Secondary Metabolite Profiling of Species of the Genus Usnea by UHPLC-ESI-OT-MS-MS.
Lichens are symbiotic associations of fungi with microalgae and/or cyanobacteria, which are considered among the slowest growing organisms, with strong tolerance to adverse environmental conditions. There are about 400 genera and 1600 species of lichens and those belonging to the Usnea genus comprise about 360 of these species. Usnea lichens have been used since ancient times as dyes, cosmetics, preservatives, deodorants and folk medicines. The phytochemistry of the Usnea genus includes more than 60 compounds which belong to the following classes: depsides, depsidones, depsones, lactones, quinones, phenolics, polysaccharides, fatty acids and dibenzofurans. Due to scarce knowledge of metabolomic profiles of Usnea species (U. barbata, U. antarctica, U. rubicunda and U. subfloridana), a study based on UHPLC-ESI-OT-MS-MS was performed for a comprehensive characterization of their secondary metabolites. From the methanolic extracts of these species a total of 73 metabolites were identified for the first time using this hyphenated technique, including 34 compounds in U. barbata, 21 in U. antarctica, 38 in U. rubicunda and 37 in U. subfloridana. Besides, a total of 13 metabolites were not identified and reported so far, and could be new according to our data analysis. This study showed that this hyphenated technique is rapid, effective and accurate for phytochemical identification of lichen metabolites and the data collected could be useful for chemotaxonomic studies.


Incidence of hepatocellular carcinoma among US patients with cirrhosis of viral or nonviral etiologies.
We aimed to identify risk factors for hepatocellular carcinoma (HCC) in patients with cirrhosis in the United States. We performed a prospective study to identify associations between etiologies of cirrhosis and ethnicity with HCC incidence. We used convenience sampling to select a cohort of 379 patients with cirrhosis who visited the liver clinic at the Stanford University Medical Center from 2001 to 2009 (65% male, 75% white or Hispanic, and 20% Asian). Study end points were HCC diagnosis by histology or noninvasive criteria, liver transplantation, or last screening without HCC. Patients were followed up, with ultrasound or computed tomographic imaging analyses and measurements of serum levels of α-fetoprotein, approximately every 6 months, for a median time of 34 months (range, 6-99 mo). The etiologies of cirrhosis in the cohort were 68% hepatitis C, 7% hepatitis B, and 25% nonviral. Forty-four patients (12%) were diagnosed with HCC during the follow-up period. Patients with cirrhosis related to viral hepatitis had a statistically significantly higher incidence of HCC than those with nonviral diseases in Kaplan-Meier analysis (P = .04). There was no statistically significant difference in HCC incidence between Asian and non-Asian patients. In a multivariate Cox proportional hazards model that included age, sex, ethnicity, etiology, and Child-Pugh-Turcotte score, viral cirrhosis was associated significantly with HCC, compared with nonviral cirrhosis (hazard ratio, 3.6; 95% confidence interval, 1.3-10.1; P = .02) but Asian ethnicity was not. In a diverse cohort of patients in the United States with cirrhosis, a viral etiology of cirrhosis was associated with increased incidence of HCC, but Asian ethnicity was not. These findings indicate the importance of cirrhosis etiology in determining risk for HCC.


Seqcrawler: biological data indexing and browsing platform.
Seqcrawler takes its roots in software like SRS or Lucegene. It provides an indexing platform to ease the search of data and meta-data in biological banks and it can scale to face the current flow of data. While many biological bank search tools are available on the Internet, mainly provided by large organizations to search their data, there is a lack of free and open source solutions to browse one's own set of data with a flexible query system and able to scale from a single computer to a cloud system. A personal index platform will help labs and bioinformaticians to search their meta-data but also to build a larger information system with custom subsets of data. The software is scalable from a single computer to a cloud-based infrastructure. It has been successfully tested in a private cloud with 3 index shards (pieces of index) hosting ~400 millions of sequence information (whole GenBank, UniProt, PDB and others) for a total size of 600 GB in a fault tolerant architecture (high-availability). It has also been successfully integrated with software to add extra meta-data from blast results to enhance users' result analysis. Seqcrawler provides a complete open source search and store solution for labs or platforms needing to manage large amount of data/meta-data with a flexible and customizable web interface. All components (search engine, visualization and data storage), though independent, share a common and coherent data system that can be queried with a simple HTTP interface. The solution scales easily and can also provide a high availability infrastructure.


[Satisfaction with life overall and with specific life domains among elderly persons with a lower limb amputation].
To examine a group of elderly persons who had had a lower limb amputation and who were receiving care at the outpatient clinic of a teaching hospital in Campinas, São Paulo, Brazil, in order to: 1) identify relationships between their perceived overall life satisfaction and their functional capacity; 2) assess their perceived satisfaction with the domains of health, physical functioning/dependence, mental health, and social integration/involvement; and 3) identify relationships between overall life satisfaction and satisfaction with the specific domains. An assessment was done of a group of 40 elderly persons (30 men and 10 women) who had had an amputation above the malleolus at least 1 year earlier and who were undergoing rehabilitation between June 1994 and June 1999. Their mean age was 74.5 years (range, 60 to 79 years). A questionnaire was used for data collection to assess: 1) functional capacity (Barthel index); 2) general life satisfaction (Cantrill model); and 3) satisfaction with the domains of health, physical functioning/dependence, mental health, and social integration/involvement, with the 40 elderly persons assessing themselves both in individual terms and in comparison to other persons of the same age group. Among the 40 elderly persons, the level of general life satisfaction was high. Measured on a scale of 1 to 10, the mean was 7.1 and the median 7.5, with a standard deviation of 2.73. There was no correlation between overall life satisfaction and functional capacity. There was no significant difference between individual perceived satisfaction with the specific domains and the perception of these domains in comparison to other persons of the same age group; in both of these cases, the elderly persons who had had an amputation reported a high degree of satisfaction. A positive correlation was found only between overall life satisfaction and the domains of health (individual and comparative) and of physical functioning (comparative). These results suggest that this group of elderly persons who had had an amputation tended to assess their situation positively. This finding provides new insights into the rehabilitation of elderly persons with lower limb amputations. Taken together with the dearth of studies concerning the subject, this finding also indicates the need for additional research focusing on the subjective well-being of the elderly.


How to design a good case series.
A case series is a descriptive study that follows a group of patients who have a similar diagnosis or who are undergoing the same procedure over a certain period of time. As there is no experimental protocol or control for allocation of patients to treatment, surgeons and patients decide on whether or not treatment is given, making the clinical sample representative of a common clinical population. Results of case series can generate hypotheses that are useful in designing further studies, including randomized controlled trials. However, no causal inferences should be made from case series regarding the efficacy of the investigated treatment. This article will provide principles for the design, analysis, and reporting of case series, illustrated by examples from the orthopaedic surgical literature.


Evans blue nanocarriers visually demarcate margins of invasive gliomas.
Aggressive surgical resection is the primary therapy for glioma. However, aggressive resection may compromise functional healthy brain tissue. Currently, there are no objective cues for surgeons to distinguish healthy tissue from tumor and determine tumor borders; surgeons skillfully rely on subjective means such as tactile feedback. This often results in incomplete resection and recurrence. The objective of the present study was to design, develop, and evaluate, in vitro and in vivo, a nanoencapsulated visible dye for intraoperative, visual delineation of tumor margins in an invasive tumor model. Liposomal nanocarriers containing Evans blue dye (nano-EB) were developed, characterized, and tested for safety in vitro and in vivo. 3RT1RT2A glioma cells were implanted into brains of Fischer 344 rats. Nano-EB or EB solution was injected via tail vein into tumor-bearing animals. To assess tumor staining, tissue samples were analyzed visibly and using fluorescence microscopy. Area, perimeter ratios, and Manders overlap coefficients were calculated to quantify extent of staining. Nano-EB clearly marked tumor margins in the invasive tumor model. Area ratio of nano-EB staining to tumor was 0.89 ± 0.05, perimeter ratio was 0.94 ± 0.04, Manders R was 0.51 ± 0.08, and M1 was 0.97 ± 0.06. Microscopic tumor border inspection under high magnification verified that nano-EB did not stain healthy tissue. Nano-EB clearly aids in distinguishing tumor tissue from healthy tissue in an invasive tumor model, while injection of unencapsulated EB results in false identification of healthy tissue as tumor due to diffusion of dye from the tumor into healthy tissue.


Mechanism of 4-aminopyridine action on voltage-gated potassium channels in lymphocytes.
The mechanism by which 4-aminopyridine (4-AP) blocks the delayed rectifier type potassium (K+) channels present on lipopolysaccharide-activated murine B lymphocytes was investigated using whole-cell and single channel patch-clamp recordings. 4-AP (1 microM-5 mM) was superfused for 3-4 min before applying depolarizing pulses to activate the channel. During the first pulse after application of 4-AP above 50 microM, the current inactivated faster, as compared with the control, but its peak was only reduced at high concentrations of 4-AP (Kd = 3.1 mM). During subsequent pulses, the peak current was decreased (Kd = 120 microM), but the inactivation rate was slower than in the control, a feature that could be explained by a slow unblocking process. After washing out the drug, the current elicited by the first voltage step was still markedly reduced, as compared with the control one, and displayed very slow activation and inactivation kinetics; this suggests that the K+ channels move from a blocked to an unblocked state slowly during the depolarizing pulse. These results show that 4-AP blocks K+ channels in their open state and that the drug remains trapped in the channel once it is closed. On the basis of the analysis of the current kinetics during unblocking, we suggest that two pathways lead from the blocked to the unblocked states. Computer simulations were used to investigate the mechanism of action of 4-AP. The simulations suggest that 4-AP must bind to both an open and a nonconducting state of the channel. It is postulated that the latter is either the inactivated channel or a site on closed channels only accessible to the drug once the cell has been depolarized. Using inside- and outside-out patch recordings, we found that 4-AP only blocks channels from the intracellular side of the membrane and acts by reducing the mean burst time. 4-AP is a weak base (pK = 9), and thus exists in ionized or nonionized form. Since the Kd of channel block depends on both internal and external pH, we suggest that 4-AP crosses the membrane in its nonionized form and acts from inside the cell in its ionized form.


Identification and characterization of novel conserved RNA structures in Drosophila.
Comparative genomics approaches have facilitated the discovery of many novel non-coding and structured RNAs (ncRNAs). The increasing availability of related genomes now makes it possible to systematically search for compensatory base changes - and thus for conserved secondary structures - even in genomic regions that are poorly alignable in the primary sequence. The wealth of available transcriptome data can add valuable insight into expression and possible function for new ncRNA candidates. Earlier work identifying ncRNAs in Drosophila melanogaster made use of sequence-based alignments and employed a sliding window approach, inevitably biasing identification toward RNAs encoded in the more conserved parts of the genome. To search for conserved RNA structures (CRSs) that may not be highly conserved in sequence and to assess the expression of CRSs, we conducted a genome-wide structural alignment screen of 27 insect genomes including D. melanogaster and integrated this with an extensive set of tiling array data. The structural alignment screen revealed ∼30,000 novel candidate CRSs at an estimated false discovery rate of less than 10%. With more than one quarter of all individual CRS motifs showing sequence identities below 60%, the predicted CRSs largely complement the findings of sliding window approaches applied previously. While a sixth of the CRSs were ubiquitously expressed, we found that most were expressed in specific developmental stages or cell lines. Notably, most statistically significant enrichment of CRSs were observed in pupae, mainly in exons of untranslated regions, promotors, enhancers, and long ncRNAs. Interestingly, cell lines were found to express a different set of CRSs than were found in vivo. Only a small fraction of intergenic CRSs were co-expressed with the adjacent protein coding genes, which suggests that most intergenic CRSs are independent genetic units. This study provides a more comprehensive view of the ncRNA transcriptome in fly as well as evidence for differential expression of CRSs during development and in cell lines.


TPC2 is a novel NAADP-sensitive Ca2+ release channel, operating as a dual sensor of luminal pH and Ca2+.
Nicotinic acid adenine dinucleotide phosphate (NAADP) is a molecule capable of initiating the release of intracellular Ca(2+) required for many essential cellular processes. Recent evidence links two-pore channels (TPCs) with NAADP-induced release of Ca(2+) from lysosome-like acidic organelles; however, there has been no direct demonstration that TPCs can act as NAADP-sensitive Ca(2+) release channels. Controversial evidence also proposes ryanodine receptors as the primary target of NAADP. We show that TPC2, the major lysosomal targeted isoform, is a cation channel with selectivity for Ca(2+) that will enable it to act as a Ca(2+) release channel in the cellular environment. NAADP opens TPC2 channels in a concentration-dependent manner, binding to high affinity activation and low affinity inhibition sites. At the core of this process is the luminal environment of the channel. The sensitivity of TPC2 to NAADP is steeply dependent on the luminal [Ca(2+)] allowing extremely low levels of NAADP to open the channel. In parallel, luminal pH controls NAADP affinity for TPC2 by switching from reversible activation of TPC2 at low pH to irreversible activation at neutral pH. Further evidence earmarking TPCs as the likely pathway for NAADP-induced intracellular Ca(2+) release is obtained from the use of Ned-19, the selective blocker of cellular NAADP-induced Ca(2+) release. Ned-19 antagonizes NAADP-activation of TPC2 in a non-competitive manner at 1 μM but potentiates NAADP activation at nanomolar concentrations. This single-channel study provides a long awaited molecular basis for the peculiar mechanistic features of NAADP signaling and a framework for understanding how NAADP can mediate key physiological events.


Episodic syncope in hypertrophic cardiomyopathy: evidence for inappropriate vasodilation.
Symptoms of impaired consciousness (syncope and pre-syncope) occur in 15-25% of patients with hypertrophic cardiomyopathy (HCM).1 In young patients a history of recurrent syncope is associated with an increased risk of sudden death.2(-)5 Syncope usually occurs without warning or symptoms suggestive of the cause. Detailed investigations identify a probable mechanism in a minority, usually paroxysmal atrial fibrillation or ventricular tachycardia. In the majority however no likely mechanism is found despite repeated 24-hour ambulatory echocardiography (ECG) or patient-activated monitoring, exercise testing and invasive electrophysiological studies.1 6 Empirical treatment with amiodarone, a pacemaker or an implantable cardioverter-defibrillator is commonly employed, but is often unsuccessful in relieving the symptoms. We have previously observed that approximately 30% of patients with HCM have abnormal blood pressure response during maximal upright exercise.7 8 This was due in the majority of patients to an exaggerated fall in systemic vascular resistance, possibly arising from abnormal activation of stretch-sensitive left ventricular mechanoreceptors,9 10 by a mechanism similar to that described in aortic stenosis.11 However, in some patients an inadequate cardiac output response to exercise may be responsible.12 We hypothesised that abnormal vasodepressor-mediated hypotension may also occur during daily life in patients with HCM, and that this may be an important mechanism of syncope when conventional investigations fail to reveal a cause.


Validity of irritability in Huntington's disease: A scoping review.
To scope the literature concerning irritability in Huntington's disease to determine whether or not irritability is a valid and meaningful construct within this population. A scoping literature review was conducted based on findings from a search of five databases (Academic Search Ultimate, PsycINFO, CINAHL, Scopus and Web of Science) in November 2018. From an initial return of 453 papers, 40 were found suitable for review. Review of the 40 studies highlighted several aspects of irritability in people with HD which influence its validity as an independent construct in context of the disease. While various measures are used to assess irritability, a gold standard has yet to be identified and consequently irritability is assessed inconsistently across the literature. In addition, the results suggest that irritability may not reflect pathological disease processes in HD, but rather comprises a multidimensional construct which appears to be strongly associated with other psychological difficulties such as depression and anxiety. The current concept of irritability in people with HD continues to lack a general consensus in the clinical literature, in terms of both operationalisation and assessment. Consequently, further research is warranted in order to determine the extent to which irritability is a valid construct within the context of HD, including its associated behavioural, cognitive and affective dimensions.


Solubility-pH profile of desipramine hydrochloride in saline phosphate buffer: Enhanced solubility due to drug-buffer aggregates.
Although solubility-pH data for desipramine hydrochloride (DsHCl) have been reported previously, the aim of the present study was to critically examine the aqueous solubility-pH behavior of DsHCl in buffer-free and buffered solutions, in the presence of physiologically-relevant chloride concentration, using experimental practices recommended in the recently-published "white paper" (Avdeef et al., 2016). The computer program pDISOL-X was used to design the structured experiments (pH-RSF method), to process the data, and to refine the equilibrium constants. Low-to-high and high-to-low pH assays (using HCl, H3PO4, or NaOH to adjust pH) were performed on phosphate-buffered (0.12‑0.15 M) saturated solutions of DsHCl in the pH 1.3-11.6 range. After equilibration (stirring 6 h, followed by 18 h stir-free sedimentation), filtration or centrifugation was used for phase separation. Concentration was measured using HPLC with UV/VIS detection. The 2:1 drug-phosphate solubility product (Ksp2:1 = [DsH+]2[HPO42-]) was determined from data in the pH 4-9 region. The free base of desipramine was prepared and used to determine the Ksp1:1 ([DsH+][H2PO4-]) in chloride-free acidified suspension. In addition, phosphate-free titrations were conducted to determine the intrinsic solubility, S0, and the 1:1 drug-chloride solubility product, KspDsHCl = [DsH+][Cl-]. Under the assay conditions, only the phosphate-free solutions showed some supersaturation near pHmax 8.0. In phosphate-containing solutions, pHmax was indicated at higher pH (8.8-9.6). Oils mixed with solids were observed to form in alkaline solutions (pH > 11). Notably, soluble drug-phosphate complexes appeared to form below pH 3.9 and above pHmax in saturated phosphate‑containing saline solutions. This was indicated by the systematic pH shift to higher values in the log S-pH curve in alkaline solution than expected from the Henderson-Hasselbalch equation. For pH < 3.9, saturated phosphate-containing saline solutions exhibited elevated solubility, with drug-hydrochloride as the sole precipitate. Salt solubility products, intrinsic solubility, and complexation constants, which rationalized the data, were determined. Elemental, thermogravimetric (TGA), differential scanning calorimetric (DSC), and powder X-ray diffraction (PXRD) analyses were used to characterize the precipitates isolated from suspensions at different pH.


MiR-148a the epigenetic regulator of bone homeostasis is increased in plasma of osteoporotic postmenopausal women.
Osteoporosis is a prevalent skeletal disorder characterized by reduced bone mineral density and microarchitectural deterioration of bone tissue, resulting in bone fragility and low-trauma fractures. Imaging techniques are routinely used to detect low bone mass; however, they are unable to identify deterioration of bone quality. Recently, microRNAs have emerged as regulators of bone remodelling and potentially also as a new class of sensitive biomarkers of bone health to aid in diagnosis and treatment monitoring of osteoporosis. To identify new plasma-based biomarkers associated with osteoporosis we analyzed microRNAs isolated from plasma samples of 74 postmenopausal women divided into osteoporotic (N = 17) and control groups (N = 57). A prior microRNA screening was performed where a few showed promise for further analysis. Quantitative polymerase chain reaction was used to investigate differences in expression of let-7d-5p, let-7e-5p, miR-30d-5p, miR-30e-5p, miR-126-3p, miR-148a-3p, miR-199a-3p, miR-423-5p and miR-574-5p between the two groups. Furthermore, correlation analysis between microRNA expression levels and patient bone mineral density measurements and fracture risk assessment tool (FRAX) as well as trabecular bone scores were performed. Expression of miR-148a-3p was significantly higher (p = 0.042) in the osteoporotic patient group compared to the controls. In addition, we identified correlations between miR-126-3p (ρ = 0.253, p = 0.032) and 423-5p (ρ = -0.230, p = 0.049) and parameters of bone quality and quantity. The results from our study, together with the functional role of miR-148a-3p in bone suggest that this microRNA could be considered as a potential new plasma-based biomarker for pathological changes associated with osteoporosis.


Health care professional workstations: where are we now? ... where should we be tomorrow?
This article looks back over four years during which major changes have occurred in healthcare informatics, both technically and from a policy perspective. A remarkable portion of what medical-informatics professionals were proposing in 1989 has subsequently come to pass. Thus, one lesson from reflections on the recent past is that now is the time for us to devise realistic expectations of what we will see happen in the next four years. Possible scenarios for the future are outlined, as are suggestions for how the informatics community might best prepare for what lies ahead.


[Microbiological threat from buildings and rooms and its influence on human health (sick building syndrome)].
In buildings we can observe many different strains of bacteria, over 400 species of mould fungi, many strains of fungus causing the rotting of wood and wood like materials, many species of algae, aphids, and other types of growths and seed plants and also over 30 types of mites especially those seen in house dust. Buildings, especially their interiors have a very specific microclimate. Within it areas of so called ecological lows are formed in which conditions for settlement, growth and reproduction of these organisms take place. A building, which is a hazard to the health of its residents, is called a "sick building" from the term "sick building syndrome". The incidence and development of some types of mould fungus is associated with the production of very toxic metabolites which are called secondary metabolites i.e. mycotoxins. Long term human, especially in relation to children, contact with the species producing the most potent mycotoxins like aflatoxin--Apergillus flavus, ochratoxins--Aspergillus ochraceus, rubratoxins--Penicillium rubrum or strachybotrytoxins--Strachybotrys chartarum may even be the cause of death. Mould fungus or just mould is a saprophytic fungus derived from many different systemic groups (Mucor, Aspergillus, Penicillium, Fusarinum). Fungi can produce lethal mycotoxins such as: alternariol, aflatoxins, gliotoxins, ochratoxins, nivalenol, cytinine, dicumarol, rugulosine, trichoviridine and about 200 more which considering their mutagenicity are potentially dangerous to humans, animals, flora and microorganisms. Research which was begun by Prof. Julian Aleksandrowicz and Prof. Bolesław Smyk in 1970 and 1971 showed that the so called "leukaemia houses" of leukaemia victims had an abundance of toxinogenic fungus in them, particularly the most potent fungus which turned out to be Aspergillus flavus. Toxinogenic funguses are abundant in many living spaces and cellars in older and also in new housing. Mycotoxins have been shown to be very toxic and harmful and it is no wonder that many inhabitants of these living spaces are constantly ill, mainly upper respiratory tract infections, lethargy, constant headaches, nausea and a general ill feeling. Inhabiting these living spaces for a considerable period may lead to cancer.


Method for Identification of Threonine Isoforms in Peptides by Ultraviolet Photofragmentation of Cold Ions.
Identification of isomeric amino acid residues in peptides and proteins is challenging but often highly desired in proteomics. One of the practically important cases that require isomeric assignments is that associated with single-nucleotide polymorphism substitutions of Met residues by Thr in cancer-related proteins. These genetically encoded substitutions can yet be confused with the chemical modifications, arising from protein alkylation by iodoacetamide, which is commonly used in the standard procedure of sample preparation for proteomic analysis. Similar to the genetically encoded mutations, the alkylation also induces a conversion of methionine residues, but to the iso-threonine form. Recognition of the mutations therefore requires isoform-sensitive detection techniques. Herein, we demonstrate an analytical method for reliable identification of isoforms of threonine residues in tryptic peptides. It is based on ultraviolet photodissociation mass spectrometry of cryogenically cooled ions and a machine-learning algorithm. The measured photodissociation mass spectra exhibit isoform-specific patterns, which are independent of the residues adjacent to threonine or iso-threonine in a peptide sequence. A comprehensive metric-based evaluation demonstrates that, being calibrated with a set of model peptides, the method allows for isomeric identification of threonine residues in peptides of arbitrary sequence.


Silver square nanospirals mimic optical properties of U-shaped metamaterials.
We present a study of the optical properties of three-armed square nanospirals made of silver and realized as nanostructured thin films with Glancing Angle Deposition. Calculation of current flows in the nanospirals show excited resonant modes resembling those observed in U-shaped resonators. Four principal resonances were determined: near 200 THz and 480 THz for one polarization and 250 THz and 650 THz for the polarization orthogonal to the first one. In particular, a mode with anti-parallel current flow in opposite arms, associated with the observed resonance near 650 THz, indicates the existence of a magnetic-like resonance in the square nanospiral arrays. The robustness of the resonances against variations in the structural parameters of the nanospirals was investigated. This study revealed that the main parameter driving the position of the resonances was the overall dimension of the nanospiral, directly related to the length of their arms. Optical properties of a sample were measured by generalized spectroscopic ellipsometry at near-normal incidence, and evidence conversion between polarization states even for light polarized in the plane containing one of the arms in agreement with the numerical study. The measurements compared favorably to the results of the numerical simulations taking into account the disorder in the sample.


Lens redox fluorometry: pyridine nucleotide fluorescence and analysis of diabetic lens.
We performed both ex vivo and in vivo fluorometric analyses of pyridine nucleotides (PN) in rabbit and rat lenses. Rabbit lens PN fluorescence (99% NADH) was found to have an excitation maximum at 366 nm and an emission maximum at 462 nm (366:462). The only other fluorescent chromophore in that region of the spectrum has excitation and emission peaks at 328 and 460 nm, respectively. Anaerobic glycolysis in the lens was stimulated by KCN, a known inhibitor of mitochondrial respiration, after which a time-study of fluorescence intensities was performed. Over the course of a 3.5 hr period following treatment with KCN, the PN signal showed a statistically significant increase relative to that in the control lenses (those treated with KCl). while the 328:460 signal (which may be due to some protein involved in energy transfer with the PN) had a significantly greater decrease. We also found that fluorescence intensity of NADH in solution is linearly proportional to physiologic-range concentration. Moreover, there was a close correlation between fluorescence intensity of rat lens PN as measured on a specular microscope-coupled redox fluorometer capable of in vivo use, and the lens PN levels as determined by the analytical cycling assay technique. This fluorometer was then employed to assess the redox state in rats with streptozotocin-induced diabetes. The normalized ratio of PN to flavoproteins (Fp) in the lens epithelium increased from 0.96 +/- 0.12 in the normal state to 1.48 +/- 0.30 2 weeks after diabetes induction. In contrast, the ratio in the diabetic lens treated with an aldose reductase inhibitor, sorbinil, did not increase. The increase in the PN:Fp ratio therefore reflects activation of the polyol pathway and its associated metabolic activities, which results in an increase in the NADH:NAD ratio in the diabetic rat lenses. Our results indicate that the non-invasive, real-time method of redox fluorometry may be useful in the early detection and evaluation of cataracts and other disorders in lens metabolism, long before opacities occur. It can be used to monitor the disease process and evaluate the efficacy of such drugs as aldose reductase inhibitors on a biochemical level.


[Incidence of vancomycin-resistant Enterococcus at a university hospital in Brazil].
Vancomycin-resistant Enterococcus (VRE) is today one of the principal microorganisms implicated in nosocomial infections. Thus, a study was carried out with the objective of evaluating its epidemiology at a tertiary-level teaching hospital. This was a three-year retrospective epidemiological study conducted from 2000 to 2002. Samples of VRE-positive clinical cultures at a 660-bed university hospital were analyzed. The incidence of VRE and the main anatomical sites and hospital units from which it was isolated were defined. Differences between the variables over the three years of the study were verified, and these were considered significant when p<0.05. There was a progressive increase in the vancomycin resistance in the clinical cultures that were positive for Enterococcus spp., over the three years of the study. In 2000, 9.5% of the samples were vancomycin-resistant, and this increased to 14.7% in 2001 and 15.8% in 2002. The hospital units with the largest numbers of isolates were, respectively, the emergency ward (19.5%) and the general intensive care unit (15%). The anatomical sites with the highest amounts of isolates included: urine (36%) and blood (20%). With the progressive increase in the incidence of vancomycin resistance and the VRE rate, it is concluded that more effective control measures are needed for deterring the dissemination of VRE.


Herpes simplex virus type 2 mediated acute retinal necrosis in a pediatric population: case series and review.
We report 15 eyes with herpes simples virus type 2 (HSV-2) mediated acute retinal necrosis (ARN) in order to better characterize pathogenesis, clinical course, diagnosis, and outcomes of the disease. Retrospective observational case series of 14 patients (15 eyes) all aged 21 years or younger with acute retinal necrosis resulting from HSV-2 and examined between 1995 and 2009. Patients were diagnosed by various techniques, including polymerase chain reaction (PCR) of aqueous, vitreous, and serum, antibody determination of serum and intraocular fluids, fundoscopic exam, a therapeutic trial of antivirals active against HSV-2, or a combination thereof. Mean age of presentation was 11.7 years (range, newborn to 21.0 years) with a standard deviation of 7.0 years. Mean initial vision was 20/200 (median, 20/400; range, 20/20 to LP). Eleven patients (73.3 %) had received oral, injectable, or topical corticosteroids, and 14 (93.3 %) had received antiviral therapy. All patients were diagnosed based on evaluation of intraocular fluids and tissue by antibody determinations, culture, PCR, histopathologic examination, or a combination thereof. Mean final visual acuity was 20/400 (median, CF; range, 20/25 to LP) with worsened visual acuity in five eyes (33.3 %). Anatomically, 14 of 15 eyes had healed or improved retinal appearance. In a pediatric population with acute retinal necrosis, HSV-2 should be considered as the prime candidate virus. Diagnosis of HSV-2 acute retinal necrosis is accomplished mainly by PCR of ocular specimens. Prompt diagnosis may lead to appropriate anti-viral therapy.


Saxagliptin-induced recurrent acute pancreatitis.
Although dipeptidyl peptidase-4 (DPP-4) inhibitors have been implicated in the development of acute pancreatitis, the causality of this phenomenon is not well established. We herein report the case of an 85-year-old woman who presented with epigastric pain after taking saxagliptin for five months. A high serum lipase level with characteristic computed tomography findings confirmed the diagnosis of acute pancreatitis. The patient's symptoms rapidly resolved after admission, although they recurred when she resumed treatment with saxagliptin for 18 days after discharge. In the absence of any identifiable causes of pancreatitis and considering the temporal sequence of events, the saxagliptin therapy was highly suspected to be the triggering factor. Although drug-induced pancreatitis is rare, treatment with DPP-4 inhibitors should be included as a potential etiology of acute pancreatitis.


Gamma interferon enhances macrophage transcription of the tumor necrosis factor/cachectin, interleukin 1, and urokinase genes, which are controlled by short-lived repressors.
Exposure of mouse resident and thioglycollate-elicited peritoneal macrophages to IFN-gamma leads to a marked increase in the TNF-alpha (tumor necrosis factor/cachectin), IL-1 and u-PA (urokinase-type plasminogen activator) mRNA levels. Nuclear run-on experiments show that IFN-gamma acts by enhancing the transcription of these three genes. Transcription of these three genes is also rapidly and transiently induced by cycloheximide, an inhibitor of protein synthesis, indicating that they are under the control of short-lived repressors.


Stepwise collapse of a giant pore metal-organic framework.
Defect engineering is a powerful tool that can be used to tailor the properties of metal-organic frameworks (MOFs). Here, we incorporate defects through ball milling to systematically vary the porosity of the giant pore MOF, MIL-100 (Fe). We show that milling leads to the breaking of metal-linker bonds, generating additional coordinatively unsaturated metal sites, and ultimately causes amorphisation. Pair distribution function analysis shows the hierarchical local structure is partially retained, even in the amorphised material. We find that solvents can be used to stabilise the MIL-100 (Fe) framework against collapse, which leads to a substantial retention of porosity over the non-stabilised material.


Estimation of oxygen uptake during fast running using accelerometry and heart rate.
Previous investigations have reported that accelerometer counts plateau during running at increasingly faster speeds. To assess whether biomechanical and/or device limitations cause this phenomenon and the feasibility of generating oxygen uptake (.VO2) prediction equations from the combined use of accelerometry and heart rate during walking and running. : Sixteen endurance-trained subjects completed two exercise tests on a treadmill. The first was a continuous incremental test to volitional exhaustion to determine ventilatory threshold and peak .VO2. The second was a discontinuous incremental exercise test while walking (3, 5, and 7 km.h(-1)) and running (8, 10, 12, 14, 16, 18, and 20 km.h(-1), or until volitional exhaustion). Subjects completed 3 min of exercise at each speed, followed by 3-5 min of recovery. Activity counts from uni- and triaxial accelerometers, heart rate, and gas exchange were measured throughout exercise. All accelerometer outputs rose linearly with speed during walking. During running, uniaxial accelerometer outputs plateaued, whereas triaxial output rose linearly with speed up to and including 20 km.h(-1). Prediction of .VO2 during walking and running using heart rate (R2 = 0.42 and 0.59, respectively), accelerometer counts (R2 = 0.48-0.83 and 0.76, respectively), the combined methodologies (R2 = 0.54-0.85 and 0.80, respectively), and the combined methodologies calibrated with individual data (R2 = 0.99-1.00 and 0.99, respectively) was completed by linear regression. Uni- and triaxial accelerometer outputs have a linear relationship with speed during walking. During running, uniaxial accelerometer outputs plateau because of the biomechanics of running, whereas triaxial accelerometer output has a linear relationship. The combined methodologies predict .VO2 better than either predictor alone; a subject's individually calibrated data further improves .VO2 estimation.


Supramolecular reactivity in the gas phase: investigating the intrinsic properties of non-covalent complexes.
The high vacuum inside a mass spectrometer offers unique conditions to broaden our view on the reactivity of supramolecules. Because dynamic exchange processes between complexes are efficiently suppressed, the intrinsic and intramolecular reactivity of the complexes of interest is observed. Besides this, the significantly higher strength of non-covalent interactions in the absence of competing solvent allows processes to occur that are unable to compete in solution. The present review highlights a series of examples illustrating different aspects of supramolecular gas-phase reactivity ranging from the dissociation and formation of covalent bonds in non-covalent complexes through the reactivity in the restricted inner phase of container molecules and step-by-step mechanistic studies of organocatalytic reaction cycles to cage contraction reactions, processes induced by electron capture, and finally dynamic molecular motion within non-covalent complexes as unravelled by hydrogen-deuterium exchange processes performed in the gas phase.


Anxiety and depression in adults in their eighties: do gender differences remain?
Women report higher rates of depression and anxiety than men; however, it is uncertain whether this gender difference continues into advanced old age. 78 men and 111 women aged 82-87 years from the Men, Women and Ageing Project completed measures of anxiety (Geriatric Anxiety Inventory), depression (Patient Health Questionnaire; PHQ9), general psychological well-being (Mental Health subscale of SF-36), general health (general health item of SF-36) and cognitive status (Telephone Interview for Cognitive Status; TICS). Results revealed no significant gender differences on any of the psychological measures, after controlling for cognitive status, general health and education. These results support the proposition that the female predominance in psychological distress diminishes with increasing age. The congruence between men and women may reflect changes in identity associated with age or the effect of decreased emotional valence of some social roles.


Structural analysis of PEO-PBO copolymer monolayers at the air-water interface.
X-ray reflectivity (XR) and grazing incidence X-ray diffraction (GIXD) have been used to examine an oxyethylene-b-oxybutylene (E(23)B(8)) copolymer film at the air-water interface. The XR data were fitted using both a one- and a two-layer model that outputted the film thickness, roughness, and electron density. The best fit to the experimental data was obtained using a two-layer model (representing the oxyethylene and oxybutylene blocks, respectively), which showed a rapid thickening of the copolymer film at pressures above 7 mN/m. The large roughness values found indicate a significant degree of intermixing between the blocks and back up the GIXD data, which showed no long range lateral ordering within the layer. It was found from the electron density model results that there is a large film densification at 7 mN/m, possibly suggesting conformational changes within the film, even though no such change occurs on the pressure-area isotherm at the same surface pressure.


Impact of Socioeconomic Factors on Prognosis and Clinical Management in Patients with Hepatocellular Carcinoma.
The prognosis for patient survival using the tumor-node-metastasis (TNM) staging system may be imperfect, as it based only on biological factors and does not include the socioeconomic factors (SEFs). We integrated the SEFs into the TNM system (TNMSEF), and evaluated whether the novel TNM-SEF staging system showed better prediction capacity and improved clinical guidance in hepatocellular carcinoma (HCC). We selected data of 12 514 cases with HCC between 2010 and 2015 from the SEER database. The Kaplan-Meier survival curves and Cox proportional hazards regression were used to analyze cancer-specific survival (CSS) among the TNM-SEF stages. Multivariate Cox analyses showed that insurance status, marital status, year of diagnosis, and income were prominent prognostic SEFs (all P < .05). When compared with the SEF0 stage, the SEF1 stage was significantly associated with a 36.1% increased risk of cancer-specific mortality in HCC overall, a 22.2% increased risk of metastatic HCC, and a 41.8% increased risk of non-metastatic HCC (all P < .001). The concordance index of the TNM-SEF stage (0.768) was better than that of the TNM stage (0.764). Furthermore, patients with SEF0 stage showed higher 5-year CSS than those with SEF1 stage (I: 48.7% vs. 28.1%; II: 41.0% vs. 25.1%; IIIA: 12.8% vs. 5.0%; IIIB: 7.8% vs. 6.0%; IIIC: 6.4% vs. 6.7%; IVA: 8.4% vs. 2.5%; IVB: 2.1% vs. 0.8%; all P < .05). We have proved that the SEF stage is an independent predictor for HCC. The combined SEF stage with TNM staging warrants more clinical attention, for improved prognostic prediction and clinical guidance.


Tension-Free Vaginal Tape Failure After Robotic Sacrocolpopexy and Tension-Free Vaginal Tape for Concomitant Prolapse and Stress Incontinence.
Evidence of surgical cure with tension free vaginal tape (TVT) is robust for isolated stress urinary incontinence, but rigorous studies investigating combined prolapse and incontinence are lacking. Our study measured cure of stress incontinence in concomitant robotic sacrocolpopexy and retropubic sling (TVT). We hypothesized a higher rate of objective failure as measured by the cough stress test (CST) compared to failures reported in recent randomized trials of TVT in patients without prolapse (aggregate 8% failure). Prospective cohort of patients with stress incontinence and prolapse, scheduled for robotic sacrocolpopexy and TVT. Outcomes assessed at 12 months: CST (primary aim), Patient Global Impression of Improvement (PGI-I), Pelvic Floor Distress Inventory, and the Sandvik questionnaire. Sixty-six of 77 subjects (86%) completed follow-up. Average age was 65 years, 96% were white, with mean body mass index of 28.1 kg/m2. Mean parity was 2.7, 50% had a previous hysterectomy. Mean leading edge of prolapse was +2.3 cm. All patients underwent the planned surgery; additionally, 50% underwent hysterectomy and 38% posterior colporrhaphy.The TVT failure (+CST) was 19.7% (95% confidence interval, 11.3%-31.7%; P < 0.001 compared to 8%). Neither preoperative disease severity, nor preoperative prolapse stage affected risk of failure of TVT. Eighty-three percent of the subjects were happy or very happy (PGI-I). However, those with a positive CST (failure) had significantly less satisfaction on PGI-I, UDI-6, and Pelvic Floor Distress Inventory-20. In this population with advanced prolapse, cure of stress urinary incontinence by TVT in setting of robotic sacrocolpopexy is lower compared to published trials where prolapse is absent. Women are less satisfied when the postoperative CST is positive.


Control of Size and Composition of Colloidal Nanocrystals of Manganese Oxide.
A comprehensive study on the effects of experimental parameters on the composition and size of manganese oxide nanocrystals was completed using colloidal chemistry. The reactions studied involved the thermolysis of Mn2+ acetate and Mn3+ acetylacetonate in oleylamine. Temperature was found to be the dominant factor affecting the composition and size of the products. Reactions completed below 200 °C favored the formation of nanocrystals smaller than 20 nm, with the presence of even impurity amounts of oxidizing agents leading to the formation of Mn3O4. Nanocrystals of MnO could only be synthesized below 200 °C if Mn2+ acetate was used, and the reaction was carefully controlled to have no O2 and H2O contamination. In turn, particle growth was rapid above this temperature. In this case, regardless of the oxidizing agents used or oxidation state of the Mn precursor, nanocrystals of MnO formed after annealing for at least 1 h at temperatures higher than 200 °C. This finding suggests the role of oleylamine as solvent, surfactant, and reducing agent at sufficiently high annealing temperatures. These results increase the understanding of redox stability of manganese during the colloidal synthesis of semiconductor metal oxide nanocrystals.


Pondering the Concept of Abstraction in (Illustrative) Visualization.
We explore the concept of abstraction as it is used in visualization, with the ultimate goal of understanding and formally defining it. Researchers so far have used the concept of abstraction largely by intuition without a precise meaning. This lack of specificity left questions on the characteristics of abstraction, its variants, its control, or its ultimate potential for visualization and, in particular, illustrative visualization mostly unanswered. In this paper we thus provide a first formalization of the abstraction concept and discuss how this formalization affects the application of abstraction in a variety of visualization scenarios. Based on this discussion, we derive a number of open questions still waiting to be answered, thus formulating a research agenda for the use of abstraction for the visual representation and exploration of data. This paper, therefore, is intended to provide a contribution to the discussion of the theoretical foundations of our field, rather than attempting to provide a completed and final theory.


Adenocarcinoma of the Uterine Cervix Shows Impaired Recruitment of cDC1 and CD8+ T Cells and Elevated β-Catenin Activation Compared with Squamous Cell Carcinoma.
Adenocarcinoma of the uterine cervix is the second most common type of cervical cancer after squamous cell carcinoma (SCC). Although both subtypes are treated similarly, patients with adenocarcinoma have a worse prognosis. In this study, immunologic features of the tumor microenvironment in these two subsets were pursued with potential therapeutic implications. The immune microenvironment of primary tumors and nonmetastatic tumor-draining lymph nodes (TDLN) was compared between patients with cervical adenocarcinoma (n = 16) and SCC (n = 20) by polychromatic flow cytometry and by transcriptional profiling of the primary tumors (n = 299) using publicly available data from The Cancer Genome Atlas (TCGA). Flow cytometric analyses revealed intact T-cell differentiation in TDLNs, but hampered effector T-cell trafficking to the primary tumors in adenocarcinoma, as compared with SCC. TCGA analysis demonstrated higher expression of chemokines involved in effector T-cell homing (CXCL9/10/11) in SCC primary tumors as compared with adenocarcinoma primary tumors, which was highly correlated to a transcriptional signature for type I conventional dendritic cells (cDC1). This was consistent with elevated frequencies of CD141/BDCA3+cDC1 in primary tumor SCC samples relative to adenocarcinoma and correspondingly elevated levels of CXCL9 and CXCL10 in 24-hour ex vivo cultures. Hampered cDC1 recruitment in adenocarcinoma was in turn related to lower transcript levels of cDC1-recruiting chemokines and an elevated β-catenin activation score and was associated with poor overall survival. Our data have identified an opportunity for the investigation of potentially novel therapeutic interventions in adenocarcinoma of the cervix, that is, β-catenin inhibition and cDC1 mobilization.


In vivo apoptosis in Shigella flexneri infections.
Shigella flexneri, an etiological agent of bacillary dysentery, causes apoptosis in vitro. Here we show that it also induces apoptosis in vivo. We were able to quantify the number of apoptotic cells in rabbit Peyer's patches infected with S. flexneri by detecting cells with fragmented DNA. Infection with virulent S. flexneri results in massive numbers of apoptotic cells within the lymphoid follicles. In contrast, neither an avirulent strain nor an avirulent strain capable of colonizing Peyer's patches increases the background level of apoptotic cells. Macrophages, T cells, and B cells are shown to undergo apoptosis in vivo. These results indicate that apoptosis may play a crucial role in the pathogenesis of shigellosis.


Hepatitis C prevalences in the psychiatric setting: Cost-effectiveness of scaling-up screening and direct-acting antiviral therapy.
Patients hospitalised because of mental illness often have risk factors for contracting HCV. Scaling-up HCV screening for all psychiatric inpatients as a case-detection strategy for viral elimination is underexplored. This study aimed to evaluate the cost-effectiveness of scaling-up HCV screening and treatment for psychiatry hospital admissions in Switzerland vs. the current standard-of-care risk-based approach, where only those with a history of substance misuse disorder are offered testing. HCV prevalence by history of substance misuse disorder was analysed in medical records from inpatient admissions to a Swiss psychiatry department. Cost-effectiveness was analysed from a healthcare provider perspective through a decision-tree screening model, using these HCV prevalence data. Model and parameter uncertainty were assessed using deterministic and probabilistic sensitivity analyses. Prevalence of HCV in psychiatry inpatients with a history of substance misuse disorder (n = 1,013) was 25.7%, compared with 3.5% among the remaining inpatients (n = 3,535). Scaling up HCV screening and treatment for all psychiatry admissions was cost-effective vs. the risk-based approach, with an incremental cost-effectiveness ratio of US$9,188 per quality-adjusted life-year gained. The incremental cost-effectiveness ratio remained cost-effective considering a HCV prevalence as low as 0.07%. The population-level net monetary benefit of the generalised screening approach was US$435,156,348, with 917 additional patients per year detected and treated at a cost of US$3,294 per person (vs. US$2,122 under risk-based screening). Scaling up HCV screening and treatment at diagnosis with all-oral, interferon-free regimens as a generalised approach for psychiatric admissions was cost-effective and could support reaching World Health Organization targets for HCV elimination by 2030. Patients hospitalised because of mental illness often have risk factors for HCV. We found that testing all psychiatry patients in hospital for HCV was cost-effective compared with testing only patients who have a history of substance misuse. Scaling up HCV testing and treatment could help to wipe out HCV.


Does percutaneous transluminal renal artery angioplasty improve blood pressure control and renal function in patients with atherosclerotic renal artery stenosis?
Percutaneous angioplasty (PTA) and stenting is an established procedure for the treatment of hypertension caused by atherosclerotic renal artery stenosis. However recently, the decision whether or notto perform this procedure has raised considerable debate. To examine the association between the basic clinical and radiological characteristics of candidates for renal artery PTA and the clinical outcome of the procedure in terms of improvement of blood pressure control and renal function. We conducted a retrospective cohort study of all patients who underwent percutaneous transluminal renal artery angioplasty (PTRA) and stent implantation in a tertiary medical center during the period 2000-2007. The clinical and radiological data were extracted from the medical file of each patient. Blood pressure measurements and creatinine level were recorded before the procedure and 1 month, 6 months, 12 months and 18 months after PTRA. Thirty-two patients were included in the final statistical analysis. The mean age of the study population was 66.6 +/- 8.8 years old and 75% were men. There was a significant reduction in both systolic and diastolic blood pressure 1 month after the procedure: 160.5 +/- 24.7 vs. 141.8 +/- 23.6 mmHg and 83.8 +/- 12.9 vs. 68.8 +/- 11.8 mmHg respectively (P < 0.001). The reduction in blood pressure was constant throughout the follow-up period and was evident 18 months after the procedure: 160.5 +/- 24.7 vs. 135.0 +/- 35.1 mmHg and 83.8 +/- 12.9 vs. 71.3 +/- 16.5 mmHg respectively (P < 0.001). However, no improvement in renal function was observed at any time during the follow-up period. We could not demonstrate an association between clinical or radiological features and the clinical outcome after PTRA. Our findings show that PTRA can be considered an effective procedure for improving blood pressure control in patients with atherosclerotic renal artery stenosis (ARAS) and resistant hypertension. This research, together with previous studies, strengthens the knowledge that the decline in glomerular filtration rate seen in many patients with ARAS is non-reversible and is not improved by PTRA.


Relationships Among PlayerLoad, High-Intensity Intermittent Running Ability, and Injury Risk in Professional Rugby League Players.
To examine relationships among physical performance, workload, and injury risk in professional rugby league players. Maximal-effort (n = 112) and submaximal (n = 1084) running performances of 45 players were recorded from 1 club over 2 consecutive seasons. Poorer and better submaximal running performance was determined by higher and lower exercise heart rates, respectively. Exponentially weighted moving averages and daily rolling averages were used to assess microtechnology-derived acute and chronic field-based workloads. The associations among within-individual submaximal running performance, workload, and noncontact lower-limb injury were then investigated. The injury risk associated with poorer submaximal performance was "likely" greater than stable (relative risk = 1.8; 90% confidence interval, 0.9-3.7) and better submaximal performance (relative risk = 2.0; 90% confidence interval, 0.9-4.4). Compared with greater submaximal performance, poorer performance was associated with lower chronic workloads (effect size [d] = 0.82 [0.13], large) and higher acute:chronic workload ratios (d = 0.49 [0.14], small). Chronic workload demonstrated a "nearly perfect" positive relationship with maximal-effort running performance (exponentially weighted moving average, R2 = .91 [.15]; rolling average, R2 = .91 [.14]). At acute:chronic workload ratios >1.9, no differences in injury risk were found between rolling average and exponentially weighted moving average methods (relative risk = 1.1; 90% confidence interval, 0.3-3.8; unclear). Reductions in submaximal running performance are related with low chronic workloads, high acute:chronic workload ratios, and increased injury risk. These findings demonstrate that a submaximal running assessment can be used to provide information on physical performance and injury risk in professional rugby league players.


Comparative Principles of DNA Methylation Reprogramming during Human and Mouse In Vitro Primordial Germ Cell Specification.
Primordial germ cell (PGC) development is characterized by global epigenetic remodeling, which resets genomic potential and establishes an epigenetic ground state. Here we recapitulate PGC specification in vitro from naive embryonic stem cells and characterize the early events of epigenetic reprogramming during the formation of the human and mouse germline. Following rapid de novo DNA methylation during priming to epiblast-like cells, methylation is globally erased in PGC-like cells. Repressive chromatin marks (H3K9me2/3) and transposable elements are enriched at demethylation-resistant regions, while active chromatin marks (H3K4me3 or H3K27ac) are more prominent at regions that demethylate faster. The dynamics of specification and epigenetic reprogramming show species-specific differences, in particular markedly slower reprogramming kinetics in the human germline. Differences in developmental kinetics may be explained by differential regulation of epigenetic modifiers. Our work establishes a robust and faithful experimental system of the early events of epigenetic reprogramming and regulation in the germline.


Mobile phone messaging reminders for attendance at healthcare appointments.
This review is an update of the original Cochrane review published in July 2012. Missed appointments are a major cause of inefficiency in healthcare delivery with substantial monetary costs for the health system, leading to delays in diagnosis and appropriate treatment. Patients' forgetfulness is one of the main reasons for missed appointments. Patient reminders may help reduce missed appointments. Modes of communicating reminders for appointments to patients include face-to-face communication, postal messages, calls to landlines or mobile phones, and mobile phone messaging. Mobile phone messaging applications, such as Short Message Service (SMS) and Multimedia Message Service (MMS), could provide an important, inexpensive delivery medium for reminders for healthcare appointments. To update our review assessing the effects of mobile phone messaging reminders for attendance at healthcare appointments. Secondary objectives include assessment of costs; health outcomes; patients' and healthcare providers' evaluation of the intervention and perceptions of safety; and possible harms and adverse effects associated with the intervention. Original searches were run in June 2009. For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL,The Cochrane Library 2012, Issue 8), MEDLINE (OvidSP) (January 1993 to August 2012), EMBASE (OvidSP) (January 1993 to August 2012), PsycINFO (OvidSP) (January 1993 to August 2012) and CINAHL (EbscoHOST) (January 1993 to August 2012). We also reviewed grey literature (including trial registers) and reference lists of articles. Randomised controlled trials (RCTs) assessing mobile phone messaging as reminders for healthcare appointments. We only included studies in which it was possible to assess effects of mobile phone messaging independent of other technologies or interventions. Two review authors independently assessed all studies against the inclusion criteria, with any disagreements resolved by a third review author. Study design features, characteristics of target populations, interventions and controls, and results data were extracted by two review authors and confirmed by a third author. Two authors assessed the risk of bias of the included studies. As the intervention characteristics and outcome measures were similar across included studies, we conducted a meta-analysis to estimate an overall effect size. We included eight randomised controlled trials involving 6615 participants. Four of these studies were newly identified during this update.We found moderate quality evidence from seven studies (5841 participants) that mobile text message reminders improved the rate of attendance at healthcare appointments compared to no reminders (risk ratio (RR) 1.14 (95% confidence interval (CI) 1.03 to 1.26)). There was also moderate quality evidence from three studies (2509 participants) that mobile text message reminders had a similar impact to phone call reminders (RR 0.99 (95% CI 0.95 to 1.02). Low quality evidence from one study (291 participants) suggests that mobile text message reminders combined with postal reminders improved the rate of attendance at healthcare appointments compared to postal reminders alone (RR 1.10 (95% CI 1.02 to 1.19)). Overall, the attendance to appointment rates were 67.8% for the no reminders group, 78.6% for the mobile phone messaging reminders group and 80.3% for the phone call reminders group. One study reported generally that there were no adverse effects during the study period; none of the studies reported in detail on specific adverse events such as loss of privacy, data misinterpretation, or message delivery failure. Two studies reported that the costs per text message per attendance were respectively 55% and 65% lower than costs per phone call reminder. The studies included in the review did not report on health outcomes or people's perceptions of safety related to receiving reminders by text message. Low to moderate quality evidence included in this review shows that mobile phone text messaging reminders increase attendance at healthcare appointments compared to no reminders, or postal reminders.Text messaging reminders were similar to telephone reminders in terms of their effect on attendance rates, and cost less than telephone reminders. However, the included studies were heterogeneous and the quality of the evidence therein is low to moderate. Further, there is a lack of information about health effects, adverse effects and harms, user evaluation of the intervention and user perceptions of its safety. The current evidence therefore still remains insufficient to conclusively inform policy decisions.There is a need for more high-quality randomised trials of mobile phone messaging reminders, that measure not only patients' attendance rates, but also focus on the cost-effectiveness of these interventions. Health outcomes, patients' and healthcare providers' evaluation and perceptions of the safety of the interventions, potential harms, and adverse effects of mobile phone messaging reminders should be assessed. Studies should report message content and timing in relation to the appointment.


Regression-based norms improve the sensitivity of the National MS Society Consensus Neuropsychological Battery for Pediatric Multiple Sclerosis (NBPMS).
The National Multiple Sclerosis Society Consensus Neuropsychological Battery for Pediatric Multiple Sclerosis (NBPMS) was designed to detect cognitive impairment in children and adolescents with multiple sclerosis. One weakness of the battery is the reliance on published manual-based normative samples varying in size and quality. These primary sources base interpretation on discrete age bands, a practice which may be particularly problematic during periods of rapid development in childhood and adolescence. A further impediment to valid NBPMS interpretation is the lack of control for demographic factors other than age. We endeavored to develop regression-based norms for the NBPMS by gathering a demographically balanced sample of 102 healthy control children and using their performance to derive normalization, controlling for multiple demographic variables (i.e., age, age(2), gender, parent education). The regression-based normative equations were applied to the performance of 51 children with MS. For many of the major test scores, the regression-based norms more readily detected impairment. As in the case of adult MS, these results indicate that regression-based norms offer interpretive benefits over their manual-based counterparts.


The retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer.
The retinoblastoma tumor suppressor (RB) protein is functionally inactivated in the majority of human cancers and is aberrant in one-third of all breast cancers. RB regulates G(1)/S-phase cell-cycle progression and is a critical mediator of antiproliferative signaling. Here the specific impact of RB deficiency on E2F-regulated gene expression, tumorigenic proliferation, and the response to 2 distinct lines of therapy was investigated in breast cancer cells. RB knockdown resulted in RB/E2F target gene deregulation and accelerated tumorigenic proliferation, thereby demonstrating that even in the context of a complex tumor cell genome, RB status exerts significant control over proliferation. Furthermore, the RB deficiency compromised the short-term cell-cycle inhibition following cisplatin, ionizing radiation, and antiestrogen therapy. In the context of DNA-damaging agents, this bypass resulted in increased sensitivity to these agents in cell culture and xenograft models. In contrast, the bypass of antiestrogen signaling resulted in continued proliferation and xenograft tumor growth in the presence of tamoxifen. These effects of aberrations in RB function were recapitulated by ectopic E2F expression, indicating that control of downstream target genes was an important determinant of the observed responses. Specific analyses of an RB gene expression signature in 60 human patients indicated that deregulation of this pathway was associated with early recurrence following tamoxifen monotherapy. Thus, because the RB pathway is a critical determinant of tumorigenic proliferation and differential therapeutic response, it may represent a critical basis for directing therapy in the treatment of breast cancer.


Switching to Clozapine Using Immediate Versus Gradual Antipsychotic Discontinuation: A Pilot, Double-Blind, Randomized Controlled Trial.
To examine effects of different antipsychotic discontinuation strategies on clinical outcomes in patients with schizophrenia undergoing a switch to clozapine. This pilot, 8-week, double-blind, randomized controlled trial was conducted from May 1999 to July 2004. Outpatients with a diagnosis of schizophrenia or schizoaffective disorder based on the Structured Clinical Interview for DSM-IV and eligible for a switch to clozapine were included. Participants were randomly assigned to the immediate discontinuation (prior antipsychotics were discontinued at baseline) or gradual discontinuation (prior antipsychotics were reduced by 25% each week) group. For each group, clozapine was gradually increased to 300 mg/d at day 12, with this dose maintained for 3 weeks and thereafter adjusted as needed. Clinical outcome measures included the Brief Psychiatric Rating Scale (BPRS), UKU Side Effect Rating Scale, and extrapyramidal symptoms scales. Thirty-three patients were enrolled; 15 and 18 patients were assigned to the immediate and gradual discontinuation groups, respectively. While significant improvements were observed in BPRS total scores after the switch to clozapine in both groups (P values < .001), no significant differences were found on any clinical outcome measures between the groups; however, additional analyses revealed a significant interaction between group and time for the UKU Psychic Side Effects subscale scores (P = .038). This preliminary study demonstrated no statistically significant differences in efficacy or tolerability between immediate and gradual antipsychotic discontinuation strategies when switching to clozapine in patients with schizophrenia; however, due to the small sample size, larger-scale trials are needed to confirm these results. ClinicalTrials.gov identifier: NCT02640300.


Obesity among adolescents of affluent public schools in Meerut.
The prevalence of obesity has increased worldwide in all segments of the population due to increased industrialization, urbanization, mechanization, and associated changes in diet and lifestyles. Change in diet habit of consuming more high energy fast foods and shifting to sedentary lifestyle has affected our children and also increased the risk of chronic diseases among adolescents. Childhood obesity has association with increased risk of coronary heart disease, stroke, and cancer in later life. Therefore, its control and prevention is one of the major concerns for all developing nations. The present school-based cross-sectional study was carried out among 2785 affluent adolescents of six public schools in Meerut during the period October 2003 to March 2004. The objective is to assess the magnitude of overweight and obesity in adolescents and associated risk factors, with the help of the ELIZ health pathway based on body mass index criteria. Prevalence of overweight and obesity was found to be 19.7% and 5.3% in girls and 18.36% and 10.82% in boys. Obesity was found to be significantly associated with high intake of junk foods (P < 0.05), binge eating, high calorie intake (P < 0.05), lower physical activity (P < 0.05), and prolonged TV watching (P < 0.05).


Visual information about past, current and future properties of irregular target paths in isometric force tracking.
In visual-motor tracking, information about past, current, and future properties of a target path can be available but, because they are typically manipulated independently, the relative contribution of these information categories to tracking performance is not well understood. The aim of the current study was to investigate the role of visual information pertaining to past, current, and future states of the target path in guiding isometric tracking performance as a function of the irregularity of the target path (sine wave, brown/pink noise, white noise). The findings from local and global properties of the force output showed that the role of visual information about the past, current, and future states of target paths is dependent on the regularity of the signal to be tracked. The brown/pink noise pathway condition was most strongly influenced by future and past-future visual information for both local error properties (lead/lag, root mean square error (RMSE)) and global properties of the force output (ApEn, cross correlation). The highly irregular white noise pathway did not benefit from past or future information and the highly regular sine wave was only influenced for the local error properties of RMSE and lead/lag. It appears that visual information about past and future tracking states is more effective with a pathway that is middling with respect to regularity/irregularity. This is consistent with the role of visual information in tracking to be dependent on the potential adaptability for change in the dimension of the motor output.


Chlorogenic acid: A comprehensive review of the dietary sources, processing effects, bioavailability, beneficial properties, mechanisms of action, and future directions.
Chlorogenic acids (CGAs), a group of hydroxycinnamates, are generally abundant in everyday foods and beverages, most prominently in certain coffee drinks. Among them, the chlorogenic acid (CGA), also termed as 5-O-caffeoylquinic acid (5-CQA), is one of the most abundant, highly functional polyphenolic compounds in the human diet. The evidence of its health benefits obtained from clinical studies, as well as basic research, indicates an inverse correlation between 5-CQA consumption and a lower risk of metabolic syndromes and chronic diseases. This review focuses on the beneficial properties for health and mechanisms of action of 5-CQA, starting with its history, isomers, dietary sources, processing effects, preparation methods, pharmacological safety evaluation, and bioavailability. It also provides the possible molecular mechanistic bases to explain the health beneficial effects of 5-CQA including neuroprotective, cardiovascular protective, gastrointestinal protective, renoprotective, hepatoprotective, glucose and lipid metabolism regulatory, and anticarcinogenic effects. The information summarized here could aid in the basic and clinical research on 5-CQA as a natural dietary additive, potential drug candidate, as well as a natural health promoter.


Patterns in the Development of Pediatric Allergy.
Describe clinical and epidemiologic patterns of pediatric allergy using longitudinal electronic health records (EHRs) from a multistate consortium of US practices. Using the multistate Comparative Effectiveness Research through Collaborative Electronic Reporting EHR database, we defined a cohort of 218 485 children (0-18 years) who were observed for ≥5 years between 1999 and 2020. Children with atopic dermatitis (AD), immunoglobulin E-mediated food allergy (IgE-FA), asthma, allergic rhinitis (AR), and eosinophilic esophagitis (EoE) were identified using a combination of diagnosis codes and medication prescriptions. We determined age at diagnosis, cumulative incidence, and allergic comorbidity. Allergic disease cumulative (and peak age of) incidence was 10.3% (4 months) for AD, 4.0% (13 months) for IgE-FA, 20.1% (13 months) for asthma, 19.7% (26 months) for AR, and 0.11% (35 months) for EoE. The most diagnosed IgE-FAs were peanut (1.9%), egg (0.8%), and shellfish (0.6%). A total of 13.4% of children had ≥2 allergic conditions, and respiratory allergies (ie, asthma, AR) were commonly comorbid with each other, and with other allergic conditions. We detail pediatric allergy patterns using longitudinal, health care provider-based data from EHR systems across multiple US states and varied pediatric practice types. Our results support the population-level allergic march progression and indicate high rates of comorbidity among children with food and respiratory allergies.


Acidovorax valerianellae sp. nov., a novel pathogen of lamb's lettuce [Valerianella locusta (L.) Laterr].
Bacterial spot disease of lamb's lettuce [Valerianella locusta (L.) Laterr.] was first observed in fields in 1991. This new bacterial disease is localized in western France in high-technology field production of lamb's lettuce for the preparation of ready-to-use salad. Nineteen strains isolated in 1992 and 1993 from typical black leaf spots of naturally infected lamb's lettuce were characterized and compared with reference strains of Acidovorax and Delftia. The pathogenicity of the 19 strains was confirmed by artificial inoculation. Biochemical and physiological tests, fatty acid profiles, DNA-DNA hybridization and other nucleic acid-based tests were performed. A numerical taxonomic analysis of the 19 lamb's lettuce strains showed a single homogeneous phenon closely related to previously described phytopathogenic taxa of the genus Acidovorax. DNA-DNA hybridization studies showed that the lamb's lettuce strains were 91-100% related to a representative strain, strain CFBP 4730(T), and constituted a discrete DNA hybridization group, indicating that they belong to the same novel species. Results from DNA-rRNA hybridization, 16S rRNA sequence analysis and fatty acid analysis studies confirmed that this novel species belongs to the beta-subclass of the Proteobacteria and, more specifically, to the family Comamonadaceae and the genus Acidovorax. The name Acidovorax valerianellae sp. nov. is proposed for this novel taxon of phytopathogenic bacteria. The type strain is strain CFBP 4730(T) (= NCPPB 4283(T)).


Examining the double burden of malnutrition for preschool children and women of reproductive age in low-income and middle-income countries: a scoping review protocol.
The majority of the populations in low-income and middle-income countries (LMICs) are encountering the double burden of malnutrition (DBM): the coexistence of both undernutrition and overnutrition sequalae. With DBM being a new phenomenon in research, little is known about its aetiology, operational definitions and risk factors influencing its manifestation. The proposed scoping review is aimed at mapping literature with regard to the DBM phenomenon among preschool children and women of reproductive age in LMICs who are among the most high-risk groups to encounter DBM. A comprehensive literature search will be conducted in the following electronic databases: MEDLINE, EMBASE, Scopus, CINAHL, LILACS and ProQuest Dissertations and Thesis Global. Additionally, searches in other government and institutional sources (WHO website and university repositories) and forward and backward citation tracking of seminal articles will also be done. Two reviewers will independently conduct title and abstract screening and full-text screening. Similarly, data extraction and coding will independently be done by two reviewers. Information extracted from included literature will be analysed qualitatively using thematic analysis approach and reported as per the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews guidelines. Ethical approval is not required for this study because the review is based on literature from publicly available sources. The dissemination of our findings will be done through presentations in relevant conferences and publication in a peer-reviewed journal.


Nematodes in a polar desert reveal the relative role of biotic interactions in the coexistence of soil animals.
Abiotic factors are major determinants of soil animal distributions and their dominant role is pronounced in extreme ecosystems, with biotic interactions seemingly playing a minor role. We modelled co-occurrence and distribution of the three nematode species that dominate the soil food web of the McMurdo Dry Valleys (Antarctica). Abiotic factors, other biotic groups, and autocorrelation all contributed to structuring nematode species distributions. However, after removing their effects, we found that the presence of the most abundant nematode species greatly, and negatively, affected the probability of detecting one of the other two species. We observed similar patterns in relative abundances for two out of three pairs of species. Harsh abiotic conditions alone are insufficient to explain contemporary nematode distributions whereas the role of negative biotic interactions has been largely underestimated in soil. The future challenge is to understand how the effects of global change on biotic interactions will alter species coexistence.


A survey of tools for variant analysis of next-generation genome sequencing data.
Recent advances in genome sequencing technologies provide unprecedented opportunities to characterize individual genomic landscapes and identify mutations relevant for diagnosis and therapy. Specifically, whole-exome sequencing using next-generation sequencing (NGS) technologies is gaining popularity in the human genetics community due to the moderate costs, manageable data amounts and straightforward interpretation of analysis results. While whole-exome and, in the near future, whole-genome sequencing are becoming commodities, data analysis still poses significant challenges and led to the development of a plethora of tools supporting specific parts of the analysis workflow or providing a complete solution. Here, we surveyed 205 tools for whole-genome/whole-exome sequencing data analysis supporting five distinct analytical steps: quality assessment, alignment, variant identification, variant annotation and visualization. We report an overview of the functionality, features and specific requirements of the individual tools. We then selected 32 programs for variant identification, variant annotation and visualization, which were subjected to hands-on evaluation using four data sets: one set of exome data from two patients with a rare disease for testing identification of germline mutations, two cancer data sets for testing variant callers for somatic mutations, copy number variations and structural variations, and one semi-synthetic data set for testing identification of copy number variations. Our comprehensive survey and evaluation of NGS tools provides a valuable guideline for human geneticists working on Mendelian disorders, complex diseases and cancers.


Lightness identification of patterned three-dimensional, real objects.
Conventional studies of lightness constancy have almost exclusively used flat plain stimuli and have shown that lightness matches across illuminants cannot be explained by physical matches of reflectance or luminance. The perceptual qualities that underlie lightness judgments still remain largely unknown. Real objects are often 3-D and patterned, giving additional cues for identification. We examine the perceptual strategies that underlie material identification of real objects. Stimuli were randomly crumpled papers printed with achromatic patterns with precisely calibrated mean reflectance and reflectance contrast, placed in backgrounds under varying levels of illumination. Observers were asked to identify objects based on physical reflectance differences. Reflectance identification functions were simulated by simple models that perform object identification based on dissimilarities in perceived brightness (luminance dissimilarity modified by light adaptation) or perceived contrast (contrast dissimilarity modified by mean luminance). The reflectance identification results were also recreated in two control experiments, using identical stimuli conditions, where choices were based explicitly on dissimilarities in perceived brightness or contrast. Rather than a reverse optics model of lightness perception where observers first estimate illuminant intensity and then extract relative lightness by discounting the illuminant, this study supports the use of simple percepts such as brightness and contrast.


[Bridging the divide: global lessons from evidence-based health policy in Mexico].
During the past six years, Mexico has undergone a large-scale transformation of its health system. This paper provides an overview of the main features of the Mexican reform experience. Because of its high degree of social inequality, Mexico is a microcosm of the range of problems that affect countries at all levels of development. Its health system had not kept up with the pressures of the double burden of disease, whereby malnutrition, common infections, and reproductive health problems coexist with non-communicable disease and injury. With half of its population uninsured, Mexico was facing an unacceptable paradox: whereas health is a key factor in the fight against poverty, a large number of families became impoverished by expenditures in health care and drugs. The reform was designed to correct this paradox by introducing a new scheme called Popular Health Insurance (Seguro Popular). This innovative initiative is gradually protecting the 50 million Mexicans, most of them poor, who had until now been excluded from formal social insurance. This paper reports encouraging results in the achievement of the ultimate objective of the reform: universal access to high-quality services with social protection for all.


Emergency illumination panel that displays different pictures depending on room brightness.
We fabricated an emergency illumination panel by stacking two translucent pictures, one of which was painted with ink and the other with phosphors. When the panel was illuminated by backlight or room light, only the ink-printed picture was visible to the human eye and only the phosphorescent picture was visible in darkness. A two-way mirror was inserted between the two pictures both to prevent super-imposition of the two images and to enhance phosphorescence. This phosphorescent emergency sign acted as an illuminator independently of electric power sources and provided sufficient brightness for reading newspaper headlines.


Mitochondrial water in myocardial ischemia: investigation with nuclear magnetic resonance.
Nuclear magnetic resonance studies of mitochondria isolated from ischemic hearts after coronary vessel occlusion indicated a decrease in water proton relaxation times. This change coincided with a decrease in the hydration of the samples. It is suggested that in ischemia, changes in macromolecular hydration may be one of the first mechanisms to alter function in the mitochondria, which are vital to the energy-transducing process in heart muscle.


Representation of ophthalmology concepts by electronic systems: intercoder agreement among physicians using controlled terminologies.
To assess intercoder agreement for ophthalmology concepts by 3 physician coders using 5 controlled terminologies (International Classification of Diseases 9, Clinical Modification [ICD9CM]; Current Procedural Terminology, fourth edition; Logical Observation Identifiers, Names, and Codes [LOINC]; Systematized Nomenclature of Medicine, Clinical Terms [SNOMED-CT]; and Medical Entities Dictionary). Noncomparative case series. Five complete ophthalmology case presentations selected from a publicly available journal. Each case was parsed into discrete concepts. Electronic or paper browsers were used independently by 3 physician coders to assign a code for every concept in each terminology. A match score representing adequacy of assignment for each concept was assigned on a 3-point scale (0, no match; 1, partial match; 2, complete match). For every concept, the level of intercoder agreement was determined by 2 methods: (1) based on exact code matching with assignment of complete agreement when all coders assigned the same code, partial agreement when 2 coders assigned the same code, and no agreement when all coders assigned different codes, and (2) based on manual review for semantic equivalence of all assigned codes by an independent ophthalmologist to classify intercoder agreement for each concept as complete agreement, partial agreement, or no agreement. Subsequently, intercoder agreement was calculated in the same manner for the subset of concepts judged to have adequate coverage by each terminology, based on receiving a match score of 2 by at least 2 of the 3 coders. Intercoder agreement in each controlled terminology: complete, partial, or none. Cases were parsed into 242 unique concepts. When all concepts were analyzed by manual review, the proportion of complete intercoder agreement ranged from 12% (LOINC) to 44% (SNOMED-CT), and the difference in intercoder agreement between LOINC and all other terminologies was statistically significant (P<0.004). When only concepts with adequate terminology were analyzed by manual review, the proportion of complete intercoder agreement ranged from 33% (LOINC) to 64% (ICD9CM), and there were no statistically significant differences in intercoder agreement among any pairs of terminologies. The level of intercoder agreement for ophthalmic concepts in existing controlled medical terminologies is imperfect. Intercoder reproducibility is essential for accurate and consistent electronic representation of medical data.


[Zinc deficiency and associated factors in colombian children; results from the 2010 national nutrition survey; a cross sectional study].
Zinc (Zn) is an essential micronutrient for cell growth, protein synthesis and cell differentiation. This deficiency affects the growth, development, energy metabolism and immune response in Colombian children's. To examine factors associated with Zn deficiency in a representative sample of Colombian children. A cross-sectional descriptive study was conducted of data from the 2010 National Nutrition Survey of Colombia (ENSIN 2010), in 4.279 children aged between 12-59 months of age. Plasma levels of Zn were determined by atomic absorption spectrophotometry, and associated factors (sex, age, ethnicity, SISBEN score, and geographic region) were collected by structured questionnaire. Associations were established through a multivariable regression model. We found a range of Zn of 78.5 μg/dl, (95% CI 76.7 to 80.4 μg/dl). 43.3% (95% CI 42.2%-44.3%) of children had lower Zn levels to 65 μg/dl. Children belonging to an ethnic groups (indigenous) or residing in rural areas; showed Zn deficiency (56.3% and 47.8%) respectively. Regression models show that to be indigenous (OR 1.76, 95% CI 1.29 to 2.41), and to reside in rural areas (OR 1.39, 95% CI 1.16 to 1.67) were associated with Zn deficiency. The study population shows a high prevalence of Zn deficiency, so it is recommended that comprehensive interventions which are involved nutritional and educational component.


Cigarette smoking, intracellular vitamin deficiency, and occurrence of micronuclei in epithelial cells of the buccal mucosa.
The study focuses on the assessment of chromosomal damage associated with folate and vitamin B12 deficiency, and with cigarette smoking in a tissue directly exposed to cigarette smoke (buccal mucosa) while controlling for potential confounding factors. A cross-sectional study was carried out among 39 current smokers (CSs) and 60 noncurrent smokers (NCSs). Buccal mucosal cells, saliva, and blood samples were collected from each subject. The Health Habits and History Questionnaire (Block et al., 1986) was modified to obtain dietary and other relevant information. Methods used to measure folate, vitamin B12 levels, and the frequency of micronucleated cells in buccal mucosal cells gave reproducible results. The study results suggest that CSs have buccal mucosal folate and vitamin B12 levels that are lower than those among NCSs. CSs were three times more likely to have micronucleated buccal mucosal cells compared to NCSs. There appeared to be no association between low buccal folate and vitamin B12 levels chromosomal damage. The salivary vitamin B12 concentrations and plasma vitamin C and E concentrations, however, seem to be marginally protective against the occurrence of buccal mucosal micronuclei, whereas plasma beta-carotene seems to increase the occurrence of micronuclei. Overall, the results do not support the concept that localized folate and vitamin B12 deficiencies in the buccal mucosal cells of smokers are associated with chromosomal damage in those cells. The presence of vitamin B12 deficiencies in the buccal mucosal cells of smokers are associated with chromosomal damage in those cells. The presence of vitamin B12 in the immediate environment (saliva) and vitamin C and E in the plasma, however, appear to be marginally protective against chromosomal damage in buccal mucosal cells.


Integrated Hydrologic Modeling to Untangle the Impacts of Water Management During Drought.
Over the past century, groundwater levels in California's San Joaquin Valley have dropped by more than 30 m in some areas mostly due to excessive groundwater extraction used to irrigate agricultural lands and sustain a growing population. Between 2012 and 2015, California experienced the worst drought in its recorded history, depleting surface water supplies and further exacerbating groundwater depletion in the region. Due to a lack of groundwater regulation, exact quantities of extracted groundwater in California are unknown and hard to quantify. Recent adoption of the Sustainable Groundwater Management Act has intensified efforts to identify sustainable groundwater use. However, understanding sustainable use in a highly productive agricultural system with an extremely complex surface water allocation system, variable groundwater use, and spatially extensive and diverse irrigation practices is no easy task. Using an integrated hydrologic model coupled with a land surface model, we evaluated how water management activities, specifically a suite of irrigation and groundwater pumping scenarios, impact surface water-groundwater fluxes and storage components and how those activities and the relationships between them change during drought. Results showed that groundwater pumping volume had the most significant impact on long-term water storage changes. A comparison with total water storage anomaly (TWSA) estimates from NASA's Gravity Recover and Climate Experiment (GRACE) provided some insight regarding which combinations of pumping and irrigation matched the GRACE TWSA estimates, lending credibility to these scenarios. In addition, the majority of long-term water storage changes during the recent drought occurred in groundwater storage in the deeper subsurface.


Determination of tissue-specific interaction between vitamin C and vitamin E in vivo using senescence marker protein-30 knockout mice as a vitamin C synthesis deficiency model.
Vitamin E (α-tocopherol; VE) is known to be regenerated from VE radicals by vitamin C (L-ascorbic acid; VC) in vitro. However, their in vivo interaction in various tissues is still unclear. Therefore, we alternatively examined the in vivo interaction of VC and VE by measurement of their concentrations in various tissues of senescence marker protein-30 (SMP30) knockout (KO) mice as a VC synthesis deficiency model. Male SMP30-KO mice were divided into four groups (VC+/VE+, VC+/VE-, VC-/VE+ and VC-/VE-), fed diets with or without 500 mg/kg VE and given water with or without 1·5 g/l VC ad libitum. Then, VC and VE concentrations in the plasma and various tissues were determined. Further, gene expression levels of transporters associated with VC and VE, such as α-tocopherol transfer protein (α-TTP) and sodium-dependent vitamin C transporters (SVCTs), were examined. These results showed that the VE levels in the VC-depleted (VC-/VE+) group were significantly lower than those in the VC+/VE+ group in the liver and heart; the VC levels in the VE-depleted (VC+/VE-) group were significantly lower than those in the VC+/VE+ group in the kidneys. The α-TTP gene expression in the liver and kidneys was decreased by VC and/or VE depletion. Moreover, SVCT1 gene expression in the liver was decreased by both VC and VE depletion. In conclusion, these results indicate that VC spares VE mainly in the liver and heart and that VE spares VC in the kidneys of SMP30-KO mice. Thus, interaction between VC and VE is likely to be tissue specific.


Health Care Utilization and Mental Health Diagnoses Among Veterans With Tinnitus.
Purpose Tinnitus is prevalent among military Veterans and may frequently co-occur with mental health disorders. This study examined health care utilization and mental health diagnoses among Veterans with and without tinnitus who receive Department of Veterans Affairs (VA) health care. Method We randomly sampled 10% of VA health care users for a 5-year period between 2011 and 2016. Tinnitus and other diagnoses were identified using International Classification of Diseases diagnosis codes; Veterans assigned 1 or more inpatient codes or 2 or more outpatient codes were considered to have the respective diagnosis. We examined demographics, military service, clinical characteristics, and health care utilization of Veterans with and without tinnitus diagnoses. Bivariable and multivariable logistic regression was used to estimate associations between tinnitus and mental health diagnoses of interest. Results Among 617,534 eligible Veterans, 3.8% met criteria for tinnitus diagnosis. Prevalence of tinnitus was associated with sex, age, race, marital status, and VA service connection status; additionally, hearing loss and traumatic brain injury were frequently codiagnosed with tinnitus. Veterans with tinnitus had higher annual health care utilization than those without. While controlling for potential confounders, tinnitus diagnoses were associated with mental health diagnoses, including anxiety, depression, and substance use disorders. Conclusion Findings suggest that Veterans who are diagnosed with tinnitus have more health care utilization and are more frequently diagnosed with mental health disorders than Veterans who are not diagnosed with tinnitus. This suggests a need for coordinated tinnitus and mental health care services for Veterans in the VA system of care.