acids containing high bulkiness at the β-carbon, such as leucine-NTA.


Developmental validation of the HIrisPlex system: DNA-based eye and hair colour prediction for forensic and anthropological usage.
Forensic DNA Phenotyping or 'DNA intelligence' tools are expected to aid police investigations and find unknown individuals by providing information on externally visible characteristics of unknown suspects, perpetrators and missing persons from biological samples. This is especially useful in cases where conventional DNA profiling or other means remain non-informative. Recently, we introduced the HIrisPlex system, capable of predicting both eye and hair colour from DNA. In the present developmental validation study, we demonstrate that the HIrisPlex assay performs in full agreement with the Scientific Working Group on DNA Analysis Methods (SWGDAM) guidelines providing an essential prerequisite for future HIrisPlex applications to forensic casework. The HIrisPlex assay produces complete profiles down to only 63 pg of DNA. Species testing revealed human specificity for a complete HIrisPlex profile, while only non-human primates showed the closest full profile at 20 out of the 24 DNA markers, in all animals tested. Rigorous testing of simulated forensic casework samples such as blood, semen, saliva stains, hairs with roots as well as extremely low quantity touch (trace) DNA samples, produced complete profiles in 88% of cases. Concordance testing performed between five independent forensic laboratories displayed consistent reproducible results on varying types of DNA samples. Due to its design, the assay caters for degraded samples, underlined here by results from artificially degraded DNA and from simulated casework samples of degraded DNA. This aspect was also demonstrated previously on DNA samples from human remains up to several hundreds of years old. With this paper, we also introduce enhanced eye and hair colour prediction models based on enlarged underlying databases of HIrisPlex genotypes and eye/hair colour phenotypes (eye colour: N = 9188 and hair colour: N = 1601). Furthermore, we present an online web-based system for individual eye and hair colour prediction from full and partial HIrisPlex DNA profiles. By demonstrating that the HIrisPlex assay is fully compatible with the SWGDAM guidelines, we provide the first forensically validated DNA test system for parallel eye and hair colour prediction now available to forensic laboratories for immediate casework application, including missing person cases. Given the robustness and sensitivity described here and in previous work, the HIrisPlex system is also suitable for analysing old and ancient DNA in anthropological and evolutionary studies.


[Distribution and mechanism of the regulation of the pleurocercoid population count of Triaenophorus nodulosus (Cestoda, Triaenophoridae)].
The character of the distribution of pleurocercoids of Triaenophorus nodulosus depending on the host age is shown. Their distribution in perch at the age of 0+-4+ is over dispersed in its character and is described by negative binomial. At the age of 5+ to 8+ the distribution of parasites is of regular character that is apparently due to changes in the mechanism of regulation of the parasites number. The regulation mechanism of the number of pleurocercoids of T. nodulosus is discussed.


Divergent Approach to Highly Substituted Arenes via [3 + 3] Annulation of Vinyl Sulfoxonium Ylides with Ynones.
Herein, we report the divergent benzannulation for highly substituted arenes using vinyl sulfoxonium ylides and ynones. The addition of ynone at the γ-position of vinyl sulfoxonium ylides leads to dienyl sulfoxonium ylide that can undergo selective annulation under different conditions to give m-terphenyls and parabens. Moreover, control experiments and quantum chemical calculations reveal two distinct reaction mechanisms for both annulations.


Macroaneurysms of the retinal arteries.
Six patients with spontaneous retinal and/or vitreous hemorrhages were found, on evaluation by fluorescein angiography, to have macroaneurysms involving the major retinal arteries. All showed evidence of other vascular disease. With absorption of the hemorrhages, five patients experienced appreciable improvement in vision. The aneurysms appeared to diminish in size as a result of fibrous changes within the arterial walls. In one patient, however, a second vitreous hemorrhage occurred several months later. The possibility of repeated hemorrhage suggests that more consideration should be given to treatment of these aneurysms.


Positron emission tomography in the management of unknown primary head and neck carcinoma.
To assess the role of positron emission tomography (PET) in the management of unknown primary carcinoma of the head and neck region. Prospective case series at an academic medical center. Twenty-six patients with an open excisional biopsy or a fine-needle aspiration biopsy finding that confirmed squamous cell carcinoma of the cervical lymph nodes and no visible primary tumor (as determined by results of a comprehensive physical examination and computed tomography and/or magnetic resonance imaging) underwent PET. The standard evaluation consisted of a comprehensive head and neck examination that included fiberoptic laryngoscopy/nasopharyngoscopy, computed tomography and/or magnetic resonance imaging, and PET followed by panendoscopy with selected biopsies and tonsillectomy. Sensitivity, specificity, and positive and negative predictive values of PET to detect an occult primary tumor. The PET detected 8 occult primary tumors in 26 patients (detection rate, 30.8%). Four occult primary tumors (2 at the base of the tongue and 2 in the tonsil) were detected during routine panendoscopy with negative PET findings. The sensitivity of PET was 66.0%, with a specificity of 92.9%. The positive predictive value was 88.8%, and the negative predictive value was 76.5%. Positron emission tomography can be a valuable tool to identify a subset of patients with an occult primary tumor in the head and neck region. In addition, it can be used to screen for primary tumors below the clavicle. Early identification of the primary tumor may allow for more accurate tumor staging and targeted radiotherapy to minimize adverse effects and complications. A normal PET finding, however, does not eliminate the need for a careful panendoscopy with directed biopsies and tonsillectomy.


Dbx1-expressing cells are necessary for the survival of the mammalian anterior neural and craniofacial structures.
Development of the vertebrate forebrain and craniofacial structures are intimately linked processes, the coordinated growth of these tissues being required to ensure normal head formation. In this study, we identify five small subsets of progenitors expressing the transcription factor dbx1 in the cephalic region of developing mouse embryos at E8.5. Using genetic tracing we show that dbx1-expressing cells and their progeny have a modest contribution to the forebrain and face tissues. However, their genetic ablation triggers extensive and non cell-autonomous apoptosis as well as a decrease in proliferation in surrounding tissues, resulting in the progressive loss of most of the forebrain and frontonasal structures. Targeted ablation of the different subsets reveals that the very first dbx1-expressing progenitors are critically required for the survival of anterior neural tissues, the production and/or migration of cephalic neural crest cells and, ultimately, forebrain formation. In addition, we find that the other subsets, generated at slightly later stages, each play a specific function during head development and that their coordinated activity is required for accurate craniofacial morphogenesis. Our results demonstrate that dbx1-expressing cells have a unique function during head development, notably by controlling cell survival in a non cell-autonomous manner.


Water relations and photosynthetic capacity of two species of Calotropis in a tropical semi-arid ecosystem.
Calotropis procera and Calotropis gigantea, originally from warm parts of Africa and Asia, are now pan-tropical and in ecological terms considered an indicator of overgrazed, disturbed lands; they grow successfully in dry areas. Variations in water relations, morphology and photosynthesis of the two species growing in the same habitat were studied to assess possible mechanisms of tolerance to drought and how these relate to their ecophysiological success. Also the hypothesis that their photosynthetic rate (A) under drought would be affected by stomatal and non-stomatal limitations was tested. Water relations, gas exchange, water use efficiency (WUE), fluorescence parameters, pubescence and specific leaf area (SLA) of Calotropis procera and C. gigantea plants growing in the field were evaluated during the wet (WS) and dry (DS) seasons. The xylem water potential (ψ) was similar in both species during the WS and DS; drought caused a 28 % decrease of ψ. In C. procera, A, stomatal conductance (g(s)) and carboxylation efficiency (CE) were higher in the WS with half the values of those during the DS, this species being more affected by drought than C. gigantea. A high δ(13)C of C. gigantea (-26·2 ‰) in the WS indicated a higher integrated WUE, in agreement with its lower g(s). Leaves of C. gigantea were more pubescent than C. procera. Relative stomatal and non-stomatal limitation of A increased with drought in both species; no changes in maximum quantum yield of photosystem II (PSII; F(v)/F(m)) were observed. The decrease in the relative quantum yield of PSII (ϕ(PSII)) and in the photochemical quenching coefficient (q(P)) was more pronounced in C. procera than in C. gigantea. The photosynthetic capacity of C. procera was higher than that of C. gigantea. During the DS, A was regulated by stomatal and non-stomatal factors in a coordinated manner and drought did not cause chronic photoinhibition. A higher density of trichomes and leaf angle in C. gigantea may contribute to the maintenance of A and confer more efficient protection of photochemical activity in the DS. Ecophysiological traits such as high photosynthetic rate throughout the year even during the DS, and high WUE, highly pubescent leaves and low SLA observed in both species contribute to the establishment and growth of Calotropis in dry conditions.


Sensitivity of Puccinia triticina f. sp. tritici from China to Triadimefon and Resistance Risk Assessment.
Wheat leaf rust, caused by Puccinia triticina f. sp. tritici (Pt), is distributed widely in wheat-producing areas and results in serious yield losses worldwide. In China, leaf rust has been largely controlled with a demethylation inhibitor (DMI) fungicide, triadimefon. Although high levels of fungicide resistance in pathogens have been reported, no field failure of wheat leaf rust to DMI fungicides has been reported in China. A resistance risk assessment of triadimefon to Pt was investigated in the present study. The sensitivity of 197 Pt isolates across the country to triadimefon was determined, and the density distribution of EC50 values (concentration at which mycelial growth is inhibited by 50%) showed a continuous multimodal curve because of the extensive use of this fungicide in wheat production, with a mean value of 0.46 μg/ml. The majority of the tested Pt isolates were sensitive to triadimefon, whereas 10.2% developed varying degrees of resistance. Characterization of parasitic fitness revealed that the triadimefon-resistant isolates exhibited strong adaptive traits in urediniospore germination rate, latent period, sporulation intensity, and lesion expansion rate. No correlation was observed between triadimefon and tebuconazole and hexaconazole, which have the similar mode of action, or pyraclostrobin and flubeneteram, which have different modes of action. Overexpression of the target gene Cyp51 led to the triadimefon resistance of Pt. The risk of resistance to triadimefon in Pt may be low to moderate. This study provided important data for fungicide resistance risk management against wheat leaf rust.


Domain-specific knowledge as the "dark matter" of adult intelligence: Gf/Gc, personality and interest correlates.
An enduring controversy in intelligence theory and assessment, the argument that middle-aged adults are, on average, less intelligent than young adults, is addressed in this study. A sample of 228 educated adults between ages 21 and 62 years was given an array of tests that focused on a broad assessment of intelligence-as-knowledge, traditional estimates of fluid intelligence (Gf) and crystallized intelligence (Gc), personality, and interests. The results indicate that middle-aged adults are more knowledgeable in many domains, compared with younger adults. A coherent pattern of ability, personality, and interest relations is found. The results are consistent with a developmental perspective of intelligence that includes both traditional ability and non-ability determinants of intelligence during adulthood. A reassessment of the nature of intelligence in adulthood is provided, in the context of a lifelong learning and investment model, called PPIK, for intelligence-as-Process, Personality, Interests, and intelligence-as-Knowledge (Ackerman, 1996).


[Mechanisms of action of peroral antidiabetics. Sulfonylurea preparations block the ATP-dependent potassium channels].
Although hypoglycaemic sulphonylureas have been used to treat non-insulin-dependent diabetes mellitus (NIDDM) for the past forty years, their mechanisms of action at the molecular level have only recently been elucidated. A combination of electrophysiological and molecular biological techniques showed the target of sulphonylureas to be a sulphonylurea receptor (SUR1) and potassium channel (Kir6.2) complex. Together, these two proteins form the ATP-dependent potassium (KATP) channel occurring in insulin-secreting cells. An increase in the blood glucose level triggers a chain of events in insulin-secreting cells and K(ATP) channel closure which is a prerequisite for insulin secretion. In NIDDM, however, an increase in blood glucose fails to close the K(ATP) channel satisfactorily, but this can be remedied by the administration of sulphonylureas.


[Cytostatic action of semisynthetic derivatives of carminomycin].
The cytostatic effect of some semi-synthetic derivatives of carminomycin on the tumor cells of mouse lymphadenosis (NK/Ly was studied in primary suspended cultures. A rapid method developed by the authors was used for determination of the drug cytostatic effect. The method is based on measuring the intensity of 3H-thimidine incorporation into the tumor cells. Simultaneously a method based on estimation of the increase of the total amount of the nucleic acids was used. No derivative superior to the initial drug by the level of the cytostatic effect on the tumor cells was found.


IgE blockade in autoimmunity: Omalizumab induced remission of bullous pemphigoid.
Bullous pemphigoid (BP) is a blistering dermopathy and a prototypic antibody-mediated autoimmune disease. Detection of IgG autoantibodies against hemidesmosomal proteins BP180 and/or BP230 are diagnostic and levels can correlate with disease activity. Therapies include corticosteroids and oral immunosuppressants, while intravenous immunoglobulin and rituximab are reserved for treatment resistant cases. Here we describe a patient with severe BP which was refractory to standard first line therapy, intravenous immunoglobulin and rituximab induced depletion of peripheral B cells. Use of the monoclonal anti-IgE antibody omalizumab resulted in rapid resolution of blistering despite ongoing high levels of anti-skin IgG antibodies. To our knowledge this is the first case of BP responsive to omalizumab after failure of rituximab to be reported. This case adds to emerging data on omalizumab as a novel BP treatment as well as providing new evidence of an independent role for autoreactive IgE-mediated inflammation in the formation of BP skin lesions.


A genotype-first approach for the molecular and clinical characterization of uncommon de novo microdeletion of 20q13.33.
Subtelomeric deletions of the long arm of chromosome 20 are rare, with only 11 described in the literature. Clinical features of individuals with these microdeletions include severe limb malformations, skeletal abnormalities, growth retardation, developmental and speech delay, mental retardation, seizures and mild, non-specific dysmorphic features. We characterized microdeletions at 20q13.33 in six individuals referred for genetic evaluation of developmental delay, mental retardation, and/or congenital anomalies. A comparison to previously reported cases of 20q13.33 microdeletion shows phenotypic overlap, with clinical features that include mental retardation, developmental delay, speech and language deficits, seizures, and behavior problems such as autistic spectrum disorder. There does not appear to be a clinically recognizable constellation of dysmorphic features among individuals with subtelomeric 20q microdeletions. Based on genotype-phenotype correlation among individuals in this and previous studies, we discuss several possible candidate genes for specific clinical features, including ARFGAP1, CHRNA4 and KCNQ2 and neurodevelopmental deficits. Deletion of this region may play an important role in cognitive development.


AIDS diagnosis and depression in the Multicenter AIDS Cohort Study: the ameliorating impact of pet ownership.
The impact of pet ownership on depression was tested among a sample of gay and bisexual men (n = 1,872). Multivariate analyses, controlling for demographics and baseline depressive symptomatology, showed that neither pet ownership nor the presence of HIV infection was associated with depression. Depression was influenced by the presence of AIDS and by having relatively few confidants. Analyses among HIV-infected men only showed that persons with AIDS who owned pets reported less depression than persons with AIDS who did not own pets. This beneficial effect of pet ownership occurred principally among persons who reported fewer confidants. These results suggest that by enhancing companionship for some HIV-infected persons, pets may buffer the stressful impact of AIDS.


Subantimicrobial dose doxycycline efficacy as a matrix metalloproteinase inhibitor in chronic periodontitis patients is enhanced when combined with a non-steroidal anti-inflammatory drug.
Administration of subantimicrobial dose doxycycline (SDD) to chronic periodontitis (CP) patients has repeatedly been found to reduce mammalian collagenase and other matrix metalloproteinase (MMP) activity in gingival tissues and crevicular fluid, in association with clinical efficacy, without the emergence of antibiotic-resistant bacteria either orally or extra-orally. More recently, SDD adjunctive to repeated mechanical debridement resulted in dramatic clinical improvement in patients (>50% smokers) with generalized aggressive periodontitis. As an additional pharmacologic approach, non-steroidal anti-inflammatory drugs (NSAIDs) can reduce gingival inflammation and alveolar bone resorption, at least under experimental conditions. In the current study, we determined the effect of administering a combination (combination) of these two host-modulating drugs (SDD plus low-dose NSAID) to CP patients, on selected neutral proteinases in gingiva, enzymes believed to mediate periodontal breakdown. Earlier preliminary studies in humans with bullous pemphigoid, which is also associated with excessive levels of host-derived proteinases including MMPs, indicated improved clinical efficacy of combination therapy. Nineteen CP patients, scheduled for mucoperiosteal flap surgery bilaterally in the maxillary arch, were randomly distributed into three experimental groups administered either 1) low-dose flurbiprofen (LDF) alone, 50 mg q.d.; 2) SDD (20 mg b.i.d.) alone; or 3) a combination of SDD plus LDF (combination). The gingival tissues were biopsied during surgery from right and left maxillary posterior sextants, before and after a 3-week regimen of medication, respectively. The tissues were then extracted, the extracts partially purified, then analyzed for the endogenous proteinase inhibitor, alpha1-PI, and its breakdown product, and for host-derived matrix metalloproteinases (i.e., collagenases, gelatinases) and neutrophil elastase activities. Short-term therapy with SDD alone produced a significant reduction and LDF alone produced no reduction in host-derived neutral proteinases. However, the combination therapy produced a statistically significant synergistic reduction of collagenase, gelatinase, and serpinolytic (alpha1-PI degrading) activities (69%, 69%, and 75% reductions, respectively) and a lesser reduction of the serine proteinase, elastase (46%). Consistent with previous studies on animal models of chronic destructive disease (e.g., rheumatoid arthritis), the SDD and NSAID combination therapy synergistically suppressed MMP and other neutral proteinases in the gingiva of CP patients. A mechanism, suggested by earlier animal studies, involves the NSAID, in the combination regimen, increasing the uptake of the tetracycline-based MMP inhibitor in the inflammatory lesion, thus synergistically enhancing the efficacy of this medication.


[Outcome of surgical treatment of cancer of the stomach. Report of 330 cases].
The study concerned 330 cases of gastric adenocarcinoma operated from January 1969 to June 1996. Clinical, histological and therapeutic features were analyzed and compared during 3 periods (Group 1: 1969-79, Group 2: 1979-88, Group 3: 1989-96). The aim was to evaluate changes and results occurred in gastric carcinoma. The median age was 65 +/- 11 year (range 25-90), the sex ratio 2. The most common location was in the lower third of the stomach and the cancer was often far advanced (71 percent of stages III and IV). Subtotal gastrectomy was replaced by total gastrectomy and large lymph node dissection was systematically performed in group 3. Curative resection rate increased from 28 to 60 percent between group 1 and group 3. Despite the more radical surgery, post-operative mortality rates decreased respectively 22%, 9%, 8% for the groups 1, 2, 3 (p < 0.01) and global morbidity remained stable while the rate of intra-abdominal infection have changed in group 3 (4.8% vs 2.7% and 2.1% in respectively groups 1 and 2; p = ns). Two year survival rates were 20% for group 1.25% for group 2 and 35% for group 3 (p < 0.01). This results can be considered as encouraging but have to be confirmed at 5 year survival.


Y-STR variation in the Basque diaspora in the Western USA: evolutionary and forensic perspectives.
Individuals of Basque origin migrated in large numbers to the Western USA in the second half of the nineteenth century, and the flow continued with less intensity during the last century. The European source population, that of the Basque Country, has long been a cultural and geographical isolate. Previous studies have demonstrated that Y-STR frequencies of Basques are different from those of other Spanish and European populations [1]. The Basque diaspora in the Western USA is a recent migration, but the founder effect and the incorporation of new American Y chromosomes into the paternal genetic pool of the Basque diaspora could have influenced its genetic structure and could thus have practical implications for forensic genetics. To check for genetic substructure among the European source and Basque diaspora populations and determine the most suitable population database for the Basque diaspora in the Western USA, we have analysed the haplotype distribution of 17 Y-STRs in both populations. We have found that the Basque diaspora in the Western USA largely conserve the Y chromosome lineage characteristic of the autochthonous European Basque population with no statistically significant differences. This implies that a common 17 Y-STR Basque population database could be used to calculate identification or kinship parameters regardless of whether the Basque individuals are from the European Basque Country or from the Basque diaspora in the Western USA.


Investigation of JAM-A (rs790056) and LFA-1 (rs8058823) gene variants in Turkish colorectal cancer patients.
Lymphocyte function-associated antigen 1 (LFA-1) is a transmembrane glycoprotein expressed on the surface of leukocytes and containing the binding domain for junctional adhesion molecule-A (JAM-A). The aim of the present study was to evaluate the effects of JAM-A and LFA-1 variants on the formation of colorectal cancer and metastasis. A total of 82 subjects with colorectal cancer and 67 healthy subjects were studied. DNA was isolated from blood samples, and variations were determined using the polymerase chain reaction and restriction fragment length polymorphism method. JAM-A rs790056 CC genotype and C allele were found to be higher in the colorectal cancer group (p<0.05), and approximately 3-fold increased colorectal cancer risk with CC genotype was determined (p=0.029). Haplotype analysis showed that GC haplotype (LFA-1 rs8058823G and JAM-A rs790056C) frequency was significantly higher in the patient group (p=0.041) than in controls. JAM-A rs790056 variation may be effective in the development of colorectal cancer.


Exploring Trends of C and N Isotope Fractionation to Trace Transformation Reactions of Diclofenac in Natural and Engineered Systems.
Although diclofenac ranks among the most frequently detected pharmaceuticals in the urban water cycle, its environmental transformation reactions remain imperfectly understood. Biodegradation-induced changes in 15N/14N ratios (εN = -7.1‰ ± 0.4‰) have indicated that compound-specific isotope analysis (CSIA) may detect diclofenac degradation. This singular observation warrants exploration for further transformation reactions. The present study surveys carbon and nitrogen isotope fractionation in other environmental and engineered transformation reactions of diclofenac. While carbon isotope fractionation was generally small, observed nitrogen isotope fractionation in degradation by MnO2 (εN = -7.3‰ ± 0.3‰), photolysis (εN = +1.9‰ ± 0.1‰), and ozonation (εN = +1.5‰ ± 0.2‰) revealed distinct trends for different oxidative transformation reactions. The small, secondary isotope effect associated with ozonation suggests an attack of O3 in a molecular position distant from the N atom. Model reactants for outer-sphere single electron transfer generated large inverse nitrogen isotope fractionation (εN = +5.7‰ ± 0.3‰), ruling out this mechanism for biodegradation and transformation by MnO2. In a river model, isotope fractionation-derived degradation estimates agreed well with concentration mass balances, providing a proof-of-principle validation for assessing micropollutant degradation in river sediment. Our study highlights the prospect of combining CSIA with transformation product analysis for a better assessment of transformation reactions within the environmental life of diclofenac.


UV Photodissociation Dynamics of the CH3CHOO Criegee Intermediate: Action Spectroscopy and Velocity Map Imaging of O-Atom Products.
UV excitation of jet-cooled CH3CHOO on the B(1)A'-X(1)A' transition results in dissociation to two spin-allowed product channels: CH3CHO X(1)A' + O (1)D and CH3CHO a(3)A″ + O (3)P. The O (1)D and O (3)P products are detected using 2 + 1 REMPI at 205 and 226 nm, respectively, for action spectroscopy and velocity map imaging studies. The O (1)D action spectrum closely follows the previously reported UV absorption spectrum for jet-cooled CH3CHOO [Beames et al. J. Chem. Phys. 2013 , 138 , 244307]. Velocity map images of the O (1)D products following excitation of CH3CHOO at 305, 320, and 350 nm exhibit anisotropic angular distributions indicative of rapid (ps) dissociation, along with broad and unstructured total kinetic energy (TKER) distributions that reflect the internal energy distribution of the CH3CHO X(1)A' coproducts. The O (3)P action spectrum turns on near the peak of the UV absorption spectrum (ca. 324 nm) and extends to higher energy with steadily increasing O (3)P yield. Excitation of CH3CHOO at 305 nm, attributed to absorption of the more stable syn-conformer, also results in an anisotropic angular distribution of O (3)P products arising from rapid (ps) dissociation, but a narrower TKER distribution since less energy is available to the CH3CHO a(3)A″ + O (3)P products. The threshold for the higher energy CH3CHO a(3)A″ + O (3)P product channel is determined to be ca. 88.4 kcal mol(-1) from the termination of the TKER distribution and the onset of the O (3)P action spectrum. This threshold is combined with the singlet-triplet spacings of O atoms and acetaldehyde to establish the dissociation energy for syn-CH3HOO X(1)A' to the lowest spin-allowed product channel, CH3CHO X(1)A' + O (1)D, of ≤55.9 ± 0.4 kcal mol(-1). A harmonic normal-mode analysis is utilized to identify the vibrational modes of CH3CHO likely to be excited upon dissociation into the two product channels.


Monovalent selectivity of the cyclic guanosine monophosphate-activated ion channel.
Monovalent cation selectivity has been characterized for the 3',5'-cyclic guanosine monophosphate (cGMP)-activated channel in vertebrate photoreceptor outer segment plasma membranes without divalent cations. Macroscopic currents in excised, inside-out patches were activated with saturating concentrations of cGMP (200 microM). Using a bi-ionic protocol with symmetrical 120 mM ion concentrations across the membrane, alkali metal ions and certain organic cations were substituted for sodium on the cytoplasmic face. The relative permeabilities, determined from shifts in the reversal potential (Erev), were NH4 much greater than Na greater than guanidinium greater than K greater than Li greater than Rb greater than Cs (3.34: 1.0: 0.97: 0.93: 0.92: 0.74: 0.50, respectively). Erev's were also measured as a function of [Na], [NH4], and [Cs], and the slope of the relation was -59.8, -52.1, and -49.1 mV/decade, respectively. The slopes for NH4 and Cs differ significantly from the Nernst-Planck prediction of -58.2 mV/decade expected for a single ion channel. Relative permeabilities were also determined for the alkali metal series of ions with 20 mM ionic concentrations on both sides of the membrane. The permeability sequence at 20 mM was unchanged, but the relative permeability for NH4 and Cs deviated significantly from the measurements at 120 mM with 1.46 and 0.75 ratios, respectively. The dependence of Erev on absolute concentrations and the deviation from Nernst-Planck predictions are best explained by multi-ion occupancy of the cGMP-activated channel. Selectivity was also examined by comparing the conductance ratios as a function of potential.(ABSTRACT TRUNCATED AT 250 WORDS)


The Hypothetical Impact of Accelerate Pheno on Time to Effective Therapy and Time to Definitive Therapy for Bloodstream Infections Due to Drug-Resistant Gram-Negative Bacilli.
Strategies are needed to improve time to optimal therapy in patients with bloodstream infections (BSI) due to resistant Gram-negative (GN) pathogens. Accelerate Pheno (ACC) can provide antimicrobial susceptibility results within 7 h of a positive culture and may more rapidly optimize therapy. The primary objective of this study was to evaluate the hypothetical impact of ACC on time to effective therapy (TTET) and time to definitive therapy (TTDT) among patients with BSI due to resistant GN pathogens. ACC was performed on resistant GN BSI isolates, and results were not available to clinicians in real time. A potential benefit of having ACC on TTET or TTDT was determined if modifications to antimicrobial regimens could have been made sooner with ACC. Comparisons on the impact of ACC in the presence or absence of testing by the Verigene Gram-negative blood culture test (Verigene GN-BC) were performed. Sixty-one patients with resistant GN BSI were evaluated. The median actual TTET and TTDT in the cohort were 25.9 h (interquartile range [IQR], 18.5, 42.1) and 47.6 h (IQR, 24.9, 79.6), respectively. Almost half of the patients had potential improvement in TTET and/or TTDT with ACC. In patients who would have had a benefit the median potential decreases in TTET and TTDT were 16.6 h (IQR, 5.5 to 30.6) and 29.8 h (IQR, 13.6 to 43), respectively. The largest potential improvements were seen in patients for whom Verigene results were not available. In conclusion, among patients with resistant GN BSI in a setting where other rapid diagnostic technologies are utilized, ACC results could have further improved TTET and TTDT.


Combined ultrasound and near infrared diffused light imaging in a test object.
We have investigated the use of combining near infrared (NIR) diffuse light and ultrasound imaging methods to increase the detection sensitivity and to reduce the false alarm rate in small target detection. A line-of-sight optical projection through a test object is identified from an amplitude null and a sharp phase transition produced by diffusive waves originating from two in-phase (initial phase 0 degrees ) and out-of-phase (initial phase 180 degrees ) light emitting diode sources. This line-of-sight is scanned across a scattering phantom. A complete ultrasound B-scan image is recorded at each projected line in the optical scan. Each acoustic image plane is bisected by the optical beam path and lies in the optical scan plane. The scattering phantom simulates acoustic and optical properties of homogeneous tissue. A single small cylinder-like object simulating some acoustic and optical breast tumor properties is inserted at various places in the scattering phantom. With this single object, the optical scanning identifies the line-of-sight passing through the simulated tumor quite well. Most of these simulated tumors were at or below the threshold for acoustic detection and were not seen consistently with unguided ultrasound. For tests in which a target was apparently detected optically, the selected line-of-sight was indicated in each of three adjacent ultrasound images. Two radiologist observers were statistically more accurate (83%) in identifying the target location on the optically-selected ultrasound images than in the unmarked images (52%). That is, in these single-targets of homogeneous scattering background, the optical technique usually provided the correct line-of-sight, and ultrasound generally showed the location along that line.


Comparison of brachial and carotid artery ultrasound for assessing extent of subclinical atherosclerosis in HIV: a prospective cohort study.
Non-invasive surrogate measures which are valid and responsive to change are needed to study cardiovascular risks in HIV. We compared the construct validity of two noninvasive arterial measures: carotid intima medial thickness (IMT), which measures anatomic disease; and brachial flow-mediated vasodilation (FMD), a measure of endothelial dysfunction. A sample of 257 subjects aged 35 years or older, attending clinics in five Canadian centres, were prospectively recruited into a study of cardiovascular risk among HIV subjects. The relationship between baseline IMT or FMD and traditional vascular risk factors was studied using regression analysis. We analyzed the relationship between progression of IMT or FMD and risk factors using fixed-effects models. We adjusted for use of statin medication and CD4 count in both models. Baseline IMT was significantly associated with age (p < 0.001), male gender (p = 0.034), current smoking status (p < 0.001), systolic blood pressure (p < 0.001) and total:HDL cholesterol ratio (p = 0.004), but not statin use (p = 0.904) and CD4 count (p = 0.929). IMT progression was significantly associated with age (p < 0.001), male gender (p = 0.0051) and current smoking status (p = 0.011), but not statin use (p = 0.289) and CD4 count (p = 0.927). FMD progression was significantly associated with current statin use (p = 0.019), but not CD4 count (p = 0.84). Neither extent nor progression of FMD was significantly associated with any of the examined vascular risk factors. IMT correlates better than FMD with established cardiovascular risk factors in this cohort of HIV patients. Standardization of protocols for FMD and IMT will facilitate the comparison of results across studies.


Anatomy of the chinchilla bulla and eustachian tube: I. Gross and microscopic study.
The middle ear mucosa and eustachian tube of the normal chinchilla were studied quantitatively and under light microscopy to determine the distribution of each cell type of the lining epithelium and subepithelial gland. The middle ear mucosa consisted of columnar epithelium, cuboidal epithelium, and squamous epithelium. The lining epithelium of the eustachian tube was ciliated pseudostratified columnar epithelium. These epithelia were composed of ciliated, secretory, nonciliated (nonsecretory), and basal cells. The density of the ciliated cells was highest in the columnar epithelium area of the transitional zone of the middle ear mucosa. However, the density of the secretory cells was highest in the pharyngeal orifice of the eustachian tube. The nonciliated cell density was highest in the squamous epithelium area of the middle ear mucosa and decreased progressively toward the tympanic orifice of the eustachian tube. In the eustachian tube, the nonciliated cell density was highest in the pharyngeal portion of the eustachian tube, especially in the upper portion of the lateral wall. The subepithelial glands were tubuloacinar mixed glands composed of serous demilunes and mucous acini. The glands were localized primarily in the pharyngeal orifice and pharyngeal portion of the eustachian tube, and their ductal openings were present primarily in the inferior portion of the eustachian tube.


Serum Neutralization Anti-IgG Test for Psittacosis.
Levels of antibodies in sera from patients with diagnoses of subclinical or established psittacosis infections were determined by the serum neutralization anti-IgG test and by conventional tests. Relatively high levels of serum neutralizing anti-bodies were detected in tests in which anti-IgG was used, whereas conventional tests disclosed only marginal levels of antibody. Use of the serum neutralization anti-IgG test in conjunction with the fluorescent cell-counting technique permitted serum antibody determinations within 24 hr.


Multistable circular currents of polariton condensates trapped in ring potentials.
We demonstrate the formation and trapping of different stationary solutions, oscillatory solutions, and rotating solutions of a polariton condensate in a planar semiconductor microcavity with a built-in ring-shaped potential well. Multistable ring-shaped solutions are trapped in shallow potential wells. These solutions have the same ring-shaped density distribution but different topological charges, corresponding to different orbital angular momentum (OAM) of the emitted light. For stronger confinement potentials, besides the fundamental modes, higher excited (dipole) modes can also be trapped. If two modes are excited simultaneously, their beating produces a complex oscillation or rotation dynamics. When the two modes have the same OAM, a double-ring solution forms for which the density oscillates between the inner and the outer ring. When the two modes have different OAM, a rotating solution with fractional OAM is created.


Vectorial aberrations of biconic surfaces.
For non-rotationally symmetric systems, spherical surfaces provide a non-sufficient effect in correcting aberrations. In anamorphic systems, biconic surfaces are used to provide different focal power in tangential and sagittal directions. The biconic surface shape is also used as the basic shape of the freeform surface representation. The different focal power in tangential and sagittal planes generates large field-constant astigmatism, which is decoupled from a coma generated by the biconic surface. In this paper, the biconic surface sag is expanded up to the fourth order and decomposed into the spherical part, the aspherical part, and the freeform part. The vectorial aberrations of the biconic surface are derived based on the extended nodal aberration theory. When biconic surfaces are used to obtain the initial setup of off-axis systems, it is beneficial due to the decoupling of astigmatism and coma. For instance, in the initial system design of reflective camera systems, biconic surfaces provide the possibility to obtain the nodal point in the center of the field of view, which is beneficial for systems with large field of view. This paper provides the insight of aberration analysis of biconic surfaces and the conversion of biconic surfaces into Zernike fringe freeform surfaces.


A double-flowered variety of lesser periwinkle (Vinca minor fl. pl.) that has persisted in the wild for more than 160 years.
Homeotic transitions are usually dismissed by population geneticists as credible modes of evolution due to their assumed negative impact on fitness. However, several lines of evidence suggest that such changes in organ identity have played an important role during the origin and subsequent evolution of the angiosperm flower. Better understanding of the performance of wild populations of floral homeotic varieties should help to clarify the evolutionary potential of homeotic mutants. Wild populations of plants with changes in floral symmetry, or with reproductive organs replacing perianth organs or sepals replacing petals have already been documented. However, although double-flowered varieties are quite popular as ornamental and garden plants, they are rarely found in the wild and, if they are, usually occur only as rare mutant individuals, probably because of their low fitness relative to the wild-type. We therefore investigated a double-flowered variety of lesser periwinkle, Vinca minor flore pleno (fl. pl.), that is reported to have existed in the wild for at least 160 years. To assess the merits of this plant as a new model system for investigations on the evolutionary potential of double-flowered varieties we explored the morphological details and distribution of the mutant phenotype. The floral morphology of the double-flowered variety and of a nearby population of wild-type plants was investigated by means of visual inspection and light microscopy of flowers, the latter involving dissected or sectioned floral organs. The double-flowered variety was found in several patches covering dozens of square metres in a forest within the city limits of Jena (Germany). It appears to produce fewer flowers than the wild-type, and its flowers are purple rather than blue. Most sepals in the first floral whorl resemble those in the wild-type, although occasionally one sepal is broadened and twisted. The structure of second-whorl petals is very similar to that of the wild-type, but their number per flower is more variable. The double-flowered character is due to partial or complete transformation of stamens in the third whorl into petaloid organs. Occasionally, 'flowers within flowers' also develop on elongated pedicels in the double-flowered variety. The flowers of V. minor fl. pl. show meristic as well as homeotic changes, and occasionally other developmental abnormalities such as mis-shaped sepals or loss of floral determinacy. V. minor fl. pl. thus adds to a growing list of natural floral homeotic varieties that have established persistent populations in the wild. Our case study documents that even mutant varieties that have reproductive organs partially transformed into perianth organs can persist in the wild for centuries. This finding makes it at least conceivable that even double-flowered varieties have the potential to establish new evolutionary lineages, and hence may contribute to macroevolutionary transitions and cladogenesis.


Non-Interferon-Dependent Role of STING Signaling in Pulmonary Hypertension.
Patients with constitutive activation of DNA-sensing pathway through stimulator of IFN (interferon) genes (STING), such as those with STING-associated vasculopathy with onset in infancy, develop pulmonary hypertension (PH). However, the role of STING signaling in general PH patients is heretofore undescribed. Here, we seek to investigate the role of STING in PH development. STING expression in patient lung samples was examined. PH was induced in global STING-deficient mice and global type I IFN receptor 1-deficient mice using bleomycin or chronic hypoxia exposure. PH development was evaluated by right ventricular systolic pressure and Fulton index, with additional histological and flow cytometric analysis. VEGF (vascular endothelial growth factor) expression on murine immune cells was quantified and evaluated with multiplex and flow cytometry. Human myeloid-derived cells were differentiated from peripheral blood mononuclear cells and treated with either STING agonist or STING antagonist for evaluation of VEGF secretion. Global STING deficiency protects mice from PH development, and STING-associated PH seems independent of type I IFN signaling. Furthermore, a role for STING-VEGF signaling pathway in PH development was demonstrated, with altered VEGF secretion in murine pulmonary infiltrated myeloid cells in a STING-dependent manner. In addition, pharmacological manipulation of STING in human myeloid-derived cells supports in vivo findings. Finally, a potential role of STING-VEGF-mediated apoptosis in disease development and progression was illustrated, providing a roadmap toward potential therapeutic applications. Overall, these data provide concrete evidence of STING involvement in PH, establishing biological plausibility for STING-related therapies in PH treatment.


Ultrastructural and autoradiographic studies of the role of nucleolar vacuoles in soybean root meristem.
Ultrastructural and autoradiographic studies of nucleoli in soybean root meristematic cells in seedlings: (1) grown for 3 days at 25 degrees C (control), (2) grown for three days at 25 degrees C and for 4 days at 10 degrees C, and (3) grown as in (2) and recovered for 1 day at 25 degrees C were carried out. Control nucleoli had dense structure and a few small nucleolar vacuoles. Chilled plant nucleoli had less dense structure and no vacuoles. Nucleoli of plants recovered at 25 degrees C had big nucleolar vacuoles. In autoradiograms of squashed preparations, the labeling of nucleoli and cytoplasm after 20-min incubation in 3H-uridine was 5- and 6-fold stronger, respectively, in control than in chilled roots. Following recovery, the labeling of nucleoli and cytoplasm was much stronger than after chilling or even than in control roots. After 80-min postincubation in non-radioactive medium, average labeling of particular areas of cells was the highest in recovered plants which indicated intensification of rRNA synthesis, maturation and transport into cytoplasm resulting from the resumption of optimal conditions which was correlated with the appearance of big nucleolar vacuoles. In autoradiograms of semi-thin sections from roots of seedlings chilled for 4 days then recovered and incubated for 20 min in 3H-uridine, practically only extravacuolar parts of nucleoli were labeled. After 80-min postincubation, the labeling of nucleolar vacuoles was observed. Thus, during postincubation the labeled molecules were translocated from the nucleolar periphery into nucleolar vacuoles in cells where intensive transport of these molecules to the cytoplasm takes place. On the basis of these results, a hypothesis has been put forward that nucleolar vacuoles may be involved in the intensification of pre-ribosome transport outside nucleolus.


Models for the analysis of radon-exposed populations.
Radon-222 is a radioactive decay product of radium-226 and uranium-238, which are found throughout the crust of the earth. Studies of underground miners clearly show that exposure to radon and its decay products increases the risk of developing lung cancer. Data on standardized mortality ratios from eight cohort studies indicate that the radon-lung cancer relationship is statistically homogeneous, even though cohorts are from different types of mines and from different countries. Regression methods for cohort data based on a Poisson probability model permit a thorough consideration of risk patterns. In this report, we review these methods, wherein the disease rate in each cell of a multi-way table is modeled as a function of the cross-classifying variables. The National Academy of Sciences' Committee on the Biological Effects of Ionizing Radiation uses the Poisson regression approach to develop a model for age-specific lung cancer risk which depends on cumulative exposure, age at risk, and time since exposure. This model is reviewed and its implications discussed. The most important determinant of lung cancer is cigarette smoking. This paper discusses relative risk models for analysis of joint exposure to radon and tobacco products. The review of available studies suggests that the joint relationship of radon and smoking with lung cancer is consistent with a multiplicative model, but a submultiplicative relationship is most likely. An additive model is rejected.


Methane Seepage on Mars: Where to Look and Why.
Methane on Mars is a topic of special interest because of its potential association with microbial life. The variable detections of methane by the Curiosity rover, orbiters, and terrestrial telescopes, coupled with methane's short lifetime in the martian atmosphere, may imply an active gas source in the planet's subsurface, with migration and surface emission processes similar to those known on Earth as "gas seepage." Here, we review the variety of subsurface processes that could result in methane seepage on Mars. Such methane could originate from abiotic chemical reactions, thermogenic alteration of abiotic or biotic organic matter, and ancient or extant microbial metabolism. These processes can occur over a wide range of temperatures, in both sedimentary and igneous rocks, and together they enhance the possibility that significant amounts of methane could have formed on early Mars. Methane seepage to the surface would occur preferentially along faults and fractures, through focused macro-seeps and/or diffuse microseepage exhalations. Our work highlights the types of features on Mars that could be associated with methane release, including mud-volcano-like mounds in Acidalia or Utopia; proposed ancient springs in Gusev Crater, Arabia Terra, and Valles Marineris; and rims of large impact craters. These could have been locations of past macro-seeps and may still emit methane today. Microseepage could occur through faults along the dichotomy or fractures such as those at Nili Fossae, Cerberus Fossae, the Argyre impact, and those produced in serpentinized rocks. Martian microseepage would be extremely difficult to detect remotely yet could constitute a significant gas source. We emphasize that the most definitive detection of methane seepage from different release candidates would be best provided by measurements performed in the ground or at the ground-atmosphere interface by landers or rovers and that the technology for such detection is currently available. Key Words: Mars-Methane-Seepage-Clathrate-Fischer-Tropsch-Serpentinization. Astrobiology 17, 1233-1264.


Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis.
Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D. We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test. Using a Bonferroni-corrected significance threshold of P<1.6×10-4, we identified 3 genes (ATP1B1, ARVCF, and LIPG) associated with CAC and 2 genes (ABCG8 and EIF2B2) associated with carotid intima-media thickness and carotid plaque, respectively, through gene-based rare variant set analysis. Both ATP1B1 and ARVCF also had significantly different associations for CAC in T2D cases versus controls. No significant interaction tests were identified through the candidate single-variant analysis. These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC.


Quantitation of thick-walled peripheral lung vessels in chronic airways obstruction.
The number of thick-walled peripheral lung vessels (defined as vessels of less than 100 mu diameter with two distinct elastic laminae) was calculated in 50 postmortem lungs. The size of the right ventricle, the amount and type of emphysema, and the proportion of small airways lumen in the lung were also quantitated. Eighteen patients had died as a result of chronic airways obstruction, 17 had symptoms of chronic chest disease but died from some unrelated cause, and 15 had no symptoms related to the respiratory system. The mean number of thick-walled peripheral lung vessels (TWPV) was found to be significantly greater in the fatal disease group than in both of the other groups. No significant difference was found between the mean values of the symptomatic and asymptomatic groups. The mean number of TWPV was significantly greater in cases with a right ventricular weight of more than 80 g than in those with a weight of less than 65 g. Positive correlations were found between the number of TWPV and right ventricular weight, total amount of emphysema in the lung, and the amounts of centrilobular and panlobular emphysema. Significant negative correlations were found between the number of TWPV and both the ratio of the weight of the left ventricle to the right ventricle and the proportion of small airways lumen in the lung.


Hyperspectral in vivo two-photon microscopy of intrinsic contrast.
In vivo two-photon imaging of intrinsic contrast can provide valuable information about structural tissue elements such as collagen and elastin and fluorescent metabolites such as nicotinamide adenine dinucleotide. Yet low signal and overlapping emission spectra can make it difficult to identify and delineate these species in vivo. We present a novel approach that combines excitation scanning with spectrally resolved emission two-photon microscopy, allowing distinct structures to be delineated based on their characteristic spectral fingerprints. The amounts of intrinsic fluorophores present in each voxel can also be evaluated. We demonstrate our method using in vivo imaging of nude mouse skin.


Pediatric generalized joint hypomobility and musculoskeletal complaints: a new entity? Clinical, biochemical, and osseal characteristics.
To describe the clinical features, osseal characteristics, and collagen biochemistry in children who attended our clinic with predominantly generalized hypomobility of the joints, in combination with musculoskeletal complaints or abnormal walking, and no known syndrome or known rheumatic, neurologic, skeletal, metabolic, or connective tissue disorder was present. Nineteen children who attended the Children's Hospital of the University Medical Center Utrecht for generalized hypomobility of the joints (mean age: 11.6; standard deviation: 2.7), in combination with musculoskeletal complaints or abnormal walking as primary complaints (symptomatic generalized hypomobility [SGH]), were compared with an age-matched reference group of 284 healthy children with normal mobility of the joints. Anthropometrics, range of joint motion, muscle strength, exercise tolerance, motor development, quantitative ultrasound measurements of bone, and degradation products of collagen in urine were studied. Collagen modifications were determined in skin biopsies of 3 children and in hypertrophic scar tissue of another child, all with SGH. The range of joint motion was significantly decreased in almost all joints of all 19 children and after adjustment for age, gender, body weight, and height, significantly lower than that of the reference group (-108.3 degrees; 95% confidence interval [CI]: -136.9 to -79.8). Quantitative ultrasound measurements as well as urinary pyridinoline cross-link levels were, after adjustment for possible confounders, significantly lower in SGH children (broad-band ultrasound attenuation: -9.6 dB/MHz [95% CI: -17.4 to -1.9]; speed of sound: -25.0 m/s [95% CI: -39.7 to -10.3]; hydroxylysylpyridinoline: -50.1 micromol/mmol [95% CI: -87.6 to -12.6], lysylpyridinoline: -21.3 micromol/mmol [95% CI: -34.0 to -8.6]). An increased amount of pyridinoline cross-links per collagen molecule was observed in skin and hypertrophic scar tissue, in combination with increased amounts of collagen. SGH in children is considered a new clinical entity with specific clinical characteristics and might be related to an increased stiffness of connective tissue as a result of higher amounts of collagen with increased cross-linking.


FEN1 ensures telomere stability by facilitating replication fork re-initiation.
Telomeres are terminal repetitive DNA sequences whose stability requires the coordinated actions of telomere-binding proteins and the DNA replication and repair machinery. Recently, we demonstrated that the DNA replication and repair protein Flap endonuclease 1 (FEN1) is required for replication of lagging strand telomeres. Here, we demonstrate for the first time that FEN1 is required for efficient re-initiation of stalled replication forks. At the telomere, we find that FEN1 depletion results in replicative stress as evidenced by fragile telomere expression and sister telomere loss. We show that FEN1 participation in Okazaki fragment processing is not required for efficient telomere replication. Instead we find that FEN1 gap endonuclease activity, which processes DNA structures resembling stalled replication forks, and the FEN1 interaction with the RecQ helicases are vital for telomere stability. Finally, we find that FEN1 depletion neither impacts cell cycle progression nor in vitro DNA replication through non-telomeric sequences. Our finding that FEN1 is required for efficient replication fork re-initiation strongly suggests that the fragile telomere expression and sister telomere losses observed upon FEN1 depletion are the direct result of replication fork collapse. Together, these findings suggest that other nucleases compensate for FEN1 loss throughout the genome during DNA replication but fail to do so at the telomere. We propose that FEN1 maintains stable telomeres by facilitating replication through the G-rich lagging strand telomere, thereby ensuring high fidelity telomere replication.