Direct evidence of genic differentiation between sex ratio and standard gene arrangements of X chromosome in Drosophila pseudoobscura.
Evidence of strong association of alleles at the Esterase-5 and adult Acid phosphatase-6 loci with the Sex Ratio and the Standard X chromosome arrangements in D. pseudoobscura is presented. There is no differentiation at these two loci, either in the Sex Ratio or the Standard arrangement from two widely separated geographic populations. At the Esterase-5 locus, alleles characteristic of one arrangement are found in low frequencies in the other arrangement. It is concluded, from these and other observations that the differentiation between the Sex Ratio and the Standard arrangement, at these two loci, is a result of natural selection favoring different coadapted gene blocks in these arrangements. The average heterozygosity at these two loci in different karyotypes is in the following order: ST/SR > ST/ST >> SR/SR which agrees very well with the fitness estimates of these karyotypes.


Wirelessly activated device with an integrated ionic polymer metal composite (IPMC) cantilever valve for targeted drug delivery.
This paper reports a wirelessly powered ionic polymer-metal composite (IPMC) soft actuator operated by external radio frequency (RF) magnetic fields for targeted drug delivery. A 183 μm thick IPMC cantilever valve was fitted with an embedded LC resonant circuit to wirelessly control the actuator when the field frequency is tuned to its resonant frequency of approximately 25 MHz. Experimental characterization of the fabricated actuator showed a cumulative cantilever deflection of 160 μm for three repeated RF ON-OFF cycles at 0.6 W input power. The device was loaded with a dye solution and immersed in DI water to demonstrate wireless drug release. The qualitative result shows the successful release of the dye solution from the device reservoir. The release rate can be controlled by tuning the RF input power. We achieved a maximum average release rate of ∼0.1 μl s-1. We further conducted an in vitro study with human tumor cells (HeLa) to demonstrate the proof of concept of the developed device. The experiments show promising results towards the intended drug delivery application.


Serotonin and nitric oxide interaction in the control of bioluminescence in northern krill, Meganyctiphanes norvegica (M. Sars).
The role of nitric oxide (NO) in the control of bioluminescence (light production) in the crustacean Meganyctiphanes norvegica (krill) was investigated using pharmacological and immunohistochemical methods. All nitrergic drugs tested failed to induce bioluminescence per se but modulated light production stimulated by 5-hydroxytryptamine (5-HT). NO donors [sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP)] injected in live specimens significantly reduced light production stimulated by 5-HT, whereas inhibition of the enzyme NO synthase (NOS) with l-NAME (N(G)-nitro-l-arginine methyl ester) resulted in an enhancement of the 5-HT response. The effects of NO do not seem to be mediated via production of cGMP as injections of a cGMP analogue (8-Bromoguanosine 3',5'-cyclic monophosphate) gave inconclusive effects on the 5-HT-stimulated light response. Inhibition of cGMP production with ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) did not affect the light response. Moreover, a few individuals showed a considerably higher response to 5-HT in April and June compared with specimens collected in the autumn and winter. Furthermore, both NOS-like and 5-HT-like materials were detected by immunohistochemistry inside the light organs. NOS-like immunoreactivity was primarily observed in structures associated with vessels inside the light organs, whereas 5-HT-like material was abundant in nerve fibres throughout the whole light organ. The results suggest that NO has a modulatory role at several levels in the control of light production in M. norvegica and that NO and 5-HT interact in this regulation.


A decrease in nasal CO2 stimulates breathing in the tegu lizard.
Tegu lizards decrease ventilatory frequency (f) when constant CO2, as low as 0.4%, is delivered to the nasal cavities. In contrast, CO2, as high as 6%, pulsed into the nasal cavities during the expiratory phase of the breathing cycle does not alter f. The purpose of the present study was to investigate further the effect of nasal CO2 pattern on f in tegu lizards. Specifically, we tested: (1) whether f was affected by CO2 delivered to the nasal cavities during the inspiratory phase of the breathing cycle, and (2) whether pulsed decreases in nasal CO2 from 4% to 2% and from 4% to 0% would remove the f inhibition caused by constant nasal CO2. Ventilation was measured using a pneumotachograph and pressure transducer in-line with an endotracheal T-tube inserted through the glottis. CO2 was delivered to the nasal cavities through small tubes inserted into the external nares. Ventilatory frequency was not significantly altered when 4% CO2 was pulsed into the nasal cavities during inspiration. Dropping the CO2 in the nasal cavities from 4% to 0% at either 15 cycles/min (0.25 Hz) or for one cycle stimulated breathing. There was no significant difference between the f response to a drop in CO2 from 4% to 0% and that to a drop in CO2 from 4% to 2%. The failure to link the phasic CO2 ventilatory response to a phase in the respiratory cycle indicates that the nasal CO2 receptors do not participate in the breath-by-breath regulation of breathing in these lizards. The observation that small decreases in nasal CO2 abolished the f inhibition caused by constant nasal CO2 provides further evidence for the ability of the nasal CO2 receptors to distinguish between pulsed and constant CO2.


Bronchial adenoma. Clinicopathologic study and results of treatment.
Among 1,700 primary tumors of the lung, there were 53 cases of bronchial adenoma (3.1 percent); 38 (72 percent) of the 53 were typical carcinoids, and the remaining 15 were of a higher grade of malignant neoplasm. There was a slight predominance of female patients, and the age of greatest incidence was between 30 and 50 years (31/53; 58 percent). The most frequent localization was in the main bronchi and in the left bronchial tree. In cases of higher grades of malignant neoplasm, extensive bronchopulmonary resections were performed, while in the less active and less metastatic carcinoids, partial resections were generally performed, using bronchoplastic techniques, sleeve resections, and grafts, except in those cases in which bronchial obstruction had produced extensive and irreversible lesions. Survival at five and ten years after surgery is presented.


To determine the efficacy of bilateral inferior petrosal sinus sampling in differentiating Cushing disease from ectopic Cushing syndrome.
Management of endogenous Cushing syndrome is based on its aetiology. Increased Adrenocorticotropic Hormone (ACTH) levels are the most common cause of this disorder and, therefore, it is critical to determine the source of ACTH before further management. Dynamic post contrast MRI is currently the most common investigation implied to diagnose pituitary adenoma; however, it comes with the drawback of low specificity and high false positive results. Inferior petrosal sinus sampling (IPSS) is an established invasive procedure performed to differentiate central versus peripheral source of ACTH which, in turn, results in hypercortesolaemia. This is a series of 14 patients who underwent IPSS at the Department of Radiology, Aga Khan University Hospital, Karachi, from January 2006 to December 2018. The case series emphasises the role of IPSS in the management of ACTH-dependent Cushing syndrome and combined efficacy of Dynamic post-contrast MRI and the procedure under focus.


Improving follow-up care for women with a history of gestational diabetes: perspectives of GPs and patients.
This paper investigates factors influencing women's engagement with diabetes preventative care after a pregnancy with gestational diabetes (GDM) from the perspectives of GPs and women and explores the role of the GP in that care. Qualitative research using semi-structured interviews with women who had experienced GDM (n=16) and GPs (n=18) were conducted and a thematic content analysis conducted. Women's interviews explored their experience of GDM, factors influencing, and engagement with, follow-up care for diabetes prevention and role of the GP in that care. GP interviews explored postnatal care provided to women with GDM, the role of the GP in that care and perceived factors influencing a mother's engagement in her self-care. Three themes were identified: (1) advice and testing; (2) role of the GP; and (3) barriers and enablers to care. Significant consensus about the role of the GP and barriers and enablers to care existed. Both groups believed post GDM follow-up is best done by GPs and suggested recall and reminders would improve care. GPs gave consistent exercise advice, but lacked consensus on follow-up testing, dietary and weight-loss advice. Women's health literacy influenced how they viewed their GPs role. Consensus guidelines on follow-up testing and diabetes prevention advice, tailored advice according to health literacy and addressing barriers to care would likely improve the capacity of GPs to prevent unnecessary conversion to type 2 diabetes in these at-risk women.


Characterization of PVA/glutaraldehyde hydrogels obtained using Central Composite Rotatable Design (CCRD).
Hydrogels are made from natural or synthetic polymers and, currently, they have many biomedical applications. In this work, the conditions for obtaining a hydrogel with similar physicochemical characteristics to the vitreous humor were defined using polyvinyl alcohol (PVA) and glutaraldehyde (GLUT) as cross-linker. The concentration of PVA and GLUT were modified, and their effect was analyzed in terms of the refractive index, density, and dynamic viscosity. The hydrogel which was obtained using 3.98% (w/V) of PVA, 3.13 mL (1.57 g) of GLUT in 100 mL, and the initial pH of 7.2 showed similar characteristics to the vitreous humor (density = 1.0174 ± 0.0050 g mL-1 , dynamic viscosity = 3.7425 ± 0.1800 mPa s and refractive index = 1.3410 ± 0.0010). The hydrogels were further investigated by rheological measurements, infrared spectroscopy, differential scanning calorimetry, X-ray diffraction and determination of swelling degree. The reticulation with GLUT promoted an increase in viscosity and glass transition temperature. On the other hand, it stimulated a decrease in the swelling degree, crystallinity, melting temperature, and intensity of the band related to the -OH bond, compared with the PVA without reticulation. The reticulated hydrogel displayed Newtonian behavior and a higher apparent viscosity than the PVA. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1558-1566, 2018.


Maximum 11C-methionine PET uptake as a prognostic imaging biomarker for newly diagnosed and untreated astrocytic glioma.
This study aimed whether the uptake of amino tracer positron emission tomography (PET) can be used as an additional imaging biomarker to estimate the prognosis of glioma. Participants comprised 56 adult patients with newly diagnosed and untreated World Health Organization (WHO) grade II-IV astrocytic glioma who underwent surgical excision and were evaluated by 11C-methionine PET prior to the surgical excision at Osaka City University Hospital from July 2011 to March 2018. Clinical and imaging studies were retrospectively reviewed based on medical records at our institution. Preoperative Karnofsky Performance Status (KPS) only influenced progression-free survival (hazard ratio [HR] 0.20; 95% confidence interval [CI] 0.10-0.41, p < 0.0001), whereas histology (anaplastic astrocytoma: HR 5.30, 95% CI 1.23-22.8, p = 0.025; glioblastoma: HR 11.52, 95% CI 2.27-58.47, p = 0.0032), preoperative KPS ≥ 80 (HR 0.23, 95% CI 0.09-0.62, p = 0.004), maximum lesion-to-contralateral normal brain tissue (LN max) ≥ 4.03 (HR 0.24, 95% CI 0.08-0.71, p = 0.01), and isocitrate dehydrogenase (IDH) status (HR 14.06, 95% CI 1.81-109.2, p = 0.011) were factors influencing overall survival (OS) in multivariate Cox regression. OS was shorter in patients with LN max ≥ 4.03 (29.3 months) than in patients with LN max < 4.03 (not reached; p = 0.03). OS differed significantly between patients with IDH mutant/LN max < 4.03 and patients with IDH mutant/LN max ≥ 4.03. LN max using 11C-methionine PET may be used in prognostic markers for newly identified and untreated WHO grade II-IV astrocytic glioma.


Harmonic ultrasonography for the detection of microlithiasis in the gallbladder.
To validate the use of harmonic ultrasonography (US) in the detection of gallbladder microlithiasis. From November 30, 2012, to January 18, 2014, fundamental US (FUS) and harmonic US with a high background noise (HUS-N) were performed for evaluation of gallbladder during the routine abdomen US. During the US, a dot-like stone (or stones) with Brownian motion was regarded as a positive finding of microlithiasis. Fifty-five patients with microlithiasis in the gallbladder detected on US were enrolled as the subjects of a retrospective review. With respect to the obtained images, two abdominal radiologists independently scored the conspicuity of gallbladder microlithiasis on FUS and HUS-N by using a 4-grade scale. The statistical analysis employed a kappa test and a Wilcoxon rank-sum test. For FUS, the conspicuity grades of gallbladder microlithiasis were G1 in 25 and 37, G2 in 21 and 9, G3 in 6 and 6, G4 in 3 and 3 patients, while HUS-N showed G1 in 0 and 0, G2 in 3 and 2, G3 in 12 and 15, and G4 in 40 and 38 patients, respectively, by each of the two radiologists. The kappa value was 0.633 for FUS between the two radiologists and 0.708 for HUS-N. HUS-N showed better conspicuity of gallbladder microlithiasis than FUS with significant P-values of less than 0.001 and 0.001 for the two radiologists, respectively. Compared with FUS, HUS-N enables better detection of microlithiasis in the gallbladder.


The impact of rare variants in FUS in essential tremor.
We analyzed the coding region of the Fused in Sarcoma (FUS) gene in familial essential tremor (ET) and reviewed previous studies assessing FUS variants in ET. ET is often a familial disorder with an autosomal dominant inheritance pattern. A potentially causative variant in FUS has been identified in one ET family. Subsequent studies described further putatively causal variants. We performed DNA sequencing of FUS in 85 unrelated, familial German and French definite ET patients. We did not find novel variants affecting the protein sequence. Seven previously published studies and data from the exome variant server (EVS) showed that rare exonic variants in FUS are not more frequent in ET than in the general population. Our findings provide no evidence for a role of rare genetic variants in the pathogenesis of ET, apart from the initially published FUS mutation segregating in a large ET family.


Alcohol Use Disorders Identification Test (AUDIT) and mortality risk: a systematic review and meta-analysis.
We summarise the evidence for an association between screening scores from the Alcohol Use Disorders Identification Test (AUDIT) and all-cause mortality. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, prospective cohort studies reporting all-cause mortality risk by AUDIT scores (complete AUDIT-10 or AUDIT-C) were identified through MEDLINE, Embase, PubMed and Web of Science up to September 2016. Risk estimates were pooled using random effects meta-analyses. Seven observational studies with 18 920 observed deaths among 309 991 participants were identified. At-risk drinking (ie, hazardous/harmful consumption, AUDIT-10 ≥8 and AUDIT-C ≥4) was associated with elevated mortality risk after 2-10 years of follow-up (pooled relative risk (RR)=1.24, 95% CI 1.12 to 1.37) compared with moderate drinking (AUDIT-10=1-7, AUDIT-C=1-3). Compared to past year abstainers (AUDIT=0), moderate drinkers had a lower mortality risk (RR=0.75, 95% CI 0.71 to 0.79) in US Veterans and a similar mortality risk (RR=0.99, 95% CI 0.72 to 1.38) in population-based studies. Most data came from studies among Veterans using the short AUDIT-C in men and showed a dose-response relationship (RR=1.04, 95% CI 1.04 to 1.05 for each AUDIT-C score among drinkers). Data for women and young adults were scarce. AUDIT screening scores were associated with mortality risk. The association was differential depending on the population examined, which may be related to prevalence of former drinkers among current abstainers. Due to heterogeneity between studies and the small number of populations examined, generalisability may be limited.


Patient preferences for notification of normal laboratory test results: a report from the ASIPS Collaborative.
Many medical errors occur during the laboratory testing process, including lost test results. Patient inquiry concerning results often represents the final safety net for locating lost results. This qualitative study sought to identify, from a patient perspective, specific preferences and factors that influence the process of communicating normal (negative) laboratory test results to patients. We conducted 30-minute guided interviews with 20 adult patients. Patients were recruited from two practice-based research networks in Colorado that were participating in a medical errors study. A semi-structured interview elicited the participant's experience with and preference for laboratory test result notification. Quantitative descriptive statistics were generated for demographic and preference data. Qualitative results were analyzed by a team of experienced qualitative researchers using multiple styles of qualitative analyses, including a template approach and an editing approach. Ninety percent of participants wanted to be notified of all tests results. Important issues related to notification included privacy, responsive and interactive feedback, convenience, timeliness, and provision of details. Telephone notification was preferred, followed by regular mail. Electronic notification was perceived as uncomfortable because it was not secure. While 65% preferred being notified by a provider, participants acknowledge that this may be impractical; thus, they wanted to be notified by someone knowledgeable enough to answer questions. Participants do not normally discuss their preferences for test result notification with their providers. Privacy, responsive and interactive feedback, convenience, and timeliness with detailed information may be critical for patient satisfaction and for improving patient safety, and are features that may be incorporated into emerging communication channels.


The de winter electrocardiogram pattern is a transient electrocardiographic phenomenon that presents at the early stage of ST-segment elevation myocardial infarction.
The de Winter electrocardiogram (EKG) pattern is a novel sign that indicates left anterior descending coronary artery (LAD) occlusion in patients with chest pain. This study aimed to assess the prevalence and clinical characteristics of patients with this pattern. The de Winter EKG pattern is an special anterior ST-segment elevation myocardial infarction (STEMI) equivalents without obvious ST-segment elevation. This retrospective study included all patients with anterior myocardial infarction admitted between January 2011 and December 2017. Patients were categorized into two groups: those with the de Winter EKG pattern and those with typical STEMI. Of 441 patients, 15 (3.4%) with anterior myocardial infarction had the de Winter EKG pattern. Similar to those with typical STEMI, the majority of patients with the de Winter EKG pattern had ST-segment elevation, pathologic Q wave, and absence of R wave at follow-up. The median time from recognition of this pattern until its evolution was 114 minutes. The ST-segment in leads V3R to V5R and leads V7 to V9 were normal or slightly depressed when a typical de Winter EKG pattern was noted in leads V1 to V6. The culprit lesion was mainly in the proximal LAD or the diagonal branch. Patients with this EKG pattern responded poorly to thrombolytic therapy. We believe that the de Winter EKG pattern may be a sign of ischemia and presents at the early stage of STEMI rather than being an independent pattern. In patients with this pattern, a percutaneous coronary intervention rather than follow-up and thrombolytic strategy should be performed.


Adaptive coevolutionary networks: a review.
Adaptive networks appear in many biological applications. They combine topological evolution of the network with dynamics in the network nodes. Recently, the dynamics of adaptive networks has been investigated in a number of parallel studies from different fields, ranging from genomics to game theory. Here we review these recent developments and show that they can be viewed from a unique angle. We demonstrate that all these studies are characterized by common themes, most prominently: complex dynamics and robust topological self-organization based on simple local rules.


Core restoration for crown preparation.
This article will review the relevant literature fom 1991-2003, a period of time when adhesive resin luting materials became available and luting crowns with zinc phosphate cements decreased. The review wtill look at the principles suggesting when a core should be placed, what core materials function best, preparation design with a core, luting material choice with a core, and results of clinical trials. Amalgam cores are regarded as the strongest material, best able to withstand adverse stress and restore teeth having the greatest loss of tooth structure. Composite resins, whether chemically cured or light cured, reinforced or not, appear best capable of core restorationfor moderately broken down teeth. Glass ionomer materials are considered too weak to withstand stress as a core material, but are recommended as a base material tofill in undercuts and improve the accuracy of impression and fit of a crown.


Resource partitioning during reproduction in the Norway rat.
Rat pups nursed by pregnant dams grow as fast as pups reared by dams that are not pregnant. Moreover, litters that were in utero during a lactation are as numerous at birth and grow as fast as pups developing in a nonlactating, pregnant mother. These litters continue to grow as fast as pups born to nonlactating dams whether or not the first litter remains after the birth of the second litter. When pregnant and lactating dams have a restricted food supply, some dams are capable of extending the duration of their pregnancies by over 2 weeks past that of nonlactating, pregnant dams. This facultative prolongation of pregnancy apparently allows females to carry normal litters to term.


Rhizobium free-living nitrogen fixation occurs in specialized nongrowing cells.
A model for free-living N(2) fixation by Rhizobium sp. RC3200 is presented that asserts that this process occurs in nongrowing cells. Cultures containing mixed populations of cell types, N(2)-fixing and vegetative, grow cooperatively. In nitrogen-limited liquid suspension cultures, cooperative growth occurs by means of ammonium that is produced and exported by nongrowing, N(2)-fixing cells and transported to vegetative cells. This model implies prokaryotic differentiation: the creation of metabolically specialized cells, terminally nonviable, that functionally cooperate in a higher cell order. Here, the switch to a Rhizobium N(2)-fixing cell state is regulated by both O(2) and utilizable nitrogen.


Polyserositis and meningitis associated with Escherichia coli infection in piglets.
Two piglets which had a history of anorexia and weakness were examined pre and postmortem. Other piglets in the same herd had died within 24 hours of the onset of similar signs. The two piglets examined had a fibrinous polyserositis. Grossly, the pleura, peritoneum and joints were affected and an acute meningitis was noted on microscopic examination of the brains. Pure cultures of Escherichia coli were recovered from all but one of the organs and exudates cultured.


The natural history of post-traumatic neurohypophysial dysfunction.
Posterior pituitary function remains poorly investigated after traumatic brain injury (TBI). We report the results of a study designed to prospectively define the natural history of post-traumatic diabetes insipidus (DI) and syndrome of inappropriate antidiuretic hormone secretion (SIADH) using standard reliable methodology. 50 consecutive patients with severe or moderate TBI (initial Glasgow Coma Scale (GCS) score 3/15-13/15) were prospectively studied on three occasions: at the acute phase and at 6 months and at 12 months following TBI. In the acute phase, DI was diagnosed either by the presence of hypernatraemia in association with hypotonic polyuria or by the water-deprivation test (WDT) and, at 6 and 12 months by the WDT in all patients. Normative data on response to the WDT were obtained from healthy matched volunteers. Functional outcome was assessed using the Glasgow Outcome Scale (GOS). 13 patients (26%) had DI in the acute post-TBI phase, of whom nine patients recovered by 6 months and one additional patient recovered by 12 months. Of the remaining three patients with permanent DI, two had partial vasopressin deficiency. Acute-phase peak plasma osmolality correlated negatively with the initial GCS scores (r = -0.39, P = 0.005) and with the GOS scores (r = -0.45, P = 0.001). Seven patients had SIADH in the acute phase of TBI but none did at 6 or 12 months. No new cases of DI or SIADH were noted after the acute phase. This prospective study shows that posterior pituitary dysfunction is common following TBI. Most cases recover completely but there is an appreciable frequency of long-term DI which can be subtle and should be recognized and managed appropriately.


Artificial-intelligence-based MRI brain volumetry in patients with essential tremor and tremor-dominant Parkinson's disease.
Essential tremor and Parkinson's disease patients may present with various tremor types. Overlapping tremor features can be challenging to diagnosis and misdiagnosis is common. Although underlying neurodegenerative mechanisms are suggested, neuroimaging studies arrived at controversial results and often the different tremor types were not considered. We investigated whether different tremor types displayed distinct structural brain features. Structural MRI of 61 patients with essential tremor and 29 with tremor-dominant Parkinson's disease was analysed using a fully automated artificial-intelligence-based brain volumetry to compare volumes of several cortical and subcortical regions. Furthermore, essential tremor subgroups with and without rest tremor or more pronounced postural and kinetic tremor were investigated. Deviations from an internal reference collective of age- and sex-adjusted healthy controls and volumetric differences between groups were examined; regression analysis was used to determine the contribution of disease-related factors on volumetric measurements. Compared with healthy controls, essential tremor and tremor-dominant Parkinson's disease patients displayed deviations in the occipital lobes, hippocampus, putamen, pallidum and mesencephalon while essential tremor patients exhibited decreased volumes within the nucleus caudatus and thalamus. Analysis of covariance revealed similar volumetric patterns in both diseases. Essential tremor patients without rest tremor showed a significant atrophy within the thalamus compared to tremor-dominant Parkinson's disease and atrophy of the mesencephalon and putamen were found in both subgroups compared to essential tremor with rest tremor. Disease-related factors contribute to volumes of occipital lobes in both diseases and to volumes of temporal lobes in essential tremor and the putamen in Parkinson's disease. Fully automated artificial-intelligence-based volumetry provides a fast and rater-independent method to investigate brain volumes in different neurological disorders and allows comparisons with an internal reference collective. Our results indicate that essential tremor and tremor-dominant Parkinson's disease share structural changes, indicative of neurodegenerative mechanisms, particularly of the basal-ganglia-thalamocortical circuitry. A discriminating, possibly disease-specific involvement of the thalamus was found in essential tremor patients without rest tremor and the mesencephalon and putamen in tremor-dominant Parkinson's disease and essential tremor without rest tremor.


Structure of Leishmania major methionyl-tRNA synthetase in complex with intermediate products methionyladenylate and pyrophosphate.
Leishmania parasites cause two million new cases of leishmaniasis each year with several hundreds of millions of people at risk. Due to the paucity and shortcomings of available drugs, we have undertaken the crystal structure determination of a key enzyme from Leishmania major in hopes of creating a platform for the rational design of new therapeutics. Crystals of the catalytic core of methionyl-tRNA synthetase from L. major (LmMetRS) were obtained with the substrates MgATP and methionine present in the crystallization medium. These crystals yielded the 2.0 Å resolution structure of LmMetRS in complex with two products, methionyladenylate and pyrophosphate, along with a Mg(2+) ion that bridges them. This is the first class I aminoacyl-tRNA synthetase (aaRS) structure with pyrophosphate bound. The residues of the class I aaRS signature sequence motifs, KISKS and HIGH, make numerous contacts with the pyrophosphate. Substantial differences between the LmMetRS structure and previously reported complexes of Escherichia coli MetRS (EcMetRS) with analogs of the methionyladenylate intermediate product are observed, even though one of these analogs only differs by one atom from the intermediate. The source of these structural differences is attributed to the presence of the product pyrophosphate in LmMetRS. Analysis of the LmMetRS structure in light of the Aquifex aeolicus MetRS-tRNA(Met) complex shows that major rearrangements of multiple structural elements of enzyme and/or tRNA are required to allow the CCA acceptor triplet to reach the methionyladenylate intermediate in the active site. Comparison with sequences of human cytosolic and mitochondrial MetRS reveals interesting differences near the ATP- and methionine-binding regions of LmMetRS, suggesting that it should be possible to obtain compounds that selectively inhibit the parasite enzyme.


Theoretical Encapsulation of Fluorouracil (5-FU) Anti-Cancer Chemotherapy Drug into Carbon Nanotubes (CNT) and Boron Nitride Nanotubes (BNNT).
Chemotherapy with anti-cancer drugs is considered the most common approach for killing cancer cells in the human body. However, some barriers such as toxicity and side effects would limit its usage. In this regard, nano-based drug delivery systems have emerged as cost-effective and efficient for sustained and targeted drug delivery. Nanotubes such as carbon nanotubes (CNT) and boron nitride nanotubes (BNNT) are promising nanocarriers that provide the cargo with a large inner volume for encapsulation. However, understanding the insertion process of the anti-cancer drugs into the nanotubes and demonstrating drug-nanotube interactions starts with theoretical analysis. First, interactions parameters of the atoms of 5-FU were quantified from the DREIDING force field. Second, the storage capacity of BNNT (8,8) was simulated to count the number of drugs 5-FU encapsulated inside the cavity of the nanotubes. In terms of the encapsulation process of the one drug 5-FU into nanotubes, it was clarified that the drug 5-FU was more rapidly adsorbed into the cavity of the BNNT compared with the CNT due to the higher van der Waals (vdW) interaction energy between the drug and the BNNT. The obtained values of free energy confirmed that the encapsulation process of the drug inside the CNT and BNNT occurred spontaneously with the free energies of -14 and -25 kcal·mol-1, respectively. However, the lower value of the free energy in the system containing the BNNT unraveled more stability of the encapsulated drug inside the cavity of the BNNT comparing the system having CNT. The encapsulation of Fluorouracil (5-FU) anti-cancer chemotherapy drug (commercial name: Adrucil®) into CNT (8,8) and BNNT (8,8) with the length of 20 Å in an aqueous solution was discussed herein applying molecular dynamics (MD) simulation.


A randomized RSA study concentrating especially on continuous migration.
Background and purpose - There is a general call for phased introduction of new implants, and one step in the introduction is an early evaluation of micromotion. We compared the micromotion in the Triathlon and its predecessor, the Duracon total knee prosthesis, concentrating especially on continuous migration over 5 years of follow-up. Patients and methods - 60 patients were randomized to receive either a cemented Triathlon total knee prosthesis or a cemented Duracon total knee prosthesis. 3-D tibial component migration was measured by radiostereometric analysis (RSA) at 3 months and at 1, 2, and 5 years. Results - There was no statistically significant difference in maximum total point motion (MTPM) between the 2 groups (p = 0.1). The mean MTPM at 5 years for the Duracon was 1.10 (SD 1.21) mm and for the Triathlon it was 0.66 (SD 0.38) mm. The numbers of continuously migrating prostheses were similar in the groups at the fifth year of follow-up; 6 of 21 prostheses in the Duracon group and 3 of 21 in the Triathlon group had migrated more than 0.3 mm between the second year and the fifth year of follow-up (p = 0.2). Interpretation - The Triathlon has a micromotion pattern similar to that of the Duracon total knee system at both short-term and medium-term follow-up, and may therefore, over time, show the same good long-term mechanical stability.


A review on laboratory liver function tests.
Laboratory liver tests are broadly defined as tests useful in the evaluation and treatment of patients with hepatic dysfunction. The liver carries out metabolism of carbohydrate, protein and fats. Some of the enzymes and the end products of the metabolic pathway which are very sensitive for the abnormality occurred may be considered as biochemical marker of liver dysfunction. Some of the biochemical markers such as serum bilirubin, alanine amino transferase, aspartate amino transferase, ratio of aminotransferases, alkaline phosphatase, gamma glutamyl transferase, 5' nucleotidase, ceruloplasmin, α-fetoprotein are considered in this article. An isolated or conjugated alteration of biochemical markers of liver damage in patients can challenge the clinicians during the diagnosis of disease related to liver directly or with some other organs. The term "liver chemistry tests" is a frequently used but poorly defined phrase that encompasses the numerous serum chemistries that can be assayed to assess hepatic function and/or injury.


Diurnal variation of retinal thickness with spectral domain OCT.
To investigate whether diurnal variation occurs in retinal thickness measures derived from spectral domain optical coherence tomography (SD-OCT). Twelve healthy adult subjects had retinal thickness measured with SD-OCT every 2 h over a 10 h period. At each measurement session, three average B-scan images were derived from a series of multiple B-scans (each from a 5 mm horizontal raster scan along the fovea, containing 1500 A-scans/B-scan) and analyzed to determine the thickness of the total retina, as well as the thickness of the outer retinal layers. Average thickness values were calculated at the foveal center, at the 0.5 mm diameter foveal region, and for the temporal parafovea (1.5 mm from foveal center) and nasal parafovea (1.5 mm from foveal center). Total retinal thickness did not exhibit significant diurnal variation in any of the considered retinal regions (p > 0.05). Evidence of significant diurnal variation was found in the thickness of the outer retinal layers (p < 0.05), with the most prominent changes observed in the photoreceptor layers at the foveal center. The photoreceptor inner and outer segment layer thickness exhibited mean amplitude (peak to trough) of daily change of 7 ± 3 μm at the foveal center. The peak in thickness was typically observed at the third measurement session (mean measurement time, 13:06). The total retinal thickness measured with SD-OCT does not exhibit evidence of significant variation over the course of the day. However, small but significant diurnal variation occurs in the thickness of the foveal outer retinal layers.


Birth in Brazil survey: neonatal mortality, pregnancy and childbirth quality of care.
This study examined neonatal deaths in the live-births cohort in the Birth in Brazil survey, which interviewed and examined medical records of 23,940 mothers from February 2011 to October 2012. Potential risk factors were analyzed using hierarchical modeling. Neonatal mortality rate was 11.1/1,000, the highest rates occurring in the North and Northeast regions and in lower social classes. Low birth weight, risks during pregnancy and conditions of the newborn were the main factors associated with neonatal death. Inadequate prenatal and childbirth care point to unsatisfactory quality of health care. Difficulty in gaining hospital admission for delivery, and children with birth weight<1,500g born at hospitals without a neonatal intensive care unit, indicate gaps in health system organization. Deaths from intra-partum asphyxia in term babies and late prematurity express preventable neonatal mortality. Better quality health care, especially hospital care during labor and birth, poses the main public policy challenge to progress in reducing mortality and inequalities in Brazil.


Factors associated with participation in employment for high school leavers with autism.
This study aimed to identify the factors associated with participation in employment for high school leavers with autism. A secondary data analysis of the National Longitudinal Transition Study 2 (NLTS2) data was performed. Potential factors were assessed using a weighted multivariate logistic regression. This study found that annual household income, parental education, gender, social skills, whether the child had intellectual disability, whether the child graduated from high school, whether the child received career counseling during high school, and whether the child's school contacted postsecondary vocational training programs or potential employers were the significant factors associated with participation in employment. These findings may have implications for professionals who provide transition services and post-secondary programs for individuals with autism.


An Affordable and Easy-to-Construct Zebrafish Housing System for Stable Long-Term Laboratory Research.
Zebrafish have become a go-to model organism for in vivo studies, in part because of their reputation as being inexpensive to rear and house. Multiple do-it-yourself designs are currently available that provide laboratories with cost-effective housing systems. Unfortunately, these designs suffer from a range of issues ranging from poor water cycling rates and fragile housing tanks to inconsistent water conditions and designs that are prohibitively expensive for smaller laboratories to construct and maintain. These issues cause many of these housing systems to fall far short of the quality of commercially available zebrafish housing facilities. In this article, we present a novel, affordable, and easy-to-construct zebrafish housing system that improves upon previously published systems. The system utilizes three-dimensional printing technology to construct adaptable zebrafish tanks allowing for the housing of zebrafish at any stage of development. In addition, the water recirculation system utilizes multiple layers of filtration and no chemical adhesives, which allows for stable, long-term, housing of zebrafish in conditions suitable for research and teaching laboratories. The build described herein has been used by our laboratory to house zebrafish for over 3 years, representing multiple generations of housed fish.


Is "aseptic" loosening of the prosthetic cup after total hip replacement due to nonculturable bacterial pathogens in patients with low-grade infection?
Loosening of the prosthetic cup is the limiting factor in the service life of total hip prostheses (THPs). Despite effective culture methods, the detection of low-grade infection in patients with loose implants still presents a challenge. It is crucial to distinguish between "aseptic" loosening and loosening due to periprosthetic infection, so that appropriate treatment can be administered. We investigated whether aseptic loosening of the acetabular components of THPs is due to unrecognized infection. From October through December 2002, a total of 24 patients with acetabular cup loosening were investigated. Only patients without clinical signs of infection and with negative results of bacteriologic culture of synovial fluid (obtained by preoperative aspiration) were included in the study. Intraoperative biopsy samples obtained from the neocapsule and synovia (e.g., the interface membrane) were examined by means of routine culture methods and by polymerase chain reaction (PCR) for detection of 16S ribosomal RNA (rRNA). Control subjects included 9 patients undergoing primary hip arthroplasty. C-reactive protein levels and erythrocyte sedimentation rates were slightly elevated in the group with loosening, compared with the control group, but the difference was not statistically significant. PCR and routine culture showed no microorganisms in either group, with the exception of 1 patient in the loosening group. PCR for detection of 16S rRNA in tissue specimens obtained from hip joints is not superior to routine bacteriologic culture techniques for detection of low-grade infections. However, these results demonstrate that the loosening of cups in THPs do not usually result from nonculturable periprosthetic infection, if the microbiological processing is adequate.


Puumala hantavirus genetic variability in an endemic region (Northern Sweden).
Puumala hantavirus (PUUV), naturally harboured and shed by bank voles (Myodes [Clethrionomys] glareolus), is the etiological agent to nephropathia epidemica (NE), a mild haemorrhagic fever with renal syndrome. Both host and virus are found throughout much of the European continent and in northern Sweden NE is the second most prevalent serious febrile viral infection after influenza. The reliability of diagnostics by PCR depends on genetic variability for the detection of viral nucleic acids in unknown samples. In the present study we evaluated the genetic variability of PUUV isolated from bank voles in an area of northern Sweden highly endemic for NE. Genetic variability among bank voles was also investigated to evaluate co-evolutionary patterns. We found that the viral sequence appeared stable across the 80km study region, with the exception of the southernmost sampling site, which differed from its nearest neighbour by 7%, despite a geographical separation of only 10km. The southernmost sampling site demonstrated a higher degree of genetic similarity to PUUV previously isolated 100km south thereof; two locations appear to constitute a separate PUUV phylogenetic branch. In contrast to the viral genome, no phylogenetic variance was observed in the bank vole mtDNA in this study. Previous studies have shown that as a result of terrestrial mammals' postglacial re-colonization routes, bank voles and associated PUUV of a southern and a northern lineage established a dichotomous contact zone across the Scandinavian peninsula approximately 100-150km south of the present study sites. Our observations reveal evolutionary divergence of PUUV that has led to dissimilarities within the restricted geographical scale of the northern host re-colonization route as well. These results suggest either a static situation in which PUUV strains are regionally well adapted, or an ongoing process in which strains of PUUV circulate on a geographical scale not yet reliably described.


Cognitive Dysfunction Survey of the Japanese Patients with Moyamoya Disease (COSMO-JAPAN Study): study protocol.
Moyamoya disease is a cerebrovascular occlusive disease characterized by progressive stenosis or by occlusion at the terminal portion of the bilateral internal carotid arteries. The unusual vascular network (moyamoya vessels) at the base of the brain with this disease as collateral channels is developed in this disease. Social independence because of cognitive impairment has recently been recognized as an important unsolved social issue with adult moyamoya disease. The patients with cognitive impairment have difficulty in proving their status because the standard neuroradiological and neuropsychological methods to define cognitive impairment with moyamoya disease are not determined. These patients with cognitive impairment should be supported by social welfare as psychologically handicapped persons. Thus Cognitive Dysfunction Survey of the Japanese Patients with Moyamoya Disease (COSMO-JAPAN study) is planned. In this study, we want to establish a standard finding of the cognitive impairment in patients with moyamoya disease.


Neuroimaging features of epidermal nevus syndrome.
Epidermal nevus syndrome is a kind of neurocutaneous syndrome that is associated with epidermal nevus and a variety of congenital CNS disorders. Clinical presentations include seizures, paresis, mental retardation, and developmental delay. We report three cases with MR imaging and magnetoencephalography findings; one patient underwent ictal and interictal single photon emission CT. Both structural and functional imaging studies indicated that the frontal lobes had lesser involvement or were intact. One patient underwent hemispherectomy because of the medically intractable seizure. He remained seizure free with topiramate monotherapy.


Body temperature, activity patterns and hunting in free-living cheetah: biologging reveals new insights.
As one of the few felids that is predominantly diurnal, cheetahs (Acinonyx jubatus) can be exposed to high heat loads in their natural habitat. Little is known about long-term patterns of body temperature and activity (including hunting) in cheetahs because long-term concurrent measurements of body temperature and activity have never been reported for cheetahs, or, indeed, for any free-living felid. We report here body temperature and locomotor activity measured with implanted data loggers over 7 months in 5 free-living cheetahs in Namibia. Air temperature ranged from a maximum of 39 °C in summer to -2 °C in winter. Cheetahs had higher (∼0.4 °C) maximum 24-h body temperatures, later acrophase (∼1 h), with larger fluctuations in the range of the 24-h body temperature rhythm (approximately 0.4 °C) during a hot-dry period than during a cool-dry period, but maintained homeothermy irrespective of the climatic conditions. As ambient temperatures increased, the cheetahs shifted from a diurnal to a crepuscular activity pattern, with reduced activity between 900 and 1500 hours and increased nocturnal activity. The timing of hunts followed the general pattern of activity; the cheetahs hunted when they were on the move. Cheetahs hunted if an opportunity presented itself; on occasion they hunted in the midday heat or in total darkness (new moon). Biologging revealed insights into cheetah biology that are not accessible by traditional observer-based techniques.


Regional [18F]flortaucipir PET is more closely associated with disease severity than CSF p-tau in Alzheimer's disease.
In vivo Alzheimer's disease (AD) biomarkers for tau pathology are cerebrospinal fluid (CSF) phosphorylated tau (p-tau) and [18F]flortaucipir positron emission tomography (PET). Our aim was to assess associations between CSF p-tau with [18F]flortaucipir PET and the associations of both tau biomarkers with cognition and atrophy. We included 78 amyloid positive cognitively impaired patients (clinical diagnoses mild cognitive impairment (MCI, n = 8) and AD dementia (n = 45) and 25 cognitively normal subjects with subjective cognitive decline (SCD) (40% amyloid-positive)). Dynamic 130 min [18F]flortaucipir PET scans were acquired to generate binding potential (BPND) images using receptor parametric mapping and standardized uptake values ratios of 80-100 min (SUVr80-100min) post injection. We obtained regional BPND and SUVr from entorhinal, limbic, and neocortical regions-of-interest (ROIs), closely aligning to the neuropathological tau staging schemes. Cognition was assessed using MMSE and composite scores of four cognitive domains, and atrophy was measured using gray matter volume covering the major brain lobes. First, we used linear regressions to investigate associations between CSF p-tau (independent variable) and tau PET (dependent variable). Second, we used linear regressions to investigate associations between CSF p-tau, tau PET (separate independent variables, model 1), and cognition (dependent variable). We then assessed the independent effects of CSF p-tau and tau PET on cognition by simultaneously adding the other tau biomarker as a predictor (model 2). Finally, we performed the same procedure for model 1 and 2, but replaced cognition with atrophy. Models were adjusted for age, sex, time lag between assessments, education (cognition only), and total intracranial volume (atrophy only). Higher [18F]flortaucipir BPND was associated with higher CSF p-tau (range of standardized betas (sβ) across ROIs, 0.43-0.46; all p < 0.01). [18F]flortaucipir BPND was more strongly associated with cognition and atrophy than CSF p-tau. When [18F]flortaucipir BPND and CSF p-tau were entered simultaneously, [18F]flortaucipir BPND (range sβ = - 0.20 to - 0.57, all p < 0.05) was strongly associated with multiple cognitive domains and atrophy regions. SUVr showed comparable results to BPND. Regional [18F]flortaucipir BPND correlated stronger with cognition and neurodegeneration than CSF p-tau, suggesting that tau PET more accurately reflects disease severity in AD.


Real World Efficacy and Safety of Sofosbuvir + Velpatasvir + Voxilaprevir in Romanian Patients with Genotype 1b HCV Infection Non-reponders to DAAs Therapy.
The sofosbuvir (SOF) / velpatasvir (VEL) / voxilaprevir (VOX) combination has been evaluated in more than 800 patients enrolled in phase II and phase III studies, where it demonstrated excellent safety and efficacy, achieving overall sustained viral response (SVR) rates of more than 95%. We aimed to assess the efficacy and safety of SOF/VEL/VOX in a real-world study, including patients previously treated for genotype 1b hepatitis C virus (HCV) infection that did not obtain a sustained viral response with previous direct-acting antivirals (DAAs) therapy. In Romania, through a nationwide government-funded program in 2019-2020, 213 patients with chronic hepatitis C non-responders to previous DAAs therapy, received treatment with SOF/VEL/ VOX 400/100/100 mg/day for 12 weeks. We performed a retrospective longitudinal study that included 143 individuals who were treated in Bucharest, Iași, Craiova and Constanța clinics, all with genotype 1b HCV infection. Efficacy was assessed by the percentage of patients achieving SVR 12 weeks post-treatment (SVR12). Serious adverse events (SAE) were registered. Our cohort comprised 53% males with a median age of 60 years (27÷77); 47% were pre-treated with ombitasvir/paritaprevir/ritonavir+dasabuvir ± ribavirin, 40% with ledipasvir/SOF, 13% with elbasvir/ grazoprevir. 42% of patients associated co-morbidities, 45% had compensated liver cirrhosis, 2% had treated hepatocellular carcinoma (HCC) and 1% had hepatitis B virus co-infection. SVR by intention to treat was reported in 139/143 (97.2%) and per protocol in 141/143 (98.6%). No predictive factors for SVR were identified. Rate of liver decompensation in patients with cirrhosis was 6% and was statistically associated in multivariate analysis with Child-Pugh score (p<0.01) and with severe steatosis (p=0.004). Occurrence of new HCC was reported in 3.6% of all patients with cirrhosis and was associated with poor liver function [higher Child-Pugh score (p=0.001) and low albumin levels (p=0.02)]. Serious adverse events related to therapy were reported in 1/143(0.7%). SOF/VEL/VOX was highly efficient in our population of patients with a 97.2% SVR. Liver decompensation occurred in 6% of cirrhotic patients at SVR, related to hepatic dysfunction.


WHSC1 promotes oncogenesis through regulation of NIMA-related kinase-7 in squamous cell carcinoma of the head and neck.
Squamous cell carcinoma of the head and neck (SCCHN) is a relatively common malignancy with suboptimal long-term prognosis, thus new treatment strategies are urgently needed. Over the last decade, histone methyltransferases (HMT) have been recognized as promising targets for cancer therapy, but their mechanism of action in most solid tumors, including SCCHN, remains to be elucidated. This study investigated the role of Wolf-Hirschhorn syndrome candidate 1 (WHSC1), an NSD family HMT, in SCCHN. Immunohistochemical analysis of locoregionally advanced SCCHN, dysplastic, and normal epithelial tissue specimens revealed that WHSC1 expression and dimethylation of histone H3 lysine 36 (H3K36me2) were significantly higher in SCCHN tissues than in normal epithelium. Both WHSC1 expression and H3K36me2 levels were significantly correlated with histologic grade. WHSC1 knockdown in multiple SCCHN cell lines resulted in significant growth suppression, induction of apoptosis, and delay of the cell-cycle progression. Immunoblot and immunocytochemical analyses in SCCHN cells demonstrated that WHSC1 induced H3K36me2 and H3K36me3. Microarray expression profile analysis revealed NIMA-related kinase-7 (NEK7) to be a downstream target gene of WHSC1, and chromatin immunoprecipitation (ChIP) assays showed that NEK7 was directly regulated by WHSC1 through H3K36me2. Furthermore, similar to WHSC1, NEK7 knockdown significantly reduced cell-cycle progression, indicating that NEK7 is a key player in the molecular pathway regulated by WHSC1. WHSC1 possesses oncogenic functions in SCCHN and represents a potential molecular target for the treatment of SCCHN.


Early outcomes of total hip arthroplasty using point-of-care manufactured patient-specific instruments: a single university hospital's initial experience.
The use of 3D-printed Patient-Specific Instruments (PSI) has been investigated to enhance the postoperative functional results in total hip arthroplasty (THA) and has been recognized as an innovative approach for the optimal alignment of hip implant components. Point-of-care production is gradually becoming the norm for PSI manufacturing. The purpose of this article is to assess the accuracy and safety of PSI for total hip arthroplasty performed at the point-of-care in Vietnam. 34 THA cases were assessed in this prospective study. A template for the size and orientation of the implant and the design of the PSI was generated using data from preoperative 3D computed tomography (CT) scanning of the lower limb. The principal surgeon determined the implants' position and PSI design directly using the software. The PSI is then produced using a 3D-compatible resin printer in our manufacturing hospital. The PSI, consisting of an acetabulum and a femoral component placed press-fit on the bony surface, guided surgeons to precisely ream the acetabulum and cut the femoral neck according to the pre-planned plane. Postoperative CT scanning was obtained and superimposed onto the 3D model of the implant to evaluate the accuracy of the procedure by comparing the orientation values of the cup and the alignment of the stem between the planned and the actual results. Intra- and postoperative clinical parameters of surgery, including surgical time, intra-operative blood loss, complications, and the first ambulation, were also recorded to evaluate the safety of the surgery. The preparation for PSI required an average of 3 days. 94% of cup size and 91% of stem size were correctly selected. The mean values of postoperative inclination and anteversion were 44.2° ± 4.1° and 19.2° ± 5.6°, respectively. 64.7% of cases deviated from planned within the ± 50 range and 94.1% within the ± 10° range. There was no significant statistical difference between the planned and the achieved values of stem anteversion, osteotomy height, and leg length discrepancy (p > 0.05). The average surgical time was 82.5° ± 10.8 min, and the intraoperative blood loss was estimated at 317.7° ± 57.6 ml. 64.7% of patients could walk on the day of surgery. There were no complications reported. The point-of-care manufactured PSI is a useful solution for improving the accuracy of total hip arthroplasty surgery, especially in restoring implant orientation and reducing leg length discrepancy. However, long-term clinical follow-up evaluation is needed to confirm the efficacy and safety of this approach.


Propranolol Suppresses the T-Helper Cell Depletion-Related Immune Dysfunction in Cirrhotic Mice.
Bacterial translocation (BT) and splenomegaly contribute to cirrhosis-associated immune dysfunction (CAID) including T cell depletion, infection, and chronic inflammation. β-blockers have been reported to decrease BT and improve splenomegaly. This study explores the modulation of β1 and β2 adrenergic receptors (ADRB1/ADRB2) by propranolol treatment on the peripheral and splenic immune dysfunction of cirrhotic mice. In vivo experiments were performed in bile duct ligation (BDL)- and thioacetamide (TAA)-cirrhotic mice receiving two weeks of propranolol treatment. Acute effects of propranolol were evaluated in T-helper (Th) cells isolated from spleen of cirrhotic mice. Over-expression of β1 and β2 adrenergic receptors (ADRB1/ADRB2) in spleen and T lymphocytes was associated with high peripheral/splenic lipopolysaccharide binding protein levels. Moreover, a decrease in Th cells percentage, increase in Treg subset, and cytokines were accompanied by increased apoptosis, proliferation, and reduced white pulp hyperplasia in cirrhotic mice, which were counteracted by propranolol treatment. The Th-cell depletion, systemic inflammation, BT, and infection were improved by chronic propranolol treatment. Acute propranolol treatment inhibited apoptosis, Treg-conditioned differentiation, and promoted Th2-conditioned differentiation through ADRB-cyclic adenosine monophosphate (cAMP) signals in cirrhotic mice. In conclusion, suppression of ADRB1 and ADRB2 expressions in spleen and splenic T lymphocytes by acute and chronic propranolol treatment ameliorate systemic and splenic immune dysfunction in cirrhosis.


Nucleolin-targeted Extracellular Vesicles as a Versatile Platform for Biologics Delivery to Breast Cancer.
Small interfering RNAs (siRNA)/microRNAs (miRNA) have promising therapeutic potential, yet their clinical application has been hampered by the lack of appropriate delivery systems. Herein, we employed extracellular vesicles (EVs) as a targeted delivery system for small RNAs. EVs are cell-derived small vesicles that participate in cell-to-cell communication for protein and RNA delivery. We used the aptamer AS1411-modified EVs for targeted delivery of siRNA/microRNA to breast cancer tissues. Tumor targeting was facilitated via AS1411 binding to nucleolin, which is highly expressed on the surface membrane of breast cancer cells. This delivery vesicle targeted let-7 miRNA delivery to MDA-MB-231 cells in vitro as confirmed with fluorescent microscopic imaging and flow cytometry. Also, intravenously delivered AS1411-EVs loaded with miRNA let-7 labeled with the fluorescent marker, Cy5, selectively targeted tumor tissues in tumor-bearing mice and inhibited tumor growth. Importantly, the modified EVs were well tolerated and showed no evidence of nonspecific side effects or immune response. Thus, the RNAi nanoplatform is versatile and can deliver siRNA or miRNA to breast cancer cells both in vitro and in vivo. Our results suggest that the AS1411-EVs have a great potential as drug delivery vehicles to treat cancers.


Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression.
Induction of compensatory mechanisms and ERK reactivation has limited the effectiveness of Raf and MEK inhibitors in RAS-mutant cancers. We determined that direct pharmacologic inhibition of ERK suppressed the growth of a subset of KRAS-mutant pancreatic cancer cell lines and that concurrent phosphatidylinositol 3-kinase (PI3K) inhibition caused synergistic cell death. Additional combinations that enhanced ERK inhibitor action were also identified. Unexpectedly, long-term treatment of sensitive cell lines caused senescence, mediated in part by MYC degradation and p16 reactivation. Enhanced basal PI3K-AKT-mTOR signaling was associated with de novo resistance to ERK inhibitor, as were other protein kinases identified by kinome-wide siRNA screening and a genetic gain-of-function screen. Our findings reveal distinct consequences of inhibiting this kinase cascade at the level of ERK.


Aerobic and anaerobic urethral flora of healthy females in various physiological age groups and of females with urinary tract infections.
We characterized the aerobic and anaerobic urethral flora of healthy females in three physiological age groups (premenarcheal, reproductive, and postmenopausal) and of females with urinary tract infections. The mean number of species per sample was 6.5, 7.7, and 10.3 for each of the physiological age groups, respectively, and 6.5 for the urinary tract infection group. Marked quantitative changes were seen with age and disease. Aerobes accounted for 65.6 and 73.8% of the flora of the premenarcheal and reproductive age groups, respectively, whereas anaerobes were dominant in the postmenopausal age group, accounting for 65.5% of the flora. Aerobic gram-negative rods were not isolated from any of the premenarcheal or reproductive-age subjects. Of the 10 postmenopausal subjects, 5 carried aerobic gram-negative rods, but these organisms accounted for only 1% of the flora. In contrast, they constituted 95% of the urethral flora of the urinary tract infection group. Bacteroides melaninogeneicus was commonly isolated and was the dominant isolate in the postmenopausal age group. Bacteroides fragilis was recovered from 7 of the 10 postmenopausal subjects, but these organisms constituted only 3% of the total flora. The factors responsible for the changes in urethral flora with age remain to be determined.


The rate of transient beta frequency events predicts behavior across tasks and species.
Beta oscillations (15-29Hz) are among the most prominent signatures of brain activity. Beta power is predictive of healthy and abnormal behaviors, including perception, attention and motor action. In non-averaged signals, beta can emerge as transient high-power 'events'. As such, functionally relevant differences in averaged power across time and trials can reflect changes in event number, power, duration, and/or frequency span. We show that functionally relevant differences in averaged beta power in primary somatosensory neocortex reflect a difference in the number of high-power beta events per trial, i.e. event rate. Further, beta events occurring close to the stimulus were more likely to impair perception. These results are consistent across detection and attention tasks in human magnetoencephalography, and in local field potentials from mice performing a detection task. These results imply that an increased propensity of beta events predicts the failure to effectively transmit information through specific neocortical representations.


Tertiary syphilis in the cervical spine: a case report and review of the literature.
As the prevalence of syphilis rises, an increase in tertiary syphilis with spinal involvement is predicted. We report what we believe to be the first case of compressive cervical spine syphilitic gummata, with central cord compression signs. We also review the relevant literature to date. The diagnosis of syphilis in the spine relies on the physician to be aware of it as part of the differential diagnosis. Treponemal laboratory tests are an important aid in establishing a diagnosis.


Transient expression of wild-type or biologically inactive telomerase allows the formation of artificial telomeres in mortal human cells.
Telomere seeding, the formation of artificial telomeres, has been routinely successful in immortalized but not normal human cells. We compared seeding efficiencies in preimmortal and immortal SV40-transformed cells using plasmid telomeres with T(2)AG(3) tracts of 1600 and 3200 bp. Seeding occurred only in immortal cells, indicating that transformed preimmortal cells behave like normal cells vis à vis formation of new telomeres and that T-antigen inhibition of cellular checkpoints is insufficient to allow seeding. Telomerase is active in immortal but not preimmortal cells, which do not express the reverse transcriptase hTERT. Upon transient expression of hTERT, seeds with 1600 bp of T(2)AG(3) formed telomeres in preimmortal cells. Comparable seeding efficiencies were obtained with wild-type hTERT or the HA-tagged protein that is catalytically active but unable to maintain endogenous telomeres. No seeding occurred with catalytically inactive hTERT. Given that telomerase expression was transient and that longer seeds did not form telomeres in the absence of the enzyme, seeding may not be elicited merely by elongation of telomeric sequences. We propose that modification of the telomeric terminus by telomerase may contribute to telomere seeding by leading to formation of a structure that impedes rejoining of this terminus with chromosomal sequences.


Precision Medicine for Cardiac Resynchronization: Predicting Quality of Life Benefits for Individual Patients-An Analysis From 5 Clinical Trials.
Clinical trials have established the average benefit of cardiac resynchronization therapy (CRT), but estimating benefit for individual patients remains difficult because of the heterogeneity in treatment response. Accordingly, we created a multivariable model to predict changes in quality of life (QoL) with and without CRT. Patient-level data from 5 randomized trials comparing CRT with no CRT were used to create a prediction model of change in QoL at 3 months using a partial proportional odds model for no change, small, moderate, and large improvement, or deterioration of any magnitude. The C statistics for not worsening or obtaining at least a small, moderate, and large improvement were calculated. Among the 3614 patients, regardless of assigned treatment, 33.3% had a deterioration in QoL, 9.2% had no change, 9.2% had a small improvement, 13.5% had a moderate improvement, and the remaining 34.9% had a large improvement. Patients undergoing CRT were less likely to have a decrement in their QoL (28.2% versus 38.9%; P<0.001) and more likely to have a large QoL improvement (38.7% versus 30.6%; P<0.001). A partial proportional odds model identified baseline QoL, age, and an interaction of CRT with QRS duration as predictors of QoL benefits 3 months after randomization. C statistics of 0.65 for not worsening, 0.68 for at least a small improvement, 0.69 for at least a moderate improvement, and 0.73 for predicting a large improvement were observed. There is marked heterogeneity of treatment benefit of CRT that can be predicted based on baseline QoL, age, and QRS duration.


Vision 20/20: Single photon counting x-ray detectors in medical imaging.
Photon counting detectors (PCDs) with energy discrimination capabilities have been developed for medical x-ray computed tomography (CT) and x-ray (XR) imaging. Using detection mechanisms that are completely different from the current energy integrating detectors and measuring the material information of the object to be imaged, these PCDs have the potential not only to improve the current CT and XR images, such as dose reduction, but also to open revolutionary novel applications such as molecular CT and XR imaging. The performance of PCDs is not flawless, however, and it seems extremely challenging to develop PCDs with close to ideal characteristics. In this paper, the authors offer our vision for the future of PCD-CT and PCD-XR with the review of the current status and the prediction of (1) detector technologies, (2) imaging technologies, (3) system technologies, and (4) potential clinical benefits with PCDs.


Recognizing and managing obstructive sleep apnea in primary care.
This review aims to impart information regarding recognition of obstructive sleep apnea (OSA) and associated excessive sleepiness (ES) in the primary care setting in order to provide optimal care to patients with this common but serious condition. This review will also discuss the prevalence and treatment of depression in patients with OSA. A MEDLINE search of articles published between 1990 and 2008 was conducted using the search terms obstructive sleep apnea AND excessive sleepiness, obstructive sleep apnea AND depression, and obstructive sleep apnea AND primary care. Searches were limited to articles in English concerned with adult patients. In total, 239 articles were identified. Articles concerning other sleep disorders and forms of apnea were excluded. The reference lists of identified articles were searched manually to find additional articles of interest. Primary care physicians can aid in the diagnosis of OSA and associated ES by being vigilant for lifestyle and physical risk factors associated with this condition. In addition, primary care physicians should maintain a high level of clinical suspicion when presented with illnesses that are commonly comorbid with OSA, such as psychiatric disorders and depression, in particular. Conversely, assessment of patients with OSA for common comorbidities may also improve a patient's prognosis and quality of life. Primary care physicians play a vital role in recognizing OSA and ES. These clinicians are crucial in supporting their patients during treatment by ensuring that they have clear, concise information regarding available therapies and the correct application and maintenance of prescribed devices.


Nonadherence to antihypertensive drugs: A systematic review and meta-analysis.
Hypertension drives the global burden of cardiovascular disease and its prevalence is estimated to increase by 30% by the year 2025. Nonadherence to chronic medication regimens is common; approximately 43% to 65.5% of patients who fail to adhere to prescribed regimens are hypertensive patients. Nonadherence to medications is a potential contributing factor to the occurrence of concomitant diseases. This systematic review applied a meta-analytic procedure to investigate the medication nonadherence in adult hypertensive patients. Original research studies, conducted on adult hypertensive patients, using the 8-item Morisky medication adherence scale (MMAS-8) to assess the medication adherence between January 2009 and March 2016 were included. Comprehensive search strategies of 3 databases and MeSH keywords were used to locate eligible literature. Study characteristics, participant demographics, and medication adherence outcomes were recorded. Effect sizes for outcomes were calculated as standardized mean differences using random-effect model to estimate overall mean effects. A total of 28 studies from 15 countries were identified, in total comprising of 13,688 hypertensive patients, were reviewed. Of 25 studies included in the meta-analysis involving 12,603 subjects, a significant number (45.2%) of the hypertensive patients and one-third (31.2%) of the hypertensive patients with comorbidities were nonadherent to medications. However, a higher proportion (83.7%) of medication nonadherence was noticed in uncontrolled blood pressure (BP) patients. Although a higher percentage (54%) of nonadherence to antihypertensive medications was noticed in females (P < 0.001), the risk of nonadherence was 1.3 times higher in males, with a relative risk of 0.883. Overall, nearly two-thirds (62.5%) of the medication nonadherence was noticed in Africans and Asians (43.5%). Nonadherence to antihypertensive medications was noticed in 45% of the subjects studied and a higher proportion of uncontrolled BP (83.7%) was nonadherent to medication. Intervention models aiming to improve adherence should be emphasized.


[Clinical and experimental study on shenghong kangyan su in treating 144 cases of pelvic inflammation with blood stasis syndrome].
Using the method of clearing up heat and resolving stasis, the authors treated 144 cases of pelvic inflammation with blood stasis syndrome (BSS) with Shenghong Kangyan Su. The total effective rate was up to 97.92%, cure rate up to 68.75%, without toxicity and side effects. Clinical and experimental study showed that the crux of pelvic inflammation with BSS had some relations with microcirculation obstruction. Inflammation may cause microcirculation obstruction and blood stasis, and is one forms of BSS. Therefore dull purple-tongue, undertongue vein dilated, abdominal pain in lower-part, pathologic mass can be regarded as the basis of diagnosis of pelvic inflammation with BSS The drug of clearing heat and resolving status has the functions of anti-inflammation, anti-pain, diminishing the obstruction of microcirculation, particularly in speeding up the blood flowing, lowering the aggregation of erythrocyte, P less than 0.001.


Tensing and stiffening of skin grafts.
Many surgeons have difficulty in cutting small split thickness skin grafts of consistent thickness and width. We demonstrate techniques using equipment and supplies almost always available for expeditious cutting and handling of small split thickness skin grafts. The methods suggested should allow surgeons to eliminate some of the problems that they have had with this basic technique of reconstruction.


Hydroxytyrosol and Cytoprotection: A Projection for Clinical Interventions.
Hydroxytyrosol (HT) ((3,4-Dihydroxyphenyl)ethanol) is a polyphenol mainly present in extra virgin olive oil (EVOO) but also in red wine. It has a potent antioxidant effect related to hydrogen donation, and the ability to improve radical stability. The phenolic content of olive oil varies between 100 and 600 mg/kg, due to multiple factors (place of cultivation, climate, variety of the olive and level of ripening at the time of harvest), with HT and its derivatives providing half of that content. When consumed, EVOO's phenolic compounds are hydrolyzed in the stomach and intestine, increasing levels of free HT which is then absorbed in the small intestine, forming phase II metabolites. It has been demonstrated that HT consumption is safe even at high doses, and that is not genotoxic or mutagenic in vitro. The beneficial effects of HT have been studied in humans, as well as cellular and animal models, mostly in relation to consumption of EVOO. Many properties, besides its antioxidant capacity, have been attributed to this polyphenol. The aim of this review was to assess the main properties of HT for human health with emphasis on those related to the possible prevention and/or treatment of non-communicable diseases.


Autophagic pathways as new targets for cancer drug development.
Autophagy is an evolutionarily conserved lysosomal self-digestion process involved in degradation of long-lived proteins and damaged organelles. In recent years, increasing evidence indicates that autophagy is associated with a number of pathological processes, including cancer. In this review, we focus on the recent studies of the evolutionarily conserved autophagy-related genes (ATGs) that are implicated in autophagosome formation and the pathways involved. We discuss several key autophagic mediators (eg, Beclin-1, UVRAG, Bcl-2, Class III and I PI3K, mTOR, and p53) that play pivotal roles in autophagic signaling networks in cancer. We discuss the Janus roles of autophagy in cancer and highlighted their relationship to tumor suppression and tumor progression. We also present some examples of targeting ATGs and several protein kinases as anticancer strategy, and discuss some autophagy-modulating agents as antitumor agents. A better understanding of the relationship between autophagy and cancer would ultimately allow us to harness autophagic pathways as new targets for drug discovery in cancer therapeutics.


A case of Osmotic demyelination syndrome despite normal rate of Sodium correction with good recovery.
The Osmotic demyelination syndrome (ODS) primarily occurs with rapid correction of severe hyponatraemia that has been present for more than two or three days. Some patients are, however at risk and can develop ODS at higher sodium concentration and lower rates of correction. A case of Osmotic demyelination Syndrome which developed despite an 'optimal' rate of correction of serum Sodium with good clinical outcome is described. The risk factors that contribute to development of ODS and strategies to prevent this complication are discussed, along with recommendations on how to manage this condition in hospital inpatients.


Pleiotropic effects of the melanocortin 1 receptor (MC1R) gene on human pigmentation.
Variants of the melanocortin 1 receptor (MC1R) gene are common in individuals with red hair and fair skin, but the relative contribution to these pigmentary traits in heterozygotes, homozygotes and compound heterozygotes for variants at this locus from the multiple alleles present in Caucasian populations is unclear. We have investigated 174 individuals from 11 large kindreds with a preponderance of red hair and an additional 99 unrelated redheads, for MC1R variants and have confirmed that red hair is usually inherited as a recessive characteristic with the R151C, R160W, D294H, R142H, 86insA and 537insC alleles at this locus. The V60L variant, which is common in the population may act as a partially penetrant recessive allele. These individuals plus 167 randomly ascertained Caucasians demonstrate that heterozygotes for two alleles, R151C and 537insC, have a significantly elevated risk of red hair. The shade of red hair frequently differs in heterozygotes from that in homozygotes/compound heterozygotes and there is also evidence for a heterozygote effect on beard hair colour, skin type and freckling. The data provide evidence for a dosage effect of MC1R variants on hair as well as skin colour.


Long-term effects of the treatment of depressive female inpatients in a naturalistic study: is early improvement a valid predictor of outcome?
Objectives. To examine the predictive value of early improvement for short- and long-term outcome in the treatment of depressive female inpatients and to explore the influence of comorbid disorders (CD). Methods. Archival data of a naturalistic sample of 277 female inpatients diagnosed with a depressive disorder was analyzed assessing the BDI at baseline, after 20 days and 30 days, posttreatment, and after 3 to 6 months at follow-up. Early improvement, defined as a decrease in the BDI score of at least 30% after 20 and after 30 days, and CD were analyzed using binary logistic regression. Results. Both early improvement definitions were predictive of remission at posttreatment. Early improvement after 30 days showed a sustained treatment effect in the follow-up phase, whereas early improvement after 20 days failed to show a persistent effect regarding remission at follow-up. CD were not significantly related neither at posttreatment nor at follow-up. At no time point CD moderated the prediction by early improvement. Conclusions. We show that early improvement is a valid predictor for short-term remission and at follow-up in an inpatient setting. CD did not predict outcome. Further studies are needed to identify patient subgroups amenable to more tailored treatments.


The hog-badger is not an edentate: systematics and evolution of the genus Arctonyx (Mammalia: Mustelidae).
Hog-badgers (mustelid carnivorans classified in the genus Arctonyx) are distributed throughout East and Southeast Asia, including much of China, the eastern Indian Subcontinent, Indochina and the large continental Asian island of Sumatra. Arctonyx is usually regarded as monotypic, comprising the single species A. collaris F. Cuvier, 1825, but taxonomic boundaries in the genus have never been revised on the basis of sizeable series from throughout this geographical range. Based on a review of most available specimens in world museums, we recognize three distinctive species within the genus, based on craniometric analyses, qualitative craniodental features, external comparisons, and geographical and ecological considerations. Arctonyx albogularis (Blyth, 1853) is a shaggy-coated, medium-sized badger widely distributed in temperate Asia, from Tibet and the Himalayan region to eastern and southern China. Arctonyx collaris F. Cuvier, 1825, is an extremely large, shorter-haired badger, distributed throughout Southeast Asia, from eastern India to Myanmar, Thailand, Vietnam, Cambodia and Laos. The world's largest extant badger, A. collaris co-occurs with A. albogularis in eastern India and probably in southern China, and fossil comparisons indicate that its geographical range may have extended into central China in the middle Pleistocene. The disjunctly distributed species Arctonyx hoevenii (Hubrecht, 1891), originally described within the order 'Edentata' by a remarkable misunderstanding, is the smallest and darkest member of the genus and is endemic to the Barisan mountain chain of Sumatra. Apart from A. hoevenii, no other Arctonyx occurs on the Sunda Shelf below peninsular Thailand. The natural history of each species of Arctonyx, so far as is known, is briefly reviewed. No claim to original US Government works.


A Comparison of Factors Associated with Running-Related Injuries between Adult and Adolescent Runners.
There are multiple personal and environmental factors that influence the risk of developing running-related injuries (RRIs). However, it is unclear how these key clinical factors differ between adult and adolescent runners. The purpose of this study was to compare anthropometric, training, and self-reported outcomes among adult and adolescent runners with and without lower extremity musculoskeletal RRIs. Cross-sectional study. Questionnaire responses and clinical assessment data were extracted from 38 adult runners (F: 25, M: 13; median age: 23 [range 18-36]) and 91 adolescent runners (F: 56, M: 35; median age: 15 [range 14-16]) who underwent a physical injury prevention evaluation at a hospital-affiliated sports injury prevention center between 2013 and 2021. Participants were sub-grouped into those with (adults: 25; adolescents: 38) and those without (adults: 13; adolescents: 53) a history of self-reported RRIs based on questionnaire responses. Multivariate analyses of covariance (MANCOVA) covarying for gender were conducted to compare outcomes across groups. Adult runners had lower Functional Movement Screen™ (FMS™) scores (mean differences [MD]: -1.4, p=0.01), were more likely to report intentional weight-loss to improve athletic performance (% difference: 33.0%; p:<.001), and more frequently included resistance training into their training routines (% difference: 21.0%, p=0.01) compared to adolescents. Those with a history of RRIs were more likely to report intentional weight-loss compared to uninjured runners (% difference: 21.3; p=0.02) and had shorter single leg bridge durations than those without RRIs (RRI: 57.9±30, uninjured: 72.0±44, p=0.01). The findings indicate that addressing aspects of biomechanics identified by the FMS™ and behaviors of weight loss as an effort to improve performance may represent targets for the prevention of RRIs for adult and adolescent runners, given the association with history of RRIs. 3.


A data-driven prediction of lifetime resilience of dairy cows using commercial sensor data collected during first lactation.
Reliable prediction of lifetime resilience early in life can contribute to improved management decisions of dairy farmers. Several studies have shown that time series sensor data can be used to predict lifetime resilience rankings. However, such predictions generally require the translation of sensor data into biologically meaningful sensor features, which involve proper feature definitions and a lot of preprocessing. The objective of this study was to investigate the hypothesis that data-driven random forest algorithms can equal or improve the prediction of lifetime resilience scores compared with ordinal logistic regression, and that these algorithms require considerably less effort for data preprocessing. We studied this by developing prediction models that forecast lifetime resilience of a cow early in her productive life using sensor data from the first lactation. We used an existing data set from a Dutch experimental herd, with data of culled cows for which birth dates, insemination dates, calving dates, culling dates, and health treatments were available to calculate lifetime resilience scores. Moreover, 4 types of first-lactation sensor data, converted to daily aggregated values, were available: milk yield, body weight, activity, and rumination. For each sensor, 14 sensor features were calculated, of which part were based on absolute daily values and part on relative to herd average values. First, we predicted lifetime resilience rank with stepwise logistic regression using sensor features as predictors and a P-value of <0.2 as the cut-off. Next, we applied a random forest with the 6 features that remained in the final logistic regression model. We then applied a random forest with all sensor features, and finally applied a random forest with daily aggregated values as features. All models were validated with stratified 10-fold cross-validation with 90% of the records in the training set and 10% in the validation set. Model performances expressed in percentage of correctly classified cows (accuracy) and percentage of cows being critically misclassified (i.e., high as low and vice versa) ± standard deviation were 45.1 ± 8.1% and 10.8% with the ordinal logistic regression model, 45.7 ± 8.4% and 16.0% with the random forest using the same 6 features as the logistic regression model, 48.4 ± 6.7% and 10.0% for the random forest with all sensor features, and 50.5 ± 6.3% and 8.4% for the random forest with daily sensor values. This random forest also revealed that data collected in early and late stages of first lactation seem to be of particular importance in the prediction compared with that in mid lactation. Accuracies of the models were not significantly different, but the percentage of critically misclassified cows was significantly higher for the second model than for the other models. We concluded that a data-driven random forest algorithm with daily aggregated sensor data as input can be used for the prediction of lifetime resilience classification with an overall accuracy of ~50%, and provides at least as good prediction as models with sensor features as input.


Effects of neighborhood trait composition on tree survival differ between drought and postdrought periods.
Although direct tree demographic responses to drought are widely recognized, studies of drought-mediated changes in tree interactions are rare. We hypothesize that drought exacerbates soil-water limitation and intensifies competition for water, but reduces light limitation and competition for light. We predict that competition would be stronger for trees (1) consuming more water or more susceptible to water deficits during drought and (2) intercepting more light or more susceptible to shade during postdrought periods. We tested these predictions in a 50-ha tropical forest plot by quantifying the effects of neighborhood mean trait values on tree survival during versus after a severe drought. We used wood density (WD) and leaf mass per area (LMA) as proxies for water and light use strategies, respectively. Tree survival was lower, canopy loss was greater, and sapling recruitment was greater during the drought relative to postdrought census intervals. This suggests that drought pushed water deficits to lethal extremes and increased understory light availability. Relationships between survival and neighborhood WD were independent of drought, which is inconsistent with our first prediction. In contrast, relationships between survival and neighborhood LMA differed strongly with drought. Survival time was unaffected by neighborhood LMA during drought, but was longer for trees of all sizes in low-LMA neighborhoods in the postdrought census interval, consistent with the prediction of reduced competition for light during drought. Our results suggest that severe drought might increase light availability and reduce competition for light in moist tropical forests.


Privacy aware access controls for medical data disclosure on European healthgrids.
To be processed within a healthgrid environment, medical data goes through a complete lifecycle and several stages until it is finally used for the primary reason it has been collected for. This stage is not always the final occurrence of when the data would have been manipulated. The data could rather continue to be needed for secondary purposes of legitimate or non legitimate nature. Although other privacy issues are related to the processing of patient data while it is residing on a healthgrid environment, the control of data disclosure is our primary interest. When sharing medical data between different Healthcare and biomedical research organizations in Europe, it is important that the different parties involved in the sharing handle the data in the same way indicated by the legislation of the member state where the data was originally collected as the requirements might differ from one state to another. Privacy requirements, such as patient consent, may be subject to conflicting conditions between different national frameworks as well as between different legal and ethical frameworks within a single member state. These circumstances have made the compliance management process in European healthgrid very challenging. In this paper we are presenting an approach to tackle these issues by relying on several technologies contained in the semantic web stack. Our work suggests a direct mapping from high level legislation on privacy and data protection to operational level privacy aware controls. Additionally we suggest an architecture for the enforcement of these controls on access control models adopted by healthgrids security infrastructures.


Dosing Limitation for Intra-Renal Arterial Infusion of Mesenchymal Stromal Cells.
The immunomodulatory and regenerative properties of mesenchymal stromal cells (MSCs) make MSC therapy a promising therapeutic strategy in kidney disease. A targeted MSC administration via the renal artery offers an efficient delivery method with limited spillover to other organs. Although local administration alleviates safety issues with MSCs in systemic circulation, it introduces new safety concerns in the kidneys. In a porcine model, we employed intra-renal arterial infusion of ten million allogenic adipose tissue-derived MSCs. In order to trigger any potential adverse events, a higher dose (hundred million MSCs) was also included. The kidney function was studied by magnetic resonance imaging after the MSC infusion and again at two weeks post-treatment. The kidneys were assessed by single kidney glomerular filtration rate (skGFR) measurements, histology and inflammation, and fibrosis-related gene expression. None of the measured parameters were affected immediately after the administration of ten million MSCs, but the administration of one hundred million MSCs induced severe adverse events. Renal perfusion was reduced immediately after MSC administration which coincided with the presence of microthrombi in the glomeruli and signs of an instant blood-mediated inflammatory reaction. At two weeks post-treatment, the kidneys that were treated with one hundred million MSCs showed reduced skGFR, signs of tissue inflammation, and glomerular and tubular damage. In conclusions, the intra-renal administration of ten million MSCs is well-tolerated by the porcine kidney. However, higher concentrations (one hundred million MSCs) caused severe kidney damage, implying that very high doses of intra-renally administered MSCs should be undertaken with caution.


Variable immune molecules in invertebrates.
Recently it has become evident that invertebrates may mount a highly variable immune response that is dependent on which pathogen is involved. The molecular mechanisms behind this diversity are beginning to be unravelled and in several invertebrate taxa immune proteins exhibiting a broad range of diversity have been found. In some cases, evidence has been gathered suggesting that this molecular diversity translates into the ability of an affected invertebrate to mount a defence that is specifically aimed at a particular pathogen.


Retinopathy of Prematurity in Neonates and its Risk Factors: A Seven Year Study in Northern Iran.
An important cause of avoidable childhood blindness is retinopathy of prematurity (ROP) in countries with high human development index and also in some emerging economies countries. To date, no research have been conducted on analyzing data of ROP prevalence in Babol, and this is the first research performed on ROP in this area. All VLBW babies who referred to Babol ophthalmology center over the seven years, from February 2007 to December 2013 were enrolled in this descriptive cross-sectional research. A team of researchers recorded patients' information completely in check lists. A single experienced ophthalmologist performed ophthalmologic examination of patients. The incidence of ROP of any stage in Babol was determined to be 306 (45%) of all babies enrolled in this study. In present study, key risk factors of ROP were low gestational age, oxygen therapy more than five days and low birth weight. The findings of current study demonstrate that the main risk factors of developing ROP in newborns are multiple gestation, low birth weight, oxygen therapy for more than five day. Therefore, the progression of ROP to blindness will be prevented by a high index of suspicion, suitable screening, prompt diagnosis, and early treatment.


A Novel Homozygous Missense Mutation in the FU-CRD2 Domain of the R-spondin1 Gene Associated with Familial 46,XX DSD.
R-spondin proteins are secreted agonists of canonical WNT/β-catenin signaling. Homozygous RSPO1 mutations cause a syndrome of 46,XX disorder of sexual development (DSD), palmoplantar keratoderma (PPK), and predisposition to squamous cell carcinoma. We report exome sequencing data of two 46,XX siblings, one with testicular DSD and the other with suspected ovotesticular DSD. Both have PPK and hearing impairment and carried a novel homozygous mutation c.332G>A (p.Cys111Tyr) located in the highly conserved furin-like cysteine-rich domain-2 (FU-CRD2). Cysteines in the FU-CRDs are strictly conserved, indicating their functional importance in WNT signaling through interaction with the leucine-rich repeat-containing G-protein-coupled receptors. This is the first RSPO1 missense mutation reported in association with human disease.


[Malnutrition in the elderly: the Mini Nutritional Assessment (MNA)].
Frail elderly in the community, in nursing homes or in hospitals are at increased risk of malnutrition. In many instances, their existing nutritional disorders go unrecognised and adversely affect their health, ability to overcome disease, and so is associated with poor clinical outcome. The prevalence of malnutrition ranges from 5-10% in free-living elderly to 30-85% in homebound, nursing home, and hospitalised elderly. Possibilities exist to prevent or correct this malnutrition, but have not been frequently used until now due to the lack of a specific validated tool to screen for malnutrition. The goal of the Mini Nutritional Assessment (MNA) is to determine who is at risk of malnutrition, and hence to permit early nutritional intervention. It has been designed for easy use by general practitioners as well as health professionals involved in admitting patients to hospitals and nursing homes. The test, which comprises simple measurements and a brief questionnaire, can be performed in about 10 minutes. It involves: anthropometric assessment (weight, height and weight loss) general assessment (lifestyle, medication and mobility) dietary assessment (number of meals, food and fluid intake, autonomy of eating self assessment (self-perception of health and nutrition). The MNA has now been validated in three studies involving more than 600 elderly individuals, from the very frail to the very active in free-living and long-term care environments. The MNA was validated against a clinical evaluation and a comprehensive nutritional assessment. It can classify the elderly as well-nourished, undernourished, or at risk of malnutrition. The MNA can be an important tool in evaluating the risk of malnutrition in the elderly, if integrated into geriatric assessment programs.


Brain adducin: a protein kinase C substrate that may mediate site-directed assembly at the spectrin-actin junction.
Erythrocyte adducin is a membrane skeletal protein that binds to calmodulin, is a major substrate for protein kinase C, and associates preferentially with spectrin-actin complexes. Erythrocyte adducin also promotes association of spectrin with actin, and this activity is inhibited by calmodulin. This study describes the isolation and characterization of a brain peripheral membrane protein closely related to erythrocyte adducin. Brain and erythrocyte adducin have at least 50% antigenic sites in common, each contains a protease-resistant core of Mr = 48,000-48,500, and both proteins are comprised of two partially homologous polypeptides of Mr = 103,000 and 97,000 (erythrocytes) and Mr = 104,000 and 107,000-110,000 (brain). Brain and erythrocyte adducin associate preferentially with spectrin-actin complexes as compared to spectrin or actin alone, and both proteins also promote binding of spectrin to actin. Brain adducin binds calmodulin in a calcium-dependent manner, although the Kd of 1.3 microM is weaker by 5-6-fold than the Kd of erythrocyte adducin for calmodulin. Brain adducin is a substrate for protein kinase C in vitro and can accept up to 2 mol of phosphate/mol of protein. Adducin provides a potential mechanism in cells for mediating site-directed assembly of additional spectrin molecules and possibly other proteins at the spectrin-actin junction. Brain tissue contains 12 pmol of adducin/mg of membrane protein, which is the most of any tissue examined other than erythrocytes, which have 50 pmol/mg. The presence of high amounts of adducin in brain suggests some role for this protein in specialized activities of nerve cells.