Human tRNA-Derived Small RNAs Modulate Host-Oral Microbial Interactions.
Coevolution of the human host and its associated microbiota has led to sophisticated interactions to maintain a delicate homeostasis. Emerging evidence suggests that in addition to small molecules, peptides, and proteins, small regulatory noncoding RNAs (sRNAs) might play an important role in cross-domain interactions. In this study, we revealed the presence of diverse host transfer RNA-derived small RNAs (tsRNAs) among human salivary sRNAs. We selected 2 tsRNAs (tsRNA-000794 and tsRNA-020498) for further study based on their high sequence similarity to specific tRNAs from a group of Gram-negative oral bacteria, including Fusobacterium nucleatum, a key oral commensal and opportunistic pathogen. We showed that the presence of F. nucleatum triggers exosome-mediated release of tsRNA-000794 and tsRNA-020498 by human normal oral keratinocyte cells. Furthermore, both tsRNA candidates exerted a growth inhibition effect on F. nucleatum, likely through interference with bacterial protein biosynthesis, but did not affect the growth of Streptococcus mitis, a health-associated oral Gram-positive bacterium whose genome does not carry sequences bearing high similarity to either tsRNA. Our data provide the first line of evidence for the modulatory role of host-derived tsRNAs in the microbial-host interaction.


Locating and appraising systematic reviews.
Several methods can be used to identify systematic reviews. These include bibliographic databases, such as MEDLINE, Best Evidence, and the Cochrane Library. In the future, the Cochrane Library could become the source of choice for systematic reviews because it provides the full text for Cochrane reviews and citations to many other systematic reviews. Moreover, the Library is growing rapidly and becoming more readily available, and its searching capabilities are being improved with each update. Although Best Evidence contains fewer systematic reviews than the Cochrane Library, it is specifically designed for practicing internists and primary care physicians and includes systematic reviews on diagnosis, cause, prognosis, and quality improvement. At present, however, MEDLINE and other bibliographic databases are probably the most up-to-date and readily available sources of systematic reviews. Systematic reviews are a powerful and useful way to assemble evidence; however, just because a review has been done using systematic review methods does not guarantee that its results are credible. Regardless of the source, all systematic reviews (like all types of research evidence) require critical appraisal to determine their validity and to establish whether and how they will be useful in practice.


Immune system irregularities in lysosomal storage disorders.
Lysosomal storage disorders (LSDs) are genetically inherited diseases characterized by the accumulation of disease-specific biological materials such as proteolipids or metabolic intermediates within the lysosome. The lysosomal compartment's central importance to normal cellular function can be appreciated by examining the various pathologies that arise in LSDs. These disorders are invariably fatal, and many display profound neurological impairment that begins in childhood. However, recent studies have revealed that several LSDs also have irregularities in the function of the immune system. Gaucher disease, mucopolysaccharidosis VII, and alpha-mannosidosis are examples of a subset of LSD patients that are predisposed towards immune suppression. In contrast, GM2 gangliosidosis, globoid cell leukodystrophy, Niemann-Pick disease type C1 and juvenile neuronal ceroid lipofuscinosis are LSDs that are predisposed towards immune system hyperactivity. Antigen presentation and processing by dedicated antigen presenting cells (APCs), secretion of pore-forming perforins by cytotoxic-T lymphocytes, and release of pro-inflammatory mediators by mast cells are among the many crucial immune system functions in which the lysosome plays a central role. Although the relationship between the modification of the lysosomal compartment in LSDs and modulation of the immune system remains unknown, there is emerging evidence for early neuroimmune responses in a variety of LSDs. In this review we bridge biochemical studies on the lysosomal compartment's role in the immune system with clinical data on immune system irregularities in a subset of LSDs.


[Comparison of acceptor activity of rabbit liver tRNA in ontogenesis].
The rabbit liver tRNA was studied in such functional states when there occurred essential qualitative and quantitative changes in the protein synthesis. On the basis of the maximum level of aminoacylation it is established that the contents of corresponding biologically active individual tRNA in the total preparation for adult animals is 1.5-3 times as high as that for 3-5 day rabbits. Exception is alanine tRNA whose number decreases sharply in the total preparation of the liver tRNA of one- and two-year animals. No correlation was found for any age group between the quantitative ratio of active individual tRNA and the amino acid composition of albumins whose synthesis in the liver is intensive. Thus, the synthesis and, respectively, the content of certain types of tRNA in the liver characterized by a wide spectrum of proteins with different functions are governed by other regularities, whose search is one of the most difficult and at the same time high-promising problems.


On the measurement of lactate turnover in humans.
It has been shown in studies of turnover in vivo of lactate and several amino acids that the specific activity in blood depends on the site of tracer administration and of sampling. Theoretical and experimental studies have established that to obtain valid estimation of turnover in vivo for these compounds, tracers should be administered into the left heart, ideally the ventricle, and blood sampled from the right heart, ideally the pulmonary artery. Alternately, tracer may be infused into the pulmonary artery and blood sampled from the right ventricle. The insertion of such in-dwelling catheters for turnover studies is difficult in small animals and not justified on ethical grounds in humans. We describe here a method to calculate valid turnover rates when the tracer is administered in a peripheral vein and blood sampled from any peripheral artery. In humans, infusion into a hand vein and sampling from the contralateral heated hand vein can be used. The true turnover rate can then be calculated if the cardiac output is determined. Several noninvasive methods for the determination of cardiac output are available. Thus a correct estimate, avoiding major catheterization, for turnover for many blood-borne compounds is possible.


[Ulcerative herpetic keratitis. Clinical and pathological findings and prognosis of the graft].
Between 1971 and 1982 33 corneae were excised for therapeutic keratoplasty because of ulcerative herpetic keratitis. The histologic findings and the clinical course enabled distinction of a nonreactive form with a rather good prognosis for keratoplasty (62% clear grafts) and an inflammatory form with bad prognosis (20% clear grafts) because of many herpetic recurrences. Perforating keratoplasty and first interventions in particular did better than lamellar keratoplasty or retransplantation. Existence of preoperative corneal vascularization compromised the prognosis of the graft. Preoperative perforation of the ulcer occurred rather often in nonvascularized corneae without compromising the prognosis of the graft.


Adaptation of Human Enterovirus to Warm Environments Leads to Resistance against Chlorine Disinfection.
Sunlight, temperature, and microbial grazing are among the environmental factors promoting the inactivation of viral pathogens in surface waters. Globally, these factors vary across time and space. The persistence of viral pathogens, and ultimately their ecology and dispersion, hinges on their ability to withstand the environmental conditions encountered. To understand how virus populations evolve under changing environmental conditions, we experimentally adapted echovirus 11 (E11) to four climate regimes. Specifically, we incubated E11 in lake water at 10 and 30 °C and in the presence and absence of sunlight. Temperature was the main driver of adaptation, resulting in an increased thermotolerance of the 30 °C adapted populations, whereas the 10 °C adapted strains were rapidly inactivated at higher temperatures. This finding is consistent with a source-sink model in which strains emerging in warm climates can persist in temperate regions, but not vice versa. A microbial risk assessment revealed that the enhanced thermotolerance increases the length of time in which there is an elevated probability of illness associated with swimming in contaminated water. Notably, 30 °C-adapted viruses also exhibited an increased tolerance toward disinfection by free chlorine. Viruses adapting to warm environments may thus become harder to eliminate by common disinfection strategies.


Plasma Pyruvate Kinase M2 as a marker of vascular inflammation in giant cell arteritis.
GCA is a large vessel vasculitis in which metabolically active immune cells play an important role. GCA diagnosis is based on CRP/ESR and temporal artery biopsies (TABs), in combination with 18F-fluorodeoxyglucose ([18F]FDG)-PET/CT relying on enhanced glucose uptake by glycolytic macrophages. Here, we studied circulating Pyruvate Kinase M2 (PKM2), a glycolytic enzyme, as a possible systemic marker of vessel wall inflammation in GCA. Immunohistochemical detection of PKM2 was performed on inflamed (n = 12) and non-inflamed (n = 4) TABs from GCA patients and non-GCA (n = 9) patients. Dimeric PKM2 levels were assessed in plasma of GCA patients (n = 44), age-matched healthy controls (n = 41), metastatic melanoma patients (n = 7) and infection controls (n = 11). CRP, ESR and macrophage markers calprotectin and YKL-40 were correlated with plasma PKM2 levels. To detect the cellular source of plasma PKM2 in tissue, double IF staining was performed on inflamed GCA TABs. [18F]FDG-PET scans of 23 GCA patients were analysed and maximum standard uptake values and target to background ratios were calculated. PKM2 is abundantly expressed in TABs of GCA patients. Dimeric PKM2 plasma levels were elevated in GCA and correlated with CRP, ESR, calprotectin and YKL-40 levels. Elevated plasma PKM2 levels were downmodulated by glucocorticoid treatment. PKM2 was detected in both macrophages and T cells at the site of vascular inflammation. Circulating PKM2 levels correlated with average target to background ratios PET scores. Elevated plasma PKM2 levels reflect active vessel inflammation in GCA and may assist in disease diagnosis and in disease monitoring.


Prevalence, outcome and risk factors for postoperative pyothorax in 232 dogs undergoing thoracic surgery.
To determine the prevalence, outcome and risk factors for postoperative pyothorax in dogs undergoing thoracic surgery. Case records were reviewed retrospectively to identify dogs with post thoracic surgery pyothorax, defined as septic neutrophilic inflammation within the pleural space based on cytology and/or a positive bacterial culture of pleural fluid. Those identified were reviewed for potential risk factors for postoperative pyothorax based on biological plausibility and previously published data. These potential risk factors were explored by multivariable logistic regression. Of 232 dogs undergoing thoracic surgery, 15 (6.5%) dogs developed pyothorax. Bacteria cultured included methicillin-resistant Staphylococcus aureus and multi-resistant Escherichia coli. Of these dogs, six died, four were euthanased and five were treated successfully. A diagnosis of idiopathic chylothorax [Odds Ratio (OR)=12.5, 95% Confidence Interval (CI)=2.7-58.5, P=0.001], preoperative intrathoracic biopsy (OR=14.3, 95% CI=1.7-118.7, P=0.014) and preoperative thoracocentesis (OR=11.2, 95% CI=1.6-78.2, P=0.015) were identified as independent risk factors for development of postoperative pyothorax. Idiopathic chylothorax, intrathoracic biopsy and prior thoracocentesis are independent risk factors for postoperative pyothorax, which was associated with a 67% mortality rate.


Multidisciplinary cardiogenic shock team approach improves the long-term outcomes of patients suffering from refractory cardiogenic shock treated with short-term mechanical circulatory support.
Short-term mechanical circulatory support (STMCS) may be used as an intentional escalation strategy to treat cardiogenic shock refractory (rCS). However, with growing technical possibilities, making the right choice at the right time can be challenging. We established a shock team in January 2013 comprising a cardiac anaesthetist-intensivist, an interventional cardiologist, and a cardiac surgeon. Since then, a diagnosis of rCS has triggered a multidisciplinary team meeting based on a common algorithm. This study aimed to compare the decision-making process for STMCS for rCS before (2007-2013) and after (2013-2019) the creation of the shock team. This before-and-after cohort study was conducted over a 156-month period. Post-cardiotomy rCS were excluded. The primary outcome was a 1-year survival rate. In total, 250 consecutive adult patients were included in the analysis (84 in the control group and 166 in the shock team group). At baseline, the CardShock score was not different between the two groups (5[3-5] vs. 5[4-6], p=0.323). The 1-year survival rate was significantly higher in the shock team group compared to the control group (59% vs. 45%, p = 0.043). After a Cox regression analysis, the shock team intervention was independently associated with a significantly improved 1-year survival rate (HR: 0.592, 95% CI: 0.398-0.880, p=0.010). A multidisciplinary shock team-based decision for STMCS device implantation in rCS is associated with better 1-year survival rates.


Clinical determinants and prognostic implications of renin and aldosterone in patients with symptomatic heart failure.
Activation of the renin-angiotensin-aldosterone system plays an important role in the pathophysiology of heart failure (HF) and has been associated with poor prognosis. There are limited data on the associations of renin and aldosterone levels with clinical profiles, treatment response, and study outcomes in patients with HF. We analysed 2,039 patients with available baseline renin and aldosterone levels in BIOSTAT-CHF (a systems BIOlogy study to Tailored Treatment in Chronic Heart Failure). The primary outcome was the composite of all-cause mortality or HF hospitalization. We also investigated changes in renin and aldosterone levels after administration of mineralocorticoid receptor antagonists (MRAs) in a subset of the EPHESUS trial and in an acute HF cohort (PORTO). In BIOSTAT-CHF study, median renin and aldosterone levels were 85.3 (percentile25-75 = 28-247) μIU/mL and 9.4 (percentile25-75 = 4.4-19.8) ng/dL, respectively. Prior HF admission, lower blood pressure, sodium, poorer renal function, and MRA treatment were associated with higher renin and aldosterone. Higher renin was associated with an increased rate of the primary outcome [highest vs. lowest renin tertile: adjusted-HR (95% CI) = 1.47 (1.16-1.86), P = 0.002], whereas higher aldosterone was not [highest vs. lowest aldosterone tertile: adjusted-HR (95% CI) = 1.16 (0.93-1.44), P = 0.19]. Renin and/or aldosterone did not improve the BIOSTAT-CHF prognostic models. The rise in aldosterone with the use of MRAs was observed in EPHESUS and PORTO studies. Circulating levels of renin and aldosterone were associated with both the disease severity and use of MRAs. By reflecting both the disease and its treatments, the prognostic discrimination of these biomarkers was poor. Our data suggest that the "point" measurement of renin and aldosterone in HF is of limited clinical utility.


Effect of timing of corn silage supplementation to Holstein dairy cows given limited daily access to pasture: intake and performance.
The timing in which supplements are provided in grazing systems can affect dry matter (DM) intake and productive performance. The objective of this study was to evaluate the effect of timing of corn silage supplementation on ingestive behaviour, DM intake, milk yield and composition in grazing dairy cows. In total, 33 Holstein dairy cows in a randomized block design grazed on a second-year mixed grass-legume pasture from 0900 to 1500 h and received 2.7 kg of a commercial supplement at each milking. Paddock sizes were adjusted to provide a daily herbage allowance of 15 kg DM/cow determined at ground level. The three treatments imposed each provided 3.8 kg DM/day of corn silage offered in a single meal at 0800 h (Treatment AM), equally distributed in two meals 0800 and 1700 h (Treatment AM-PM) or a single meal at 1700 h (Treatment PM). The experiment was carried out during the late autumn and early winter period, with 1 week of adaptation and 6 weeks of measurements. There were no differences between treatments in milk yield, but 4% fat-corrected milk yield tended to be greater in AM-PM than in AM cows, which did not differ from PM (23.7, 25.3 and 24.6±0.84 kg/day for AM, AM-PM and PM, respectively). Fat percentage and yield were greater for AM-PM than for AM cows and intermediate for PM cows (3.89 v. 3.66±0.072% and 1.00 v. 0.92±0.035 kg/day, respectively). Offering corn silage in two meals had an effect on herbage DM intake which was greater for AM-PM than AM cows and was intermediate in PM cows (8.5, 11.0 and 10.3±0.68 kg/day for AM, AM-PM and PM, respectively). During the 6-h period at pasture, the overall proportion of observations on which cows were grazing tended to be different between treatments and a clear grazing pattern along the grazing session (1-h observation period) was identified. During the time at pasture, the proportion of observations during which cows ruminated was positively correlated with the DM intake of corn silage immediately before turn out to pasture. The treatment effects on herbage DM intake did not sufficiently explain differences in productive performance. This suggests that the timing of the corn silage supplementation affected rumen kinetics and likewise the appearance of hunger and satiety signals as indicated by observed changes in temporal patterns of grazing and ruminating activities.


Circulating Th17/Treg as a promising biomarker for patients with rheumatoid arthritis in indicating comorbidity with atherosclerotic cardiovascular disease.
Immune and inflammatory responses have a pivotal role in the pathogenesis of rheumatoid arthritis (RA) and atherosclerotic cardiovascular disease (ASCVD). This study aims to explore the change of peripheral lymphocytes, especially the absolute and relative changes in peripheral T cells in RA patients with and without ASCVD. The changes in the lymphocyte subsets were assessed to provide a novel insight in diagnosing and preventing ASCVD in patients with RA. A propensity score matching system (1:1) was conducted to perform a matched case-control study with 169 pairs RA-ASCVD and RA participants. Univariate and multivariate analyses were performed to determine the association between peripheral lymphocytes and RA-ASCVD. Multivariate logistic regression analysis demonstrated that Th17 cell absolute, Th17 cell Ratio, Th17/Treg were associated with a significantly higher risk of ASCVD after model adjustment. Then we focused on Th17/Treg, multivariate logistic analyses in tri-sectional Th17/Treg groups showed that the odds of ASCVD is gradually increasing with Th17/Treg rank's rising after model adjustment. Finally, the restricted cubic spline of Th17/Treg and odds ratio of RA-ASCVD was conducted. Interestingly, we found a critical point of Th17/Treg (critical point = 0.2399). Th17/Treg shows a protective role in the odds of ASCVD when Th17/Treg < 0.2399. With smaller Th17/Treg, the protective efficiency is more obvious when Th17/Treg < 0.2399. Our study suggested that increasing absolute and percentage of Th17 cells in the peripheral blood of patients with RA was associated with the development of ASCVD. And Th17/Treg may be a promising biomarker for patients with RA in indicating comorbidity with ASCVD.


Potential role of immune cell genetic variants associated with tumor microenvironment response in laryngeal squamous cell carcinoma (LSCC) in terms of clinicopathological features.
Immunomodulatory signals regulate the self-tolerance, activation, priming and survival processes of T cells. Programmed cell death protein 1 (PD1), Programmed death-ligand 1 (PD-L1) inhibitory signals and CD27, CD28 costimulators have been detected for many solid organ cancers in tumor-infiltrating T cells. It was aimed to investigate the immune cell-based regulatory genetic variants in laryngeal squamous cell carcinoma (LSCC) in terms of clinicopathological features. Genotyping was performed by PCR-RFLP method for PD-1 rs2227981, PD-L1 rs2890658, CD28 rs3116496, CD27 rs2267966 genetic variants from genomic DNAs extracted from peripheral blood samples in One Hundred Thirty-Six individuals (Sixty-one LSCC and seventy-five controls). Analysis of SNPs was carried out according to multiple inheritance models (co-dominant, dominant, recessive, over-dominant and log-additive). There was no difference between LSCC and control groups in genotype/allele distribution for PD-1 and PD-L1 (p > 0.05). In the PD-1 overdominant model, the CT genotype was found to be high (p = 0.036) in those without a family history. The frequency of C allele (AC+CC) in the PD-L1 dominant model was higher in alcohol users and those with reflux (p = 0.024; p = 0.001 respectively). In the Dominant model for PD-L1, the AA genotype was lower in moderately and well-differentiated tumors than in poorly differentiated tumors (p = 0.02). CD27 AT and CD28 CT genotypes were found to be higher in LSCC patients compared to the control group (p = 0.009; p = 0.01 respectively), while linkage disequilibrium (LD) was detected between CD27 and CD28 (p = 0.02). In the CD28 dominant model, C allele (CT+CC) carriage was found to be high in those with family history and in those without reflux and perineural invasion (p = 0.01; p = 0.01; p = 0.03 respectively). In LSCC, PD-L1 rather than PD-1 has a prognostic effect in terms of clinicopathology, and the LD and clinicopathological relationships detected between CD28 and CD27 genotypes suggest that the hereditary immune checkpoint-dependent T cell traffic may be pathophysiologically important.


Adherence to the Australian dietary guidelines during pregnancy: evidence from a national study.
To assess dietary intake of pregnant women against the Australian Dietary Guidelines with respect to the Five Food Group recommendations and determine predictors of adherence to the recommendations. Cross-sectional web-based survey. Data were analysed using descriptive statistics and logistic regression. Pregnant women living in Australia. A national sample was recruited using an online panel provider and a South Australian sample was recruited through the antenatal clinic of a large public maternity hospital. A total of 857 pregnant women. Fifty-six per cent, 29% and less than 10% of women met the recommendations for the fruit, dairy and other core food groups, respectively. None of the women met the recommendations for all Five Food Groups. Women who were born overseas and who were less physically active pre-pregnancy were less likely to adhere to the fruit and dairy recommendations. Women who smoked during pregnancy, were overweight pre-pregnancy and had lower household incomes were also less likely to meet the fruit recommendations; and women living in metropolitan areas were less likely to meet the vegetable recommendations. Sixty-one per cent believed their diet during this pregnancy was healthy. The majority of pregnant women in Australia perceive their diets to be healthy yet they do not consume the recommended daily servings from the Five Food Groups. Intervention strategies are warranted, particularly those that increase women's ability to evaluate their diet and also encourage positive dietary changes. These strategies may increase adoption of dietary guidelines and optimise pregnancy and other long-term health outcomes.


The effects of HIV/AIDS on rural communities in East Africa: a 20-year perspective.
Much of the research on implications of the HIV epidemic for individual households and broader rural economies in the 1980s and early 1990s predicted progressive declines in agricultural production, with dire consequences for rural livelihoods. Restudies in Tanzania and Uganda show that from 1986 to the present, HIV and AIDS have sometimes thrown households into disarray and poverty, but more often have reduced development. The progressive and systematic decline predicted in earlier work has not come to pass. However, poverty remains, as does endemic HIV disease.


Bisulfite Conversion of DNA: Performance Comparison of Different Kits and Methylation Quantitation of Epigenetic Biomarkers that Have the Potential to Be Used in Non-Invasive Prenatal Testing.
Epigenetic alterations, including DNA methylation, play an important role in the regulation of gene expression. Several methods exist for evaluating DNA methylation, but bisulfite sequencing remains the gold standard by which base-pair resolution of CpG methylation is achieved. The challenge of the method is that the desired outcome (conversion of unmethylated cytosines) positively correlates with the undesired side effects (DNA degradation and inappropriate conversion), thus several commercial kits try to adjust a balance between the two. The aim of this study was to compare the performance of four bisulfite conversion kits [Premium Bisulfite kit (Diagenode), EpiTect Bisulfite kit (Qiagen), MethylEdge Bisulfite Conversion System (Promega) and BisulFlash DNA Modification kit (Epigentek)] regarding conversion efficiency, DNA degradation and conversion specificity. Performance was tested by combining fully methylated and fully unmethylated λ-DNA controls in a series of spikes by means of Sanger sequencing (0%, 25%, 50% and 100% methylated spikes) and Next-Generation Sequencing (0%, 3%, 5%, 7%, 10%, 25%, 50% and 100% methylated spikes). We also studied the methylation status of two of our previously published differentially methylated regions (DMRs) at base resolution by using spikes of chorionic villus sample in whole blood. The kits studied showed different but comparable results regarding DNA degradation, conversion efficiency and conversion specificity. However, the best performance was observed with the MethylEdge Bisulfite Conversion System (Promega) followed by the Premium Bisulfite kit (Diagenode). The DMRs, EP6 and EP10, were confirmed to be hypermethylated in the CVS and hypomethylated in whole blood. Our findings indicate that the MethylEdge Bisulfite Conversion System (Promega) was shown to have the best performance among the kits. In addition, the methylation level of two of our DMRs, EP6 and EP10, was confirmed. Finally, we showed that bisulfite amplicon sequencing is a suitable approach for methylation analysis of targeted regions.


Chemical and biological warfare (I): the research program.
Biological warfare is the intentional use of living organisms or their toxic products to cause death, disability, or damage in man, animals, or plants. The target is man, either by causing his sickness or death, or through limitation of his food supplies or other agricultural resources. Man must wage a continuous fight to maintain and defend himself, his animals, and his plants in competition with insects and microorganisms. The object of BW is to overcome these efforts by deliberately distributing large numbers of organisms of native or foreign origin, or their toxic products, taking full advantage of the ability to utilize more effective methods of dissemination and unusual portals of entry. BW has been aptly described as public health in reverse.-"Effects of Biological Warfare Agents," pamphlet published by Department of Health, Education, and Welfare, July 1959.


Novice Shooters With Lower Pre-shooting Alpha Power Have Better Performance During Competition in a Virtual Reality Scenario.
Competition changes the environment for athletes. The difficulty of training for such stressful events can lead to the well-known effect of "choking" under pressure, which prevents athletes from performing at their best level. To study the effect of competition on the human brain, we recorded pilot electroencephalography (EEG) data while novice shooters were immersed in a realistic virtual environment representing a shooting range. We found a differential between-subject effect of competition on mu (8-12 Hz) oscillatory activity during aiming; compared to training, the more the subject was able to desynchronize his mu rhythm during competition, the better was his shooting performance. Because this differential effect could not be explained by differences in simple measures of the kinematics and muscular activity, nor by the effect of competition or shooting performance per se, we interpret our results as evidence that mu desynchronization has a positive effect on performance during competition.


Antenatal management of the expectant mother and extreme preterm infant at the limits of viability.
We explored the opinions of healthcare providers on the antenatal management and outcome of preterm delivery at less than 28 weeks gestation. An anonymous postal questionnaire was sent to health care providers. The response rate was 55% (74% Obstetrician, 70% neonatologist). Twenty four weeks is the limit at which most would advocate intervention. At 23 weeks 67% of neonatologists advocate antenatal steroids. 50% of all health care providers advocate cardiotocographic monitoring at 24 weeks gestation. Written information on survival and long-term outcome is provided by 8% of the respondents. Neonatologists (50%) were more likely than obstetrician (40%) to advocate caesarean section at 25 weeks. We conclude that 24 weeks is the limit at which most would advocate intervention. Significant variation exists both between and within each health care group at less than 25 weeks. Establishment and provision of national outcome data may aid decision making at the limits of viability.


Photography enhancement based on the fusion of tone and color mappings in adaptive local region.
Existing tone reproduction schemes are generally based on a single image and are, therefore, unable to accurately recover the local details and colors of scene since the limited available information. Accordingly, the proposed tone reproduction system utilizes two images with different exposures (one low and one high) to capture the local detail and color information of low- and high-luminance regions of scene, respectively. The adaptive local region of each pixel is developed in order to appropriately reveal the details and maintain the overall impression of scene. Our system implements the local tone mapping and color mapping based on the adaptive local region by taking the lowly-exposed image as the basis and referencing the information of highly-exposed image. The local tone mapping compresses the luminance range in the image and enhances the local contrast to reveal the details, while the local color mapping maps the precise color information from the highly-exposed image to the lowly-exposed image. Finally, a fusion process is proposed to mix the local tone mapping and local color mapping results to produce the output image. A multiresolution approach is also developed to reduce time cost. The experimental results confirm that the system generates realistic reproductions of HDR scenes.


Has submarine groundwater discharge been overlooked as a source of mercury to coastal waters?
We measured the mercury (Hg) in groundwater, aquifer sediments, and surface water in Waquoit Bay (Massachusetts) and found that this toxic metal (range: <3.2-262 pM) was being released within the subterranean estuary, with similarly high levels (range: 18-256 pM) found in the surface waters of the bay. None of the dissolved species (DOC, chloride, and Fe) normally observed to influence Hg partitioning correlated well with the observed Hg concentrations. It was hypothesized that this was in part due to the variable loading in time and space of Hg onto the aquifer sands in combination with the seasonality of groundwater flow through the aquifer. Aquifer sediment samples from the study site ranged from <1 to 12.5 pmol of Hg/g of sediment, suggesting log Kd values on the order of 1. We hypothesize that this was due to the low organic carbon content typical of the aquifer sediments. Last, itwas estimated that submarine groundwater discharge supplied 0.47-1.9 nmol of Hg m(-2) day(-1) to the bay, which is an order of magnitude higher than the atmospheric deposition rate for the northeastern U.S.


Synergistic interaction of novel lactate dehydrogenase inhibitors with gemcitabine against pancreatic cancer cells in hypoxia.
Hypoxia is a driving force in pancreatic-ductal-adenocarcinoma (PDAC) growth, metastasis and chemoresistance. The muscle-isoform of lactate dehydrogenase (LDH-A) constitutes a major checkpoint for the switch to anaerobic glycolysis, ensuring supply of energy and anabolites in hypoxic-environments. Therefore, we investigated the molecular mechanisms underlying the pharmacological interaction of novel LDH-A inhibitors in combination with gemcitabine in PDAC cells. Lactate dehydrogenase A levels were studied by quantitative RT-PCR, western blot, immunofluorescence and activity assays in 14 PDAC cells, including primary-cell-cultures and spheroids, in normoxic and hypoxic conditions. Cell proliferation, migration and key determinants of drug activity were evaluated by sulforhodamine-B-assay, wound-healing assay, PCR and LC-MS/MS. Lactate dehydrogenase A was significantly increased under hypoxic conditions (1% O2), where the novel LDH-A inhibitors proved to be particularly effective (e.g., with IC50 values of 0.9 vs 16.3 μM for NHI-1 in LPC006 in hypoxia vs normoxia, respectively). These compounds induced apoptosis, affected invasiveness and spheroid-growth, reducing expression of metalloproteinases and cancer-stem-like-cells markers (CD133+). Their synergistic interaction with gemcitabine, with combination index values <0.4 in hypoxia, might also be attributed to modulation of gemcitabine metabolism, overcoming the reduced synthesis of phosphorylated metabolites. Lactate dehydrogenase A is a viable target in PDAC, and novel LDH-A inhibitors display synergistic cytotoxic activity with gemcitabine, offering an innovative tool in hypoxic tumours.


Sustained release biodegradable solid lipid microparticles: Formulation, evaluation and statistical optimization by response surface methodology.
For preparing nebivolol loaded solid lipid microparticles (SLMs) by the solvent evaporation microencapsulation process from carnauba wax and glyceryl monostearate, central composite design was used to study the impact of independent variables on yield (Y1), entrapment efficiency (Y2) and drug release (Y3). SLMs having a 10-40 μm size range, with good rheological behavior and spherical smooth surfaces, were produced. Fourier transform infrared spectroscopy, differential scanning calorimetry and X-ray diffractometry pointed to compatibility between formulation components and the zeta-potential study confirmed better stability due to the presence of negative charge (-20 to -40 mV). The obtained outcomes for Y1 (29-86 %), Y2 (45-83 %) and Y3 (49-86 %) were analyzed by polynomial equations and the suggested quadratic model were validated. Nebivolol release from SLMs at pH 1.2 and 6.8 was significantly (p < 0.05) affected by lipid concentration. The release mechanism followed Higuchi and zero order models, while n > 0.85 value (Korsmeyer- Peppas) suggested slow erosion along with diffusion. The optimized SLMs have the potential to improve nebivolol oral bioavailability.


Role of monomer arrangement in the amyloid self-assembly.
Assembly of amyloid proteins into aggregates requires the ordering of the monomers in oligomers and especially in such highly organized structures as fibrils. This ordering is accompanied by structural transitions leading to the formation of ordered β-structural motifs in proteins and peptides lacking secondary structures. To characterize the effect of the monomer arrangements on the aggregation process at various stages, we performed comparative studies of the yeast prion protein Sup35 heptapeptide (GNNQQNY) along with its dimeric form CGNNQQNY-(d-Pro)-G-GNNQQNY. The (d-Pro)-G linker in this construct is capable of adopting a β-turn, facilitating the assembly of the dimer into the dimeric antiparallel hairpin structure (AP-hairpin). We applied Atomic Force Microscopy (AFM) techniques to follow peptide-peptide interactions at the single molecule level, to visualize the morphology of aggregates formed by both constructs, thioflavin T (ThT) fluorescence to follow the aggregation kinetics, and circular dichroism (CD) spectroscopy to characterize the secondary structure of the constructs. The ThT fluorescence data showed that the AP-hairpin aggregation kinetics is insensitive to the external environment such as ionic strength and pH contrary to the monomers the kinetics of which depends dramatically on the ionic strength and pH. The AFM topographic imaging revealed that AP-hairpins primarily assemble into globular aggregates, whereas linear fibrils are primary assemblies of the monomers suggesting that both constructs follow different aggregation pathways during the self-assembly. These morphological differences are in line with the AFM force spectroscopy experiments and CD spectroscopy measurements, suggesting that the AP-hairpin is structurally rigid regardless of changes of environmental factors.


The Influence of Perceived Stress and Depression on Suicide-Related Beliefs in Caucasian and Indian Adults.
Suicidality research in developing countries, including India, faces logistical and cultural challenges. Technology may help address these challenges and offer data to providers treating a diverse clientele. The relationship between perceived stress and suicide-related beliefs was examined in two populations: Indians in India (n = 374) and Caucasians in English-speaking countries (n = 326); the influence of depression on that relationship was also explored. The study was conducted via an Internet-based survey. Three-way interactions (Ethnicity × Perceived stress × Depression status) were observed, predicting strength of the belief that suicide is a solution to problems, F(1,679) = 4.18, p < .05, and that suicide is a good option if quality of life worsens, F(1,675) = 9.53, p < .01. For both beliefs, Caucasians screening positive for depression exhibited the strongest relationship between stress and suicide-related beliefs; for Indians, that relationship was not moderated by depression status. Caucasians also exhibited a stronger association between higher stress and greater belief strength that suicide is a good option assuming a steady quality of life than did Indians, F(1,680) = 6.05, p < .05. Participants were recruited through a depression screening website; results may not generalize to those who are uninterested in depression screening or to those who are unwilling or unable to use the internet for that purpose. Our findings may help to better target interventions to reduce suicidality, for example, employ stress reduction techniques for Caucasians who are depressed, and monitor suicidality for Indians reporting high stress regardless of depression.


A cell separation checkpoint that enforces the proper order of late cytokinetic events.
Eukaryotic cell division requires dependency relationships in which late processes commence only after early ones are appropriately completed. We have discovered a system that blocks late events of cytokinesis until early ones are successfully accomplished. In budding yeast, cytokinetic actomyosin ring contraction and membrane ingression are coupled with deposition of an extracellular septum that is selectively degraded in its primary septum immediately after its completion by secreted enzymes. We find this secretion event is linked to septum completion and forestalled when the process is slowed. Delay of septum degradation requires Fir1, an intrinsically disordered protein localized to the cytokinesis site that is degraded upon septum completion but stabilized when septation is aberrant. Fir1 protects cytokinesis in part by inhibiting a separation-specific exocytosis function of the NDR/LATS kinase Cbk1, a key component of "hippo" signaling that induces mother-daughter separation. We term this system enforcement of cytokinesis order, a checkpoint ensuring proper temporal sequence of mechanistically incompatible processes of cytokinesis.


Combined lenvatinib and pembrolizumab as salvage therapy in advanced adrenal cortical carcinoma.
There is no effective systemic therapy for metastatic adrenal cortical carcinoma (ACC) after failure of platinum-based chemotherapy. The efficacies of single-agent oral multikinase inhibitors (MKIs) or salvage immune checkpoint inhibitors (CPIs) have been very limited. It is unknown whether combining CPIs, such as pembrolizumab (PEM), with other therapies, such as MKIs, could yield higher response rates in ACC, yet this combination has shown promise in other cancers. Herein, we describe the first case series using PEM in combination with the MKI lenvatinib (LEN) in patients with progressive, metastatic ACC. A retrospective case series describing the use of LEN/PEM as salvage therapy in patients with progressive/metastatic ACC. Eight patients were treated with the LEN/PEM combination therapy. Half were female, and the median age at time of diagnosis was 38 years (range 21-49). Three (37.5%) patients had hormonally active ACC. The median number of prior lines of systemic therapy was 4 (range 2-9). Six (75%) patients had had disease progression on prior CPIs and five (62.5%) patients had progressed on prior MKI therapy. The median progression-free survival was 5.5 months (95% CI 1.8-not reached) and median duration of therapy was 8.5 months (range 2-22). Two (25%) patients had a partial response, one (12.5%) patient had stable disease, and five (62.5%) patients had progressive disease. None of the eight patients stopped therapy because of adverse events. In our small cohort of heavily pretreated patients with ACC, the combination of LEN/PEM was associated with objective responses in a subset of patients without significant toxicity. This combination should be formally investigated in phase II clinical trial with robust correlative studies to identify predictors for response.


Sterols in Recent Aquatic Sediments.
The presence of sterols in recent fresh-water sediments was confirmed and, for the first time, sterols were found to be widely distributed throughout recent marine sediments. Quantities ranged from 60 to 300 parts of cholesterol carbon per million parts of organic carbon in the sediments. No correlation of sterol content with environment or depth of burial in the sediment was apparent.


Impact of FDA-Required Cardiovascular Outcome Trials on Type 2 Diabetes Clinical Study Initiation From 2008 to 2017.
Since 2008, the US Food and Drug Administration (FDA) has required that drug manufacturers conduct postmarket cardiovascular outcomes trials (CVOTs) for approved type 2 diabetes mellitus (T2DM) drugs. The utility and impact of these studies in determining atherosclerotic cardiovascular risk was reviewed during an FDA Advisory Committee Meeting held on October 24, 2018. Drug manufacturers and patient advocates at this meeting contended that the FDA-required CVOT studies discouraged private sector investment into developing novel T2DM drugs. Here, we explore these contentions by reviewing private sector investment in T2DM drug development from 2000 through 2008, followed by a deductive analysis of how associated events-including the implementation of the CVOT requirement-may have precipitated any observed changes. We collected and analyzed industry-sponsored interventional trials for T2DM initiated between January 1, 2000, and December 31, 2017, and compared observed trends with those seen across all trials, specific diseases, and against patent filings of novel antidiabetic agents. The analysis shows a marked decline in initiated T2DM clinical trials from 2008 through 2017. Possible influencing factors, including the 2008 financial crisis and a slow in the discovery of novel antidiabetic agents may have contributed, but could not fully account for this decline in T2DM studies. These observations are consistent with the statements made by industry representatives and patient advocates at the 2018 Advisory Committee meeting. As the FDA reconsiders postmarket requirements for T2DM products, these observations underscore the importance of considering more efficient postmarket study structures to assess cardiovascular safety beyond mandatory CVOTs.


Caregiver Burden in Pulmonary Patients.
Caregiving has become an increasingly important medical and social issue in recent decades. We performed a cross-sectional study on pulmonary patients and accompanying informal caregivers who were hospitalized in the chest disease ward of a tertiary center in Turkey between January 2020 and April 2021. Informal caregivers were asked to complete the Zarit Caregiver Burden Interview. A total of 141 inpatients (39% female, mean age: 76.8 ± 10.2 years) and their informal caregivers (77% female, mean age: 54 ± 11.9 years) were evaluated. The caregivers were classified as light to medium burden (group 1, burden score ≤40) and medium to heavy burden (group 2, burden score >40). The mean burden score was 35.7 ± 13.3 points. The number of female caregivers was higher in group 2 (p = 0.025). There was a positive correlation between the burden score and female gender (p = 0.002) and the number of chronic diseases of caregivers (p = 0.020). Statistical analysis revealed a negative correlation between the burden score and the level of education (r = > -0.174, p = 0.040). Caregiver burden is related to the characteristics of the caregiver rather than those of the patient being cared for. Female caregivers with lower education and more than one chronic disease perceive a higher caregiver burden.


Association between bile acid metabolism and bone mineral density in postmenopausal women.
Previous studies have not shown any correlation between bile acid metabolism and bone mineral density (BMD) in women with postmenopausal osteoporosis. Thus, the current study evaluated the association between bile acid levels as well as BMD and bone turnover marker levels in this group of women. This single-center cross-sectional study included 150 postmenopausal Chinese women. According to BMD, the participants were divided into three groups: osteoporosis group, osteopenia group, and healthy control group. Serum bile acid, fibroblast growth factor 19 (FGF19), and bone turnover biomarker levels were assessed. Moreover, the concentrations of parathyroid hormone, 25-hydroxy vitamin D [25(OH)D], procollagen type I N-peptide (P1NP), and beta-CrossLaps of type I collagen containing cross-linked C-terminal telopeptide (β-CTX) were evaluated. The BMD of the lumbar spine and proximal femur were examined via dual-energy X-ray absorptiometry. The serum total bile acid levels in the osteoporosis and osteopenia groups (5.28±1.56 and 5.31±1.56 umol/L, respectively) were significantly lower than that in the healthy control group (6.33±2.04 umol/L; p=0.002 and 0.018, respectively). Serum bile acid level was positively associated with the BMD of the lumbar spine, femoral neck, and total hip. However, it negatively correlated with β-CTX concentration. Moreover, no correlation was observed between bile acid and P1NP levels, and the levels of the other biomarkers that were measured did not differ between the groups. Serum bile acid was positively correlated with BMD and negatively correlated with bone turnover biomarkers reflecting bone absorption in postmenopausal women. Thus, bile acid may play an important role in bone metabolism.


The concept and treatment methodology for inducing ovulation in women in apparent premature menopause.
To provide the concept and details of the methodology of inducing ovulation in women in apparent menopause. A recent case is discussed and other previous publications described illustrating how to induce ovulation and achieve pregnancies despite what appears to be menopause. The various methods of lowering serum follicle stimulating hormone (FSH) and restoring down-regulated FSH receptors in granulosa theca cells of the follicle are described. The newly reported case had two successful pregnancies after having a trisomy 15 in her first pregnancy. Women aged 42 and younger in apparent menopause have a reasonably good chance of ovulation induction and pregnancy by adhering to the tenets discussed, especially including lowering the elevated FSH in some way (the easiest and cheapest with ethinyl estradiol), using minimal or no gonadotropins, and supporting the luteal phase with progesterone.


Early patient screening and intervention to address individual-level occupational factors ("blue flags") in back disability.
To develop a consensus plan for research and practice to encourage routine clinician screening of occupational factors associated with long-term back disability. A 3-day conference workshop including 21 leading researchers and clinicians (the "Decade of the Flags Working Group") was held to review the scientific evidence concerning clinical, occupational, and policy factors in back disability and the development of feasible assessment and intervention strategies. The Working Group identified seven workplace variables to include in early screening by clinicians: physical job demands, ability to modify work, job stress, workplace social support or dysfunction, job satisfaction, expectation for resuming work, and fear of re-injury. Five evaluation criteria for screening methods were established: reliability, predictive performance, feasibility, acceptability, and congruence with plausible interventions. An optimal screening method might include a stepped combination of questionnaire, interview, and worksite visit. Future research directions include improving available assessment methods, adopting simpler and more uniform conceptual frameworks, and tying screening results to plausible interventions. There is a clear indication that occupational factors influence back disability, but to expand clinician practices in this area will require that patient screening methods show greater conceptual clarity, feasibility, and linkages to viable options for intervention.


Structural insight into tanapoxvirus-mediated inhibition of apoptosis.
Premature programmed cell death or apoptosis of cells is a strategy utilized by multicellular organisms to counter microbial threats. Tanapoxvirus (TANV) is a large double-stranded DNA virus belonging to the poxviridae that causes mild monkeypox-like infections in humans and primates. TANV encodes for a putative apoptosis inhibitory protein 16L. We show that TANV16L is able to bind to a range of peptides spanning the BH3 motif of human proapoptotic Bcl-2 proteins and is able to counter growth arrest of yeast induced by human Bak and Bax. We then determined the crystal structures of TANV16L bound to three identified interactors, Bax, Bim and Puma BH3. TANV16L adopts a globular Bcl-2 fold comprising 7 α-helices and utilizes the canonical Bcl-2 binding groove to engage proapoptotic host cell Bcl-2 proteins. Unexpectedly, TANV16L is able to adopt both a monomeric and a domain-swapped dimeric topology where the α1 helix from one protomer is swapped into a neighbouring unit. Despite adopting two different oligomeric forms, the canonical ligand binding groove in TANV16L remains unchanged from monomer to domain-swapped dimer. Our results provide a structural and mechanistic basis for tanapoxvirus-mediated inhibition of host cell apoptosis and reveal the capacity of Bcl-2 proteins to adopt differential oligomeric states whilst maintaining the canonical ligand binding groove in an unchanged state. DATABASE: Structural data are available in the Protein Data Bank (PDB) under the accession numbers 6TPQ, 6TQQ and 6TRR.


Computational methods for the analysis of tag sequences in metagenomics studies.
Metagenomics commonly refers to the study of genetic materials directly derived from environments without culturing. Several ongoing large-scale metagenomics projects related to human and marine life, as well as pedology studies, have generated enormous amounts of data, posing a key challenge for efficient analysis, as we try to 1) understand microbial organism assemblage under different conditions, 2) compare different communities, and 3) understand how microbial organisms associate with each other and the environment.To address such questions, investigators are using new sequencing technologies, including Sanger, Illumina Solexa, and Roche 454, to sequence either particular genes, called tag sequences, mostly 16S or 18S ribosomal RNA sequences or other conserved genes, or whole metagenome shotgun sequences of all the genetic materials in a given community. In this paper, we review computational methods used for the analysis of tag sequences.


Psychotropic medication use in human immunodeficiency virus-infected youth receiving treatment at a single institution.
A cross-sectional study designed to document the use of psychotropic medication in a population of human immunodeficiency virus (HIV)-infected children and adolescents (n = 64) found 45% of the sample had been prescribed at least one psychotropic medication over a 4-year period. The most common medication category prescribed was antidepressants (30%), followed by stimulant-type medications (25%). This study suggests that psychotropic medications are commonly prescribed to HIV-infected children and adolescents. Close partnership with mental health professionals to develop treatment approaches for psychiatric disorders in youth living with HIV is recommended.


A protein nanocontainer targeting epithelial cancers: rational engineering, biochemical characterization, drug loading and cell delivery.
The development of drug delivery and imaging tools is a major challenge in human health, in particular in cancer pathologies. This work describes the optimization of a protein nanocontainer, belonging to the lectin protein family, for its use in epithelial cancer diagnosis and treatment. Indeed, it specifically targets a glycosidic marker, the T antigen, which is known to be characteristic of epithelial cancers. Its quaternary structure reveals a large hydrated inner cavity able to transport small therapeutic molecules. Optimization of the nanocontainer by site directed mutagenesis allowed controlling loading and release of confined drugs. Doxorubicin confinement was followed, both theoretically and experimentally, and provided a proof of concept for the use of this nanocontainer as a vectorization system. In OVCAR-3 cells, a human ovarian adenocarcinoma cell line that expresses the T antigen, the drug was observed to be delivered inside late endosomes/lysosomes. These results show that this new type of vectorization and imaging device opens new exciting perspectives in nano-theranostic approaches.


Surgical treatment of catamenial pneumothorax: a single centre experience.
We retrospectively reviewed our experience with catamenial pneumothorax (CP) in terms of treatment and follow-up. From 1993 to 2008, ten women presented at our department with CP. CP was right-sided in all patients: seven presented diaphragmatic defects including one endometriosis, five had apical bulla or blebs that in three patients were the only pathological findings. Surgical approach was thoracoscopic with a muscle-sparing thoracotomy when diaphragmatic defects where present. All patients underwent apical resection and apical pleurectomy associated in seven cases with diaphragmatic plication and chemical pleurodesis. After surgery nine patients underwent hormonal treatment: three were put on estrogen-progesterone complex treatment and six received gonadotropin-releasing hormone agonist (GnRH agonist). Recurrence rate was 40% and it was significantly correlated with estrogen-progesterone treatment (P<0.005). The mean follow-up was 52+/-32 months (range 14-168). At the present time, no recurrence has occurred in all women. Occurrence of CP is often underestimated. At the time of surgery the diaphragm should be carefully inspected for defects and/or endometriosis. Standard pleurodesis may not suffice and we suggest apical resection and apical pleurectomy associated with a diaphragmatic procedure when indicated. Hormonal treatment with GnRH agonist seems to improve the outcome.


SUMOylation of HSP27 regulates PKM2 to promote esophageal squamous cell carcinoma progression.
A previous proteomic screening of differentially expressed biomarkers between Kazakh patients with esophageal squamous cell carcinoma (ESCC) and normal adjacent tissues demonstrated that heat shock protein 27 (HSP27) and pyruvate kinase isoenzyme M2 (PKM2) were both highly expressed in ESCC samples compared with normal controls. However, the regulatory association between HSP27 and PKM2 in ESCC remains elusive. In the present study, immunohistochemistry and immunoblotting were adopted to examine the expression of HSP27, PKM2 and other relevant biomarkers involved in epithelial‑to‑mesenchymal transition in clinical tissue samples. The interactions between proteins were detected by co‑immunoprecipitation (Co‑IP) assay and further confirmed by immunofluorescence assay. The growth and motility of ESCC cells were examined by MTT, Transwell and wound healing assays. Overexpression of HSP27 was found to be significantly associated with T‑cell classification, lymph node metastasis and poor prognosis in ESCC. In addition, HSP27 expression was significantly correlated with PKM2 expression in ESCC specimens. Functionally, knockdown of HSP27 inhibited the growth and motility of ESCC cells. Moreover, HSP27 was found to directly interact with small ubiquitin‑related modified protein 2/3 (SUMO2/3) in ESCC cell lines, as evidenced by Co‑IP and laser confocal imaging. In addition, downregulation of HSP27 was shown to decrease PKM2 and E‑cadherin expression. Knockdown of SUMO2/3 was observed to reduce the expression of HSP27, PKM2 and EMT‑related biomarkers. The results of the present study indicated that the SUMOylation of HSP27 enhances the proliferation, invasion and migration of ESCC cells via PKM2.


US mortality in an international context: age variations.
Compared to other developed countries, the United States ranks poorly in terms of life expectancy at age 50. We seek to shed light on the US's low life expectancy ranking by comparing the age-specific death rates of 18 developed countries at older ages. A striking pattern emerges: between ages 40 and 75, US all-cause mortality rates are among the poorest in the set of comparison countries. The US position improves dramatically after age 75 for both males and females. We consider four possible explanations of the age patterns revealed by this analysis: (1) access to health insurance; (2) international differences in patterns of smoking; (3) age patterns of health care system performance; and (4) selection processes. We find that health insurance and smoking are not plausible sources of this age pattern. While we cannot rule out selection, we present suggestive evidence that an unusually vigorous deployment of life-saving technologies by the US health care system at very old ages is contributing to the age-pattern of US mortality rankings. Differences in obesity distributions are likely to be making a moderate contribution to the pattern but uncertainty about the risks associated with obesity prevents a precise assessment.


Association between mammographic breast density and histologic features of benign breast disease.
Over 40% of women undergoing breast screening have mammographically dense breasts. Elevated mammographic breast density (MBD) is an established breast cancer risk factor and is known to mask tumors within the dense tissue. However, the association of MBD with high risk benign breast disease (BBD) is unknown. We analyzed data for 3400 women diagnosed with pathologically confirmed BBD in the Mayo Clinic BBD cohort from 1985-2001, with a clinical MBD measure (either parenchymal pattern (PP) or Breast Imaging Reporting and Data Systems (BI-RADS) density) and expert pathology review. Risk factor information was collected from medical records and questionnaires. MBD was dichotomized as dense (PP classification P2 or DY, or BI-RADS classification c or d) or non-dense (PP classification N1 or P1, or BI-RADS classification a or b). Associations of clinical and histologic characteristics with MBD were examined using logistic regression analysis to estimate odds ratios (ORs) with 95% confidence intervals (CIs). Of 3400 women in the study, 2163 (64%) had dense breasts. Adjusting for age and body mass index (BMI), there were positive associations of dense breasts with use of hormone therapy (HT), lack of lobular involution, presence of atypical lobular hyperplasia (ALH), histologic fibrosis, columnar cell hyperplasia/flat epithelia atypia (CCH/FEA), sclerosing adenosis (SA), cyst, usual ductal hyperplasia, and calcifications. In fully adjusted multivariate models, HT (1.3, 95% CI 1.1-1.5), ALH (1.5, 95% CI 1.0-2.2), lack of lobular involution (OR 1.6, 95% CI 1.2-2.1, compared to complete involution), fibrosis (OR 2.2, 95% CI 1.9-2.6) and CCH/FEA (OR 1.3, 95% CI 1.0-1.6) remained significantly associated with high MBD. Our findings support an association between high risk BBD and high MBD, suggesting that risks associated with the latter may act early in breast carcinogenesis.


Cutaneous leishmaniasis in a patient with ankylosing spondylitis using adalimumab.
Leishmaniasis is an anthropozoonosis caused by species of Leishmania and can have different clinical presentations, depending on the parasite-host relationship. Tumor necrosis factor-α (TNF-α) is a cytokine essential to infection control, especially against intracellular parasites such as Leishmania. Anti-TNF-α strategies have had a marked impact on the treatment of rheumatic diseases, but the clinical use of those antagonists has been accompanied by an increased report of infections. We report the first case of cutaneous leishmaniasis in a patient with ankylosing spondylitis treated with adalimumab and methotrexate in Brazil. We believe that, in this case, there was no association between the anti-TNF-α treatment and cutaneous leishmaniasis, because the disease was limited to only one ulcer that healed completely after treatment. More studies, however, are necessary to better understand the possible relationship between anti-TNF-α agents and leishmaniasis.


[S1 Herpes zoster localization: acute urinary retention in woman].
Acute urinary retention in women is rare. The varicella-zoster virus causes inflammatory lesions of the sensory-root ganglions, meninges and, less frequently, spinal cord. Herpes zoster has been reported to affect, although rarely, lower urinary tract innervations, and acute urinary retention can be thought to occur in the presence of sacral dermatome involvement. Usually it is located in S2-4 dermatome and the prognosis for acute urinary retention is benign resolving in about 20 days. We present a case in which the S1 dermatome was involved and acute urinary retention developed. After 10 days of specific therapy and self-catheterization the problem resolved.


Citizen science provides valuable data to evaluate elasmobranch diversity and trends throughout the French Polynesia's shark sanctuary.
Observers of the Polynesian Shark Observatory (ORP), a citizen science network organized mainly through the Polynesian dive centers, collected an unprecedented amount of data from more than 13,916 dives spanning 43% of the islands of French Polynesia between July 8, 2011, and April 11, 2018. The objective for this type of data collection, which is not accessible within the standard research context, was to provide a unique dataset, and the opportunity to explore the specific diversity, distribution, seasonality and abundance of many elasmobranch species spread out throughout the territory of French Polynesia. Since the data are based on random citizen observations, the spatial distribution was biased toward the most frequented sites and islands where scuba diving is most developed. Overall, the increase in observed abundance of rays and sharks observed in French Polynesia, and the three most sampled islands as well as the high specific diversity recorded for the region, provide first evidence on the effectiveness of the French Polynesia's Shark Sanctuary, established in 2006. These data, collected randomly by the volunteers, also provide insights into potential movement patterns and site fidelity of some of the more commonly observed species. While no final conclusions can be drawn, it is clear that the network of volunteers that regularly contributes information to the Polynesian Shark Observatory plays a very important role in the delivery of much needed data for conservation and management action, as well as providing perspectives for new directions in research on sharks and rays in French Polynesia.


U.S. Army Medical Corps Recruitment, Job Satisfaction, and Retention: Historical Perspectives and Current Issues.
This study was conducted to identify and understand the current factors affecting recruitment, job satisfaction, and retention of U.S. Army Medical Corps officers and provide historical background to understand if the current factors are dissimilar. An anonymous, voluntary questionnaire was sent to U.S. Army Medical Corps officers, and responses were tabulated and analyzed. Historical research was conducted and historical analysis applied. Recruiting, job satisfaction, and retention among Army Medical Corps Officers have been problematic throughout the 50-year history of the all-volunteer force. Recruiting has largely been of medical students, with very limited numbers of direct accessions. At times, satisfactory overall numbers have camouflaged shortages in key go-to-war specialties. Also, satisfactory numbers in a specialty have sometimes camouflaged problems in depth of experience. Satisfaction has been seen as a problem but apparently only studied informally and/or episodically. Retention has largely been addressed through service obligations, followed by monetary bonuses, although these have to be across the Department of Defense, limiting service flexibility. There has never been consistent, longitudinal sampling of opinion among Medical Corps Officers to allow senior leaders to influence the Department of Defense policy. A recent (2016) study provides substantial data but should be repeated rather than being isolated. As the situation in the Department of Defense and Army Medical Department changes, with more focus on go-to-war specialties, the Army needs to better measure opinion among Medical Corps Officers to inform policy. These studies should be conducted regularly to generate reliable information on trends and allow prioritization of effort to areas that hamper recruiting, undermine satisfaction, and prevent retention.


Rewilding wetlands: beaver as agents of within-habitat heterogeneity and the responses of contrasting biota.
Ecosystem engineers can increase biodiversity by creating novel habitat supporting species that would otherwise be absent. Their more routine activities further influence the biota occupying engineered habitats. Beavers are well-known for transforming ecosystems through dam building and are therefore increasingly being used for habitat restoration, adaptation to climate extremes and in long-term rewilding. Abandoned beaver ponds (BP) develop into meadows or forested wetlands that differ fundamentally from other terrestrial habitats and thus increase landscape diversity. Active BP, by contrast, are superficially similar to other non-engineered shallow wetlands, but ongoing use and maintenance might affect how BP contribute to aquatic biodiversity. We explored the 'within-habitat' effect of an ecosystem engineer by comparing active BP in southern Sweden with coexisting other wetlands (OW), using sedentary (plants) and mobile (water beetles) organisms as indicators. BP differed predictably from OW in environmental characteristics and were more heterogeneous. BP supported more plant species at plot (+15%) and site (+33%) scales, and plant beta diversity, based on turnover between plots, was 17% higher than in OW, contributing to a significantly larger species pool in BP (+17%). Beetles were not differentiated between BP and OW based on diversity measures but were 26% more abundant in BP. Independent of habitat creation beaver are thus significant agents of within-habitat heterogeneity that differentiates BP from other standing water habitat; as an integral component of the rewilding of wetlands re-establishing beaver should benefit aquatic biodiversity across multiple scales.This article is part of the theme issue 'Trophic rewilding: consequences for ecosystems under global change'.


Parental post-traumatic stress and psychiatric care utilisation among refugee adolescents.
Parental psychiatric morbidity related to experiences of war and trauma has been associated with adverse psychological outcomes for children. The aim of this study was to investigate parental post-traumatic stress in relation to psychiatric care utilization among children of refugees with particular attention on the child's own refugee status, sex of both child and parents, and specific psychiatric diagnoses. This was a register study in a population of 16 143 adolescents from refugee families in Stockholm County born 1995-2000 and followed between 2011 and 2017 (11-18 years old). Parental post-traumatic stress, identified in three levels of care, was analysed in relation to child and adolescent psychiatric care use. Cox regression analysis was used to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusted for duration of residence and demographic and socioeconomic variables. Having a mother with post-traumatic stress was associated with higher psychiatric care utilization, with adjusted HR 2.44 (95% CI 1.90-3.14) among foreign-born refugee children and HR 1.77 (1.33-2.36) among Swedish-born children with refugee parents, with particularly high risks for children with less than five years of residence (HR 4.03; 2.29-7.10) and for diagnoses of anxiety and depression (HR 2.71; 2.11-3.48). Having a father with post-traumatic stress was not associated with increased HRs of psychiatric care utilization. Similar results were seen for boys and girls. Treatment for post-traumatic stress should be made available in refugee reception programmes. These programmes should use a family approach that targets both parents and children.


[The forensic medical determination of the time of occurrence of subdural hemorrhages in the acute period of fatal craniocerebral trauma].
Presents the results of spectrophotometric and histologic examinations of subdural bleedings, meninges and brain matter in the acute period of a lethal craniocerebral injury. Discusses the possible use of a complex of histologic and biochemical studies in determination of the period elapsed since the injury.


Neural bases of categorization of simple speech and nonspeech sounds.
Categorization is fundamental to our perception and understanding of the environment. However, little is known about the neural bases underlying the categorization of sounds. Using human functional magnetic resonance imaging (fMRI) we compared the brain responses to a category discrimination task with an auditory discrimination task using identical sets of sounds. Our stimuli differed along two dimensions: a speech-nonspeech dimension and a fast-slow temporal dynamics dimension. All stimuli activated regions in the primary and nonprimary auditory cortices in the temporal cortex and in the parietal and frontal cortices for the two tasks. When comparing the activation patterns for the category discrimination task to those for the auditory discrimination task, the results show that a core group of regions beyond the auditory cortices, including inferior and middle frontal gyri, dorsomedial frontal gyrus, and intraparietal sulcus, were preferentially activated for familiar speech categories and for novel nonspeech categories. These regions have been shown to play a role in working memory tasks by a number of studies. Additionally, the categorization of nonspeech sounds activated left middle frontal gyrus and right parietal cortex to a greater extent than did the categorization of speech sounds. Processing the temporal aspects of the stimuli had a greater impact on the left lateralization of the categorization network than did other factors, particularly in the inferior frontal gyrus, suggesting that there is no inherent left hemisphere advantage in the categorical processing of speech stimuli, or for the categorization task itself.


Is selenium a potential treatment for cancer metastasis?
Selenium (Se) is an essential micronutrient that functions as a redox gatekeeper through its incorporation into proteins to alleviate oxidative stress in cells. Although the epidemiological data are somewhat controversial, the results of many studies suggest that inorganic and organic forms of Se negatively affect cancer progression, and that several selenoproteins, such as GPXs, also play important roles in tumor development. Recently, a few scientists have examined the relationship between Se and metastasis, a late event in cancer progression, and have evaluated the potential of Se as an anti-angiogenesis or anti-metastasis agent. In this review, we present the current knowledge about Se compounds and selenoproteins, and their effects on the development of metastasis, with an emphasis on cell migration, invasion, and angiogenesis. In the cancers of breast, prostate, colorectal, fibrosarcoma, melanoma, liver, lung, oral squamous cell carcinoma, and brain glioma, there is either clinical evidence linking selenoproteins, such as thioredoxin reductase-1 to lymph node metastasis; in vitro studies indicating that Se compounds and selenoproteins inhibited cell motility, migration, and invasion, and reduced angiogenic factors in some of these cancer cells; or animal studies showing that Se supplementation resulted in reduced microvessel density and metastasis. Together, these data support the notion that Se may be an anti-metastastatic element in addition to being a cancer preventative agent.


Quantifying the contribution of hosts with different parasite concentrations to the transmission of visceral leishmaniasis in Ethiopia.
An important factor influencing the transmission dynamics of vector-borne diseases is the contribution of hosts with different parasitemia (no. of parasites per ml of blood) to the infected vector population. Today, estimation of this contribution is often impractical since it relies exclusively on limited-scale xenodiagnostic or artificial feeding experiments (i.e., measuring the proportion of vectors that become infected after feeding on infected blood/host). We developed a novel mechanistic model that facilitates the quantification of the contribution of hosts with different parasitemias to the infection of the vectors from data on the distribution of these parasitemias within the host population. We applied the model to an ample data set of Leishmania donovani carriers, the causative agent of visceral leishmaniasis in Ethiopia. Calculations facilitated by the model quantified the host parasitemias that are mostly responsible for the infection of vector, the sand fly Phlebotomus orientalis. Our findings indicate that a 3.2% of the most infected people were responsible for the infection of between 53% and 79% (mean - 62%) of the infected sand fly vector population. Our modeling framework can easily be extended to facilitate the calculation of the contribution of other host groups (such as different host species, hosts with different ages) to the infected vector population. Identifying the hosts that contribute most towards infection of the vectors is crucial for understanding the transmission dynamics, and planning targeted intervention policy of visceral leishmaniasis as well as other vector borne infectious diseases (e.g., West Nile Fever).


Electron spin resonance studies of free radicals in gamma-irradiated soybean paste.
Free radicals in gamma-irradiated soybean paste were investigated by electron spin resonance (ESR) spectroscopy to determine the effect of temperature (77-296 K) and moisture content (1-54%) of samples irradiated at high dose (1-40 kGy). The samples were kept in liquid nitrogen (77 K) during irradiation and subsequent ESR measurements. The spectra shown at 77 K consisted of the hydrogen atom lines at low and high field and complicated symmetric spectrum. By increasing the microwave power, the line shape of ESR spectra altered, which indicated the detection of different paramagnetic centers at different microwave powers. In saturation curves, it was possible to select four types of spectra components which were different in their relaxation times. By the different irradiation doses, the change in free radical concentration showed a curvilinearly increasing relationship with irradiation dose in wet samples, whereas a proportional relationship was observed with dried samples. This might indicate that the indirect process of free radical formation was involved with the existence of free water radicals in the wet samples.


Effects of OPRM1 and ABCB1 gene polymorphisms on the analgesic effect and dose of sufentanil after thoracoscopic-assisted radical resection of lung cancer.
To study the effects of single-nucleotide polymorphisms of the OPRM1 and ABCB1 genes on the analgesic effect and consumption of sufentanil after thoracoscopic-assisted radical resection of lung cancer. A total of 225 Chinese Han nationality patients undergoing thoracoscopic-assisted radical resection of lung cancer were enrolled in the present study. Among them, 132 were males (58.67%) and 93 (41.33%) were females having American Society of Anesthesiologists statuses classified as grades I or II. The rs1799971, rs563649 and rs1323040 genotypes of the OPRM1 gene and rs2032582, rs1045642 and rs1128503 genotypes of the ABCB1 gene were detected by Sanger sequencing. The state anxiety index and pressure pain threshold were assessed preoperatively. Sufentanil was administered intravenously to maintain anesthesia. The doses and side effects of sufentanil consumed 6 h (T1), 24 h (T2) and 48 h (T3) after surgery were recorded. The sufentanil doses at T1, T2 and T3 were significantly higher in radical-operation lung cancer patients with mutant homozygous rs1799971 and rs1323040 loci in the OPRM1 gene and rs2032582 and rs1128503 loci in the ABCB1 gene. The doses of sufentanil consumed by mutant heterozygous lung cancer patients at T1, T2 and T3 were significantly higher than those consumed by patients without mutations, and the differences were statistically significant (P<0.05). There was no significant difference in sufentanil doses consumed by lung cancer patients with mutant homozygous, mutant heterozygous and wild-type rs563649 locus of the OPRM1 gene and rs1045642 locus of the ABCB1 gene at T1, T2 and T3 (P>0.05). There was no significant difference in the visual analog scale scores at T1, T2 and T3 for different genotypes of OPRM1 and ABCB1 genes in lung cancer patients (P>0.05). No significant difference was found between the adverse reactions of OPRM1 and ABCB1 genotypes in patients undergoing radical resection of lung cancer (P>0.05). The rs1799971 and rs1323040 polymorphisms of the OPRM1 gene and rs2032582 and rs1128503 polymorphisms of the ABCB1 gene are related to the analgesic effect and consumed dose of sufentanil in Chinese Han patients undergoing radical operation of lung cancer.


Discovery of molecular features underlying the morphological landscape by integrating spatial transcriptomic data with deep features of tissue images.
Profiling molecular features associated with the morphological landscape of tissue is crucial for investigating the structural and spatial patterns that underlie the biological function of tissues. In this study, we present a new method, spatial gene expression patterns by deep learning of tissue images (SPADE), to identify important genes associated with morphological contexts by combining spatial transcriptomic data with coregistered images. SPADE incorporates deep learning-derived image patterns with spatially resolved gene expression data to extract morphological context markers. Morphological features that correspond to spatial maps of the transcriptome were extracted by image patches surrounding each spot and were subsequently represented by image latent features. The molecular profiles correlated with the image latent features were identified. The extracted genes could be further analyzed to discover functional terms and exploited to extract clusters maintaining morphological contexts. We apply our approach to spatial transcriptomic data from different tissues, platforms and types of images to demonstrate an unbiased method that is capable of obtaining image-integrated gene expression trends.


Patient adherence in following a prescribed diet and micronutrient supplements after laparoscopic sleeve gastrectomy: our experience during 1 year of follow-up.
One of the most effective surgeries for sustainable weight loss in morbidly obese patients is laparoscopic sleeve gastrectomy (LSG). The present study aimed to assess the adherence of LSG patients with respect to following post-operative dietary requirements and micronutrient supplementation, as well as to investigate their perceived barriers in achieving optimal adherence. Retrospective data analysis was performed (3, 6, 9 and 12 months after LSG) using the medical records of 96 morbidly obese patients who had undergone LSG at our institution during 2011-2013. Data collected from patient records were: adherence to prescribed diet; adherence to prescribed consumption of fruit, vegetables, legumes and cereals; use of prescribed micronutrient supplements; and barriers to diet and micronutrient therapy adherence. Data were analysed using spss, version 14.0 (SPSS Inc., Chicago, IL, USA). At 3, 6, 9 and 12 months post-LSG, the rates of patient non-adherence to a prescribed diet were 39%, 45%, 51% and 74%, respectively. In particular, there was a low consumption of fruit, vegetables, legumes and cereals compared to the post-surgery prescription. In addition, the rates of patient non-adherence to prescribed micronutrient supplements at 3, 6, 9 and 12 months post-LSG were 43%, 51%, 59% and 67%, respectively. The main reasons for patient non-adherence to diet were poor self-discipline (72%) and poor family support (11%) whereas difficulty swallowing pills or capsules (61%) and cost (20%) were reported as the main barriers to post-LSG adherence. Morbidly obese patients who have undergone LSG do not follow exactly the post-operative dietary guidelines, including micronutrient therapy.


Skin tears in mammography: A narrative review.
Skin tears are classed as traumatic wounds mainly caused by shearing and frictional forces. Incidences of skin tears are noted to be significant mostly in the elderly population and those with fragile and vulnerable skin. Individuals undergoing mammography are susceptible to skin tears due to factors associated with skin breakdown such as thinning of the epidermis, use of steroids, presence of moisture, but this, when compounded with the procedure of mammography can increase the risk further. Mammography, an x-ray imaging method, which exerts adequate compression force on the breast tissue for the mammographer to obtain a high-quality image for diagnostic purposes. However, when compression force is applied during mammography resulting incidences of cutaneous skin tears can occur. Lack of and under reporting of skin tears during mammography makes it difficult to ascertain the extent of this problem and scale of its incidence. Therefore, the purpose of this narrative review is to focus on providing an overview of skin tears associated with mammography and a discussion of the current literature with regards to its incidence and diagnosis. In addition, the review will also discuss the theoretical and contextual perspective of the prevention and management strategies associated with skin tears.


Ethylenediaminedissuccinate as a new chelate for environmentally safe enhanced lead phytoextraction.
Using a soil column experiment, we compared the effect of a single dose and weekly additions of ethylenediaminetetraacetic acid (EDTA) and ethylenediaminedissuccinate (EDDS) on the uptake of Pb, Zn, and Cd by Chinese cabbage [Brassica rapa L. subsp. pekinensis (Lour.) Hanelt], and on the leaching of heavy metals through the soil profile. The analysis of plant material revealed that both chelates increased the concentrations of Pb and, to a lesser extent, also of Zn and Cd in the leaves of the test plant. The most effective applications were single doses of 10 mmol EDTA and EDDS kg(-1) soil, which caused the concentrations of Pb in the shoots to increase 94.2- and 102.3-fold, respectively, relative to the control. The same dose of EDTA increased the concentration of Zn and Cd in the leaves 4.3- and 3.8-fold and of EDDS 4.7- and 3.5-fold, respectively. In treatments with weekly additions and lower concentrations of both chelates, EDTA was more effective than EDDS in increasing the plant uptake of Pb. In soil columns treated with weekly additions of 10 mmol kg(-1) EDTA, on average 22.7, 7.0, and 39.8% of initial total Pb, Zn, and Cd in the soil were leached through the soil profile. The same amount of EDDS caused much lower leaching of Pb and Cd--only 0.8 and 1.5% of initial total concentrations. Leaching of Zn, 6.2% of the total concentration, was comparable with the EDTA treatment. A biotest with red clover (Trifolium pratense L.) indicated a greater phytotoxic effect of EDTA than EDDS addition. EDDS was also less toxic to soil fungi, as determined by phospholipid fatty acid (PLFA) analysis, and caused less stress to soil microorganisms, as indicated by the trans to cis PLFA ratio. Chelate addition did not prevent the development of arbuscular mycorrhiza on red clover.


Probiotics: a role in the treatment of intestinal infection and inflammation?
Probiotic therapy is based on the concept of normal healthy microflora. The development of novel means of characterising the gut microflora, in particular those based on the different levels of conservation in the ribosomal RNA sequences of different genera, have opened up new angles on the role of the gut microflora in health and disease. Components of the human intestinal microflora or organisms entering the intestine may have harmful or beneficial effects on human health. Abundant evidence implies that specific strains selected from the healthy gut microflora exhibit powerful antipathogenic and anti-inflammatory capabilities, and are consequently involved with enhanced colonisation resistance in the intestine. Realisation of this has led to the introduction of novel modes of therapeutic and prophylactic intervention based on the consumption of mono and mixed cultures of beneficial live microorganisms as probiotics.


Evaluation of a nonhuman primate model to study circadian rhythms of calcium metabolism.
We evaluated primate models for the study of circadian rhythms in calcium and bone metabolism. Blood and urine were collected from two cynomolgus macaques every 4 h for 24 h. Studies were initiated at three different clock times to separate the effects of repeated experimental sampling from circadian effects. Also, samples were collected from seven monkeys at times of expected maxima and minima. Some parameters exhibited the expected circadian rhythm with increases at night (serum total calcium) or in the early morning (urinary collagen cross-links). Others displayed the effects of the experimental procedure, either increasing (urinary creatinine and phosphorus) or decreasing (osteocalcin, urinary calcium) with repeated sampling. Serum phosphorus, cortisol, and type I procollagen were influenced by both clock time and experimental procedures. Alkaline phosphatase and parathyroid hormone did not show any differences with time or sampling. This data is consistent with findings in humans that bone resorption increases at night and that endogenous corticosteroids decrease bone formation. The usefulness of the monkey model is limited by the physiological stress of sample collection in these subjects.


Established and experimental medical therapy of pulmonary sarcoidosis.
The treatment options for pulmonary sarcoidosis have increased over the past 10 years. As new treatments have been introduced, the best way to assess and compare treatments remains unknown. The goal of this review is to discuss the standard treatments for pulmonary sarcoidosis, including glucocorticoids, and cytotoxic agents, such as methotrexate, azathioprine and leflunomide, and compare them to the newer biological agents, such as infliximab and adalimumab. We also discuss some novel treatments which are currently being evaluated. To compare these different regimens, we look at the measures used to assess response. These include pulmonary function, chest imaging, steroid sparing potential and, more recently, improvements in quality of life measures. While there is, as yet, no standard assessment for response, there is a growing consensus that response to treatment may include improvement of one or more of the following: forced vital capacity, chest imaging and steroid sparing. Several drugs used for pulmonary sarcoidosis have demonstrated improvement in one or more of these measures.


Decreased hepatic 5, 10-methylenetetrahydrofolate reductase activity in mice after chronic phenytoin treatment.
The effects of phenytoin (DPH) on folate metabolism have been studied in female Swiss Webster mice. Doses of DPH which produce steady-state plasma levels of DPH in the therapeutic range of 10-20 micrograms/ml were found to decrease plasma folate levels. In addition, the in vivo oxidation rate of [14C] formate and [2-14C] histidine to 14CO2 was increased. The increased metabolic rates were accompanied by a decrease in the hepatic activity of N5, N10-methylenetetrahydrofolate (5, 10-CH2-H4folate) reductase. N5-methyltetrahydrofolate-homocysteine transmethylase (methionine synthase); EC 18.104.22.168) activity in the liver was unchanged. The distribution of folates in the liver was determined by high-pressure liquid chromatography (HPLC) and it was found that the concentration of tetrahydrofolate (H4folate) was increased in DPH-treated mice whereas the concentration of N5-methyltetrahydrofolate was decreased. These effects were observed in mice treated with DPH for 4 days, but not in mice given a single DPH injection 24 hr previously. Decreased activity of hepatic 5, 10-CH2-H4folate reductase is postulated to account for the other effects which were observed. Decreased activity presumably results in increased tissue concentrations of 5, 10-CH2-H4folate, which is in equilibrium with its dissociation products, H4folate and formaldehyde. Increased concentrations of H4folate lead to increases in the oxidation rate of formate and histidine. These effects on folate metabolism may have important implications in the pharmacological and toxicological effects of DPH.


A cis-acting element 7 bp upstream of the ESF-1-binding motif is involved in E1A 13S autoregulation of the adenovirus 12 TS2 promoter.
Transcription of the E1A gene of the highly oncogenic adenovirus 12 (Ad12) initiates at two start sites (TS1 and TS2). We have previously shown that the E2F and ATF motifs distal of TS1 co-operatively participate in E1A autostimulation from the TS1 promoter region. Here we report the identification of a second E2F-like target region (E2DFII) immediately upstream of the E1A-stimulating factor 1 binding site (ESF-1), important for 13S-mediated autoactivation from TS2. Reporter constructs lacking distinct TS2 cis-acting elements were analysed for their levels of CAT expression in the absence and presence of the E1A 13S protein in transient expression assays. In the absence of 13S, full promoter activity was observed only for a construct containing all elements (the E2F-like motif, and E-Box and the TATA element). Promoter activation increased significantly in Ad12 E1A-co-transfected cells. Induction by the 13S protein was also detected for the construct containing a non-functional ESF-1 sequence. Our results indicate that the E2F-like motif is responsible for activation medicated by the 13S protein from TS2, while ESF-1-or TATA-binding protein activity were not involved. Additionally, the TATA sequence appeared to be dispensable for transactivation. Gel-shift experiments using the E2F-like promoter element as a probe indicated the binding of an E2F-5 or E2F-5-like transcription factor to this region. We conclude that transcription through the TS1 as well as the TS2 promoter region is stimulated by the Ad 12 13S protein. Moreover, transfection of the construct including both TS1 and TS2 indicates an E2F-site-mediated synergism between both regions with respect ot E1A-induced transactivation.


Frequency-doubled DBR-tapered diode laser for direct pumping of Ti:sapphire lasers generating sub-20 fs pulses.
For the first time a single-pass frequency doubled DBR-tapered diode laser suitable for pumping Ti:sapphire lasers generating ultrashort pulses is demonstrated. The maximum output powers achieved when pumping the Ti:sapphire laser are 110 mW (CW) and 82 mW (mode-locked) respectively at 1.2 W of pump power. This corresponds to a reduction in optical conversion efficiencies to 75% of the values achieved with a commercial diode pumped solid-state laser. However, the superior electro-optical efficiency of the diode laser improves the overall efficiency of the Ti:sapphire laser by a factor > 2. The optical spectrum emitted by the Ti:sapphire laser when pumped with our diode laser shows a spectral width of 112 nm (FWHM). Based on autocorrelation measurements, pulse widths of less than 20 fs can therefore be expected.


Insulin-sensitive tyrosine kinase: relationship with in vivo insulin action in humans.
To investigate the relationship of insulin receptor kinase with insulin resistance in humans, we studied insulin-sensitive tyrosine kinase activity in muscle biopsies taken from 20 Pima Indians [14 nondiabetics, 6 with non-insulin-dependent mellitus (NIDDM)] during euglycemic clamps, at insulin concentrations of approximately 68 microU/ml (low dose) and approximately 1,170 microU/ml (high dose). In the nondiabetics, the low dose, insulin-induced kinase activation in vivo was 1.5-fold the activity in the fasting state (P less than 0.05), whereas in the diabetics, the kinase activity actually decreased by 40% relative to fasting (P less than 0.05). The difference in delta-kinase in vivo was significant (P less than 0.01) between the two groups. Similarly, the kinase activation in vitro in response to 1 nM insulin was lower in diabetic subjects compared with nondiabetics (P less than 0.01). These data indicate that, in NIDDM, both in vitro and in vivo insulin-stimulated tyrosine kinase activity is impaired. Among nondiabetics, the kinase sensitivity to insulin, calculated as the ratio of the kinase activity at 1 nM insulin in vitro to the kinase activity at 100 nM insulin, was positively correlated with plasma insulin concentrations 2 h after an oral glucose load (r = 0.69, P less than 0.01). Thus, in nondiabetic subjects with insulin resistance, insulin activation of the kinase is not reduced, but the kinase sensitivity to insulin increases with increasing plasma insulin levels. Therefore, the site of insulin resistance in nondiabetic subjects is distal to the insulin receptor kinase. Furthermore, it is possible that circulating insulin, by increasing the kinase sensitivity to insulin, is a determinant of the receptor kinase activity.


Burning down the brewery: establishing and evacuating an ancient imperial colony at Cerro Baul, Peru.
Before the Inca reigned, two empires held sway over the central Andes from anno Domini 600 to 1000: the Wari empire to the north ruled much of Peru, and Tiwanaku to the south reigned in Bolivia. Face-to-face contact came when both colonized the Moquegua Valley sierra in southern Peru. The state-sponsored Wari incursion, described here, entailed large-scale agrarian reclamation to sustain the occupation of two hills and the adjacent high mesa of Cerro Baúl. Monumental buildings were erected atop the mesa to serve an embassy-like delegation of nobles and attendant personnel that endured for centuries. Final evacuation of the Baúl enclave was accompanied by elaborate ceremonies with brewing, drinking, feasting, vessel smashing, and building burning.


Deletion of apolipoprotein E receptor-2 in mice lowers brain selenium and causes severe neurological dysfunction and death when a low-selenium diet is fed.
Selenoprotein P (Sepp1) is a plasma and extracellular protein that is rich in selenium. Deletion of Sepp1 results in sharp decreases of selenium levels in the brain and testis with dysfunction of those organs. Deletion of Sepp1 also causes increased urinary selenium excretion, leading to moderate depletion of whole-body selenium. The lipoprotein receptor apolipoprotein E receptor-2 (apoER2) binds Sepp1 and facilitates its uptake by Sertoli cells, thus providing selenium for spermatogenesis. Experiments were performed to assess the effect of apoER2 on the concentration and function of selenium in the brain and on whole-body selenium. ApoER2-/- and apoER2+/+ male mice were fed a semipurified diet with selenite added as the source of selenium. ApoER2-/- mice had depressed brain and testis selenium, but normal levels in liver, kidney, muscle, and the whole body. Feeding a selenium-deficient diet to apoER2-/- mice led to neurological dysfunction and death, with some of the characteristics exhibited by Sepp1-/- mice fed the same diet. Thus, although it does not affect whole-body selenium, apoER2 is necessary for maintenance of brain selenium and for prevention of neurological dysfunction and death under conditions of selenium deficiency, suggesting an interaction of apoER2 with Sepp1 in the brain.