Correlation between coagulation function, tumor stage and metastasis in patients with renal cell carcinoma: a retrospective study.
The coagulation function in carcinoma patients is abnormal, but in renal cell carcinoma the extent and relationships of coagulation function remain unclear. This study retrospectively investigated the relationships between coagulation function, clinical stage and metastasis in patients with renal cell carcinoma. A total of 350 consecutive patients admitted to our Urology Department from 2004 to 2010 were diagnosed with renal cell carcinoma by histopathologic examination and were included in this study. A total of 231 cases of renal benign tumors were considered as the control group. Fibrinogen, prothrombin time, activated partial thromboplastin time and international normalized ratio were evaluated in all subjects. Tumor size, clinical stage, lymph node metastasis, and distant metastasis were evaluated using radiologic imaging, intraoperative findings, and histological studies. The preoperative plasma fibrinogen levels of patients with renal cell carcinoma ((383.9 ± 146.7) mg/dl) were significantly higher than those of the control group ((316.7 ± 62.0) mg/dl) (P < 0.01). We divided the renal cell carcinoma group into stages Ia, Ib, II, III, and IV. The fibrinogen values were (315.6 ± 64.6) mg/dl, (358.3 ± 91.1) mg/dl, (465.6 ± 164.7) mg/dl, (500.0 ± 202.1) mg/dl, and (585.8 ± 179.7) mg/dl, respectively. There were no significant differences in fibrinogen values between stage Ia and control groups. However, results of other stages showed significant differences when compared to control group values (P < 0.01). Using the cutoff value of 440 mg/dl, which defines hyperfibrinogenemia, plasma fibrinogen levels had a positive predictive value of 39.8% and a negative predictive value of 93.3% for predicting distant metastasis, with a sensitivity of 64.7% and specificity of 83.3%. Preoperative plasma fibrinogen levels are elevated in patients with renal cell carcinoma with distant metastasis or lymph node metastasis. Potential metastasis is more likely if the tumor size larger than 4 cm. Increased preoperative plasma fibrinogen levels, especially hyperfibrinogenemia, may be an indicator of metastasis.


Timing of Resource Addition Affects the Migration Behavior of Wood Decomposer Fungal Mycelia.
Studies of fungal behavior are essential for a better understanding of fungal-driven ecological processes. Here, we evaluated the effects of timing of resource (bait) addition on the behavior of fungal mycelia when it remains in the inoculum and when it migrates from it towards a bait, using cord-forming basidiomycetes. Experiments allowed mycelium to grow from an inoculum wood across the surface of a soil microcosm, where it encountered a new wood bait 14 or 98 d after the start of growth. After the 42-d colonization of the bait, inoculum and bait were individually moved to a dish containing fresh soil to determine whether the mycelia were able to grow out. When the inoculum and bait of mycelia baited after 14 d were transferred to new soil, there was 100% regrowth from both inoculum and bait in Pholiota brunnescens and Phanerochaete velutina, indicating that no migration occurred. However, when mycelium was baited after 98 d, 3 and 4 out of 10 replicates of P. brunnescens and P. velutina, respectively, regrew only from bait and not from inoculum, indicating migration. These results suggest that prolonged periods without new resources alter the behavior of mycelium, probably due to the exhaustion of resources.


A predictive model of the development of national mental health systems.
An emerging body of research in the field of international mental health, in part stimulated by the World Mental Health Survey Initiative, has made only limited progress in understanding variations in levels of development in mental health services across nations. However, the World Health Organization's recent initiatives involving the Assessment Instrument for Mental Health Systems (WHO-AIMS) and its publication of the Mental Health Atlas now present new opportunities for understanding transnational mental health policy development. This study, thus, aims to increase understanding of the dimensions and conditions associated with the differential levels of development of national mental health. Specifically, it addresses two questions: Are there one or multiple dimensions characteristic of this development? What are the relative contributions of demographic, economic, political, social, cultural, and geographic conditions in predicting the levels of various nations on these dimensions? This study employs a secondary analysis of existing data derived from both WHO's Mental Health Atlas and other archival sources to address the above questions. Analyses of patterns of missing data supported decisions to restrict the sample to 138 nations. The first question on dimensions of development was addressed with a Varimax factor analysis using a matrix of polychoric, tetrachoric, and Pearson correlations. Factor scores were calculated for the resulting three factors, and to address the second question on predictors, these were each analyzed with multiple regression models. Three orthogonal or uncorrelated dimensions were identified that are characteristic of the 138 nations: (i) General Mental Health Services (professionals and inpatient beds), (ii) Public Mental Health Program; and (iii) Community Mental Health that collectively accounted for 45% of the variance in the database of WHO predictors. Only one, General Mental Health Services, was substantially explained (Adj. R2 = .641) by the predictors, specifically, by democratization, distance from Paris, gross domestic product, and Inglehart's measure of self-expression (versus survival) values. This analysis reveals a complexity and diversity of developmental patterns that are not apparent in statistical results that have been previously reported. Specifically, these results show that there is no unilinear pathway of development or of associated environmental conditions, but rather national mental health systems vary dramatically in respect to three dimensions -- General Mental Health Services, Public Mental Health Programs, and Community Mental Health -- which are unrelated to one another. The multiple dimensions of mental health development identified in this study reinforce the importance of a multi-pronged strategy for the continuation of multiple developmental efforts. Mental health manpower development, including both education and training, regulation and standard setting, public mental health services, both inpatient and the range of community mental health services, are among some of the most vital elements of a comprehensive strategy on the part of both national and international authorities Limitations of this study that include the unknown reliability and validity of the WHO Mental Health Atlas data suggest the need for such data collection initiatives to utilize multiple informants for each nation. As better data is gathered, it will become increasingly feasible to undertake multi-level studies of variations not only between nations, but within them.


The influence of parachute-resisted sprinting on running mechanics in collegiate track athletes.
The influence of parachute-resisted sprinting on running mechanics in collegiate track athletes. The aim of this investigation was to compare the acute effects of parachute-resisted (PR) sprinting on selected kinematic variables. Twelve collegiate sprinters (mean age 19.58 ± 1.44 years, mass 69.32 ± 14.38 kg, height 1.71 ± 9.86 m) ran a 40-yd dash under 2 conditions: PR sprint and sprint without a parachute (NC) that were recorded on a video computer system (60 Hz). Sagittal plane kinematics of the right side of the body was digitized to calculate joint angles at initial ground contact (IGC) and end ground contact (EGC), ground contact (GC) time, stride rate (SR), stride length (SL), and the times of the 40-yd dashes. The NC 40-yd dash time was significantly faster than the PR trial (p < 0.05). The shoulder angle at EGC significantly increased from 34.10 to 42.10° during the PR trial (p < 0.05). There were no significant differences in GC time, SR, SL, or the other joint angles between the 2 trials (p > 0.05). This study suggests that PR sprinting does not acutely affect GC time, SR, SL and upper extremity or lower extremity joint angles during weight acceptance (IGC) in collegiate sprinters. However, PR sprinting increased shoulder flexion by 23.5% at push-off and decreased speed by 4.4%. While sprinting with the parachute, the athlete's movement patterns resembled their mechanics during the unloaded condition. This indicates the external load caused by PR did not substantially overload the runner, and only caused a minor change in the shoulder during push-off. This sports-specific training apparatus may provide coaches with another method for training athletes in a sports-specific manner without causing acute changes to running mechanics.


Abdominal pediatric cancer surveillance using serial computed tomography: evaluation of organ absorbed dose and effective dose.
Computed tomography (CT) is used extensively in cancer diagnosis, staging, evaluation of response to treatment, and in active surveillance for cancer reoccurrence. A review of CT technology is provided, at a level of detail appropriate for a busy clinician to review. The basis of x-ray CT dosimetry is also discussed, and concepts of absorbed dose and effective dose (ED) are distinguished. Absorbed dose is a physical quantity (measured in milligray [mGy]) equal to the x-ray energy deposited in a mass of tissue, whereas ED uses an organ-specific weighting method that converts organ doses to ED measured in millisieverts (mSv). The organ weighting values carry with them a measure of radiation risk, and so ED (in mSv) is not a physical dose metric but rather is one that conveys radiation risk. The use of CT in a cancer surveillance protocol was used as an example of a pediatric patient who had kidney cancer, with surgery and radiation therapy. The active use of CT for cancer surveillance along with diagnostic CT scans led to a total of 50 CT scans performed on this child in a 7-year period. It was estimated that the patient received an average organ dose of 431 mGy from these CT scans. By comparison, the radiation therapy was performed and delivered 50.4 Gy to the patient's abdomen. Thus, the total dose from CT represented only 0.8% of the patient's radiation dose.


Familial and genetic effects on motor coordination, laterality, and reading-related cognition.
Recent research has provided evidence for a genetically mediated association between language or reading-related cognitive deficits and impaired motor coordination. Other studies have identified relationships between lateralization of hand skill and cognitive abilities. With a large sample, the authors aimed to investigate genetic relationships between measures of reading-related cognition, hand motor skill, and hand skill lateralization. The authors applied univariate and bivariate correlation and familiality analyses to a range of measures. They also performed genomewide linkage analysis of hand motor skill in a subgroup of 195 sibling pairs. Hand motor skill was significantly familial (maximum heritability=41%), as were reading-related measures. Hand motor skill was weakly but significantly correlated with reading-related measures, such as nonword reading and irregular word reading. However, these correlations were not significantly familial in nature, and the authors did not observe linkage of hand motor skill to any chromosomal regions implicated in susceptibility to dyslexia. Lateralization of hand skill was not correlated with reading or cognitive ability. The authors confirmed a relationship between lower motor ability and poor reading performance. However, the genetic effects on motor skill and reading ability appeared to be largely or wholly distinct, suggesting that the correlation between these traits may have arisen from environmental influences. Finally, the authors found no evidence that reading disability and/or low general cognitive ability were associated with ambidexterity.


Non-photic, non-thermic circadecadal solar cycle interaction with cardiovascular circannual and circasemiannual variation in heated air-conditioned habitat.
In order to re-examine the extent to which secular circulatory variation can be resolved into possibly accountable, if not yet predictable behavior, the 15-year record of blood pressure and heart rate of an adult male cardiologist (Y.W.) is reanalyzed. Gliding spectral windows with an interval of 4 years progressively displaced throughout the data series examine monthly means from August 1987 to August 2002. A circannual variation is only intermittent and appears to drift for years. A circasemiannual variation is consistent and prominent, yet only for a fraction of the record examined. By contrast to the circadian rhythm in blood pressure and heart rate, which is reliably detectable in most subjects in clinical health, the circannual variation in the human circulation is inconsistent and hence should be monitored, as in this case for its assessment as one goes, a conclusion that also applies to the circasemiannual variation, prominent for years but not detected thereafter. The results prompt the search for interactions between the photic, thermic and societal effects of the seasons that, if solely pertinent, should yield a consistent 1-year spectral component. That non-photic effects may also play an important role may point to modulation by solar cycle stage and solar cycle number, perhaps mediated by the solar wind. This conclusion is extended in proof to the role played by the most recently discovered transannual component in human blood pressure and heart rate, which is a probable further signature of the solar wind. The beating of the transannual and circannual components documented on another data series may contribute to the lack of a consistent 1-year synchronized circannual variation in this case and many others.


Design of an electrochemically assisted radiation sensor for α-spectrometry of actinides traces in water.
We describe a new approach for the detection and identification of actinides at low activity levels directly in aqueous solution. The measurement consists initially, in immobilizing alpha emitters in the form of insoluble hydroxides onto the entrance window of an immersed alpha particles detector. For this, a boron doped diamond detector window is negatively polarized to produce a basic layer on its surface by water decomposition. Actinides elements that are known to be very sensitive to hydrolysis are precipitated as solid hydroxides onto the entrance window of the sensor. Due to the absence of an air layer between the radioactive source and the detector, there is no need for vacuum during the alpha spectrometry measurement. After analysis, the detector can be easily cleaned by anodization in the aqueous medium to be reused at once. The minimum detectable activity concentration (MDA) of the system has been evaluated with (241)Am at 0.5 Bq/L for a 0.33 cm(2) area Si PIN diode.


Molecular analysis of a case of nevus of ota showing progressive evolution to melanoma with intermediate stages resembling cellular blue nevus.
Nevus of Ota is a variant of congenital nevus, which is morphologically paucicellular and resembles a common blue nevus. Although nevus of Ota is a risk factor for uveal melanoma in white people, the development of cutaneous melanoma within nevus of Ota is a very rare occurrence with only a few reported cases. We present a case of a long-standing nevus of Ota, with radiologic imaging demonstrating a large retro-orbital mass and a biopsy showing melanoma. The histopathology of the eye exenteration specimen illustrated various stages of melanocytic progression including areas resembling a nevus of Ota, blue nevus, cellular blue nevus, and melanoma. There was heterogeneity in the overtly malignant sections with some areas displaying expansile nodules of blander appearing spindled cells, whereas other areas were composed of epithelioid cells with higher mitotic counts and zones of necrosis. The extensive lesion also infiltrated the soft tissue and bone. We performed gene mutation analysis for GNAQ, BRAF, NRAS, and KIT and fluorescence in situ hybridization (FISH) targeting commonly altered chromosomal loci in melanoma and comparative genomic hybridization (CGH). Copy number changes typical of melanoma were identified by both FISH and CGH in the morphologically malignant areas illustrating the relationship of tumor progression and the progressive acquisition of genetic aberrations.


A qualitative study of primary care clinicians' views of treating childhood obesity.
The prevalence of childhood obesity is rising and the UK Government have stated a commitment to addressing obesity in general. One method has been to include indicators relating to obesity within the GP pay-for-performance Quality and Outcomes Framework (QOF) contract. This study aimed to explore general practitioners' and practice nurses' views in relation to their role in treating childhood obesity. We interviewed eighteen practitioners (twelve GPs and six nurses) who worked in general practices contracting with Rotherham Primary Care Trust. Interviews were face to face and semi structured. The transcribed data were analysed using framework analysis. GPs and practice nurses felt that their role was to raise the issue of a child's weight, but that ultimately obesity was a social and family problem. Time constraint, lack of training and lack of resources were identified as important barriers to addressing childhood obesity. There was concern that the clinician-patient relationship could be adversely affected by discussing what was often seen as a sensitive topic. GPs and practice nurses felt ill-equipped to tackle childhood obesity given the lack of evidence for effective interventions, and were sceptical that providing diet and exercise advice would have any impact upon a child's weight. GPs and practice nurses felt that their role in obesity management was centred upon raising the issue of a child's weight, and providing basic diet and exercise advice. Clinicians may find it difficult to make a significant impact on childhood obesity while the evidence base for effective management remains poor. Until the lack of effective interventions is addressed, implementing additional targets (for example through the QOF) may not be effective.


Characterization of Cre recombinase models for the study of adipose tissue.
The study of adipose tissue in vivo has been significantly advanced through the use of genetic mouse models. While the aP2-Cre(BI) and aP2-Cre(Salk) lines have been widely used to target adipose tissue, the specificity of these lines for adipocytes has recently been questioned. Here we characterize Cre recombinase activity in multiple cell populations of the major adipose tissue depots of these and other Cre lines using the membrane-Tomato/membrane-GFP (mT/mG) dual fluorescent reporter. We find that the aP2-Cre(BI) and aP2-Cre(Salk) lines lack specificity for adipocytes within adipose tissue, and that the aP2-Cre(BI) line does not efficiently target adipocytes in white adipose depots. Alternatively, the Adiponectin-CreERT line shows high efficiency and specificity for adipocytes, while the PdgfRα-CreERUCL and PdgfRα-CreERJHU lines do not efficiently target adipocyte precursor cells in the major adipose depots. Instead, we show that the PdgfRα-Cre line is preferable for studies targeting adipocyte precursor cells in vivo.


Distinct pathways for norepinephrine- and opioid-triggered antinociception from the amygdala.
The amygdala has an important role in pain and pain modulation. We showed previously in animal studies that α2 -adrenoreceptor activation in the central nucleus of the amygdala (CeA) mediates hypoalgesia produced by restraint stress, and that direct application of an α2 -agonist in this region produces analgesia. In the present animal experiments, we investigated the pathways through which α2 -sensitive systems in the CeA produce behavioural analgesia. The CeA has dense connections to a descending pain modulatory network, centred in the midbrain periaqueductal grey (PAG) and the rostral ventromedial medulla (RVM), which is implicated in various forms of stress-related hypoalgesia and which mediates the antinociceptive effect of morphine applied in the basolateral amygdala. We investigated whether this circuit mediates the hypoalgesic effects of α2 -adrenergic agonist administration into the CeA as well as the contribution of endogenous opioids and cannabinoids. We also tested the possibility that activation of α2 -receptors in the CeA produces antinociception by recruitment of noradrenergic pathways projecting to the spinal cord. Hypoalgesia resulting from bilateral application of the α2 -adrenergic agonist clonidine in the CeA was not reversed by chemical inactivation of the RVM or by systemic injections of naloxone (μ-opioid antagonist) or rimonabant (CB1 antagonist). By contrast, spinal α2 -receptor blockade (intrathecal idazoxan) completely prevented the hypoalgesic effect of clonidine in the CeA, and unmasked a small but significant hyperalgesia. In rats, adrenergic actions in the CeA mediating hypoalgesia require spinal adrenergic neurotransmission but not the PAG-RVM pain modulatory network, or opiate or cannabinoid systems.


Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy: study protocol of a cluster randomized clinical trial (Multi-PAP project).
Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12 months, as compared with usual care. Design: pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). patients aged 65-74 years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3 months). n = 400 (200 per study arm). complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Clinicaltrials.gov, NCT02866799.


A report of an investigation of end-of-life care practices in health care facilities and the influences on those practices.
In 1992, 82.2% of deaths in Alberta occurred in acute care hospitals or continuing care facilities. This paper outlines the end-of-life care of adult inpatients who died that year in four such facilities (n = 137). CPR was an infrequent end-of-life treatment modality (2.9%), in stark contrast to the extensive use of other medical technologies. Almost every inpatient (94.2%) died with one or more technologies in continuous operation. Although reasons were infrequently given, the desire to promote patient comfort was the most frequent influence on end-of-life technology use. The findings of this study raise issues for debate and further investigation. Chief among these issues is whether or not medical technologies promote comfort during the dying process.


Hyperbaric Oxygen Therapy for the Compromised Graft or Flap.
Significance: Tissue grafts and flaps are used to reconstruct wounds from trauma, chronic disease, tumor extirpation, burns, and infection. Despite careful surgical planning and execution, reconstructive failure can occur due to poor wound beds, radiation, random flap necrosis, vascular insufficiency, or ischemia-reperfusion (IR). Traumatic avulsions and amputated composite tissues-compromised tissue-may fail from crush injury and excessively large sizes. While never intended, these complications result in tissue loss, additional surgery, accrued costs, and negative psychosocial patient effects. Recent Advances: Hyperbaric oxygen (HBO) has demonstrated utility in the salvage of compromised grafts/flaps. It can increase the likelihood and effective size of composite graft survival, improve skin graft outcomes, and enhance flap survival. Mechanisms underlying these beneficial effects include increased oxygenation, improved fibroblast function, neovascularization, and amelioration of IR injury. Critical Issues: Common strategies for the compromised graft or flap include local wound care, surgical debridement, and repeated reconstruction. These modalities are associated with added costs, time, need for reoperation, morbidity, and psychosocial effects. Preservation of the amputated/avulsed tissues minimizes morbidity and maximizes the reconstructive outcome by salvaging the compromised tissue and obviating additional surgery. HBO is often overlooked as a potential tool that can limit these issues. Future Directions: Animal studies demonstrate a benefit of HBO in the treatment of compromised tissues. Clinical studies support these findings, but are limited to case reports and series. Further research is needed to provide multicenter prospective clinical studies and cost analyses comparing HBO to other adjunctive therapies in the treatment of compromised grafts/flaps.


A computational model of liver iron metabolism.
Iron is essential for all known life due to its redox properties; however, these same properties can also lead to its toxicity in overload through the production of reactive oxygen species. Robust systemic and cellular control are required to maintain safe levels of iron, and the liver seems to be where this regulation is mainly located. Iron misregulation is implicated in many diseases, and as our understanding of iron metabolism improves, the list of iron-related disorders grows. Recent developments have resulted in greater knowledge of the fate of iron in the body and have led to a detailed map of its metabolism; however, a quantitative understanding at the systems level of how its components interact to produce tight regulation remains elusive. A mechanistic computational model of human liver iron metabolism, which includes the core regulatory components, is presented here. It was constructed based on known mechanisms of regulation and on their kinetic properties, obtained from several publications. The model was then quantitatively validated by comparing its results with previously published physiological data, and it is able to reproduce multiple experimental findings. A time course simulation following an oral dose of iron was compared to a clinical time course study and the simulation was found to recreate the dynamics and time scale of the systems response to iron challenge. A disease state simulation of haemochromatosis was created by altering a single reaction parameter that mimics a human haemochromatosis gene (HFE) mutation. The simulation provides a quantitative understanding of the liver iron overload that arises in this disease. This model supports and supplements understanding of the role of the liver as an iron sensor and provides a framework for further modelling, including simulations to identify valuable drug targets and design of experiments to improve further our knowledge of this system.


The peroxisome proliferator activated receptor gamma Pro12Ala polymorphism is associated with a lower hirsutism score and increased insulin sensitivity in women with polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and chronic anovulation. The genetic background of the insulin resistance frequently associated with PCOS is unclear. To examine the influe nce of the Pro12Ala polymorphism of the peroxisome proliferator activated receptor gamma (PPARgamma), which is thought to play a role in the regulation of insulin sensitivity, on endocrine and metabolic parameters in PCOS patients. PPARgamma alleles were analysed in 102 PCOS patients (age 27 +/- 5.3 years) and 104 age matched control women. PCOS was defined by the NIH-criteria as the presence of chronic oligo- or anovulation and hyperandrogenism. Family history and clinical parameters were evaluated by personal interview and physical examination, parameters of insulin resistance [homeostasis model assessment (HOMA) and Matsuda-index] were evaluated with a glucose tolerance test. Seventy-nine (77.5%) PCOS patients were carriers of the wild-type PPARgamma allele (Pro/Pro), while 23 (22.5%) had at least one Ala allele (X/Ala), with an equal distribution in controls. X/Ala PCOS women were more insulin-sensitive, evidenced by lower fasting insulin, HOMA index and insulin secretion. Differences in insulin resistance did not depend on body mass index. The genotype had no influence on lipid status, leptin, adiponectin, ghrelin, or family history of type 2 diabetes. A significantly lower proportion of Pro/Ala patients had hirsutism and they had on average lower hirsutism scores than Pro/Pro patients. No relationship was found between the Pro/Ala polymorphism and other signs of hyperandrogenism. The Pro12Ala polymorphism of the PPARgamma gene is associated with increased insulin sensitivity and lower hirsutism scores in PCOS women.


The thrifty phenotype as an adaptive maternal effect.
Human diseases in adulthood are increasingly associated with growth patterns in early life, implicating early-life nutrition as the underlying mechanism. The thrifty phenotype hypothesis proposed that early-life metabolic adaptations promote survival, with the developing organism responding to cues of environmental quality by selecting an appropriate trajectory of growth. Recently, some authors have proposed that the thrifty phenotype is also adaptive in the longer-term, by preparing the organism for its likely adult environment. However, windows of plasticity close early during human development, and subsequent environmental changes may result in the selected trajectory becoming inappropriate, leading to adverse effects on health. This paradox generates uncertainty as to whether the thrifty phenotype is indeed adaptive for the offspring in humans. The thrifty phenotype should not be considered a dichotomous concept, rather it refers to the capacity of all offspring to respond to environmental information during early ontogenetic development. This article argues that the thrifty phenotype is the consequence of three different adaptive processes - niche construction, maternal effects, and developmental plasticity - all of which in humans are influenced by our large brains. While developmental plasticity represents an adaptation by the offspring, both niche construction and parental effects are subject to selection on parental rather than offspring fitness. The three processes also operate at different paces. Human offspring do not become net calories-producers until around 18 years of age, such that the high energy costs of the human brain are paid primarily by the mother, even after weaning. The evolutionary expansion of human brain volume occurred in environments characterised by high volatility, inducing strong selective pressure on maternal capacity to provision multiple offspring simultaneously. The thrifty phenotype is therefore best considered as a manipulation of offspring phenotype for the benefit of maternal fitness. The information that enters offspring phenotype during early development does not predict the likely future environment of the offspring, but rather reflects the mother's own developmental experience and the quality of the environment during her own maturation. Offspring growth trajectory thus becomes aligned with long-term maternal capacity to provision. In contemporary populations, the sensitivity of offspring development to maternal phenotype exposes the offspring to adverse effects, through four distinct pathways. The offspring may be exposed to (1) poor maternal metabolic control (e.g. gestational diabetes), (2) maternally derived toxins (e.g. maternal smoking), or (3) low maternal social status (e.g. small size). Adverse consequences of these effects may then be exacerbated by (4) exposure either to the "toxic" western environment in postnatal life, in which diet and physical activity levels are mismatched with metabolic experience in utero, or at the other extreme to famine. The rapid emergence of the epidemic of the metabolic syndrome in the 20th Century reflects the rapid acceleration in the pace of niche construction relative to the slower physiological combination of developmental plasticity and parental effects.


Formation of catalytically active acetyl-S-malonate decarboxylase requires malonyl-coenzyme A:acyl carrier protein transacylase as auxiliary enzyme [corrected].
Functional malonate decarboxylase of Klebsiella pneumoniae is an acetyl-S-enzyme with an acetylated phosphoribosyl dephospho-CoA prosthetic group. The mdcH gene product acts as a malonyl-CoA:ACP transacylase and initiates the activation of (deacetyl)malonate decarboxylase by malonyl-transfer to the prosthetic group. The malonyl residue is subsequently decarboxylated to an acetyl residue by the decarboxylase itself. Purified malonate decarboxylase consists of the four subunits MdcA, D, E and C in an apparent 1 : 1 : 1 : 1 stoichiometry. In addition, the preparation contains substoichiometric amounts of MdcH comigrating on SDS/PAGE with MdcD. Malonate decarboxylase isolated from strains with a deletion of the mdcH gene was not activated with malonyl-CoA. Activity could be gained, however, in the additional presence of MdcH that has been synthesized in Escherichia coli and purified from inclusion bodies. Substrates for MdcH are malonyl-CoA or methylmalonyl-CoA but not acetyl-CoA. The enzyme has Km values of 16 microm for both substrates and Vmax for malonyl-CoA of 190 U.mg-1 and for methylmalonyl-CoA of 37 U.mg-1. Transfer of the methylmalonyl-residue to the prosthetic group proceeds via the covalent methylmalonyl-MdcH intermediate. The transacylase is specifically inhibited by N-ethylmaleimide, and preincubation with malonyl-CoA or methylmalonyl-CoA protects the enzyme from this inhibition.


The histochemical localization of acrosin in guinea-pig sperm after the acrosome reaction.
The protease acrosin is widely considered to be an essential component of a zona lysin which enables sperm to penetrate the zona pellucida of the egg. Sperm form a characteristic penetration slit little wider than the sperm head itself and this has long suggested that any zona lysin is attached to the sperm surface after an acrosome reaction. This paper provides the first ultrastructural evidence that this is the case. The protein acrosin inhibitor, Kunitz soybean trypsin inhibitor, has been covalently attached to the electron-dense marker, ferritin, and the conjugate incubated with guinea-pig sperm which have undergone an A23187-induced acrosome reaction. Electron microscopy shows that ferritin is distributed unevenly over the outer surface of the newly exposed inner acrosomal membrane but does not extend to the equatorial segment. This is further evidence that acrosin can be considered as a candidate for the role of zona lysin. The mechanism of sperm penetration of the zona is discussed in the light of these observations.


Artificial Intelligence for Participatory Health: Applications, Impact, and Future Implications.
Artificial intelligence (AI) provides people and professionals working in the field of participatory health informatics an opportunity to derive robust insights from a variety of online sources. The objective of this paper is to identify current state of the art and application areas of AI in the context of participatory health. A search was conducted across seven databases (PubMed, Embase, CINAHL, PsychInfo, ACM Digital Library, IEEExplore, and SCOPUS), covering articles published since 2013. Additionally, clinical trials involving AI in participatory health contexts registered at clinicaltrials.gov were collected and analyzed. Twenty-two articles and 12 trials were selected for review. The most common application of AI in participatory health was the secondary analysis of social media data: self-reported data including patient experiences with healthcare facilities, reports of adverse drug reactions, safety and efficacy concerns about over-the-counter medications, and other perspectives on medications. Other application areas included determining which online forum threads required moderator assistance, identifying users who were likely to drop out from a forum, extracting terms used in an online forum to learn its vocabulary, highlighting contextual information that is missing from online questions and answers, and paraphrasing technical medical terms for consumers. While AI for supporting participatory health is still in its infancy, there are a number of important research priorities that should be considered for the advancement of the field. Further research evaluating the impact of AI in participatory health informatics on the psychosocial wellbeing of individuals would help in facilitating the wider acceptance of AI into the healthcare ecosystem.


The dual-basin landscape in GFP folding.
Recent experimental studies suggest that the mature GFP has an unconventional landscape composed of an early folding event with a typical funneled landscape, followed by a very slow search and rearrangement step into the locked, active chromophore-containing structure. As we have shown previously, the substantial difference in time scales is what generates the observed hysteresis in thermodynamic folding. The interconversion between locked and the soft folding structures at intermediate denaturant concentrations is so slow that it is not observed under the typical experimental observation time. Simulations of a coarse-grained model were used to describe the fast folding event as well as identify native-like intermediates on energy landscapes enroute to the fluorescent native fold. Interestingly, these simulations reveal structural features of the slow dynamic transition to chromophore activation. Experimental evidence presented here shows that the trapped, native-like intermediate has structural heterogeneity in residues previously linked to chromophore formation. We propose that the final step of GFP folding is a "locking" mechanism leading to chromophore formation and high stability. The combination of previous experimental work and current simulation work is explained in the context of a dual-basin folding mechanism described above.


On edge detection.
Edge detection is the process that attempts to characterize the intensity changes in the image in terms of the physical processes that have originated them. A critical, intermediate goal of edge detection is the detection and characterization of significant intensity changes. This paper discusses this part of the edge detection problem. To characterize the types of intensity changes derivatives of different types, and possibly different scales, are needed. Thus, we consider this part of edge detection as a problem in numerical differentiation. We show that numerical differentiation of images is an ill-posed problem in the sense of Hadamard. Differentiation needs to be regularized by a regularizing filtering operation before differentiation. This shows that this part of edge detection consists of two steps, a filtering step and a differentiation step. Following this perspective, the paper discusses in detail the following theoretical aspects of edge detection. 1) The properties of different types of filters-with minimal uncertainty, with a bandpass spectrum, and with limited support-are derived. Minimal uncertainty filters optimize a tradeoff between computational efficiency and regularizing properties. 2) Relationships among several 2-D differential operators are established. In particular, we characterize the relation between the Laplacian and the second directional derivative along the gradient. Zero crossings of the Laplacian are not the only features computed in early vision. 3) Geometrical and topological properties of the zero crossings of differential operators are studied in terms of transversality and Morse theory.


Microencapsulated Multifunctionalized Graphene Oxide Equipped with Chloroquine for Efficient and Sustained siRNA Delivery.
A multifunctionalized graphene oxide (GO)-based carrier with conjugation of aminated-polyethylene glycol (PEG-diamine), octaarginine (R8), and folic acid (FA), which also contains chloroquine (CQ), a lysosomotropic agent, is introduced. The cellular uptake mechanisms and intracellular targeting of FA-functionalized nanocarriers are examined. The localized releases of CQ and siRNA intracellular delivery are evaluated. Microencapsulation of the nanocarrier complexed with genes in layer-by-layer coating of alginate microbeads is also investigated. The covalently coconjugated FA with PEG and R8 provides a stable formulation with increased cellular uptake compared to FA-free carrier. The CQ-equipped nanocarrier shows a 95% release of CQ at lysosomal pH. The localized release of the drug inside the lysosomes is verified which accelerates the cargo discharge into cytoplasm.


The effect of hospital organizational characteristics on postoperative complications.
To determine if there is a relationship between the risk of postoperative complications and the nonclinical hospital characteristics of bed size, ownership structure, relative urbanicity, regional location, teaching status, and area income status. This study involved a secondary analysis of 2006 administrative hospital data from a number of U.S. states. This data, gathered annually by the Agency for Healthcare Research and Quality (AHRQ) via the National Inpatient Sample (NIS) Healthcare Utilization Project (HCUP), was analyzed using probit regressions to measure the effects of several nonclinical hospital categories on seven diagnostic groupings. The study model included postoperative complications as well as additional potentially confounding variables. The results showed mixed outcomes for each of the hospital characteristic groupings. Subdividing these groupings to correspond with the HCUP data analysis allowed a greater understanding of how hospital characteristics' may affect postoperative outcomes. Nonclinical hospital characteristics do affect the various postoperative complications, but they do so inconsistently.


Comparison of relative mandibular growth vectors with high-resolution 3-dimensional imaging.
The mandibular rami and their endochondrally growing condyles develop in many directions relative to the variable anatomic patterns of the nasomaxilla and middle cranial fossae during growth and response to orthopedic treatment. High-resolution magnetic resonance images were used to compare 3-dimensional (3D) growth vectors of skeletal displacement and bone remodeling in 25 untreated subjects with Class II malocclusions, 28 subjects with Class II malocclusions who were treated with Fränkel appliance therapy, and 25 subjects with normal occlusions. Marked differences were noted over an 18-month observation period. The 3D coordinates of anatomic landmarks were registered by Procrustes fit to control for rotation, translation, and scale differences. Compared with untreated Class II and normal-occlusion subjects, the treated group showed highly significant differences in the 3D displacement/remodeling vectors of gonion and pterygomaxillary fissure relative to condylion and middle cranial fossae bilateral skeletal landmarks, by using both permutation tests ( P < .001) and a general linear multivariate model ( P < .0001). In a prospective and systematically controlled study, we quantitatively described significant 3D rami skeletal compensations in the structural assembly of facial morphogenesis at the beginning of the adolescent growth spurt using novel modeling techniques. These techniques have facilitated quantification of relative 3D growth vectors to illustrate skeletal changes with Fränkel appliance therapy. Future studies are required to assess the long-term clinical significance of our findings.


Evaluation of a national clinical programme for the management of self-harm in hospital emergency departments: impact on patient outcomes and the provision of care.
Emergency departments are important points of intervention, to reduce the risk of further self-harm and suicide. A national programme to standardise the management of people presenting to the emergency department with self-harm and suicidal ideation (NCPSHI) was introduced in Ireland in 2014. The aim of this study was to evaluate the impact of the NCPSHI on patient outcomes and provision of care. Data on self-harm presentations were obtained from the National Self-Harm Registry Ireland from 2012 to 2017. The impacts of the NCPSHI on study outcomes (3-month self-harm repetition, biopsychosocial assessment provision, admission, post-discharge referral, and self-discharge) were examined at an individual and aggregate (hospital) level, using a before and after study design and interrupted time series analyses, respectively. The 15 hospitals that implemented the programme by January 2015 (of a total of 24 between 2015 and 2017) were included in the analyses. There were 31,970 self-harm presentations during the study period. In hospitals with no service for self-harm (n = 4), risk of patients not being assessed reduced from 31.8 to 24.7% following the introduction of the NCPSHI. Mental health referral in this hospital group increased from 42.2 to 59.0% and medical admission decreased from 27.5 to 24.3%. Signs of a reduction in self-harm repetition were observed for this hospital group, from 35.1 to 30.4% among individuals with a history of self-harm, but statistical evidence was weak. In hospitals with a pre-existing liaison psychiatry service (n = 7), risk of self-discharge was lower post-NCPSHI (17.8% vs. 14.8%). In hospitals with liaison nurse(s) pre-NCPSHI (n = 4), medical admission reduced (27.5% vs. 24.3%) and there was an increase in self-harm repetition (from 5.2 to 7.8%. for those without a self-harm history). The NCPSHI was associated with improvements in the provision of care across hospital groups, particularly those with no prior service for self-harm, highlighting the need to consider pre-existing context in implementation planning. Our evaluation emphasises the need for proper resourcing to support the implementation of clinical guidelines on the provision of care for people presenting to hospital with self-harm.


Closed-loop, ultraprecise, automated craniotomies.
A large array of neuroscientific techniques, including in vivo electrophysiology, two-photon imaging, optogenetics, lesions, and microdialysis, require access to the brain through the skull. Ideally, the necessary craniotomies could be performed in a repeatable and automated fashion, without damaging the underlying brain tissue. Here we report that when drilling through the skull a stereotypical increase in conductance can be observed when the drill bit passes through the skull base. We present an architecture for a robotic device that can perform this algorithm, along with two implementations--one based on homebuilt hardware and one based on commercially available hardware--that can automatically detect such changes and create large numbers of precise craniotomies, even in a single skull. We also show that this technique can be adapted to automatically drill cranial windows several millimeters in diameter. Such robots will not only be useful for helping neuroscientists perform both small and large craniotomies more reliably but can also be used to create precisely aligned arrays of craniotomies with stereotaxic registration to standard brain atlases that would be difficult to drill by hand.


Pneumococcal immunization in adult diabetics.
The antibody responses of 102 adult insulin-treated diabetics who received 14-valent pneumococcal polysaccharide vaccine were measured. Grand mean preimmunization antibody levels were similar for diabetics, 255 ng protein N/ml, and controls, 234 ng protein N/ml. Postimmunization, the values in the diabetics, 1009 ng protein N/ml, and 834 ng protein N/ml in 48 healthy controls, were not significantly different. The height of antibody response in the diabetic group did not correlate with age, sex, duration of diabetes, insulin dose, concentration of glycosylated hemoglobin, fasting or 2-h postprandial glucose concentrations, or the presence of retinopathy. Side effects were minimal and occurred in 26%. Antibody response to pneumococcal polysaccharide vaccine is not impaired in adult diabetics. Pneumococcal immunization is safe and may reduce the frequency of pneumonia and its complications in the diabetic population.


The Environmental Acinetobacter baumannii Isolate DSM30011 Reveals Clues into the Preantibiotic Era Genome Diversity, Virulence Potential, and Niche Range of a Predominant Nosocomial Pathogen.
Acinetobacter baumannii represents nowadays an important nosocomial opportunistic pathogen whose reservoirs outside the clinical setting are obscure. Here, we traced the origins of the collection strain A. baumannii DSM30011 to an isolate first reported in 1944, obtained from the enriched microbiota responsible of the aerobic decomposition of the resinous desert shrub guayule. Whole-genome sequencing and phylogenetic analysis based on core genes confirmed DSM30011 affiliation to A. baumannii. Comparative studies with 32 complete A. baumannii genomes revealed the presence of 12 unique accessory chromosomal regions in DSM30011 including five encompassing phage-related genes, five containing toxin genes of the type-6 secretion system, and one with an atypical CRISPRs/cas cluster. No antimicrobial resistance islands were identified in DSM30011 agreeing with a general antimicrobial susceptibility phenotype including folate synthesis inhibitors. The marginal ampicillin resistance of DSM30011 most likely derived from chromosomal ADC-type ampC and blaOXA-51-type genes. Searching for catabolic pathways genes revealed several clusters involved in the degradation of plant defenses including woody tissues and a previously unreported atu locus responsible of aliphatic terpenes degradation, thus suggesting that resinous plants may provide an effective niche for this organism. DSM30011 also harbored most genes and regulatory mechanisms linked to persistence and virulence in pathogenic Acinetobacter species. This strain thus revealed important clues into the genomic diversity, virulence potential, and niche ranges of the preantibiotic era A. baumannii population, and may provide an useful tool for our understanding of the processes that led to the recent evolution of this species toward an opportunistic pathogen of humans.


Fluorescein angiography in nonischemic optic disc edema.
To determine whether nonischemic optic disc edema is associated with significant delay in fluorescein angiographic optic disc filling. Fluorescein angiograms from 16 patients with acute papillitis, five with papilledema, and one with optic disc edema from orbital cavernous hemangioma were compared with those of age-matched controls. Early views of the optic disc were evaluated for onset of central retinal artery dye filling and both onset and completion of choroidal and prelaminar optic disc dye filling. Data were compared with our previously published figures for patients with nonarteritic anterior ischemic optic neuropathy (NAION) and a new group of patients aged 46 years and younger with NAION (NAIONy). Subgroup analysis was performed on data from patients with papillitis. Mean onset or completion of filling was not significantly delayed compared with controls for the central retinal artery, choroid, or prelaminar optic disc in patients with nonischemic optic disc edema, including the subgroup of patients with papillitis. In comparison, significant delay had been detected for onset and filling of prelaminar disc in typical NAION; similar significant delay was noted in this study for patients with NAIONy. No patients with nonischemic optic disc edema (including those with papillitis) demonstrated delay of disc filling by at least 5 seconds, while this feature was detected in 76% of patients with typical NAION and 62% of those with NAIONy. Optic disc filling delay is common in typical NAION and NAIONy; it is not a feature of nonischemic optic disc edema. This characteristic may aid in the differentiation of NAION from papillitis.


Small intestinal bacterial overgrowth: what it is and what it is not.
To critically review recent literature on small intestinal bacterial overgrowth (SIBO). When originally described, SIBO was added to the list of causes of the malabsorption syndrome and the pathophysiology of its consequences for the digestion and absorption of various nutrients was gradually revealed. More recently, SIBO was incriminated as a cause of diarrhea, especially in the elderly. However, the suggestion that SIBO may be a causative factor in irritable bowel syndrome and of its constituent symptoms has sparked debate and controversy on the very definition of SIBO. This debate revolves around the tests employed and the diagnostic cut-off values (for bacterial numbers) used to diagnose SIBO in clinical practice. A fundamental problem with SIBO, and one that allows controversy to simmer, is the lack of a universally accepted and applied gold standard for the diagnosis of SIBO. Hopefully, the application of molecular microbiological methods to the characterization of the small intestinal microbiome will tell us, once and for all, what is normal and when 'abnormality' is truly responsible for symptoms and disease. Meanwhile, therapy remains, for the most part, empirical and is based on the correction, wherever possible, of any underlying cause, attention to nutritional deficiencies, and the use of antibiotics.


Decoupling stability and release in disulfide bonds with antibody-small molecule conjugates.
Disulfide bonds provide a bioactivatable connection with applications in imaging and therapy. The circulation stability and intracellular release of disulfides are problematically coupled in that increasing stability causes a corresponding decrease in cleavage and payload release. However, an antibody offers the potential for a reversible stabilization. We examined this by attaching a small molecule directly to engineered cysteines in an antibody. At certain sites this unhindered disulfide was stable in circulation yet cellular internalization and antibody catabolism generated a disulfide catabolite that was rapidly reduced. We demonstrated that this stable connection and facile release is applicable to a variety of payloads. The ability to reversibly stabilize a labile functional group with an antibody may offer a way to improve targeted probes and therapeutics.


Specific immunosuppressive effects of constant infusion of 2'-deoxycoformycin.
The effect of continuous infusion into C57BL/6J mice of 2'-deoxycoformycin (DCF), a tight-binding inhibitor of adenosine deaminase, on the biological function of bone marrow stem cells and T- and B-lymphocytes was evaluated. Greater than 85% inhibition of adenosine deaminase in erythrocytes, thymus, and bone marrow was noted after DCF infusion at 0.4 mg per kg body weight per day, while lesser extents of inhibition were characteristic of spleen and lymph nodes. The reconstitution of lethally irradiated C57BL/6J mice with bone marrow cells from DCF- and 0.9% NaCl infused mice of the same strain was compared. The two groups of animals were virtually identical with respect to (a) the number of spleen colony-forming units, (b) the response of splenic lymphocytes to both B- and T-cell mitogens, (c) hematological analysis of peripheral blood elements, and (d) survival time, thus strongly supporting the lack of effect of DCF infusion on the capacity of stem cells to differentiate. In contradistinction, DCF infusion was highly lymphocytotoxic as noted by the severe necrosis in both B- and T-cell regions in lymph nodes and spleen and by the dramatic weight reduction in spleen and thymus. Histopathology of other tissues including bone marrow was normal except for the occurrence of hepatitis. A striking decrease in blastogenesis induced by the mitogens concanavalin A, phytohemagglutinin, and Escherichia coli lipopolysaccharides was also observed after DCF infusion. Consistent with these data, in vitro incubation of bone marrow cells with DCF did not impair the number of spleen colony-forming units produced in lethally irradiated mice. These data suggest a potential use for adenosine deaminase inhibitors in the prevention of graft-versus-host disease in hematopoietic transplantation.


Medical marijuana initiatives : are they justified? How successful are they likely to be?
The principal constituent of cannabis, Delta(9)-tetrahydrocannabinol (THC), is moderately effective in treating nausea and vomiting, appetite loss, and acute and chronic pain. Oral THC (dronabinol) and the synthetic cannabinoid, nabilone, have been registered for medical use in the US and UK, but they have not been widely used because patients find it difficult to titrate doses of these drugs. Advocates for the medical use of cannabis argue that patients should be allowed to smoke cannabis to relieve these above-mentioned symptoms. Some US state governments have legislated to allow the medical prescription of cannabis, but the US federal government has tried to prevent patients from obtaining cannabis and threatened physicians who prescribe it with criminal prosecution or loss of their licence to practise. In the UK and Australia, committees of inquiry have recommended medical prescription (UK) and exemption from criminal prosecution (New South Wales, Australia), but governments have not accepted these recommendations. The Canadian government allows an exemption from criminal prosecution to patients with specified medical conditions. It has recently legislated to provide cannabis on medical prescription to registered patients, but this scheme so far has not been implemented. Some advocates argue that legalising cannabis is the only way to ensure that patients can use it for medical purposes. However, this would be contrary to international drug control treaties and is electorally unpopular. The best prospects for the medical use of cannabinoids lie in finding ways to deliver THC that do not involve smoking and in developing synthetic cannabinoids that produce therapeutic effects with a minimum of psychoactive effects. While awaiting these developments, patients with specified medical conditions could be given exemptions from criminal prosecution to grow cannabis for their own use, at their own risk.


Nuclear cathepsin D enhances TRPS1 transcriptional repressor function to regulate cell cycle progression and transformation in human breast cancer cells.
The lysosomal protease cathepsin D (Cath-D) is overproduced in breast cancer cells (BCC) and supports tumor growth and metastasis formation. Here, we describe the mechanism whereby Cath-D is accumulated in the nucleus of ERα-positive (ER+) BCC. We identified TRPS1 (tricho-rhino-phalangeal-syndrome 1), a repressor of GATA-mediated transcription, and BAT3 (Scythe/BAG6), a nucleo-cytoplasmic shuttling chaperone protein, as new Cath-D-interacting nuclear proteins. Cath-D binds to BAT3 in ER+ BCC and they partially co-localize at the surface of lysosomes and in the nucleus. BAT3 silencing inhibits Cath-D accumulation in the nucleus, indicating that Cath-D nuclear targeting is controlled by BAT3. Fully mature Cath-D also binds to full-length TRPS1 and they co-localize in the nucleus of ER+ BCC where they are associated with chromatin. Using the LexA-VP16 fusion co-activator reporter assay, we then show that Cath-D acts as a transcriptional repressor, independently of its catalytic activity. Moreover, microarray analysis of BCC in which Cath-D and/or TRPS1 expression were silenced indicated that Cath-D enhances TRPS1-mediated repression of several TRPS1-regulated genes implicated in carcinogenesis, including PTHrP, a canonical TRPS1 gene target. In addition, co-silencing of TRPS1 and Cath-D in BCC affects the transcription of cell cycle, proliferation and transformation genes, and impairs cell cycle progression and soft agar colony formation. These findings indicate that Cath-D acts as a nuclear transcriptional cofactor of TRPS1 to regulate ER+ BCC proliferation and transformation in a non-proteolytic manner.


Inhibitors of propagation of coagulation: factors V and X.
Cardiovascular diseases are still the most important cause of morbidity and mortality in western countries and antithrombotic treatment is nowadays widely used. Drugs able to reduce coagulation activation are the treatment of choice for a number of arterial and/or venous thromboembolic conditions. Some of the drugs currently used for this purpose, such as heparins (UFH or LMWH) and VKA, have limitations consisting of a narrow therapeutic window and an unpredictable response with the need of laboratory monitoring in order to assess their efficacy and safety. These drawbacks have stimulated an active research aimed to develop new drugs able to act on single factors involved in the coagulation network, with predictable response. Intense experimental and clinical work on new drugs has focused on synthetic agents, which could preferably be administered orally and at fixed doses. The most advanced clinical development with new anticoagulants has been achieved for those inhibiting FXa and some of them, like fondaparinux, are already currently used in clinical practice. Other agents, such as rivaroxaban, apixaban, otamixaban and edoxaban are under development and have already been studied or are currently under investigation in large scale phase III clinical trials for prevention and treatment of venous thromboembolism, atrial fibrillation and acute coronary syndromes. Some of them have proved to be more effective than conventional therapy. Data on some agents inhibiting FVa are still preliminary and some of these drugs have so far been considered only in patients with disseminated intravascular coagulation secondary to sepsis.


High speciation rate at temperate latitudes explains unusual diversity gradients in a clade of ectomycorrhizal fungi.
Understanding the patterns of biodiversity through time and space is a challenging task. However, phylogeny-based macroevolutionary models allow us to account and measure many of the processes responsible for diversity buildup, namely speciation and extinction. The general latitudinal diversity gradient (LDG) is a well-recognized pattern describing a decline in species richness from the equator polewards. Recent macroecological studies in ectomycorrhizal (EM) fungi have shown that their LDG is shifted, peaking at temperate rather than tropical latitudes. Here we investigate this phenomenon from a macroevolutionary perspective, focusing on a well-sampled group of edible EM mushrooms from the genus Amanita-the Caesar's mushrooms, which follow similar diversity patterns. Our approach consisted in applying a suite of models including (1) nontrait-dependent time-varying diversification (Bayesian analysis of macroevolutionary mixtures [BAMM]), (2) continuous trait-dependent diversification (quantitative-state speciation and extinction [QuaSSE]), and (3) diversity-dependent diversification. In short, results give strong support for high speciation rates at temperate latitudes (BAMM and QuaSSE). We also find some evidence for different diversity-dependence thresholds in "temperate" and "tropical" subclades, and little differences in diversity due to extinction. We conclude that our analyses on the Caesar's mushrooms give further evidence of a temperate-peaking LDG in EM fungi, highlighting the importance and the implications of macroevolutionary processes in explaining diversity gradients in microorganisms.


What mechanisms drive neural induction and neural determination in urodeles?
In our laboratory we use Urodeles (Pleurodeles waltl) and Anurans (Xenopus laevis) to perform comparative studies on neural determination. Urodeles are a good embryological system to study early events in ontogenesis since they present several advantages: slow development, external localization of chordamesoderm at the beginning of gastrulation, large size of cells, diploid genome, etc. I have focused this overview-report on the main findings on Pleurodeles neurogenesis. The determination of the two neural lineages (neuronal and astroglial) appears during gastrulation as a consequence of (a) permissive event(s) activated through a Ca(++)-dependent transducing pathway. This signaling-pathway involves L-type Ca++ channels. The activation of this Ca++ transduction route is sufficient to activate both neuronal and glial structural specific genes, via direct activation of "immediate early genes". The specification of neuronal functional differentiation depends on additional factors of chordamesoderm origin acting during gastrulation and later on. At the early neurula stage, in the neural plate, 20% of progenitor cells present a neuronal fate, 80% are at least bipotential and generate mixed clones (neurons and astrogliocytes). The issue of the state of "commitment" of the precursor cells (competent ectoderm) and the identification of specifying molecules (from Spemann organizer) are underway in Pleurodeles and Xenopus.


The emerging relationship between the airway microbiota and chronic respiratory disease: clinical implications.
Until recently, relationships between evidence of colonization or infection by specific microbial species and the development, persistence or exacerbation of pulmonary disease have informed our opinions of airway microbiology. However, recent applications of culture-independent tools for microbiome profiling have revealed a more diverse microbiota than previously recognized in the airways of patients with chronic pulmonary disease. New evidence indicates that the composition of airway microbiota differs in states of health and disease and with severity of symptoms and that the microbiota, as a collective entity, may contribute to pathophysiologic processes associated with chronic airway disease. Here, we review the evolution of airway microbiology studies of chronic pulmonary disease, focusing on asthma, chronic obstructive pulmonary disease and cystic fibrosis. Building on evidence derived from traditional microbiological approaches and more recent culture-independent microbiome studies, we discuss the implications of recent findings on potential microbial determinants of respiratory health or disease.


Different effects of intravitreally injected ranibizumab and aflibercept on retinal and choroidal tissues of monkey eyes.
Since there is evidence that the Fc domain of antivascular endothelial growth factor drugs may cause unexpected consequences in retinal and choroidal vessels, the effects of intravitreal ranibizumab and aflibercept on monkey eyes were investigated. Four cynomolgus monkeys were intravitreally injected with 0.5 mg of ranibizumab and another four with 2 mg of aflibercept. Two untreated monkeys served as controls. Funduscopy, fluorescein angiography (FA), spectral-domain-optical coherence tomography (SD-OCT) and measurement of intraocular pressure (IOP) were performed. The eyes were inspected by light, fluorescence and electron microscopy. The diameter of the choriocapillaris (CC) was measured by morphometry, and the areas of the CC with free haemoglobin, CC fenestrations and endothelial thickness were quantified. Analysis showed ranibizumab permeated the retina via intercellular clefts, whereas aflibercept was taken up by ganglion cells, cells of the inner and outer retinal layers and the retinal pigment epithelium (RPE). Stasis and haemolysis in the choriocapillaris and choroidal vessels were more frequent after aflibercept treatment, which caused hypertrophy and death of individual RPE cells. The area of the CC was significantly reduced after both drugs compared with controls, but the reduction of the CC endothelium thickness, number of fenestrations and the areas with haemolysis were more pronounced after aflibercept. Ranibizumab permeated the retina through intercellular spaces, whereas aflibercept was taken up by neuronal and RPE cells. Aflibercept induced protein complex formation and more haemolysis in the choriocapillaris, leading to individual RPE cell death. The clinical significance and relation of these findings to the Fc domain or to other characteristics of aflibercept remain to be investigated.


Dissolving Microneedles for Rapid and Painless Local Anesthesia.
Microneedles are emerging drug delivery methods for painless treatment. The current study tested dissolving microneedles containing lidocaine (Li-DMN) for use in local anesthesia. An Li-DMN patch was fabricated by centrifugal lithography with carboxymethyl cellulose as a structural polymer and assessed for physical properties by optical microscopy and a fracture force analyzer. The biocompatibility was evaluated by a histology section in vitro and by ear thickness in vivo. The efficacy of the Li-DMN patch was assessed by electrophysiological recordings in primary cultured sensory neurons in vitro and a von Frey test on rats' hind paws in vivo. The physical properties of the microneedle showed enough rigidity for transdermal penetration. The maximal capacity of lidocaine-HCl in the Li-DMN patch was 331.20 ± 6.30 µg. The cytotoxicity of the dissolving microneedle to neuronal cells was negligible under an effective dose of lidocaine for 18 h. Electrophysiological recordings verified the inhibitory effect of the voltage-gated sodium channel current by the Li-DMN patch in vitro. A skin reaction to the edema test and histologic analysis of the rats' ears after application of the Li-DMN patch were negligible. Also, the application of the Li-DMN patch reduced the nocifensive behavior of the rats almost immediately. In conclusion, the dissolving microneedle patch with carboxymethyl cellulose is a promising candidate method for the painless delivery of lidocaine-HCl.


Regio- and Enantioselective Preparation of Chiral Allylic Sulfones Featuring Elusive Quaternary Stereocenters.
We describe here the first general asymmetric synthesis of sterically encumbered α,α-disubstituted allylic sulfones via Pd-catalyzed allylic substitution. The design and application of a new and highly efficient phosphoramidite ligand (L10) proved to be crucial, and a wide variety of challenging allylic sulfones featuring quaternary stereocenters could be obtained in good yields and with good to excellent levels of regio- and enantioselectivities under attractive process conditions. The developed methodology employs easily accessible chemical feedstock including racemic allylic precursors and sodium sulfinates. The utility of the method is further demonstrated by the synthesis of the sesquiterpene (-)-Agelasidine A.


Buckling instability in ordered bacterial colonies.
Bacterial colonies often exhibit complex spatio-temporal organization. This collective behavior is affected by a multitude of factors ranging from the properties of individual cells (shape, motility, membrane structure) to chemotaxis and other means of cell-cell communication. One of the important but often overlooked mechanisms of spatio-temporal organization is direct mechanical contact among cells in dense colonies such as biofilms. While in natural habitats all these different mechanisms and factors act in concert, one can use laboratory cell cultures to study certain mechanisms in isolation. Recent work demonstrated that growth and ensuing expansion flow of rod-like bacteria Escherichia coli in confined environments leads to orientation of cells along the flow direction and thus to ordering of cells. However, the cell orientational ordering remained imperfect. In this paper we study one mechanism responsible for the persistence of disorder in growing cell populations. We demonstrate experimentally that a growing colony of nematically ordered cells is prone to the buckling instability. Our theoretical analysis and discrete-element simulations suggest that the nature of this instability is related to the anisotropy of the stress tensor in the ordered cell colony.


Biological safety testing of polymers.
The extent of testing polymer-containing medical devices is subject to a range of considerations and needs to be determined on a case-by-case basis. This article reports on recent areas of concern for device materials including biodegradation and immunogenicity potential.


[On the facial muscles in Perodicticus potto and Nycticebus coucang (author's transl)].
As descriptions of the facial muscles of lorisiform primates are lacking, the species Perodicticus potto and Nycticebus coucang are examined. The results are compared with other prosimians.


Differential expression and regulation by activin of the neurotrophins BDNF and NT4 during human and mouse ovarian development.
The tropomyosin-related kinase (Trk) B neurotrophin receptor is essential for ovarian germ cell survival and primordial follicle formation, but the contributions of its ligands, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4), are unknown. We have investigated their expression and regulation in developing human and mouse ovaries. BDNF expression increased with increasing gestation, expression of human NTF4 and of both Ntf5 and Bdnf in the mouse was unchanged. Bdnf expression was dramatically lower than Ntf5 in the mouse, but levels were comparable in the human. Human fetal ovarian somatic cells expressed BDNF. Activin A selectively regulated BDNF and Ntf5 expression in human and mouse, respectively, identifying an oocyte/somatic signaling pathway which might mediate the pro-survival effects of activin. These data reveal that expression and regulation of the TrkB ligands are differentially controlled in the developing ovaries of humans and mice, and identify BDNF as a potential regulator of germ cell fate in the human fetal ovary.


Skeletal pathology and variable anatomy in elephant feet assessed using computed tomography.
Foot problems are a major cause of morbidity and mortality in elephants, but are underreported due to difficulties in diagnosis, particularly of conditions affecting the bones and internal structures. Here we evaluate post-mortem computer tomographic (CT) scans of 52 feet from 21 elephants (seven African Loxodonta africana and 14 Asian Elephas maximus), describing both pathology and variant anatomy (including the appearance of phalangeal and sesamoid bones) that could be mistaken for disease. We found all the elephants in our study to have pathology of some type in at least one foot. The most common pathological changes observed were bone remodelling, enthesopathy, osseous cyst-like lesions, and osteoarthritis, with soft tissue mineralisation, osteitis, infectious osteoarthriti, subluxation, fracture and enostoses observed less frequently. Most feet had multiple categories of pathological change (81% with two or more diagnoses, versus 10% with a single diagnosis, and 9% without significant pathology). Much of the pathological change was focused over the middle/lateral digits, which bear most weight and experience high peak pressures during walking. We found remodelling and osteoarthritis to be correlated with increasing age, more enthesopathy in Asian elephants, and more cyst-like lesions in females. We also observed multipartite, missing and misshapen phalanges as common and apparently incidental findings. The proximal (paired) sesamoids can appear fused or absent, and the predigits (radial/tibial sesamoids) can be variably ossified, though are significantly more ossified in Asian elephants. Our study reinforces the need for regular examination and radiography of elephant feet to monitor for pathology and as a tool for improving welfare.


[Outcomes of home monitoring after palliative cardiac surgery in infants with congenital heart disease].
Common conditions, such as dehydration or respiratory infection can aggravate hypoxia and are associated with interstage mortality in infants who have undergone palliative surgery for congenital heart diseases. This study was done to evaluate the efficacy of a home monitoring program (HMP) in decreasing infant mortality. Since its inception in May 2010, all infants who have undergone palliative surgery have been enrolled in HMP. This study was a prospective observational study and infant outcomes during HMP were compared with those of previous comparison groups. Parents were trained to measure oxygen saturation, body weight and feeding volume and to contact the hospital through the hotline for emergency situations. Telephone counseling was conducted by clinical nurse specialists every week post discharge. Forty-one infants were enrolled in HMP. Nine hundred telephone counseling sessions were conducted. Seventy-three infants required telephone triage with the most common conditions being gastrointestinal (50.7%) and respiratory symptoms (32.9%). With HMP intervention, interstage mortality decreased from 18.6% (8/43) to 9.8% (4/41) (χ²=1.15, p=.283). Results indicate that active measures and treatments using the HMP decrease mortality rates, however further investigation is required to identify various factors that contribute to hemodynamic complications during the interstage period.


Activities of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine and its metabolites against herpes simplex virus types 1 and 2 in cell culture and in mice infected intracerebrally with herpes simplex virus type 2.
As measured by plaque and yield reduction assays, several metabolites of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC) were highly active against herpes simplex virus types 1 and 2. These metabolites included the 2'-deoxy-2'-fluoroarabinosyl derivatives of 5-iodouracil (FIAU), cytosine (FAC), uracil (FAU), and thymine (FMAU). In mice inoculated intracerebrally with herpes simplex virus type 2, the relative order of potency of these compounds and licensed antiviral drugs was as follows: FMAU much greater than FIAC approximately equal to FIAU greater than acyclovir approximately equal to vidarabine much greater than FAC approximately equal to FAU. One of the main metabolites of FMAU, 2'-fluoro-5-hydroxymethyl-arabinosyluracil, was essentially inactive in vivo. FIAC-, FIAU-, FMAU-, FAC-, and FAU-resistant herpes simplex virus variants prepared in cell culture were found to be (i) devoid of viral thymidine kinase, (ii) cross-resistant to one another and resistant to drugs requiring viral thymidine kinase for activation, and (iii) sensitive to vidarabine or phosphonoformate. These results indicate that FIAC, FIAU, and FMAU require the virally encoded thymidine kinase for activation and suggest that the antiviral activity of FAU and FAC in cell cultures is also mediated by this enzyme. The interaction of the fluoroarabinosyl pyrimidine nucleosides with herpes simplex virus thymidine kinase in a cell-free system is also described.


Direct and immune-mediated cytotoxicity of interleukin-21 contributes to antitumor effects in mantle cell lymphoma.
Mantle cell lymphoma (MCL) is a distinct subtype of non-Hodgkin lymphoma characterized by overexpression of cyclin D1 in 95% of patients. MCL patients experience frequent relapses resulting in median survival of 3 to 5 years, requiring more efficient therapeutic regimens. Interleukin (IL)-21, a member of the IL-2 cytokine family, possesses potent antitumor activity against a variety of cancers not expressing the IL-21 receptor (IL-21R) through immune activation. Previously, we established that IL-21 exerts direct cytotoxicity on IL-21R-expressing diffuse large B-cell lymphoma cells. Herein, we demonstrate that IL-21 possesses potent cytotoxicity against MCL cell lines and primary tumors. We identify that IL-21-induced direct cytotoxicity is mediated through signal transducer and activator of transcription 3-dependent cMyc upregulation, resulting in activation of Bax and inhibition of Bcl-2 and Bcl-XL. IL-21-mediated cMyc upregulation is only observed in IL-21-sensitive cells. Further, we demonstrate that IL-21 leads to natural killer (NK)-cell-dependent lysis of MCL cell lines that were resistant to direct cytotoxicity. In vivo treatment with IL-21 results in complete FC-muMCL1 tumor regression in syngeneic mice via NK- and T-cell-dependent mechanisms. Together, these data indicate that IL-21 has potent antitumor activity against MCL cells via direct cytotoxic and indirect, immune-mediated effects.


[Prophylaxis of muscular stress in physical labor].
The authors demonstrated that work of female molders, acquisitors and stacking packers is characterized by physical load, great number of cliched manual movements, intensive inclinations of corpse and constrained working posture. Prolonged exposure to unfavorable occupational factors results in neuromuscular and cardiovascular stress that induces pathologic changes with increasing length of service. Complex of prophylactic measures suggested by the authors proves effective as releases working strain and delays fatigue during the working shift.


Spatial Relationships Matter: Kinesin-1 Molecular Motors Transport Liposome Cargo Through 3D Microtubule Intersections In Vitro.
Kinesin-1 ensembles maneuver vesicular cargoes through intersections in the 3-dimensional (3D) intracellular microtubule (MT) network. To characterize directional outcomes (straight, turn, terminate) at MT intersections, we challenge 350 nm fluid-like liposomes transported by ∼10 constitutively active, truncated kinesin-1 KIF5B (K543) with perpendicular 2-dimensional (2D) and 3D intersections in vitro . Liposomes frequently pause at 2D and 3D intersections (∼2s), suggesting that motor teams can simultaneously engage each MT and undergo a tug-of-war. Once resolved, the directional outcomes at 2D MT intersections have a straight to turn ratio of 1.1; whereas at 3D MT intersections, liposomes more frequently go straight (straight to turn ratio of 1.8), highlighting that spatial relationships at intersections bias directional outcomes. Using 3D super-resolution microscopy (STORM), we define the gap between intersecting MTs and the liposome azimuthal approach angle heading into the intersection. We develop an in silico model in which kinesin-1 motors diffuse on the liposome surface, simultaneously engage the intersecting MTs, generate forces and detach from MTs governed by the motors' mechanochemical cycle, and undergo a tug-of-war with the winning team determining the directional outcome in 3D. The model predicts that 1-3 motors typically engage the MT, consistent with optical trapping measurements. Modeled liposomes also predominantly go straight through 3D intersections over a range of intersection gaps and liposome approach angles, even when obstructed by the crossing MT. Our observations and modeling offer mechanistic insights into how cells might tune the MT cytoskeleton, cargo, and motors to modulate cargo transport. Kinesin-1 molecular motors transport vesicles containing essential cellular resources along the dense 3D microtubule (MT) cytoskeleton, with dysfunctions linked to neurodegenerative diseases such as Alzheimer's. Despite its importance, the mechanism by which kinesin-1s maneuver intracellular cargoes through MT-MT intersections towards their destination remains unclear. Therefore, we developed a 3D in vitro model transport system, which challenges kinesin-1 motor teams to maneuver vesicle-like liposomes through MT-MT intersections. Surprisingly, liposomes are biased to pass straight through 3D MT intersections rather than turn, even when the MT intersection presents as a physical barrier. A mechanistic model informs this observation, suggesting that spatial relationships between the cargo and MT intersection influence how molecular motors maneuver intracellular cargoes towards their destination to satisfy cellular demands.


Magnesium deficiency is associated with insulin resistance in obese children.
Magnesium deficiency has been associated with insulin resistance (IR) and increased risk for type 2 diabetes in adults. This study was designed to determine whether obese children exhibit serum or dietary magnesium deficiency and its potential association with IR. We studied 24 obese nondiabetic children (BMI > or =85th percentile) and 24 sex- and puberty-matched lean control subjects (BMI <85th percentile). We measured serum magnesium, indexes of insulin sensitivity, dietary magnesium intake (using a food frequency questionnaire), and body composition (by air displacement plethysmography). Serum magnesium was significantly lower in obese children (0.748 +/- 0.015 mmol/l, means +/- SE) compared with lean children (0.801 +/- 0.012 mmol/l) (P = 0.009). Serum magnesium was inversely correlated with fasting insulin (r(s) = -0.36 [95% CI -0.59 to -0.08]; P = 0.011) and positively correlated with quantitative insulin sensitivity check index (QUICKI) (0.35 [0.06-0.58]; P = 0.015). Dietary magnesium intake was significantly lower in obese children (obese: 0.12 +/- 0.004 vs. lean: 0.14 +/- 0.004 mg/kcal; P = 0.003). Dietary magnesium intake was inversely associated with fasting insulin (-0.43 [-0.64 to -0.16]; P = 0.002) and directly correlated with QUICKI (0.43 [0.16-0.64]; P = 0.002). The association between magnesium deficiency and IR is present during childhood. Serum magnesium deficiency in obese children may be secondary to decreased dietary magnesium intake. Magnesium supplementation or increased intake of magnesium-rich foods may be an important tool in the prevention of type 2 diabetes in obese children.


Taxonomic and molecular identification of mesocriconema and criconemoides species (nematoda: criconematidae).
Populations of Mesocriconema curvatum, M. kirjanovae, M. onoense, M. ornatum, M. sphaerocephala, M. surinamense, M. vadense, M. xenoplax, and Criconemoides informis from different geographical areas in the continental United States were characterized morphologically and molecularly. A new ring nematode from Washington County, Arkansas, is also described and named Mesocriconema ozarkiense n. sp., This new species is characterized by females with small flattened submedian lobes, lower than or at the same level as the labial disc, vagina straight, very well developed spermatheca without sperm, no more than one anastomoses, L=379-512 μm, V=89-93, stylet length = 49-61 μm, R=107-119, annuli with slightly crenate margins on tail portion and a simple anterior vulval lip. The molecular characterization of M. ozarkiense n. sp. using the ITS rRNA gene sequence and the phylogenesis relationship of this new species with the ring nematodes included in this study are provided.


Effect of the duration of infusion of urogastrone on intestinal regeneration in rabbits.
Urogastrone (UG) increases the rate of mucosal regeneration on patched intestinal defects. Our aim was to determine the effect of the duration of UG administration on regeneration of serosa patched ileal defects in rabbits. Group I (n = 18) were controls. Group II (n = 15), Group III (n = 10) and Group IV (n = 5) received UG 1.5 micrograms/kg/h subcutaneously for 7 days, 14 days or 21 days respectively. Animals were sacrificed at 7 day intervals up to 21 days after patching. Neomucosal growth was significantly greater in the animals receiving UG and was greatest in Group IV. Group II and III animals had less contraction of the patched defect and greater neomucosal surface area than Group I animals at each interval but had a lesser effect than animals receiving UG continuously. Crypt cell production rate was significantly greater in UG treated animals at 7 and 14 days but fell to control levels at 21 days. Prolonging the duration of UG infusion increased the quantity of neomucosa produced by intestinal regeneration. However, UG stimulation of mucosal cell migration and proliferation occurred transiently within 14 days after patching.


The first fungal laccase with an alkaline pH optimum obtained by directed evolution and its application in indigo dye decolorization.
Engineering of fungal laccases with optimum catalytic activity at alkaline pH has been a long-lasting challenge. In this study, a mutant library containing 3000 clones was obtained by error-prone PCR to adapt the optimum pH of a fungal laccase Lcc9 from the basidiomycete Coprinopsis cinerea. After three rounds of functional screening, a mutant with three amino acid changes (E116K, N229D, I393T) named PIE5 was selected. PIE5 showed an optimum pH of 8.5 and 8.0 against guaiacol and 2,6-DMP when expressed in Pichia pastoris, representing the first fungal laccase that possesses an optimum pH at an alkaline condition. Site directed mutagenesis disclosed that N229D contributed the most to the optimum pH increment. A single N229D mutation caused an increase in optimum pH by 1.5 units. When used in indigo dye decolorization, PIE5 efficiently decolorized 87.1 ± 1.1% and 90.9 ± 0.3% indigo dye at the optimum conditions of pH 7.0-7.5 and 60 °C, and with either methyl 3,5-dimethoxy-4-hydroxybenzoate or 2,2'-azino-bis(3-ethylbenzothazoline-6-sulfonate) as the mediator. In comparison, the commercially available fungal laccase TvLac from Trametes villosa decolorized 84.3 ± 1.8% of indigo dye under its optimum conditions (opt. pH 5.0 and 60 °C). The properties of an alkaline-dependent activity and the high indigo dye decolorization ability (1.3-fold better than the parental Lcc9) make the new fungal laccase PIE5 an alternative for specific industrial applications.


Corticosteroids in acute bacterial meningitis.
Acute bacterial meningitis remains a disease with high mortality rate, ranging from 10 to 30 percent, despite advances in critical care. It has been estimated that between 5 to 40 percent of all patients can suffer hearing loss. The use of corticosteroids as adjuvant therapy in the treatment of acute bacterial meningitis is controversial despite several controlled clinical trials and three meta-analyses. In particular there are few data on the use of corticosteroids in adult meningitis. We conducted a systematic review examining the efficacy and safety of adjuvant corticosteroid therapy in children and adults with acute bacterial meningitis. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library issue 1, 2003)); MEDLINE (1966 to April 2002); EMBASE (1974 to April 2002); and HEALTHLINE (1988 to April 2002) and Current Contents for trials published before the April 1st 2002, and reference lists of articles. We also contacted manufacturers and researchers in the field. Eligible studies were published or non-published randomised controlled trials on corticosteroids as adjuvant therapy in acute bacterial meningitis. Patients of any age and in any clinical condition, treated with antibacterial agents and randomised to corticosteroid therapy (or placebo) of any type, could be included. At least case fatality rate or hearing loss had to be recorded for inclusion. Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials. Eighteen studies involving 1853 people were included. Overall, adjuvant corticosteroids were associated with lower case fatality (relative risk (RR) 0.76, 95% confidence intervals (CI) 0.59 to 0.98) and lower rates of both severe hearing loss (RR 0.36, 95% CI 0.22 to 0.60) and long-term neurological sequelae (RR 0.66, 95% CI 0.44 to 0.99). In children, corticosteroids reduced severe hearing loss in bacterial meningitis caused by Haemophilus influenzae (RR 0.31, 95% CI 0.15 to 0.62), as well as in meningitis caused by other bacteria than H. influenzae (RR 0.42, 95%CI 0.20 to 0.89). In adults there was a reduction in case-fatality (RR 0.38, 95% CI 0.18 to 0.78), however there were few data. Adverse events were not increased significantly with the use of corticosteroids. Adjuvant corticosteroids are beneficial in the treatment of children with acute bacterial meningitis. The limited data available in adults shows a trend in favour of adjuvant corticosteroids but a definite recommendation must await more studies. ERRATUM: During the review process of this systematic review the results of the European Dexamethasone in Adulthood Bacterial Meningitis Trial were published. (De Gans 2002) In this prospective, randomised, double-blind, multicenter trial, which included 301 adults with bacterial meningitis, treatment with dexamethasone was associated with a reduction in mortality (relative risk of death, 0.48; 95 CI 0.24 to 0.96; p = 0.04). Therefore, dexamethasone should be given to all adults with bacterial meningitis and should be initiated before or with the first dose of antibiotics.


Ex-CARS: exotic configuration for coherent anti-Stokes Raman scattering microspectroscopy utilizing two laser sources.
We propose and experimentally demonstrate a new coherent anti-Stokes Raman scattering setting, which relies on a coherent excitation of Raman vibration using a broadband ultrashort laser pulse and signal read-out using a conventional continuous wave laser radiation. Such an exotic arrangement does not require any synchronization of two laser sources and can be used for direct comparison of amplitudes of nonlinear and spontaneous Raman signals.


Factors associated with under-five mortality in Bhutan: an analysis of the Bhutan National Health Survey 2012.
As an important marker for health equity and access, under-five mortality (UFM) is a primary measure for socioeconomic development. The importance of reducing UFM has been further emphasized in an ambitious target under Sustainable Development Goals. The factors influencing UFM are not adequately understood in Bhutan. The most recent dataset of the Bhutan National Health Survey (BNHS) 2012 was used in this study. Multiple logistic regression analysis using a backwards elimination approach was performed to identify significant factors influencing UFM. All statistical analyses were adjusted for the complex study design due to the multistage stratified cluster sampling used in BNHS. Bhutan's UFM rate was 37 per 1000 live births. The weighted mean age of the children was 7.3 years (SD: 1.53; range: 3-12). Mother's age, household size, access to electricity and sanitation, residential region, and parity were the key factors associated with UFM. The UFM risk was significantly lower in children born to mothers aged 36-40 years, 41-45 years, and > 45 years when compared to that in children born to mothers aged < 26 years. The likelihood of mortality was 66% lower (95% CI: 0.21-0.55) among children born in households with > 5 members. Children born in households without electricity and safe sanitation had a significantly higher risk of death, by 81 and 49% respectively. Relative to those born in the west, children born in the central and eastern regions were 1.72 (95% CI: 1.07-2.77) and 2.09 (95% CI: 1.46-2.99) times more likely to die, respectively. Children born to mothers who gave birth to > 2 children were significantly more likely to die than their counterparts. These findings suggest that younger mother's age, the higher number of births and being born in the central and eastern regions are associated with a higher UFM risk, whereas a larger household size and access to electricity and safe sanitation are key factors associated with lower UFM risk in Bhutan. Women empowerment, health education and strategies promoting maternal and child health in rural areas need to be scaled-up. Additionally, socioeconomic development programs should seek to reduce regional disparities.


Continuous glass patterns for painterly rendering.
Glass patterns have been exhaustively studied both in the vision literature and from a purely mathematical point of view. We extend the related formalism to the continuous case and we show that continuous Glass patterns can be used for artistic imaging applications. The general idea is to replace natural texture present in an input image with synthetic painterly texture that is generated by means of a continuous Glass pattern, whose geometrical structure is controlled by the gradient orientation of the input image. The behavior of the proposed algorithm is analytically interpreted in terms of the theory of dynamical systems. Experimental results on a broad range of input images validate the effectiveness of the proposed method in terms of lack of undesired artifacts, which are present with other existing methods, and easy interpretability of the input parameters.


Sec23 homolog Nel1 is a novel GTPase-activating protein for Sar1 but does not function as a subunit of the coat protein complex II (COPII) coat.
The coat protein complex II (COPII) generates transport carriers from the endoplasmic reticulum (ER) under the control of the small GTPase Sar1. Sec23 is well known as a structural component of the COPII coat and as a GTPase-activating protein (GAP) for Sar1. Here, we showed that Saccharomyces cerevisiae contains a novel Sec23 paralog, Nel1, which appears not to function as a subunit of the COPII coat. Nel1 does not associate with any of the COPII components, but it exhibits strong Sar1 GAP activity. We also demonstrated that the chromosomal deletion of NEL1 leads to a significant growth defect in the temperature-sensitive sar1D32G background, suggesting a possible functional link between these proteins. In contrast to Sec23, which is predominantly localized at ER exit sites on the ER membrane, a major proportion of Nel1 is localized throughout the cytosol. Our findings highlight a possible role of Nel1 as a novel GAP for Sar1.