Use of HEp-2 cells for improved isolation and passage of Chlamydia pneumoniae.
Chlamydia pneumoniae has proved to be difficult to isolate and propagate in cell culture. We compared the growth of three strains of C. pneumoniae, TW-183 and two clinical isolates from Brooklyn, N.Y., in five cell lines, including HeLa 229, McCoy, HL, HEp-2, and HTED, an immortalized human tracheal cell line. HEp-2 was the most sensitive cell line tested. When 10-fold dilutions of three C. pneumoniae strains at known titers were inoculated into the different cell lines, the mean number of inclusion-forming units per milliliter was 1 to 2 log units higher in the HEp-2 than in the other cell lines. This difference was statistically significant. Omission of pretreatment with DEAE-dextran resulted in larger inclusions than those seen in pretreated cells, with the exception of McCoy and HTED cells. Retrieval of clinical specimens previously cultured on HeLa 229 cells and comparison of mean inclusion counts in fresh clinical specimens simultaneously inoculated on HeLa 229 and HEp-2 cells suggested that culture in HEp-2 cells may require only the initial inoculation and one passage, compared with three to four passages, as required by culture in HeLa 229 cells.


Correlates of Co-Occurring Diabetes and Obesity Among Community Mental Health Program Members With Serious Mental Illnesses.
This study examined the prevalence and correlates of co-occurring obesity and diabetes among community mental health program members. Medical screenings of 457 adults with serious mental illnesses were conducted by researchers and peer wellness specialists in four U.S. states. Body mass index was measured directly. Diabetes was assessed via glycosylated hemoglobin and interview self-report. Multivariable logistic regression analysis examined associations with known predictors. In the sample, 59% were obese, 25% had diabetes, and 19% had both conditions. When gender, diagnosis, and site were controlled, co-occurring diabetes and obesity was almost three times as likely among African Americans (OR=2.93) as among participants from other racial groups and half as likely among smokers as among nonsmokers (OR=.58). Older persons and those with poorer self-rated physical health also were more likely to have these co-occurring conditions. Results support the need for culturally competent treatment and for smoking cessation options with sensitivity to the potential for weight gain.


The genetic fate of molecularly cloned simian immunodeficiency virus in experimentally infected macaques.
We have examined genetic variation of the simian immunodeficiency virus (SIV) in four macaques inoculated with virions derived from molecular clones of proviral DNA. Our data demonstrated that the SIV genome is capable of rapid and extensive genetic variation. This variation was especially large in the env gene, where nucleotide substitution frequencies were as high as 10(-1)/site/year. In some env clones, a high G to A transition rate was observed that accounted for up to 79% of the observed nucleotide substitutions. Moreover, in env clones with a high G to A transition rate, multiple in-frame stop codons were generated exclusively at tryptophan codons. Another interesting observation was the lack of variation in the region analogous to the V3 loop in the HIV-1 Env protein. Considered together, these data have important implications for studies of pathogenesis and vaccine development in the SIV model system.


Successful treatment of fluconazole-resistant oropharyngeal candidiasis by a combination of fluconazole and terbinafine.
Increasing incidence of resistance to conventional antifungal therapy has demanded that novel therapies be introduced. Recent in vitro studies have shown that combinations involving azoles and allylamines may be effective in inhibiting fluconazole-resistant fungi. In this report, we describe the case of a 39-year-old woman who presented with white patches on her buccal mucosa, tongue, and palate with a bright erythematous erosive base. A fungal culture revealed Candida albicans. The patient failed to respond to the initially prescribed fluconazole therapy. Failure of therapy can be attributed to a developed resistance to fluconazole from the patient's intermittent use of this antifungal agent at varying dosages for the preceding 2 years due to a diagnosis of onychomycosis. In vitro testing of the culture from the patient showed elevated MICs of fluconazole, itraconzole, and terbinafine (MICs were 32, 0.5, and 64 microg/ml, respectively). Our goal was to combine therapies of fluconazole and terbinafine in an attempt to clear the fungal infection. Impressively, this combination resulted in the clearing of the clinical symptoms and the patient has successfully been asymptomatic for more than 12 months posttreatment.


Lampe1: an ENU-germline mutation causing spontaneous hepatosteatosis identified through targeted exon-enrichment and next-generation sequencing.
Using a small scale ENU mutagenesis approach we identified a recessive germline mutant, designated Lampe1 that exhibited growth retardation and spontaneous hepatosteatosis. Low resolution mapping based on 20 intercrossed Lampe1 mice revealed linkage to a ∼14 Mb interval on the distal site of chromosome 11 containing a total of 285 genes. Exons and 50 bp flanking sequences within the critical region were enriched with sequence capture microarrays and subsequently analyzed by next-generation sequencing. Using this approach 98.1 percent of the targeted DNA was covered with a depth of 10 or more reads per nucleotide and 3 homozygote mutations were identified. Two mutations represented intronic nucleotide changes whereas one mutation affected a splice donor site in intron 11-12 of Palmitoyl Acetyl-coenzyme A oxygenase-1 (Acox1), causing skipping of exon 12. Phenotyping of Acox1(Lampe1) mutants revealed a progression from hepatosteatosis to steatohepatitis, and ultimately hepatocellular carcinoma. The current approach provides a highly efficient and affordable method to identify causative mutations induced by ENU mutagenesis and animal models relevant to human pathology.


Personalized medicine: marking a new epoch in cancer patient management.
Personalized medicine (PM) is defined as "a form of medicine that uses information about a person's genes, proteins, and environment to prevent, diagnose, and treat disease." The promise of PM has been on us for years. The suite of clinical applications of PM in cancer is broad, encompassing screening, diagnosis, prognosis, prediction of treatment efficacy, patient follow-up after surgery for early detection of recurrence, and the stratification of patients into cancer subgroup categories, allowing for individualized therapy. PM aims to eliminate the "one size fits all" model of medicine, which has centered on reaction to disease based on average responses to care. By dividing patients into unique cancer subgroups, treatment and follow-up can be tailored for each individual according to disease aggressiveness and the ability to respond to a certain treatment. PM is also shifting the emphasis of patient management from primary patient care to prevention and early intervention for high-risk individuals. In addition to classic single molecular markers, high-throughput approaches can be used for PM including whole genome sequencing, single-nucleotide polymorphism analysis, microarray analysis, and mass spectrometry. A common trend among these tools is their ability to analyze many targets simultaneously, thus increasing the sensitivity, specificity, and accuracy of biomarker discovery. Certain challenges need to be addressed in our transition to PM including assessment of cost, test standardization, and ethical issues. It is clear that PM will gradually continue to be incorporated into cancer patient management and will have a significant impact on our health care in the future.


First Report of Crown Rot of Bloodroot (Sanguinaria canadensis) Caused by Fusarium oxysporum in the United States.
Bloodroot (Sanguinaria canadensis L [Papaveraceae]) is a native herbaceous perennial in eastern North America, found from Nova Scotia to Florida. Although it is a common wildflower, rhizomes of double-flowered forms are sold commercially. Rhizomes planted into a wooded area in Guilford, CT produced healthy stems and flowers for a few years and then began to collapse and die in 2008. The same symptoms were observed with a new planting in 2011. Initially, leaves were dull green and were more leathery than healthy leaves. Eventually, the leaves collapsed at the junction of the petioles and the rhizomes. Vascular discoloration, if present, was obscured by the red pigmentation in the rhizome. A Fusarium sp. sporulated on the discolored tissue at the junction between healthy and rotted tissue. Stem pieces were surface disinfested (0.53% NaClO for 1 min), rinsed, and placed on Peptone-PCNB agar (2) at room temperature for 5 days. Colonies originating from single spores were subcultured on carnation leaf agar (2) and identified as Fusarium oxysporum based on falcate, thin-walled, three-septate macroconida borne in monophialides on doliform conidiophores (2). Four rhizomes of double-flowered bloodroot were planted in potting mix in the greenhouse in October 2010; sprouts were observed in March 2011. Two plants were inoculated in March 2011 by drenching the soil with 100 ml of a conidial suspension (106 spores/ml) and two control plants were treated with deionized water. Two months later, the inoculated plants were smaller than the controls. The treated plants subsequently collapsed and F. oxysporum was reisolated. Control plants remained healthy and F. oxysporum was not isolated. DNA extracted from the F. oxysporum isolates was used to obtain partial sequences of the translational elongation factor 1-alpha (tef1) gene, which were then blasted against the GenBank database. We observed a 100% similarity with F. oxysporum f. sp. lycopersici. The bloodroot isolates were compared with a known F. oxysporum f. sp. lycopersici isolate for their ability to cause disease on 2-week-old tomato seedlings (cv. Brandywine), using pathogenicity tests as described above. The known F. oxysporum f. sp. lycopersici isolate caused severe wilt and stunting of the tomato seedlings, but the bloodroot isolate caused no symptoms in inoculated seedling compared with those not inoculated. These results suggest that there may be more hosts for isolates in the F. oxysporum f. sp. lycopersici species complex than previously thought (1). An isolate (O-2603) has been deposited at the Fusarium Research Laboratory at Pennsylvania State University, University Park. Since bloodroot is now being sold commercially as an ornamental, disease management strategies may be needed. To our knowledge, this is the first report of a Fusarium crown rot of bloodroot. References: (1).V. Edel-Hermann et al. Online publication. doi:10.1111/j.1365-3059.2011.02551.x. Plant Pathology, 2011. (2) J. Leslie and B. Summerell. The Fusarium Laboratory Manual. Blackwell Publishing, Ames, IA, 2006.


Participating in a Community of Learners enhances resident perceptions of learning in an e-mentoring program: proof of concept.
Community learning and e-mentoring, learning methods used in higher education, are not used to any extent in residency education. Yet both have the potential to enhance resident learning and, in the case of community learning, introduce residents to basic lifelong learning skills. We set out to determine whether residents participating in an Internet based e-mentoring program would, with appropriate facilitation, form a community of learners (CoL) and hold regular community meetings. We also determined resident and faculty perceptions of CoL and Internet sessions as effective learning experiences. A six-month e-mentoring pilot was offered to 10 Radiology residents in the Aga Khan University Postgraduate Medical Education Program in Nairobi, Kenya (AKUHN) with a Professor of Radiology, located at University of Virginia, USA, acting as the e-mentor. Monthly Internet case-based teaching sessions were facilitated by the e-mentor. In addition, residents were coached by a community facilitator to form CoL and collectively work through clinical cases at weekly face-to-face CoL sessions.Event logs described observed resident activity at CoL sessions; exit survey and interviews were used to elicit perceptions of CoL and Internet sessions as effective learning experiences. Resident adoption of CoL behaviors was observed, including self-regulation, peer mentoring and collaborative problem solving. Analysis revealed high resident enthusiasm and value for CoL. Surveys and interviews indicated high levels of acceptance of Internet learning experiences, although there was room for improvement in audio-visual transmission technologies. Faculty indicated there was a need for a larger multi-specialty study. The pilot demonstrated resident acceptance of community building and collaborative learning as valued learning experiences, addressing one barrier to its formal adoption in residency education curricula. It also highlighted the potential of e-mentoring as a means of expanding faculty and teaching materials in residency programs in developing countries.


Suppressed recombination and unique candidate genes in the divergent haplotype encoding Fhb1, a major Fusarium head blight resistance locus in wheat.
Fine mapping and sequencing revealed 28 genes in the non-recombining haplotype containing Fhb1 . Of these, only a GDSL lipase gene shows a pathogen-dependent expression pattern. Fhb1 is a prominent Fusarium head blight resistance locus of wheat, which has been successfully introgressed in adapted breeding material, where it confers a significant increase in overall resistance to the causal pathogen Fusarium graminearum and the fungal virulence factor and mycotoxin deoxynivalenol. The Fhb1 region has been resolved for the susceptible wheat reference genotype Chinese Spring, yet the causal gene itself has not been identified in resistant cultivars. Here, we report the establishment of a 1 Mb contig embracing Fhb1 in the donor line CM-82036. Sequencing revealed that the region of Fhb1 deviates from the Chinese Spring reference in DNA size and gene content, which explains the repressed recombination at the locus in the performed fine mapping. Differences in genes expression between near-isogenic lines segregating for Fhb1 challenged with F. graminearum or treated with mock were investigated in a time-course experiment by RNA sequencing. Several candidate genes were identified, including a pathogen-responsive GDSL lipase absent in susceptible lines. The sequence of the Fhb1 region, the resulting list of candidate genes, and near-diagnostic KASP markers for Fhb1 constitute a valuable resource for breeding and further studies aiming to identify the gene(s) responsible for F. graminearum and deoxynivalenol resistance.


Prevalence, correlates, and comorbidity of DSM-IV antisocial personality syndromes and alcohol and specific drug use disorders in the United States: results from the national epidemiologic survey on alcohol and related conditions.
The purpose of this study was to provide nationally representative data on the prevalence, sociodemographic correlates, and comorbidity of antisocial syndromes across alcohol and 8 specific drug use disorders, including sedative, tranquilizer, opiate, stimulant, hallucinogen, cannabis, cocaine, and inhalant/solvent abuse and dependence. This study is based on a nationally representative sample of adults. Lifetime prevalences of antisocial syndromes were estimated and logistic regression analyses were used to examine associations between antisocial syndromes and sociodemographic characteristics and substance use disorders. Diagnoses were made according to the criteria of the DSM-IV using the National Institute on Alcohol Abuse and Alcoholism Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV Version. The lifetime prevalences of antisocial personality disorder (APD), conduct disorder, and adult antisocial behavior were 3.6%, 1.1%, and 12.3%, respectively. Prevalences of alcohol use disorders and drug use disorders were 30.3% and 10.3%, respectively. In general, men and individuals who were younger, widowed/separated/divorced, of lower socioeconomic status, and living in urban areas or in the West were more likely to have antisocial syndromes. Native Americans were more likely and Asians and Hispanics were less likely to have APD and adult antisocial behavior. Virtually all of the associations between APD and adult antisocial behavior and specific substance use disorders were positive and statistically significant (p < .05). Significant associations between conduct disorder and substance use disorders were concentrated among women. Comorbidity of specific substance disorders with antisocial syndromes is very common in the U.S. population. Further work in many directions is indicated by the results of this study, including the factors that give rise to the associations and the treatment and prevention implications of these conditions when comorbid.


Effects of dehydroepiandrosterone and atamestane supplementation on frailty in elderly men.
It has been suggested that the age-related decline of androgens in men plays a distinct role in the development of several aspects of frailty. Therefore, hormone replacement might improve the course of frailty by increasing lean body mass and muscle strength, decreasing fat mass, and improving the subjective quality of life. The objective of the study was to assess whether hormone replacement with dehydroepiandrosterone (DHEA) and/or atamestane might improve the course of frailty. This was a double-blind, randomized, controlled trial. The study was conducted in the general community. Participants included 100 nonhospitalized, nondiseased, independently living men, aged 70 yr and over with low scores on strength tests. Seventeen participants did not complete the trial. Subjects were randomly assigned to one of four intervention arms: atamestane (100 mg/d) and placebo, DHEA (50 mg/d) and placebo, a combination of atamestane (100 mg/d) and DHEA (50 mg/d), or two placebo tablets for 36 wk. Physical frailty was measured by means of a specific test battery, including isometric grip strength, leg extensor power, and physical performance. The randomization was successful, and 83 (83%) men completed the intervention. There were no differences between the treatment arms and placebo group in any of the outcome measurements after intervention. The results of this double-blind, randomized trial do not support the hypothesis that hormone replacement with DHEA and/or atamestane might improve the course of frailty.


The role of Ibn Sina (Avicenna)'s medical poem in the transmission of medical knowledge to medieval Europe.
The Medical Poem ("Al-Urjuzah Fi Al-Tibb") of Ibn Sina (Avicenna, 980-1037), is the subject of this primary-source study evaluating its scientific value, poetics and pedagogical significance as well as assessing its role in the transmission of medical knowledge to Medieval Europe. In addition to one original manuscript and two modern editions, the English translation by Krueger was also studied. Ibn Sina's poem on medicine consisting of meticulously classified 1326 verses, can be considered as a poetic summary of his encyclopedic textbook: The Canon of Medicine; hence its popularity in the East then the West as a tool in the process of transmitting medical knowledge from master to student. Since first translated by Gerard of Cremona (1114-1187) in the middle of the 12(th) century, the Latinized poem was frequently published in Medieval Europe either independently or combined with the Latinized Canon of Medicine or with the Articella; the famous collection of Greco-Roman and Latinized Arabian medical treatises in use in the universities of Salerno, Montpelier, Bologna and Paris up to the 17(th) century. The study of the Krueger's English edition revealed few places where the full meanings of the original Arabic text were not conveyed. A list of those places is given together with the suggested corrections.


GLiMMPS: robust statistical model for regulatory variation of alternative splicing using RNA-seq data.
To characterize the genetic variation of alternative splicing, we develop GLiMMPS, a robust statistical method for detecting splicing quantitative trait loci (sQTLs) from RNA-seq data. GLiMMPS takes into account the individual variation in sequencing coverage and the noise prevalent in RNA-seq data. Analyses of simulated and real RNA-seq datasets demonstrate that GLiMMPS outperforms competing statistical models. Quantitative RT-PCR tests of 26 randomly selected GLiMMPS sQTLs yielded a validation rate of 100%. As population-scale RNA-seq studies become increasingly affordable and popular, GLiMMPS provides a useful tool for elucidating the genetic variation of alternative splicing in humans and model organisms.


Different mechanisms underlie DNA instability in Huntington disease and colorectal cancer.
Two recent lines of evidence raise the possibility that instability in germ-line or somatic cells arises by a common mechanism that involves defective mismatch repair. Mutations in mismatch-repair proteins are known to cause instability in hereditary nonpolyposis colorectal cancer, instability that is physically similar to germ-line instability observed in Huntington disease (HD). Furthermore, both germ-line and somatic-cell instability are likely to be mitotic defects, the former occurring early in embryogenesis. To test the hypothesis that defective repair is a common prerequisite for instability, we have utilized two disease groups that represent different instability "conditions." Germ-line instability within simple tandem repeats (STR) at 10 loci in 29 HD families were compared with somatic instability at the same loci in 26 colon cancer (CC) patients with identified or suspected defects in mismatch-repair enzymes. HD is known to be caused by expansion within the CAG repeat of the locus, but the extent or pattern of STR instability outside this region has not been examined systematically. We find a distinctly different pattern of STR mutation in the two disease groups, suggesting different mechanisms. Instability in HD is generally confined to a single locus, whereas instability is widespread for the same loci in CC. Our data do not support a causative role for defective mismatch-repair enzymes in instability associated with HD; rather, our data are consistent with a model in which DNA structure may inhibit normal mismatch repair at the expansion site.


Sox-4 facilitates thymocyte differentiation.
The mouse Sry-like transcription factor Sox-4 is expressed in thymus, bone marrow, and gonads of adult mice. Sox-4-deficient mice die at embryonic day E14 due to cardiac malformation. In transfer experiments to irradiated recipients, B cell development was shown to be severely impaired in Sox-4-deficient progenitor cells. However, no drastic effects on T lymphocyte development were noted, despite the high level expression of the Sox-4 gene in the thymus of normal mice. Here, we report a detailed analysis of T cell development from Sox-4-deficient progenitors. Explanted fetal thymic organ cultures (FTOC) of Sox-4-deficient thymi yielded 10-50-fold fewer CD4 CD8 double-positive and single-positive cells than FTOC of littermates. This effect was T cell-autonomous, since similar observations were made when FTOC were performed by culturing of Sox-4-deficient progenitors in wild-type thymus lobes. When Sox-4-deficient fetal liver cells were injected together with normal cells intrathymically, they did not compete efficiently for reconstitution. It is concluded that Sox-4 facilitates thymocyte development.


Compressive sensing computational ghost imaging.
The computational ghost imaging with a phase spatial light modulator (SLM) for wave field coding is considered. A transmission-mask amplitude object is reconstructed from multiple intensity observations. Compressive techniques are used in order to gain a successful image reconstruction with a number of observations (measurement experiments), which is smaller than the image size. Maximum likelihood style algorithms are developed, respectively, for Poissonian and approximate Gaussian modeling of random observations. A sparse and overcomplete modeling of the object enables the advanced high accuracy and sharp imaging. Numerical experiments demonstrate that an approximative Gaussian distribution with an invariant variance results in the algorithm that is efficient for Poissonian observations.


The effect of chemotaxis and chemokinesis on leukocyte locomotion: a new interpretation of experimental results.
A mathematical model is developed to describe the motion of leukocytes through a Boyden chamber. The model is based on the Keller-Segel model of cell motion and comprises three partial differential equations which describe the evolution of the neutrophils, the chemoattractant, and a neutrophil-derived chemokinetic factor. Where other authors have concentrated on chemotaxis, here attention is focused on the manner in which the chemokinetic factor influences neutrophil locomotion. Numerical simulations show how the number of neutrophils initially placed on top of the chamber affects cellular motion through the system and reproduce the qualitative behaviour observed by Takeuchi & Persellin (Am. J. Physiol. 236, C22-C29). In particular, the simulations show how dense packing of the neutrophils increases the levels of the chemokinetic factor. This enhances random cell motion and increases the speed with which the neutrophils reach the source of chemoattractant. For a particular asymptotic limit of the system parameters, the model reduces to a nonlinear partial differential equation for the neutrophils. Similarity solutions of this caricature model yield algebraic expressions relating the speed with which the neutrophil front penetrates into the chamber to the number of neutrophils initially placed on top of it. The implications of the results are also discussed.


The fate of neurons after traumatic spinal cord injury in rats: A systematic review.
To reach an evidence-based knowledge in the context of the temporal-spatial pattern of neuronal death and find appropriate time of intervention in order to preserve spared neurons and promote regeneration after traumatic spinal cord injury (TSCI). The study design was based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-guided systematic review. PubMed and EMBASE were searched (24 October, 2015) with no temporal or linguistic restrictions. Hand-search was performed in the bibliographies of relevant articles. Non-interventional animal studies evaluating time-dependent neuronal death following acute mechanical trauma to the spinal cord were included. We separately evaluated the fate of various populations of neurons including propriospinal neurons, ventral motor neurons, Clarke's column neurons, and supraspinal neurons. We found 11,557 non-duplicated studies. Screening through the titles and abstracts led to 549 articles, 49 of which met the inclusion criteria. Both necrotic and apoptotic neuronal deaths occur after TSCI, though necrosis is the prominent mechanism. There are differences in the responses of intrinsic neurons of the spinal cord to the TSCI. Also, the extent of neuronal death in the supraspinal neurons depends on the anatomical location of their axons. In order to develop new therapies, selection of the injury model and time of intervention has a crucial role in the efficacy of therapy. In addition, examining the safety and efficacy of an intervention by reliable methods not confounded by the injury-related changes would promote translation of therapies to the clinical application.


Mathematical modeling of noninvasive blood pressure estimation techniques--Part II: Brachial hemodynamics.
The main biomechanical factors which may affect the accuracy of the oscillometric method for indirect blood pressure measurement are analyzed using a new model of brachial hemodynamics. In a first stage of this work, the model has been used to reproduce some well-known responses of collapsing arteries, such as the sharp increase in compliance, and the nonlinear pressure-flow characteristic with negative dynamic resistance. In a second stage the model has been linked to the arm tissue mechanics description presented in a previous work. The final model so obtained has then been employed to analyze the pattern of the main hemodynamic quantities (pressure pulsations in the cuffs, blood volume changes, blood flow upstream and downstream of the cuffs) during deflation manoeuvres. The simulation results agree with those found in the recent literature quite well. Results indicate that the cuff pressure value for maximum pulsations exhibits a large plateau, located approximately around the mean arterial pressure. However, stiffness of wall artery, or stretching of the cuff internal surface, may significantly alter the obtained results causing a phenomena of "pseudo-hypertension."


Wavefront sensorless adaptive optics for large aberrations.
In some adaptive optics systems the aberration is determined not by using a wavefront sensor but by sequential optimization of the adaptive correction element. Efficient schemes for the control of such systems are essential if they are to be effective. A scheme is introduced that permits the efficient measurement of large amplitude wavefront aberrations that are represented by an appropriate series of modes. This scheme uses an optimization metric based on the root-mean-square spot radius (or focal spot second moment) and an aberration expansion using polynomials suited to the representation of lateral aberrations. Experimental correction of N aberration modes is demonstrated with a minimum of N+1 photodetector measurements. The geometrical optics basis means that the scheme can be extended to arbitrarily large aberrations.


Determination of zinc status in humans: which indicator should we use?
Zinc deficiency has serious wide-ranging health consequences and is thought to be one of the most prevalent micronutrient deficiencies in the world. However, reliable indicators or biomarkers to assess zinc status are not available at present. Indirect indicators such as the prevalence of stunting or anemia, iron deficiency, as well as more direct indicators such as plasma zinc concentrations are being used at present to estimate the prevalence of zinc deficiency in populations. However, as this paper shows by using data from a recent national micronutrient survey in Vietnam, the estimates of the prevalence of zinc deficiency using these different indicators can vary widely, leading to inconsistencies. In this paper, zinc deficiency among children is four times more prevalent than iron deficiency and 2.3 times more than stunting prevalence for example. This can lead not only to confusion concerning the real extent of the prevalence of zinc deficiency in populations, but also makes it hard to inform policy on whether action is needed or not. Moreover, evaluation of programs is hampered by the lack of a clear indicator. Efforts should be made to identify the most suitable indicator to evaluate the impact of programs aimed at improving zinc status and health of populations.


Human chorionic gonadotropin treatment of anti-Hu-associated paraneoplastic neurological syndromes.
Paraneoplastic neurological syndromes associated with anti-Hu antibodies (Hu-PNS) are mediated by a T-cell immune response that is directed against the Hu antigens. In pregnancy, many Th1-mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis regress. We hypothesised that this decreased disease activity during pregnancy may be related to high human chorionic gonadotropin (hCG) levels. 15 Hu-PNS patients were treated in a prospective, uncontrolled and unblinded trial with 10,000 IU daily of hCG administered by intramuscular injection during 12 weeks. Primary outcome measures were functional improvement defined as a decrease of one or more points on the modified Rankin Scale (mRS) or stabilisation in patients with mRS score ≤3 and improvement of neurological impairment assessed with the Edinburgh Functional Impairment Tests (EFIT). Secondary end points included the change in activities of daily living as evaluated using the Barthel Index. Seven of 15 patients (47%) improved on the mRS or stabilised at mRS score ≤3. Four patients (27%) showed significant improvement of neurological impairment as indicated by an overall Edinburgh Functional Impairment Tests score of ≥1 point. Five patients improved on the Barthel Index (33%). Comparison with previous studies suggests that hCG may have immunomodulatory activity and may modify the course of Hu-PNS, although well-established confounding factors may have contributed in this uncontrolled trial.


Clinical validation of optimised RT-LAMP for the diagnosis of SARS-CoV-2 infection.
We have optimised a reverse transcription-loop-mediated isothermal amplification (RT-LAMP) assay for the detection of SARS-CoV-2 from extracted RNA for clinical application. We improved the stability and reliability of the RT-LAMP assay by the addition of a temperature-dependent switch oligonucleotide to reduce self- or off-target amplification. We then developed freeze-dried master mix for single step RT-LAMP reaction, simplifying the operation for end users and improving long-term storage and transportation. The assay can detect as low as 13 copies of SARS-CoV2 RNA per reaction (25-μL). Cross reactivity with other human coronaviruses was not observed. We have applied the new RT-LAMP assay for testing clinical extracted RNA samples extracted from swabs of 72 patients in the UK and 126 samples from Greece and demonstrated the overall sensitivity of 90.2% (95% CI 83.8-94.7%) and specificity of 92.4% (95% CI 83.2-97.5%). Among 115 positive samples which Ct values were less than 34, the RT-LAMP assay was able to detect 110 of them with 95.6% sensitivity. The specificity was 100% when RNA elution used RNase-free water. The outcome of RT-LAMP can be reported by both colorimetric detection and quantifiable fluorescent reading. Objective measures with a digitized reading data flow would allow for the sharing of results for local or national surveillance.


Modulation of chemotherapeutic drug resistance in neuroblastoma SK-N-AS cells by the neural apoptosis inhibitory protein and miR-520f.
The acquisition of multidrug resistance is a major impediment to the successful treatment of neuroblastoma, a clinically heterogeneous cancer accounting for ∼15% of all pediatric cancer deaths. The MYCN transcription factor, whose gene is amplified in ∼30% of high-risk neuroblastoma cases, influences drug resistance by regulating a cadre of genes, including those involved with drug efflux, however, other high-risk subtypes of neuroblastoma lacking MYCN amplification, such as those with chromosome 11q deletions, also acquire multidrug resistance. To elucidate additional mechanisms involved with drug resistance in non-MYCN amplified tumour cells, an SK-N-AS subline (SK-N-AsCis24) that is significantly resistant to cisplatin and cross resistant to etoposide was developed through a pulse-selection process. High resolution aCGH analysis of SK-N-AsCis24 revealed a focal gain on chromosome 5 containing the coding sequence for the neural apoptosis inhibitory protein (NAIP). Significant overexpression of NAIP mRNA and protein was documented, while experimental modulation of NAIP levels in both SK-N-AsCis24 and in parental SK-N-AS cells confirmed that NAIP was responsible for the drug resistant phenotype by apoptosis inhibition. Furthermore, a decrease in the NAIP targeting microRNA, miR-520f, was also demonstrated to be partially responsible for increased NAIP levels in SK-N-AsCis24. Interestingly, miR-520f levels were determined to be significantly lower in postchemotherapy treatment tumours relative to matched prechemotherapy samples, consistent with a role for this miRNA in the acquisition of drug resistance in vivo, potentially through decreased NAIP targeting. Our findings provide biological novel insight into neuroblastoma drug-resistance and have implications for future therapeutic research.


Neural mechanisms of observational learning.
Individuals can learn by interacting with the environment and experiencing a difference between predicted and obtained outcomes (prediction error). However, many species also learn by observing the actions and outcomes of others. In contrast to individual learning, observational learning cannot be based on directly experienced outcome prediction errors. Accordingly, the behavioral and neural mechanisms of learning through observation remain elusive. Here we propose that human observational learning can be explained by two previously uncharacterized forms of prediction error, observational action prediction errors (the actual minus the predicted choice of others) and observational outcome prediction errors (the actual minus predicted outcome received by others). In a functional MRI experiment, we found that brain activity in the dorsolateral prefrontal cortex and the ventromedial prefrontal cortex respectively corresponded to these two distinct observational learning signals.


Interplay between Alzheimer's disease and global glucose metabolism revealed by the metabolic profile alterations of pancreatic tissue and serum in APP/PS1 transgenic mice.
Increasing evidence suggests that there is a correlation between type 2 diabetes mellitus (T2D) and Alzheimer's disease (AD). Increased Aβ polypeptide production in AD patients would promote metabolic abnormalities, insulin signaling dysfunction and perturbations in glucose utilization, thus leading to the onset of T2D. However, the metabolic mechanisms underlying the interplay between AD and its diabetes-promoting effects are not fully elucidated. Particularly, systematic metabolomics analysis has not been performed for the pancreas tissues of AD subjects, which play key roles in the glucose metabolism of living systems. In the current study, we characterized the dynamic metabolic profile alterations of the serum and the pancreas of APP/PS1 double-transgenic mice (an AD mouse model) using the untargeted metabolomics approaches. Serum and pancreatic tissues of APP/PS1 transgenic mice and wild-type mice were extracted and subjected to NMR analysis to evaluate the functional state of pancreas in the progress of AD. Multivariate analysis of principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were conducted to define the global and the local (pancreas) metabolic features associated with the possible initiation of T2D in the progress of AD. Our results showed the onset of AD-induced global glucose metabolism disorders in AD mice. Hyperglycemia and its accompanying metabolic disorders including energy metabolism down-regulation and oxidative stress were observed in the serum of AD mice. Meanwhile, global disturbance of branched-chain amino acid (BCAA) metabolism was detected, and the change of BCAA (leucine) was positively correlated to the alteration of glucose. Moreover, increased level of glucose and enhanced energy metabolism were observed in the pancreas of AD mice. The results suggest that the diabetes-promoting effects accompanying the progress of AD are achieved by down-regulating the global utilization of glucose and interfering with the metabolic function of pancreas. Since T2D is a risk factor for the pathogenesis of AD, our findings suggest that targeting the glucose metabolism dysfunctions might serve as a supplementary therapeutic strategy for Alzheimer's disease.


Iteratively weighted centroiding for Shack-Hartmann wave-front sensors.
Several techniques have been used with Shack-Hartmann wavefront sensors to determine the local wave-front gradient across each lenslet. In this article we introduce an iterative weighted technique which is specifically targeted for open-loop applications such as aberrometers and metrology. In this article the iterative centroiding technique is compared to existing techniques such as center-of-mass with thresholding, weighted center-of-gravity, matched filter and cross-correlation. Under conditions of low signal-to-noise ratio, the iterative weighted centroiding algorithm is demonstrated to produce a lower variance in the reconstructed phase than existing techniques. The iteratively weighted algorithm was also compared in closed-loop and demonstrated to have the lowest error variance along with the weighted center-of-gravity, however, the iteratively weighted algorithm removes the bulk of the aberration in roughly half the iterations than the weighted center-of-gravity algorithm. This iterative weighted algorithm is also well suited to applications such as guiding on telescopes.


Homochirality in an early peptide world.
A recently proposed model of non-autocatalytic reactions in dipeptide formation that leads to spontaneous symmetry breaking and homochirality was examined. The model is governed by activation, polymerization, epimerization, and depolymerization of amino acids. Symmetry breaking was determined to result primarily from the different rates of reactions that involve homodimers and heterodimers, i.e., stereoselective reactions, and the fact that epimerization can only occur on the N-terminal residue and not on the C-terminal residue. This corresponds to an auto-inductive cyclic process that works only in one direction. It is argued that epimerization mimics autocatalytic behavior as well as mutual antagonism, both of which are known to be crucial for the production of full homochirality.


Selection of Optimal Ancestry Informative Markers for Classification and Ancestry Proportion Estimation in Pigs.
Using small sets of ancestry informative markers (AIMs) constitutes a cost-effective method to accurately estimate the ancestry proportions of individuals. This study aimed to generate a small and effective number of AIMs from ∼60 K single nucleotide polymorphism (SNP) data of porcine and estimate three ancestry proportions [East China pig (ECHP), South China pig (SCHP), and European commercial pig (EUCP)] from Asian breeds and European domestic breeds. A total of 186 samples of 10 pure breeds were divided into three groups: ECHP, SCHP, and EUCP. Using these samples and a one-vs.-rest SVM classifier, we found that using only seven AIMs could completely separate the three groups. Subsequently, we utilized supervised ADMIXTURE to calculate ancestry proportions and found that the 129 AIMs performed well on ancestry estimates when pseudo admixed individuals were used. Furthermore, another 969 samples of 61 populations were applied to evaluate the performance of the 129 AIMs. We also observed that the 129 AIMs were highly correlated with estimates using ∼60 K SNP data for three ancestry components: ECHP (Pearson correlation coefficient (r) = 0.94), SCHP (r = 0.94), and EUCP (r = 0.99). Our results provided an example of using a small number of pig AIMs for classifications and estimating ancestry proportions with high accuracy and in a cost-effective manner.


The impact of occupation according to income on depressive symptoms in South Korean individuals: Findings from the Korean Welfare Panel Study.
In South Korea, societal perceptions on occupation are distinct, with people favouring white collar jobs. Hence both occupation type and income can have mental health effects. To examine the relationship between occupational classification and depression, along with the combined effect of occupational classification and household income. Data were from the Korean Welfare Panel Study (KOWEPS), 2010-2013. A total of 4,694 economically active participants at baseline were followed. Association between occupational classification and depression, measured using the Center for Epidemiological Studies Depression (CES-D) scale 11, was investigated using the linear mixed effects model. Blue collar (β: 0.3871, p = .0109) and sales and service worker groups (β: 0.3418, p = .0307) showed higher depression scores than the white collar group. Compared to the white collar high-income group, white collar low income, blue collar middle income, blue collar middle-low income, blue collar low income, sales and service middle-high income, sales and service middle-low income and sales and service low-income groups had higher depression scores. Occupational classification is associated with increasing depression scores. Excluding the highest income group, blue collar and sales and service worker groups exhibit higher depression scores than their white collar counterparts, implying the importance of addressing these groups.


The Energetics and Physiological Impact of Cohesin Extrusion.
Cohesin extrusion is thought to play a central role in establishing the architecture of mammalian genomes. However, extrusion has not been visualized in vivo, and thus, its functional impact and energetics are unknown. Using ultra-deep Hi-C, we show that loop domains form by a process that requires cohesin ATPases. Once formed, however, loops and compartments are maintained for hours without energy input. Strikingly, without ATP, we observe the emergence of hundreds of CTCF-independent loops that link regulatory DNA. We also identify architectural "stripes," where a loop anchor interacts with entire domains at high frequency. Stripes often tether super-enhancers to cognate promoters, and in B cells, they facilitate Igh transcription and recombination. Stripe anchors represent major hotspots for topoisomerase-mediated lesions, which promote chromosomal translocations and cancer. In plasmacytomas, stripes can deregulate Igh-translocated oncogenes. We propose that higher organisms have coopted cohesin extrusion to enhance transcription and recombination, with implications for tumor development.


Interpreting surveys to estimate the size of the monarch butterfly population: Pitfalls and prospects.
To assess the change in the size of the eastern North American monarch butterfly summer population, studies have used long-term data sets of counts of adult butterflies or eggs per milkweed stem. Despite the observed decline in the monarch population as measured at overwintering sites in Mexico, these studies found no decline in summer counts in the Midwest, the core of the summer breeding range, leading to a suggestion that the cause of the monarch population decline is not the loss of Midwest agricultural milkweeds but increased mortality during the fall migration. Using these counts to estimate population size, however, does not account for the shift of monarch activity from agricultural fields to non-agricultural sites over the past 20 years, as a result of the loss of agricultural milkweeds due to the near-ubiquitous use of glyphosate herbicides. We present the counter-hypotheses that the proportion of the monarch population present in non-agricultural habitats, where counts are made, has increased and that counts reflect both population size and the proportion of the population observed. We use data on the historical change in the proportion of milkweeds, and thus monarch activity, in agricultural fields and non-agricultural habitats to show why using counts can produce misleading conclusions about population size. We then separate out the shifting proportion effect from the counts to estimate the population size and show that these corrected summer monarch counts show a decline over time and are correlated with the size of the overwintering population. In addition, we present evidence against the hypothesis of increased mortality during migration. The milkweed limitation hypothesis for monarch decline remains supported and conservation efforts focusing on adding milkweeds to the landscape in the summer breeding region have a sound scientific basis.


Novel transmembrane GTPase of non-small cell lung cancer identified by mRNA differential display.
The technique of differential display was used previously to profile the gene expression patterns of non-small cell lung cancer, and several genes differentially expressed were thus identified. In this report, we demonstrate that a DNA fragment of 347-bp length, up-regulated in tumor tissues, showed 100% sequence similarity to human cDNA FLJ20693 for a 370-residue protein. The gene product of cDNA FLJ20693 was postulated to be a shorter isoform of transmembrane GTPase, termed TG370, based upon the results of searching for sequence homology. The nucleotide sequence alignment also indicated that the cDNA FLJ20693 and the cDNA for 741-residue human mitofusin 1 (TG741) possibly resulted from the event of alternative splicing from which a 127-bp region was retained in the latter. Analysis of the genome sequence confirmed the speculation that both cDNAs were mapped to the same chromosomal position composing of 18 exons, of which the 127-bp region of TG741 constituted exon 11. The alternative splicing in all lung cancer cell lines was also observed to occur nearly in all tissue specimens examined. The up-regulated expression of transmembrane GTPase was subsequently found in tumor tissues from at least five of seven non-small cell lung cancer patients. Also, a distinct PCR product was initially detected in cell line H520, and further sequence analysis identified the presence of the 86-bp region mapped to the genome sequence immediately followed by exon 10. To evaluate the retention of 86-bp region, it was found that, besides the predicted 486-bp product, an unexpected 332-bp product was concomitantly observed and identified as the result of exon 8 deletion. The expression and subcellular localization of the full-length TG741 and other shorter isoforms were detected by flow cytometry using three polyclonal antibodies. It was concluded that the full-length TG741 located at plasma membrane with its NH(2)-terminal domain exposed extracellularly and the shorter isoforms retained at cytosol. Finally, the up-regulation of transmembrane GTPase in tumor tissues was further illustrated using immunohistochemical staining.


Scanning electron microscopy of the endometrium of mares infused with gentamicin.
Scanning electron microscopy (SEM) was used to study the endometrium of nine 1-year-old thoroughbred mares after twice intrauterine infusions of gentamicin, on 2 consecutive days. Five mares were infused on 2 consecutive days with 40 ml gentamicin (50 mg/ml) mixed with 80 ml of normal saline. Four mares served as controls and were infused with 120 ml of saline on 2 consecutive days. Endometrial biopsies were obtained from all mares 3 days after the second intrauterine infusion. Each biopsy was processed for SEM by standard methods. The endometrial epithelium of the gentamicin-infused mares had more cellular perforations than the saline-infused mares. The gentamicin-infused mares had less and shorter microvilli. The ciliated cells were fewer and some ciliated cells had disrupted and some had drooping cilia. The endometrial epithelium of the gentamicin-infused mares had a considerable number of endometrial cells that lost their luminal surfaces and some that lost their microvilli, compared to the saline-infused mares. We suggest that the information gathered in this pilot study should be used as basis for further investigation, on a larger scale basis, of the effects of repeated intrauterine infusion of gentamicin on the endometrial mucosa of mares.


[Multiple and successive treatment failures in a patient infected by Plasmodium falciparum in Cambodia and treated by dihydroartemisinin-piperaquine].
Cases of treatment failures following administration of artemisinin-based combination therapies (ACT) remain rare in malaria endemic areas. In Cambodia, however, failures of these treatments are now commonly observed. Usually, these post-treatment recurrences occur only once and a second course of the same treatment is sufficient to cure patients.We describe here an atypical case of a Plasmodium falciparum-infected patient manifesting several malaria recrudescence episodes following dihydroartemisinin-piperaquine (Eurartesim®) treatment. This case report illustrates the current issue of resistance to the latest generation of antimalarial drugs in Southeast Asia and highlights the difficulty in efficaciously fighting malaria in this region if new therapy remains unimplemented.


Evolving trends in the initial locoregional management of male breast cancer.
The locoregional management of breast cancer in men has evolved over time. Multimodality treatment regimens currently in use are based primarily on large randomized trials that exclusively enrolled women with breast cancer. We retrospectively reviewed cases of male breast cancer treated with radiotherapy at Stanford University Medical Center with an emphasis on 22 patients treated with surgery and locoregional radiotherapy. We report trends in the surgical techniques as well as in the use of adjuvant radiotherapy, chemotherapy, and hormonal therapy. There were no isolated locoregional failures in this cohort, and 5-year disease-free survival was 65%. The use of contemporary surgical and radiotherapeutic techniques in men is discussed. We conclude that treatment guidelines designed for women should be applied to the locoregional management of breast cancer in men. However, large international prospective registries and inclusion of men in cooperative group randomized trials will be important to confirm the safety and efficacy of modern treatment modalities for male breast cancer.


Pars compacta of the substantia nigra modulates motor activity but is not involved importantly in regulating food and water intake.
Precise, bilateral radio-frequency lesions of pars compacta of the substantia nigra in rats resulted in the immediate and sustained appearance of hyperactivity, but such lesions did not produce significant alterations in food or water intake. These behavioral effects were correlated with considerable, histochemically assessed loss of dopamine terminals in the caudate-putamen complex, but dopamine innervation in nucleus accumbens and other forebrain areas was only slightly affected. The magnitude of motor activity increase was positively correlated with the degree of pars compacta involvement. Animals with lesions in the median raphe and adjacent reticular formation also displayed chronic hyperactivity. In contrast to rats receiving discrete radio-frequency lesions of pars compacta, animals with bilateral mesencephalic ablations produced by 6-hydroxydopamine (6-OHDA, 8 micrograms/4 microliters or 4 micrograms/2 microliters in combination with desipramine pretreatment) displayed poverty of movement. Furthermore, significant, dose-dependent decrements in food and water intake were seen after 6-OHDA. The nonselective component of such lesions was frequently large and irregular in shape. Occasional ablations produced by this neurotoxin, however, appeared more selective in that damage was confined primarily to pars compacta. Nonetheless, the best correlate of aphagia and adipsia associated with 6-OHDA treatment was lesion size, regardless of the extent of pars compacta or other nigral involvement. We conclude that aphagia and adipsia concomitant to 6-OHDA lesions of the substantia nigra results from the incidental destruction of extra-nigral systems. Virtually complete, but precise, lesions of pars compacta do not produce aphagia and adipsia. While our results are consistent with the notion that the substantia nigra serves an important role in the regulation of motor activity, they provide no support for the conjecture that it is importantly involved in mediating ingestive behaviors.


Optimal set anode potentials vary in bioelectrochemical systems.
In bioelectrochemical systems (BESs), the anode potential can be set to a fixed voltage using a potentiostat, but there is no accepted method for defining an optimal potential. Microbes can theoretically gain more energy by reducing a terminal electron acceptor with a more positive potential, for example oxygen compared to nitrate. Therefore, more positive anode potentials should allow microbes to gain more energy per electron transferred than a lower potential, but this can only occur if the microbe has metabolic pathways capable of capturing the available energy. Our review of the literature shows that there is a general trend of improved performance using more positive potentials, but there are several notable cases where biofilm growth and current generation improved or only occurred at more negative potentials. This suggests that even with diverse microbial communities, it is primarily the potential of the terminal respiratory proteins used by certain exoelectrogenic bacteria, and to a lesser extent the anode potential, that determines the optimal growth conditions in the reactor. Our analysis suggests that additional bioelectrochemical investigations of both pure and mixed cultures, over a wide range of potentials, are needed to better understand how to set and evaluate optimal anode potentials for improving BES performance.


Particle size distribution retrieval from multiwavelength lidar signals for droplet aerosol.
A method of retrieval of the aerosol particle size distribution (APSD) from multiwavelength lidar signals is presented. Assumed distribution (usually a bimodal combination of lognormal functions) with a few free parameters is directly substituted into the lidar equations. The minimization technique allows one to find the parameters that provide the best fit of the assumed APSD by comparison of theoretically generated and experimental signals. Prior knowledge of the lidar ratio is not required. The approach was tested on a typical synthetic APSD consisting of spherical droplets. Comparison of lidar measurements with results from a condensation particle counter was also performed. For signals registered at 3-5 wavelengths from the UV to the near IR a satisfactory retrieval of synthetic APSD is possible for the particles within the 100-3000 nm range.


Reconstitution dynamics of plasmacytoid and myeloid dendritic cell precursors after allogeneic myeloablative hematopoietic stem cell transplantation.
Dendritic cells (DCs) are fundamental for immunity. We investigated reconstitution of plasmacytoid DC (PDC) and myeloid DC (My-DC) precursors in the first 2 months after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). Circulating DCs were monitored from the earliest phase of hematopoietic reconstitution in 43 children given standard therapy to prevent graft-versus-host disease (GVHD) and either treated or untreated with granulocyte colony-stimulating factor (G-CSF) after HSCT. In patients without GVHD, both My-DCs and PDCs reached consistently high absolute values during the initial phase. Time of engraftment did not differ between My-DCs and PDCs, regardless of administration of G-CSF. Treatment with G-CSF (1) accelerated early recovery of My-DC absolute numbers; (2) was associated with lower numbers of both My-DCs and PDCs in the later phase; and (3) significantly reduced the proportion of interleukin-12 (IL-12)-secreting cells. In some patients who developed acute GVHD, we found high numbers of circulating DC precursors during the early phase of this complication. However, treatment with steroids invariably induced rapid decrease of PDCs. Altogether, these data provide an evaluation of DC release after Allo-HSCT, indicate that postgrafting administration of G-CSF impairs the appearance of IL-12-producing DCs, and suggest that DC homeostasis may be disrupted at onset of GVHD.


A biogenic secondary organic aerosol source of cirrus ice nucleating particles.
Atmospheric ice nucleating particles (INPs) influence global climate by altering cloud formation, lifetime, and precipitation efficiency. The role of secondary organic aerosol (SOA) material as a source of INPs in the ambient atmosphere has not been well defined. Here, we demonstrate the potential for biogenic SOA to activate as depositional INPs in the upper troposphere by combining field measurements with laboratory experiments. Ambient INPs were measured in a remote mountaintop location at -46 °C and an ice supersaturation of 30% with concentrations ranging from 0.1 to 70 L-1. Concentrations of depositional INPs were positively correlated with the mass fractions and loadings of isoprene-derived secondary organic aerosols. Compositional analysis of ice residuals showed that ambient particles with isoprene-derived SOA material can act as depositional ice nuclei. Laboratory experiments further demonstrated the ability of isoprene-derived SOA to nucleate ice under a range of atmospheric conditions. We further show that ambient concentrations of isoprene-derived SOA can be competitive with other INP sources. This demonstrates that isoprene and potentially other biogenically-derived SOA materials could influence cirrus formation and properties.


Geomagnetic intensity variations over the past 780 kyr obtained from near-seafloor magnetic anomalies.
Knowledge of past variations in the intensity of the Earth's magnetic field provides an important constraint on models of the geodynamo. A record of absolute palaeointensity for the past 50 kyr has been compiled from archaeomagnetic and volcanic materials, and relative palaeointensities over the past 800 kyr have been obtained from sedimentary sequences. But a long-term record of geomagnetic intensity should also be carried by the thermoremanence of the oceanic crust Here we show that near-seafloor magnetic anomalies recorded over the southern East Pacific Rise are well correlated with independent estimates of geomagnetic intensity during the past 780 kyr. Moreover, the pattern of absolute palaeointensity of seafloor glass samples from the same area agrees with the well-documented dipole intensity pattern for the past 50 kyr. A comparison of palaeointensities derived from seafloor glass samples with global intensity variations thus allows us to estimate the ages of surficial lava flows in this region. The record of geomagnetic intensity preserved in the oceanic crust should provide a higher-time-resolution record of crustal accretion processes at mid-ocean ridges than has previously been obtainable.


Lomefloxacin and temafloxacin: two new fluoroquinolone antimicrobials.
The chemistry, mechanism of action, antimicrobial spectrum, pharmacokinetics, clinical efficacy, safety, drug interactions, and dosage and administration of lomefloxacin and temafloxacin, two new antimicrobials, are presented. Lomefloxacin and temafloxacin exhibit activity comparable to that of ciprofloxacin against the Enterobacteriaceae. Lomefloxacin has only modest activity against common gram-positive organisms. Temafloxacin exhibits increased activity against the streptococci and moderate activity against many anaerobes, as compared with ciprofloxacin. Lomefloxacin and temafloxacin have only moderate antipseudomonal activity. Their elimination half-lives are 6-10 hours and they have good oral absorption, excellent penetration into many tissues and fluids, and a better drug-interaction profile than other similar agents. Lomefloxacin has demonstrated comparable efficacy to other therapies in the treatment of lower respiratory-tract infections and urinary-tract infections (UTIs) and for prophylaxis before surgical procedures in the urinary tract. Temafloxacin has been shown to be effective in the treatment of lower respiratory-tract infections, infections of the skin and associated structures, uncomplicated and complicated UTIs, bacterial prostatitis, and gonococcal and non-gonococcal urethritis and cervicitis. The most frequent adverse effects with lomefloxacin are gastrointestinal upset and headache; with temafloxacin, gastrointestinal complaints. Lomefloxacin's dosage is 400 mg p.o. daily for 10 days for treatment of acute bacterial exacerbations in chronic bronchitis or simple cystitis and for 14 days for treatment of complicated UTIs. Lomefloxacin is a new oral fluoroquinolone that is indicated for the treatment of various bacterial infections. Temafloxacin, another new fluoroquinolone, appeared to have some favourable characteristics but was withdrawn from the market.


Growth-stimulatory activity of TIMP-2 is mediated through c-Src activation followed by activation of FAK, PI3-kinase/AKT, and ERK1/2 independent of MMP inhibition in lung adenocarcinoma cells.
Tissue inhibitors of metalloproteinases (TIMPs) control extracellular matrix (ECM) homeostasis by inhibiting the activity of matrix metalloproteinases (MMPs), which are associated with ECM turnover. Recent studies have revealed that TIMPs are implicated in tumorigenesis in both MMP-dependent and MMP-independent manners. We examined a mechanism by which TIMP-2 stimulated lung adenocarcinoma cell proliferation, independent of MMP inhibition. The stimulation of growth by TIMP-2 in A549 cells required c-Src kinase activation. c-Src kinase activity, induced by TIMP-2, concomitantly increased FAK, phosphoinositide 3-kinase (PI3-kinase)/AKT, and ERK1/2 activation. Selective knockdown of integrin α3β1, known as a TIMP-2 receptor, did not significantly change TIMP-2 growth promoting activity. Furthermore, we showed that high TIMP-2 expression in lung adenocarcinomas is associated with a worse prognosis from multiple cohorts, especially for stage I lung adenocarcinoma. Through integrated analysis of The Cancer Genome Atlas data, TIMP-2 expression was significantly associated with the alteration of driving genes, c-Src activation, and PI3-kinase/AKT pathway activation. Taken together, our results demonstrate that TIMP-2 stimulates lung adenocarcinoma cell proliferation through c-Src, FAK, PI3-kinase/AKT, and ERK1/2 pathway activation in an MMP-independent manner.


Non-invasive Measures of Core Temperature versus Ingestible Thermistor during Exercise in the Heat.
The accuracy of core temperature (Tc) thermometry from temporal, tympanic, and oral thermometry devices has been variable during exercise in a hot, humid environment. The purpose of the present study was to cross-validate temporal, two tympanic devices, and oral devices compared to an ingestible thermistor during exercise in a hot, humid environment. Fourteen young, active adults (6 women) completed a graded exercise test until voluntary exhaustion in an environmental chamber (35.5 ± 0.6 °C, 53.9 ± 5.8 % RH). There was no statistical difference in mean temperature between tympanic device 1 and pill-based core temperature (PBTc) measurements across all time points and were positively correlated (0.357; P<0.001). Temperatures of tympanic device 2 were statistically higher than PBTc (37.8 ± 0.7 ºC vs. 37.6 ± 1.0 ºC; respectfully) (P=0.008). At all time points, temperatures for the second tympanic device and PBTc were positively correlated (0.192; P=0.043). Temporal and PBTc values did not differ across time points and were positively correlated (0.262; P=0.005) across all time points. Mean oral temperature was significantly less than mean PBTc across all time points. (37.0 ± 0.4 ºC vs. 37.6 ± 1.0 ºC, respectively) (P<0.001). Across all time points, oral and PBTc were positively correlated (0.262; P=0.010). Tympanic and temporal devices can reflect Tc while exercising in a hot, humid environment. However, care should be taken when selecting the tympanic or temporal measurement device and validation is advised prior to heat illness mitigation in the field.


Patterns of Virulence Diversity in Puccinia triticina on Wheat in Egypt and the United States in 1998-2000.
Frequent epidemics of leaf rust in Egypt have been attributed to the appearance of new races virulent on commonly grown wheat cultivars. In 1998, 1999, and 2000, 726 isolates of Puccinia triticina collected in Egypt were tested on a set of 20 single Lr gene differential wheat lines, and 160 races were identified. Three races, MBDLQ, MCDLQ, and TCDMQ, were found in Egypt in all 3 years. Race MCDLQ occurred at >20% frequency each year. Virulences to wheat lines with Lr1, 3, 10, 14b, 15, 17, 23, and 26 occurred at >45% each year. Seven races found in Egypt also were found in either Israel, Sudan, Turkey, or Romania in 1998 or 1999, although the one race common to Sudan and Egypt was rare in Egypt (only 1 year, <1%). Four races found in Israel also were found in Egypt, and the similarity of virulence frequencies in Israel and Egypt indicate at least some exchange of inoculum. Romania and Turkey did not appear to be major sources of inoculum for leaf rust epidemics in Egypt. The level of genetic diversity in leaf rust collections in Egypt in 1998 to 2000 was similar to that of collections from the Southern and Central Plains of the United States in 1998 to 2000. The high diversity of races and the recurrence of common races in each year in Egypt as in the Southern and Central Plains of the United States is consistent with oversummer survival of P. triticina within Egypt or in a neighboring country. The buildup of races virulent on cultivars with the most commonly used Lr genes for resistance in Egypt also is consistent with year-round survival within Egypt or cyclical exchange of inoculum between Egypt and a neighboring country.


Identifying Hotspots of Multidrug-Resistant Tuberculosis Transmission Using Spatial and Molecular Genetic Data.
We aimed to identify and determine the etiology of "hotspots" of concentrated multidrug-resistant tuberculosis (MDR-tuberculosis) risk in Lima, Peru. From 2009 to 2012, we conducted a prospective cohort study among households of tuberculosis cases from 106 health center (HC) areas in Lima, Peru. All notified tuberculosis cases and their household contacts were followed for 1 year. Symptomatic individuals were screened by microscopy and culture; positive cultures were tested for drug susceptibility (DST) and genotyped by 24-loci mycobacterial interspersed repetitive units-variable-number tandem repeats (MIRU-VNTR). 3286 individuals with culture-confirmed disease, DST, and 24-loci MIRU-VNTR were included in our analysis. Our analysis reveals: (1) heterogeneity in annual per-capita incidence of tuberculosis and MDR-tuberculosis by HC, with a rate of MDR-tuberculosis 89 times greater (95% confidence interval [CI], 54,185) in the most-affected versus the least-affected HC; (2) high risk for MDR-tuberculosis in a region spanning several HCs (odds ratio = 3.19, 95% CI, 2.33, 4.36); and (3) spatial aggregation of MDR-tuberculosis genotypes, suggesting localized transmission. These findings reveal that localized transmission is an important driver of the epidemic of MDR-tuberculosis in Lima. Efforts to interrupt transmission may be most effective if targeted to this area of the city.


Mitochondrial reprogramming induced by CaMKIIδ mediates hypertrophy decompensation.
Sustained activation of Gαq transgenic (Gq) signaling during pressure overload causes cardiac hypertrophy that ultimately progresses to dilated cardiomyopathy. The molecular events that drive hypertrophy decompensation are incompletely understood. Ca(2+)/calmodulin-dependent protein kinase II δ (CaMKIIδ) is activated downstream of Gq, and overexpression of Gq and CaMKIIδ recapitulates hypertrophy decompensation. To determine whether CaMKIIδ contributes to hypertrophy decompensation provoked by Gq. Compared with Gq mice, compound Gq/CaMKIIδ knockout mice developed a similar degree of cardiac hypertrophy but exhibited significantly improved left ventricular function, less cardiac fibrosis and cardiomyocyte apoptosis, and fewer ventricular arrhythmias. Markers of oxidative stress were elevated in mitochondria from Gq versus wild-type mice and respiratory rates were lower; these changes in mitochondrial function were restored by CaMKIIδ deletion. Gq-mediated increases in mitochondrial oxidative stress, compromised membrane potential, and cell death were recapitulated in neonatal rat ventricular myocytes infected with constitutively active Gq and attenuated by CaMKII inhibition. Deep RNA sequencing revealed altered expression of 41 mitochondrial genes in Gq hearts, with normalization of ≈40% of these genes by CaMKIIδ deletion. Uncoupling protein 3 was markedly downregulated in Gq or by Gq expression in neonatal rat ventricular myocytes and reversed by CaMKIIδ deletion or inhibition, as was peroxisome proliferator-activated receptor α. The protective effects of CaMKIIδ inhibition on reactive oxygen species generation and cell death were abrogated by knock down of uncoupling protein 3. Conversely, restoration of uncoupling protein 3 expression attenuated reactive oxygen species generation and cell death induced by CaMKIIδ. Our in vivo studies further demonstrated that pressure overload induced decreases in peroxisome proliferator-activated receptor α and uncoupling protein 3, increases in mitochondrial protein oxidation, and hypertrophy decompensation, which were attenuated by CaMKIIδ deletion. Mitochondrial gene reprogramming induced by CaMKIIδ emerges as an important mechanism contributing to mitotoxicity in decompensating hypertrophy.


The familial transmission of bipolar illness.
As part of the National Institute of Mental Health Collaborative Program on the Psychobiology of Depression study, data were collected on 2225 first-degree relatives of 612 probands. We analyzed 187 families of bipolar patients (149 probands with a diagnosis of bipolar I disorder and 38 with a diagnosis of schizoaffective, manic subtype). Using traditional genetic methods, the morbid risk of bipolar illness in relatives was found to be 5.7% in the relatives of bipolar probands as contrasted with 1.1% in the relatives of probands with major depression. These values compared closely with those obtained using survival analysis. Relatives of probands with early onset were found to have a greater risk than relatives of probands with late onset. The sex of the relative, the sex of the proband, or the subtype of the proband (bipolar I or schizoaffective bipolar) did not influence the risk in the relative. The age at onset was found to be accelerated with birth cohort, with individuals born in more recent cohorts having an earlier onset. Multifactorial analysis found significant heterogeneity for sex-specific sibling correlations (with the brother-sister correlation smaller than the same-sexed correlations), and path analysis estimated transmissibility of liability to be 71%. The mixed model, which allows for a single major locus with a multifactorial background, gave evidence for the presence of a major locus when controlling for the effects of birth cohort and age at onset. However, this evidence is tempered when comparing the mixed model with a more general transmission model.


Pisa-Like Syndrome Under Baclofen in a Patient With Spastic Hemiparesis due to Ischemic Stroke.
In its original description, Pisa syndrome was reported as an iatrogenic dystonia of the trunk caused by neuroleptic drugs. However, sometimes, not dystonic lateral flexion of the trunk is described as Pisa syndrome. These observations support the possibility of a drug-induced lateral flexion of the trunk with clinical presentation similar to Pisa syndrome, although with a different etiology and pathophysiology. Here, we describe the case of a male patient, with a previous ischemic stroke and residual spastic hemiparesis to the right side, who subacutely developed a dramatic lateral flexion of trunk (approximately 45° to the right) a few days after the introduction of Baclofen (5 mg 3 times per day). After the discontinuation of baclofen, a full recovery of the correct posture was obtained. In this respect, our case is paradigmatic: it is drug-induced but not clearly dystonic in its manifestation. Baclofen reduces the spasticity depressing the monosinaptic and polisinaptic reflex in the spinal cord by stimulating Gamma-aminobutyric acid B (GABA-B) receptors, which inhibit the release of excitatory amino acids, glutamate and aspartate. We believe that the definition of Pisa syndrome for these forms, not clearly dystonic, might be not completely appropriate, but they should be defined more correctly as Pisa-like syndromes.


Clonal spread of methicillin-resistant Staphylococcus pseudintermedius in Europe and North America: an international multicentre study.
The aim of this study was to determine the phenotypic and genotypic resistance profiles of methicillin-resistant Staphylococcus pseudintermedius (MRSP) and to examine the clonal distribution in Europe and North America. A total of 103 MRSP isolates from dogs isolated from several countries in Europe, the USA and Canada were characterized. Isolates were identified by PCR-restriction fragment length polymorphism (RFLP), antimicrobial susceptibility was determined by broth dilution or gradient diffusion, and antimicrobial resistance genes were detected using a microarray. Genetic diversity was assessed by multilocus sequence typing (MLST), PFGE and spa typing. Staphylococcal cassette chromosome mec (SCCmec) elements were characterized by multiplex PCR. Thirteen different sequence types (STs), 18 PFGE types and 8 spa types were detected. The hybrid SCCmec element II-III described in a MRSP isolate was present in 75 (72.8%) isolates. The remaining isolates either had SCCmec type III (n=2), IV (n=6), V (n=14) or VII-241 (n=4) or were non-typeable (n=2). The most common genotypes were ST71(MLST)-J(PFGE)-t02(spa)-II-III(SCCmec) (56.3%) and ST68-C-t06-V (12.6%). In addition to mecA-mediated beta-lactam resistance, isolates showed resistance to trimethoprim [dfr(G)] (90.3%), gentamicin/kanamycin [aac(6')-Ie-aph(2')-Ia] (88.3%), kanamycin [aph(3')-III] (90.3%), streptomycin [ant(6')-Ia] (90.3%), streptothricin (sat4) (90.3%), macrolides and/or lincosamides [erm(B), lnu(A)] (89.3%), fluoroquinolones (87.4%), tetracycline [tet(M) and/or tet(K)] (69.9%), chloramphenicol (cat(pC221)) (57.3%) and rifampicin (1.9%). Two major clonal MRSP lineages have disseminated in Europe (ST71-J-t02-II-III) and North America (ST68-C-t06-V). Regardless of their geographical or clonal origin, the isolates displayed resistance to the major classes of antibiotics used in veterinary medicine and thus infections caused by MRSP isolates represent a serious therapeutic challenge.


Glycosylation pathways as drug targets for cancer: glycosidase inhibitors.
The combined and ordered sequential action of glycosidases and glycosyltransferases in mammalian cell compartments leads to the addition of defined glycans to proteins and lipids. Altered glycosylation patterns, neoexpression, underexpression or overexpression of glycans are a hallmark of cancer. These changes are either found in the core or the terminal structures of the carbohydrates of glycoproteins. Affected proteins can be either cellular, cell-surface or secreted proteins, and glycosylation modifications frequently result in a modified expression, metabolism, functions, properties, stability and/or cellular localization of glycoproteins in cancer cells, resulting in part in their uncontrolled growth and aggressive behavior. Therefore glycosylation pathways, and the glycosidases and glycosyltransferases of these pathways, represent potential innovative modalities for drug development in cancer therapies which are just beginning to be explored. This review proposes to summarize the published information for glycosidases and their inhibitors in cancer.


Population dynamical consequences of climate change for a small temperate songbird.
Predicting the effects of an expected climatic change requires estimates and modeling of stochastic factors as well as density-dependent effects in the population dynamics. In a population of a small songbird, the dipper (Cinclus cinclus), environmental stochasticity and density dependence both influenced the population growth rate. About half of the environmental variance was explained by variation in mean winter temperature. Including these results in a stochastic model shows that an expected change in climate will strongly affect the dynamics of the population, leading to a nonlinear increase in the carrying capacity and in the expected mean population size.


What Is the Giant Wall Gecko Having for Dinner? Conservation Genetics for Guiding Reserve Management in Cabo Verde.
Knowledge on diet composition of a species is an important step to unveil its ecology and guide conservation actions. This is especially important for species that inhabit remote areas within biodiversity hotspots, with little information about their ecological roles. The emblematic giant wall gecko of Cabo Verde, Tarentola gigas, is restricted to the uninhabited Branco and Raso islets, and presents two subspecies. It is classified as Endangered, and locally Extinct on Santa Luzia Island; however, little information is known about its diet and behaviour. In this study, we identified the main plant, arthropods, and vertebrates consumed by both gecko subspecies using next generation sequencing (NGS) (metabarcoding of faecal pellets), and compared them with the species known to occur on Santa Luzia. Results showed that plants have a significant role as diet items and identified vertebrate and invertebrate taxa with higher taxonomic resolution than traditional methods. With this study, we now have data on the diet of both subspecies for evaluating the reintroduction of this threatened gecko on Santa Luzia as potentially successful, considering the generalist character of both populations. The information revealed by these ecological networks is important for the development of conservation plans by governmental authorities, and reinforces the essential and commonly neglected role of reptiles on island systems.


Early and sufficient feeding reduces length of stay and charges in surgical patients.
The role of perioperative nutrition in surgical patients remains controversial. We performed a Clinical Practice Improvement (CPI) study that, while controlling for severity of illness, explored the relationship between the timing and amount of parenteral or enteral nutrition, with two outcomes: length of stay (LOS) and total charges in patients undergoing open intestinal operations. A CPI study was conducted at eight hospitals to determine which process steps were associated with shorter LOS and lower charges. Hospital charts were abstracted for over 800 components of detailed patient, process, and outcome measures. Severity of illness was measured multiple times during the stay using the Comprehensive Severity Index, a disease-specific physiologic severity measurement instrument. Data on 1007 patients undergoing intestinal operations, 183 of whom received nutritional support, were then analyzed using multiple regression procedures. Early (within 48 h of surgery) and sufficient (60% of protein and calorie goals) nutrition, patient variables, and a severity of illness measure were included as independent variables and LOS and hospital charges were used as dependent variables. Mean patient age was 58 years. After controlling for severity of illness, patients who received early and sufficient nutrition had significantly shorter LOS (11.9 days) and lower charges ($34,602) than patients who received early (13.3; $36,452), sufficient (14.6, $39,883), or neither early nor sufficient (14.8, $38,578) (P < or = 0.0001 for early and sufficient versus all other groups). CPI methodology provides a detailed view of the actual relationship between the timing and the amount of nutrition with LOS and hospital charge outcomes.


The kinetic basis for dual recognition in colicin endonuclease-immunity protein complexes.
The antibacterial activity of E colicin endonucleases (DNases) is counteracted by the binding of immunity proteins; the affinities of cognate and non-cognate complexes differing by up to ten orders of magnitude. Here, we address the mechanism of complex formation using a combination of protein engineering, pre-steady-state kinetics and isothermal titration calorimetry, in order to understand the underlying basis for specificity. Contrary to previous work, we show that a pre-equilibrium mechanism does not explain the binding kinetics. Instead, the data are best explained by a modified induced-fit mechanism where cognate and non-cognate complexes alike form a non-specific, conformationally dynamic encounter complex, most likely centred on conserved interactions at the interface. The dynamics appear to be an intrinsic property of the encounter complex where the proteins move relative to one another, thereby sampling different conformations rather than being "induced" by binding. This allows optimal alignment of interface specificity sites, without producing energetically costly conformational changes, essential for high-affinity binding. Importantly, specificity is achieved without slowing the rate of association, an important requirement for rapid inhibition of the colicin in the producing bacterial cell. A rigid-body rotation model is also consistent with the observation that specificity contacts in colicin-immunity protein complexes can involve different regions of the interface. Such a kinetic discrimination mechanism explains the ability of DNase-specific immunity proteins to display dual recognition specificity, wherein they are broadly cross-reactive yet are highly specific, achieving femtomolar binding affinities in complexes with their cognate DNases.


A feasibility study of a new computerised cognitive remediation for young adults with schizophrenia.
Cognitive remediation therapy is effective for improving cognition, symptoms and social functioning in individuals with schizophrenia; however, the impact on visual episodic memory remains unclear. The objectives of this feasibility study were: (1) to explore whether or not CIRCuiTS--a new computerised cognitive remediation therapy programme developed in England--improves visual episodic memory and other cognitive domains in young adults with early course schizophrenia; and (2) to evaluate acceptability of the CIRCuiTS programme in French-Canadians. Three participants with visual episodic memory impairments at baseline were recruited from clinical settings in Canada, and consented to participate. Neuropsychological, clinical and social functioning was evaluated at baseline and post-treatment. Intervention involved 40 sessions of cognitive remediation. First, the reliable change index (RCI) revealed that each participant demonstrated significant post-therapy change in episodic memory and in other cognitive domains. The response profile was characterised by the use of organisational strategies. Second, the treatment was considered acceptable to participants in terms of session frequency (number of sessions per week), intensity (hours per week; total hours), and number of missed sessions and total completed sessions. This preliminary study yielded encouraging data demonstrating the feasibility of the CIRCuiTS programme in French-Canadian young adults with schizophrenia.


Oxidative Injury and Iron Redistribution Are Pathological Hallmarks of Marmoset Experimental Autoimmune Encephalomyelitis.
Oxidative damage and iron redistribution are associated with the pathogenesis and progression of multiple sclerosis (MS), but these aspects are not entirely replicated in rodent experimental autoimmune encephalomyelitis (EAE) models. Here, we report that oxidative burst and injury as well as redistribution of iron are hallmarks of the MS-like pathology in the EAE model in the common marmoset. Active lesions in the marmoset EAE brain display increased expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p22phox, p47phox, and gp91phox) and inducible nitric oxide synthase immunoreactivity within lesions with active inflammation and demyelination, coinciding with enhanced expression of mitochondrial heat-shock protein 70 and superoxide dismutase 1 and 2. The EAE lesion-associated liberation of iron (due to loss of iron-containing myelin) was associated with altered expression of the iron metabolic markers FtH1, lactoferrin, hephaestin, and ceruloplasmin. The enhanced expression of oxidative damage markers in inflammatory lesions indicates that the enhanced antioxidant enzyme expression could not counteract reactive oxygen and nitrogen species-induced cellular damage, as is also observed in MS brains. This study demonstrates that oxidative injury and aberrant iron distribution are prominent pathological hallmarks of marmoset EAE thus making this model suitable for therapeutic intervention studies aimed at reducing oxidative stress and associated iron dysmetabolism.


Testosterone therapy for men at risk for or with history of prostate cancer.
Since the early 1940s when Huggins showed that severe reductions in serum testosterone by castration or estrogen therapy caused regression of prostate cancer (PCa), it has been assumed that higher testosterone levels cause enhanced growth of PCa. For this reason, it has been considered taboo to offer testosterone replacement therapy (TRT) to any man with a prior history of PCa, even if all objective evidence suggests he has been cured. The fear has been that higher testosterone levels would "awaken" dormant cells and cause a recurrence. Thus, US Food and Drug Administration-mandated language in all testosterone package inserts states that testosterone is contraindicated in men with a history of, or suspected of having, PCa. Although there is little modern experience with administration of testosterone in men with known history of PCa, there is a varied and extensive literature indicating that TRT does not pose any increased risk of PCa growth in men with or without prior treatment. For instance, the cancer rate in TRT trials is only approximately 1%, similar to detection rates in screening programs, yet biopsy-detectable PCa is found in one of seven hypogonadal men. Moreover, PCa is almost never seen in the peak testosterone years of the early 20s, despite autopsy evidence that men in this age group already harbor microfoci of PCa in substantial numbers. The growing number of PCa survivors who happen to be hypogonadal and request treatment has spurred a change in attitude toward this topic, with increasing numbers of physicians now offering TRT to men who appear cured of their disease. Publications have now reported no prostate-specific antigen (PSA) recurrence with TRT in small numbers of men who had undetectable PSA values after radical prostatectomy. Although still controversial, there appears to be little reason to withhold TRT from men with favorable outcomes after definitive treatment for PCa. Monitoring with PSA and digital rectal examination at regular intervals is recommended.


Porous coordination polymers based on functionalized Schiff base linkers: enhanced CO2 uptake by pore surface modification.
We report the synthesis, structural characterization and adsorption properties of three new porous coordination polymers {[Cu(Meazpy)0.5(glut)](H2O)}n (2), {[Zn(azpy)0.5(terep)](H2O)}n (3), and {[Zn(Meazpy)0.5(terep)]}n (4) [glut = glutarate, terep = terephthalate, azpy = N,N'-bis-(pyridin-4-ylmethylene)hydrazine and Meazpy = N,N'-bis-(1-pyridin-4-ylethylidene)hydrazine] composed of mixed linkers systems. Structure determination reveals that all three compounds have three-dimensional (3D) coordination frameworks bridged by dicarboxylates and Schiff base linkers. In all cases 2D dicarboxylate layers are supported by paddle-wheel M2(CO2)4 SBUs extended in three dimensions by designed Schiff base linkers. Compound 1, which has been reported in a paper earlier by our group, is a robust porous three-dimensional (3D) framework whose pore surface was found to be decorated with the -CH=N- groups of a linear Schiff base (azpy) and it showed reversible single-crystal-to-single-crystal transformation and selective CO2 uptake. By using another linear Schiff base linker Meazpy, we have synthesized compound 2 which is isostructural with 1, having an additional methyl group pointing towards the pore. Like 1 it also shows a reversible single-crystal-to-single-crystal transformation upon dehydration and rehydration. The dehydrated framework of 2 exhibits 50% enhanced CO2 uptake compared to 1. This has been achieved by the pore surface modification effected upon changing the pillar backbone from a -CH=N- to -CMe=N- group. It also adsorbs water vapour at 298 K. In the case of the two isostructural 3D MOFs 3and 4, the use of a rigid carboxylate (terephthalate) linker arrested porosity by three-fold interpenetration. We showed that the use of aliphatic dicarboxylate (glutarate) results in a non-interpenetrated framework rather than the common interpenetrated framework with aromatic dicarboxylates in mixed ligand systems.


Metabolism of orally administered tauroursodeoxycholic acid in patients with primary biliary cirrhosis.
The metabolism of tauroursodeoxycholic acid orally administered and its effects on the bile acid pool of patients with asymptomatic/mildly symptomatic primary biliary cirrhosis is described. Patients were randomly assigned 500, 1000, or 1500 mg/day of tauroursodeoxycholate for six months. Biliary and serum bile acids were measured before and during treatment by gas chromatography-mass spectrometry and by high performance liquid chromatography. During tauroursodeoxycholate administration, the proportion of total ursodeoxycholate in bile reached mean (SEM) 34.4 (4.5)%, 32.8 (2.8)%, and 41.6 (3.0)% with doses of 500, 1000, and 1500 mg/day, respectively. Significant decreases in the proportions of chenodeoxycholate and cholate resulted. The glycine/taurine ratio of the biliary bile acid pool decreased from 1.9 at baseline, to 1.1 with the highest dose. Ursodeoxycholate in bile was conjugated with glycine and taurine, indicating that tauroursodeoxycholate undergoes significant deconjugation and reconjugation during its enterohepatic recycling. The proportion of lithocholate in bile remained unchanged. Fasting serum conjugated ursodeoxycholate concentration positively correlated with the tauroursodeoxycholate dose, and the increased proportion of ursodeoxycholate was accompanied by substantial decreases in the endogenous bile acids. Compared with previously published data for ursodeoxycholic acid therapy, these findings indicate that the shift toward a more hydrophilic bile acid pool is greater and potentially more favourable with tauroursodeoxycholate, and this is because of the reduced intestinal biotransformation of tauroursodeoxycholate.


Complete genome sequence of the myxobacterium Sorangium cellulosum.
The genus Sorangium synthesizes approximately half of the secondary metabolites isolated from myxobacteria, including the anti-cancer metabolite epothilone. We report the complete genome sequence of the model Sorangium strain S. cellulosum So ce56, which produces several natural products and has morphological and physiological properties typical of the genus. The circular genome, comprising 13,033,779 base pairs, is the largest bacterial genome sequenced to date. No global synteny with the genome of Myxococcus xanthus is apparent, revealing an unanticipated level of divergence between these myxobacteria. A large percentage of the genome is devoted to regulation, particularly post-translational phosphorylation, which probably supports the strain's complex, social lifestyle. This regulatory network includes the highest number of eukaryotic protein kinase-like kinases discovered in any organism. Seventeen secondary metabolite loci are encoded in the genome, as well as many enzymes with potential utility in industry.


An Expanded Polyproline Domain Maintains Mutant Huntingtin Soluble in vivo and During Aging.
Huntington's disease is a dominantly inherited neurodegenerative disorder caused by the expansion of a CAG repeat, encoding for the amino acid glutamine (Q), present in the first exon of the protein huntingtin. Over the threshold of Q39 HTT exon 1 (HTTEx1) tends to misfold and aggregate into large intracellular structures, but whether these end-stage aggregates or their on-pathway intermediates are responsible for cytotoxicity is still debated. HTTEx1 can be separated into three domains: an N-terminal 17 amino acid region, the polyglutamine (polyQ) expansion and a C-terminal proline rich domain (PRD). Alongside the expanded polyQ, these flanking domains influence the aggregation propensity of HTTEx1: with the N17 initiating and promoting aggregation, and the PRD modulating it. In this study we focus on the first 11 amino acids of the PRD, a stretch of pure prolines, which are an evolutionary recent addition to the expanding polyQ region. We hypothesize that this proline region is expanding alongside the polyQ to counteract its ability to misfold and cause toxicity, and that expanding this proline region would be overall beneficial. We generated HTTEx1 mutants lacking both flanking domains singularly, missing the first 11 prolines of the PRD, or with this stretch of prolines expanded. We then followed their aggregation landscape in vitro with a battery of biochemical assays, and in vivo in novel models of C. elegans expressing the HTTEx1 mutants pan-neuronally. Employing fluorescence lifetime imaging we could observe the aggregation propensity of all HTTEx1 mutants during aging and correlate this with toxicity via various phenotypic assays. We found that the presence of an expanded proline stretch is beneficial in maintaining HTTEx1 soluble over time, regardless of polyQ length. However, the expanded prolines were only advantageous in promoting the survival and fitness of an organism carrying a pathogenic stretch of Q48 but were extremely deleterious to the nematode expressing a physiological stretch of Q23. Our results reveal the unique importance of the prolines which have and still are evolving alongside expanding glutamines to promote the function of HTTEx1 and avoid pathology.