3D nanomechanical evaluations of dermal structures in skin.
Skin is a multilayered multiscale composite material with a range of mechanical and biochemical functions. The mechanical properties of dermis are important to understand in order to improve and compare on-going in vitro experiments to physiological conditions, especially as the mechanical properties of the dermis can play a crucial role in determining cell behaviour. Spatial and isotropy variations in dermal mechanics are thus critical in such understanding of complex skin structures. Atomic force microscopy (AFM) based indentation was used in this study to quantify the three dimensional mechanical properties of skin at nanoscale resolution over micrometre length scales. A range of preparation methods was examined and a mechanically non-evasive freeze sectioning followed by thawing method was found to be suitable for the AFM studies. Subsequent mechanical evaluations established macroscale isotropy of the dermis with the ground substance of the dermis dominating the mechanical response. Mechanical analysis was extended to show significant variation in the elastic modulus of the dermis between anatomical locations that suggest changes in the physiological environment influence local mechanical properties. Our results highlight dependence between an isotropic mechanical response of the dermal microenvironment at the nanoscale and anatomical location that define the variable mechanical behaviour of the dermis.


Molecular genetic analysis of virus isolates from wild and cultivated plants demonstrates that East Africa is a hotspot for the evolution and diversification of sweet potato feathery mottle virus.
Sweet potato feathery mottle virus (SPFMV, genus Potyvirus) is globally the most common pathogen of cultivated sweet potatoes (Ipomoea batatas; Convolvulaceae). Although more than 150 SPFMV isolates have been sequence-characterized from cultivated sweet potatos across the world, little is known about SPFMV isolates from wild hosts and the evolutionary forces shaping SPFMV population structures. In this study, 46 SPFMV isolates from 14 wild species of genera Ipomoea, Hewittia and Lepistemon (barcoded for the matK gene in this study) and 13 isolates from cultivated sweet potatoes were partially sequenced. Wild plants were infected with the EA, C or O strain, or co-infected with the EA and C strains of SPFMV. In East Africa, SPFMV populations in wild species and sweet potato were genetically undifferentiated, suggesting inter-host transmission of SPFMV. Globally, spatial diversification of the 178 isolates analysed was observed, strain EA being largely geographically restricted to East Africa. Recombination was frequently detected in the 6K2-VPg-NIaPro region of the EA strain, demonstrating a recombination 'hotspot'. Recombination between strains EA and C was rare, despite their frequent co-infections in wild plants, suggesting purifying selection against strain EA/C recombinants. Positive selection was predicted on 17 amino acids distributed over the entire coat protein in the globally distributed strain C, as compared to only four amino acids in the coat protein N-terminus of the EA strain. This selection implies a more recent introduction of the C strain and a higher adaptation of the EA strain to the local ecosystem. Thus, East Africa appears as a hotspot for evolution and diversification of SPFMV.


Shortened length of hospital stay with rivaroxaban in patients with symptomatic venous thromboembolism in Japan: the J-EINSTEIN pulmonary embolism and deep vein thrombosis program.
In Japan, the standard of care for the treatment of pulmonary embolism (PE) and/or deep vein thrombosis (DVT) consists of intravenous unfractionated heparin (UFH) followed by warfarin, which was recently compared with rivaroxaban, an oral factor Xa inhibitor, in randomized trials. To examine the length of hospital stay in patients with PE and/or DVT receiving rivaroxaban compared to Japanese standard therapy in the Japanese (J)-EINSTEIN PE and DVT program. Open-label, randomized clinical trials that compared 3, 6, or 12 months of rivaroxaban with UFH and warfarin in patients with acute, confirmed symptomatic proximal PE and/or DVT. Decisions regarding hospital admission and/or discharge were left to the clinical judgment of attending physicians. Analyses were conducted in the intention-to-treat (ITT) population. In the ITT population (N = 97), overall patient characteristics were similar in both treatment arms. The median length of stay in rivaroxaban patients was 10.0 days (interquartile range [IQR] 6.0 to 15.0 days) while it was 15.0 days (IQR 9.0 to 22.0) for patients on standard therapy (p = 0.016). All of the four DVT patients who were not hospitalized for the index event were in the rivaroxaban arm. Our results suggest that treatment with rivaroxaban may significantly reduce the length of hospital stay in patients hospitalized for PE and/or DVT compared with the current standard of care in Japan, thereby reducing the burden on patients and the healthcare system. The limitations of our study include small sample size and the generalizability of the findings to the real-world setting. Further research is warranted to identify PE and/or DVT patients in Japanese clinical practice who may potentially be managed as outpatients. Clinicaltrials.gov: NCT01516814 and NCT01516840.


DL-β-aminobutyric acid-induced resistance in soybean against Aphis glycines Matsumura (Hemiptera: Aphididae).
Priming can improve plant innate capability to deal with the stresses caused by both biotic and abiotic factors. In this study, the effect of DL-β-amino-n-butyric acid (BABA) against Aphis glycines Matsumura, the soybean aphid (SA) was evaluated. We found that 25 mM BABA as a root drench had minimal adverse impact on plant growth and also efficiently protected soybean from SA infestation. In both choice and non-choice tests, SA number was significantly decreased to a low level in soybean seedlings drenched with 25 mM BABA compared to the control counterparts. BABA treatment resulted in a significant increase in the activities of several defense enzymes, such as phenylalanine ammonia-lyase (PAL), peroxidase (POX), polyphenol oxidase (PPO), chitinase (CHI), and β-1, 3-glucanase (GLU) in soybean seedlings attacked by aphid. Meanwhile, the induction of 15 defense-related genes by aphid, such as AOS, CHS, MMP2, NPR1-1, NPR1-2, and PR genes, were significantly augmented in BABA-treated soybean seedlings. Our study suggest that BABA application is a promising way to enhance soybean resistance against SA.


Prolactin and alpha-1,4-glucosidase activity in normal and poorly coagulated human semen.
Prolactin and alpha-1,4-glucosidase levels in seminal plasma were measured in poorly coagulated (I), deficiently coagulated (II) and normally coagulated (III and IV) human ejaculates having 0-20%, 21-50% and 51-100% coagulum respectively 4 min after emission. The prolactin concentration (ng ml-1, mean +/- SEM) in poorly coagulated (5.2 +/- 0.48) and deficiently coagulated (7.6 +/- 0.72) samples was significantly lower than in the normally coagulated groups III (51-75% coagulum, 8.2 +/- 0.43) and IV (76-100% coagulum, 9.9 +/- 0.59) as well as the presumably fertile samples (9.2 +/- 0.74). A highly significant positive correlation was observed between the prolactin level and the percentage coagulum of the ejaculates (r = 0.686, n = 58, P less than 0.001). In contrast, the epididymal marker, alpha-glucosidase showed no relationship to seminal coagulation.


Cannabinoid CB2 Receptors in a Mouse Model of Aβ Amyloidosis: Immunohistochemical Analysis and Suitability as a PET Biomarker of Neuroinflammation.
In Alzheimer's disease (AD), one of the early responses to Aβ amyloidosis is recruitment of microglia to areas of new plaque. Microglial receptors such as cannabinoid receptor 2 (CB2) might be a suitable target for development of PET radiotracers that could serve as imaging biomarkers of Aβ-induced neuroinflammation. Mouse models of amyloidosis (J20APPswe/ind and APPswe/PS1ΔE9) were used to investigate the cellular distribution of CB2 receptors. Specificity of CB2 antibody (H60) was confirmed using J20APPswe/ind mice lacking CB2 receptors. APPswe/PS1ΔE9 mice were used in small animal PET with a CB2-targeting radiotracer, [11C]A836339. These studies revealed increased binding of [11C]A836339 in amyloid-bearing mice. Specificity of the PET signal was confirmed in a blockade study with a specific CB2 antagonist, AM630. Confocal microscopy revealed that CB2-receptor immunoreactivity was associated with astroglial (GFAP) and, predominantly, microglial (CD68) markers. CB2 receptors were observed, in particular, in microglial processes forming engulfment synapses with Aβ plaques. In contrast to glial cells, neuron (NeuN)-derived CB2 signal was equal between amyloid-bearing and control mice. The pattern of neuronal CB2 staining in amyloid-bearing mice was similar to that in human cases of AD. The data collected in this study indicate that Aβ amyloidosis without concomitant tau pathology is sufficient to activate CB2 receptors that are suitable as an imaging biomarker of neuroinflammation. The main source of enhanced CB2 PET binding in amyloid-bearing mice is increased CB2 immunoreactivity in activated microglia. The presence of CB2 immunoreactivity in neurons does not likely contribute to the enhanced CB2 PET signal in amyloid-bearing mice due to a lack of significant neuronal loss in this model. However, significant loss of neurons as seen at late stages of AD might decrease the CB2 PET signal due to loss of neuronally-derived CB2. Thus this study in mouse models of AD indicates that a CB2-specific radiotracer can be used as a biomarker of neuroinflammation in the early preclinical stages of AD, when no significant neuronal loss has yet developed.


Nanomaterials and Annelid Immunity: A Comparative Survey to Reveal the Common Stress and Defense Responses of Two Sentinel Species to Nanomaterials in the Environment.
Earthworms and leeches are sentinel animals that represent the annelid phylum within terrestrial and freshwater ecosystems, respectively. One early stress signal in these organisms is related to innate immunity, but how nanomaterials affect it is poorly characterized. In this survey, we compare the latest literature on earthworm and leeches with examples of their molecular/cellular responses to inorganic (silver nanoparticles) and organic (carbon nanotubes) nanomaterials. A special focus is placed on the role of annelid immunocytes in the evolutionarily conserved antioxidant and immune mechanisms and protein corona formation and probable endocytosis pathways involved in nanomaterial uptake. Our summary helps to realize why these environmental sentinels are beneficial to study the potential detrimental effects of nanomaterials.


[Bicillin in a complex scheme for the active prophylaxis of exacerbations and the progression of chronic bronchopulmonary diseases in children].
A complex scheme of prophylaxis of exacerbation and progression of chronic bronchopulmonary diseases in children was developed. It included the use of bicillin, stimulating therapy, desensibilizing drugs, vitamins, proteolytic enzymes, physiotherapy, physical excercises, massage, sanation of the chronic infection foci and interferone administration during influenza. 466 patients were subjected to the active prophylaxis for a period of 1-3 years. No exacerbation of progressing of chronic pneumonia was observed in 81.3 per cent of the children subjected to bicillin prophylaxis for 3 years. The number of the bronchial asthma attacks in the group of the patients with the infectious allergic form of bronchial asthma decreased 3-4 times per year under the effect of complex prophylactic therapy, the attacks became shorter and their elimanation with broncholitics was easier.


Photosynthetically Controlled Spirulina, but Not Solar Spirulina, Inhibits TNF-α Secretion: Potential Implications for COVID-19-Related Cytokine Storm Therapy.
An array of infections, including the novel coronavirus (SARS-CoV-2), trigger macrophage activation syndrome (MAS) and subsequently hypercytokinemia, commonly referred to as a cytokine storm (CS). It is postulated that CS is mainly responsible for critical COVID-19 cases, including acute respiratory distress syndrome (ARDS). Recognizing the therapeutic potential of Spirulina blue-green algae (Arthrospira platensis), in this in vitro stimulation study, LPS-activated macrophages and monocytes were treated with aqueous extracts of Spirulina, cultivated in either natural or controlled light conditions. We report that an extract of photosynthetically controlled Spirulina (LED Spirulina), at a concentration of 0.1 µg/mL, decreases macrophage and monocyte-induced TNF-α secretion levels by over 70% and 40%, respectively. We propose prompt in vivo studies in animal models and human subjects to determine the putative effectiveness of a natural, algae-based treatment for viral CS and ARDS, and explore the potential of a novel anti-TNF-α therapy.


Association of Grb2, Gads, and phospholipase C-gamma 1 with phosphorylated LAT tyrosine residues. Effect of LAT tyrosine mutations on T cell angigen receptor-mediated signaling.
The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-gamma1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca(2+) flux, and activation of AP-1 and NF-AT. We mapped the tyrosine residues in LAT responsible for interaction with these specific signaling molecules by expressing LAT mutants with tyrosine to phenylalanine mutations in LAT-deficient cells. Our results showed that three distal tyrosines, Tyr(171), Tyr(191), and Tyr(226), are responsible for Grb2-binding; Tyr(171), and Tyr(191), but not Tyr(226), are necessary for Gads binding. Mutation of Tyr(132) alone abolished PLC-gamma1 binding. Mutation of all three distal tyrosines also abolished PLC-gamma1 binding, suggesting there might be multiple binding sites for PLC-gamma1. Mutation of Tyr(132) affected calcium flux and blocked Erk and NF-AT activation. Since Grb2 binding is not affected by this mutation, these results strongly suggest that PLC-gamma activation regulates Ras activation in these cells. Mutation of individual Grb2 binding sites had no functional effect, but mutation of two or three of these sites, in combination, also affected Erk and NF-AT activation.


The implementation of acute versus chronic animal models for treatment discovery in Parkinson's disease.
Animal models for neuropsychiatric disorders are implemented for the purpose of investigating a single or multiple aspects of a specific disease entity. In Parkinson's disease (PD) several models have been utilised to study the biochemical and behavioural consequences of dopamine (DA) neurone degeneration with the intent of further understanding the aetiology of this disease and improving its treatment. While the bilateral 6-hydroxydopamine (6-OHDA) model has been used to produce a broad spectrum of neurochemical and behavioural deficits characterising DA degeneration in humans, this model is traumatic, labour intensive and is associated with high mortality due to the acute effects of the neurotoxin. Consequently, the unilateral 6-OHDA model was developed and implemented. In this model damage to the ascending DA system is produced on one side of the brain thereby inducing postural rotation. This movement is exaggerated by activating the remaining DA systems with apomorphine or amphetamine thereby making it more quantifiable. In view of the less traumatic effects on homeostasis and relative ease with which this model can be implemented it has been used routinely for the purpose of screening potential anti-Parkinsonian drugs for clinical use. However, like any model, the use of the unilateral rotation model has its limitations. It is proposed that the process of exaggerating DA function using this paradigm limits the discovery of potential anti-PD drugs to those which are effective in counteracting an exaggerated DA response. This factor may account for the high incidence of unwanted side effects including involuntary movement, tardive dyskinaesia (TD) and psychosis which are commonly observed in DA replacement therapy. Secondly, this approach limits potential drug candidates to those acting exclusively on brain DA systems. This too is a problem in the sense that PD is known to be a disease involving numerous systems in the human brain and potential therapies acting via other neurochemical systems are being excluded when this model is used exclusively. The object of the present paper is to report the discovery of a non-DA drug possessing potent anti-Parkinsonian qualities which were revealed using the bilateral 6-OHDA model of PD as a screening tool. When the same drug was retested in the traditional unilateral screening model no effect was observed, while more advanced models confirmed its efficacy. These results illustrate that the implementation of appropriate models for revealing new treatment strategies for PD should be broadly based so that single treatment entities are not exclusively pursued for diseases whose aetiologies are multifaceted. Premature extrapolation of findings from a single, early stage model to its clinical counterpart can be detrimental to advancing new treatment strategies, induce false hope, and increase morbidity in PD patients.


Morphological analysis of chiral rod clusters from a coarse-grained single-site chiral potential.
We present a coarse-grained single-site potential for simulating chiral interactions, with adjustable strength, handedness, and preferred twist angle. As an application, we perform basin-hopping global optimisation to predict the favoured geometries for clusters of chiral rods. The morphology phase diagram based upon these predictions has four distinct families, including previously reported structures for potentials that introduce chirality based on shape, such as membranes and helices. The transition between these two configurations reproduces some key features of experimental results for fd bacteriophage. The potential is computationally inexpensive, intuitive, and versatile; we expect it will be useful for large scale simulations of chiral molecules. For chiral particles confined in a cylindrical container we reproduce the behaviour observed for fusilli pasta in a jar. Hence this chiropole potential has the capability to provide insight into structures on both macroscopic and molecular length scales.


Smart scaffolds: shape memory polymers (SMPs) in tissue engineering.
Smart scaffolds based on shape memory polymer (SMPs) have been increasingly studied in tissue engineering. The unique shape actuating ability of SMP scaffolds has been utilized to improve delivery and/or tissue defect filling. In this regard, these scaffolds may be self-deploying, self-expanding, or self-fitting. Smart scaffolds are generally thermoresponsive or hydroresponsive wherein shape recovery is driven by an increase in temperature or by hydration, respectively. Most smart scaffolds have been directed towards regenerating bone, cartilage, and cardiovascular tissues. A vast variety of smart scaffolds can be prepared with properties targeted for a specific tissue application. This breadth of smart scaffolds stems from the variety of compositions employed as well as the numerous methods used to fabricated scaffolds with the desired morphology. Smart scaffold compositions span across several distinct classes of SMPs, affording further tunability of properties using numerous approaches. Specifically, these SMPs include those based on physically cross-linked and chemically cross-linked networks and include widely studied shape memory polyurethanes (SMPUs). Various additives, ranging from nanoparticles to biologicals, have also been included to impart unique functionality to smart scaffolds. Thus, given their unique functionality and breadth of tunable properties, smart scaffolds have tremendous potential in tissue engineering.


Low Levels of Hemoglobin at Admission Are Associated With Increased 30-Day Mortality in Patients With Hip Fracture.
Previous smaller studies suggest that anemia is a risk factor for mortality in patients with hip fracture. The purpose of this investigation was to assess the correlation between hemoglobin at admission with 30-day mortality following a hip fracture in a large-scale study. From January 1996 to December 2012, all patients with hip fracture (>60 years of age) admitted to Bispebjerg Hospital, Copenhagen, were identified from a local hip fracture database. We excluded conservatively treated patients and patients who died preoperatively. Seven thousand four hundred twenty-one consecutive patients with hip fracture were identified. Of those 7319 had a hemoglobin measurement on admission and were thus eligible for further analysis. Mean hemoglobin for patients alive at 30 days was 7.6 (standard deviation [SD]: 1.0) and for deceased patients 7.4 (SD: 1.1), P < .0001. Mean age was 82.6 years (SD: 8.5), and 76.5% of the population were female (Nfemales = 5600). The 30-day mortality decreases for every increase in hemoglobin of 1.0 mmol/L in a univariate analysis (P < .0001). The hazard ratio (HR) with 95% confidence interval (CI) for 30-day mortality in patients with anemia (<7.3 mmol/L for females and <8.3 mmol/L for males; Nanemic = 3235) was 1.66 (CI: 1.43-1.91, P < .0001). Adjusting for age, type of fracture, gender, and comorbidities (Charlson score) slightly attenuated the risk estimate (HR: 1.21, CI: 1.03-1.41, P = .02). This study demonstrates increased 30-day mortality in patients with low hemoglobin at admission, even after adjusting for comorbidities.


Orthodontic bonding to acid- or laser-etched prebleached enamel.
Bonding forces of brackets to enamel surfaces may be affected by the procedures used for bleaching and enamel etching. The aim of this study was to investigate the bonding strength of orthodontic brackets to laser-etched surfaces of bleached teeth. In a nonbleached control group, acid etching (group A) or Er:YAG laser application (group B) was performed prior to bracket bonding (n = 13 in each group). Similar surface treatments were performed at 1 day (groups C and D; n = 13 in each subgroup) or at 3 weeks (groups E and F; n = 13 in each subgroup) after 38% hydrogen peroxide bleaching in another set of teeth. The specimens were debonded after thermocycling. Laser etching of bleached teeth resulted in clinically unacceptable low bonding strength. In the case of acid-etched teeth, waiting for 3 weeks before attachment of brackets to the bleached surfaces resulted in similar, but not identical, bond strength values as those obtained with nonbleached surfaces. However, in the laser-etched groups, the bonding strength after 3 weeks was the same as that for the nonbleached group. When teeth bleached with 38% hydrogen peroxide are meant to be bonded immediately, acid etching is preferable.


Incomplete reproductive isolation in the blue mussel (Mytilus edulis and M. trossulus) hybrid zone in the Northwest Atlantic: role of gamete interactions and larval viability.
Reproductive isolation in free-spawning organisms may involve only small changes in the gamete surface molecules that control fertilization, linking gamete incompatibility and speciation. Most studies have focused on species in which natural hybrids are absent and reproductive isolation is complete, but how gamete incompatibility evolves remains unclear. Reproductive isolation is incomplete between two sympatric mussel species (Mytilus edulis, M. trossulus) that hybridize in nature. In this study prezygotic and postzygotic components of reproductive incompatibility were examined in laboratory crosses. Conspecific crosses showed significantly greater rates of fertilization than heterospecific crosses, although some females of both species showed heterospecific gamete compatibility. The proportion of fertilized eggs developing into normal larvae was not significantly different between conspecific and heterospecific crosses, but survival of normal larvae was greater for conspecific crosses. Mixed-species sperm experiments suggested that conspecific sperm preference may further limit hybridization. The different components of reproductive incompatibility and total incompatibility varied among females of both species. Although our study has shown that partial reproductive isolation between M. edulis and M. trossulus involves both prezygotic gamete interactions and postzygotic larval survival, further research is required to determine the potential role of gamete incompatibility in the evolution of complete reproductive isolation between these species.


Testosterone cream available at CPS; gel approved by FDA.
A major HIV-specialist pharmacy is now carrying a compounded testosterone cream for topical application, avoiding the shots or patches otherwise used to deliver this drug. Meanwhile, the FDA has approved a testosterone gel--but this gel will not be widely available for several months.


A Proof-of-Concept Numerical Ising Machine for Neural Spike Localization.
Identifying the physical locations of neurons based on the spike waveforms captured by multiple recording channels, namely spike localization, can potentially enhance spike sorting accuracy. This study proposes a new method for spike localization, where the problem is first described as a nonconvex optimization problem and then the optimization is attempted heuristically via a numerical Ising solver. The paper first presents a quadratic unconstrained binary optimization (QUBO) formulation of spike localization. Then, a MATLAB solver simulating an Ising machine is written to solve the QUBO. The proposed method is evaluated on a 2D toy problem consisting of two electrodes and a single spike event, where the neuron location search is conducted in three different regions placed at increasing distances from the electrodes. The results indicate that the neuron can be accurately identified when in one of the nearest nodes to the electrodes, whereas the accuracy decreases to 87.5% and 75% as the search region distance increases. The study for the first time formulates the spike localization problem as a QUBO and demonstrates the feasibility of solving the resultant non-convex optimization problem heuristically using an Ising machine.Clinical Relevance- High channel-count implantable neural monitoring systems allow tracking large brain regions at the cost of increased data volumes to transmit and power dissipation. The new spike localization approach presented can potentially decrease the data volume and power consumption by enabling high accuracy spike localization at the implantable system.


Zyxin is a transforming growth factor-β (TGF-β)/Smad3 target gene that regulates lung cancer cell motility via integrin α5β1.
Although TGF-β acts as a tumor suppressor in normal tissues and in early carcinogenesis, these tumor suppressor effects are lost in advanced malignancies. Single cell migration and epithelial-mesenchymal transition (EMT), both of which are regulated by TGF-β, are critical steps in mediating cancer progression. Here, we sought to identify novel direct targets of TGF-β signaling in lung cancer cells and have indentified the zyxin gene as a target of Smad3-mediated TGF-β1 signaling. Zyxin concentrates at focal adhesions and along the actin cytoskeleton; as such, we hypothesized that cytoskeletal organization, motility, and EMT in response to TGF-β1 might be regulated by zyxin expression. We show that TGF-β1 treatment of lung cancer cells caused rapid phospho-Smad3-dependent expression of zyxin. Zyxin expression was critical for the formation and integrity of cell adherens junctions. Silencing of zyxin decreased expression of the focal adhesion protein vasodilator-activated phospho-protein (VASP), although the formation and morphology of focal adhesions remained unchanged. Zyxin-depleted cells displayed significantly increased integrin α5β1 levels, accompanied by enhanced adhesion to fibronectin and acquisition of a mesenchymal phenotype in response to TGF-β1. Zyxin silencing led to elevated integrin α5β1-dependent single cell motility. Importantly, these features are mirrored in the K-ras-driven mouse model of lung cancer. Here, lung tumors revealed decreased levels of both zyxin and phospho-Smad3 when compared with normal tissues. Our data thus demonstrate that zyxin is a novel functional target and effector of TGF-β signaling in lung cancer. By regulating cell-cell junctions, integrin α5β1 expression, and cell-extracellular matrix adhesion, zyxin may regulate cancer cell motility and EMT during lung cancer development and progression.


Effects of dietary alteration of bicarbonate and magnesium on rat bone.
To study the effects of bicarbonate and magnesium on bone, mild acidosis and/or hypermagnesemia were produced in growing rats by feeding ammonium chloride and/or magnesium sulfate. Bone composition, quantitative histomorphometry, and mineral x-ray diffraction (XRD) characteristics were measured after 6 wk of treatment. The results demonstrated that both acidosis (decreased HCO3) and hypermagnesemia inhibited periosteal bone formation, and, when combined, results were summative; and the previously observed in vitro role of HCO3- and Mg2+ as inhibitors of crystal growth were confirmed in vivo. XRD measurements demonstrated that decreased plasma HCO3 resulted in larger crystals and increased Mg resulted in smaller crystals. However, the combined XRD effects of acidosis and hypermagnesemia resembled acidosis alone. It is postulated that the final composition and crystal structure of bone are strongly influenced by HCO3- and Mg2+, and the effects are mediated by the combined influence on both osteoblastic bone formation and the growth of hydroxyapatite.


Bicarbonate buffer dissolution test with gentle mechanistic stress for bioequivalence prediction of enteric-coated pellet formulations.
This study aimed to develop a dissolution test that can predict the bioequivalence (BE) of enteric-coated pellet formulations. The original duloxetine hydrochloride capsule (reference formulation (RF); Cymbalta® 30 mg capsule) and four generic test formulations (two capsules (CP) and two orally disintegrating tablets (OD)) were used as model formulations. Clinical BE studies were conducted on 24-47 healthy male subjects under fasting conditions. Dissolution tests were performed using a compendial paddle method (PD) (paddle speed: 50 rpm) and a flow-through cell method (FTC) (flow rate: 4 mL/min). For a further test, cotton balls were added to the vessel to apply gentle mechanistic stress to the formulations, and paddle speed was reduced to 10 rpm (paddle with cotton ball method (PDCB)).All the dissolution tests were conducted with 0.01 M HCl (pH 2.0) for 0.5 h followed by 10 mM bicarbonate buffer solutions (pH 6.5) for 4 h. One each of the two CP and two OD showed BE with RF. PDCB was able to discriminate between BE and non-BE formulations, while this was not possible with PD and FTC. In PDCB, the cotton balls intermittently moved the pellets near the vessel bottom. PDCB is useful for predicting BE during formulation development.


The open EEGLAB portal Interface: High-Performance computing with EEGLAB.
EEGLAB signal processing environment is currently the leading open-source software for processing electroencephalographic (EEG) data. The Neuroscience Gateway (NSG, nsgportal.org) is a web and API-based portal allowing users to easily run a variety of neuroscience-related software on high-performance computing (HPC) resources in the U.S. XSEDE network. We have reported recently (Delorme et al., 2019) on the Open EEGLAB Portal expansion of the free NSG services to allow the neuroscience community to build and run MATLAB pipelines using the EEGLAB tool environment. We are now releasing an EEGLAB plug-in, nsgportal, that interfaces EEGLAB with NSG directly from within EEGLAB running on MATLAB on any personal lab computer. The plug-in features a flexible MATLAB graphical user interface (GUI) that allows users to easily submit, interact with, and manage NSG jobs, and to retrieve and examine their results. Command line nsgportal tools supporting these GUI functionalities allow EEGLAB users and plug-in tool developers to build largely automated functions and workflows that include optional NSG job submission and processing. Here we present details on nsgportal implementation and documentation, provide user tutorials on example applications, and show sample test results comparing computation times using HPC versus laptop processing.


Automated diabetic retinopathy detection in smartphone-based fundus photography using artificial intelligence.
To assess the role of artificial intelligence (AI)-based automated software for detection of diabetic retinopathy (DR) and sight-threatening DR (STDR) by fundus photography taken using a smartphone-based device and validate it against ophthalmologist's grading. Three hundred and one patients with type 2 diabetes underwent retinal photography with Remidio 'Fundus on phone' (FOP), a smartphone-based device, at a tertiary care diabetes centre in India. Grading of DR was performed by the ophthalmologists using International Clinical DR (ICDR) classification scale. STDR was defined by the presence of severe non-proliferative DR, proliferative DR or diabetic macular oedema (DME). The retinal photographs were graded using a validated AI DR screening software (EyeArtTM) designed to identify DR, referable DR (moderate non-proliferative DR or worse and/or DME) or STDR. The sensitivity and specificity of automated grading were assessed and validated against the ophthalmologists' grading. Retinal images of 296 patients were graded. DR was detected by the ophthalmologists in 191 (64.5%) and by the AI software in 203 (68.6%) patients while STDR was detected in 112 (37.8%) and 146 (49.3%) patients, respectively. The AI software showed 95.8% (95% CI 92.9-98.7) sensitivity and 80.2% (95% CI 72.6-87.8) specificity for detecting any DR and 99.1% (95% CI 95.1-99.9) sensitivity and 80.4% (95% CI 73.9-85.9) specificity in detecting STDR with a kappa agreement of k = 0.78 (p < 0.001) and k = 0.75 (p < 0.001), respectively. Automated AI analysis of FOP smartphone retinal imaging has very high sensitivity for detecting DR and STDR and thus can be an initial tool for mass retinal screening in people with diabetes.


Waste management to improve food safety and security for health advancement.
Economic growth inevitably influences the food chain. Growing demand with changes in lifestyle and health consciousness encourage use of packaged and pre-prepared foods. The needs of environmental protection from waste generated are largely overlooked, and a lack of knowledge about the impact on the environment and its health effects constitute food security/safety problems. Food production and waste generation directly affect resource (i.e., energy and water) consumption and often contaminate the environment. More pressure on food production has inculcated the use of pesticides, herbicides, antibiotics and chemical fertilizers which add to current global pollution. At least half of food grown is discarded before and after it reaches consumers. It is estimated that one third to half of landfill waste comes from the food sector. This landfill releases green house gases (GHG) as well as leachate which worsen soil and water quality and safety. Pharmaceutical and chemical contaminations from residential, industrial and agricultural sources make their way into nearby water and soil and can eventually affect our food systems. Phthalates, PFOA, BPA, commonly used in plastics and personal care products, are found in unacceptable concentrations in Taiwanese waters. They, too, contribute to food contamination and long-term health risk. Existing waste management strategies warrant more stringent norms for waste reduction at source. Awareness through education could reduce food waste and its consequences. This review encompasses impacts of food production systems on the environment, pollution which results from food waste, costs and economic advantages in food waste management, and health consequences of waste.


Epidemiology and cost of herpes zoster and post-herpetic neuralgia in the United Kingdom.
Recent information on epidemiology and management of herpes zoster (HZ) and post-herpetic neuralgia (PHN), a painful complication of HZ, is scarce. The objective of this study was to document the burden of HZ and PHN in the United Kingdom. This retrospective analysis of the UK General Practice Research Database aimed to estimate HZ incidence and proportion of HZ patients developing PHN and to assess management costs in immunocompetent individuals aged 50 years. A cohort of 27 225 HZ patients was selected, corresponding to an incidence of 5.23/1000 person-years. Respectively 19.5% and 13.7% of patients developed PHN at least 1 and 3 months after HZ diagnosis. Mean direct cost was pound103 per HZ patient and pound341 and pound397 per PHN episode (1- and 3-month definition respectively). Both HZ and PHN costs increased markedly with pain severity. This study confirms that HZ and PHN are frequent and costly diseases in the United Kingdom.


Prevalence of underweight, overweight and obesity in poor children from Mato Grosso do Sul.
To estimate the prevalence of underweight, overweight, and obesity among children who were beneficiaries of the Brazil's conditional cash transfer program Bolsa Família during 2010, according to gender and health in the state of Mato Grosso do Sul, Brazil. Descriptive epidemiological study was conducted with a secondary database of Datasus/Sisvan. The data from 19,289 children (9,451 girls and 9,838 boys), aged 5 to 10 years, who benefited from the program Bolsa Família in the state of Mato Grosso do Sul in 2010 were collected. The variables were body weight and height. Body mass index was analyzed with Z-scores of normative tables from the World Health Organization. The prevalence of underweight was 4.8% among female and 5.6% among male participants. The prevalence of overweight and obesity was, respectively, 14.8 and 9.1% for female participants and 16.1 and 11.9% for male participants. The prevalence of underweight and obesity was lower in cities/towns with a lower Human Development Index, for female and male individuals. The prevalence of overweight in cities/towns with a lower Human Development Index was lower among female participants and higher among male participants. The higher prevalence of overweight among individuals of lower socioeconomic status indicates the need for understanding macro-factors that can influence the children's nutritional status.


An Adaptative Savitzky-Golay Kernel for Laplacian Estimation in Magnetic Resonance Electrical Property Tomography.
Magnetic Resonance electrical property tomography (MR-EPT) is a non-invasive imaging modality that reconstructs the living biological tissue's conductivity σ and εr permittivity using spatial derivatives of the measured RF field, also termed B1 data, in a magnetic resonance imaging system. The spatial derivative operator, particularly the Laplacian, amplifies the noise in the reconstructed electrical property (EP) maps, hence decreasing accuracy and increasing boundary artifacts. We propose a novel adaptative convolution kernel for generating numerical derivatives based on 3D Savitzky-Golay (SG) filters and local segmentation in a magnitude image. In comparison to typical SG kernel, the proposed kernel allows arbitrary shapes and sizes to vary with local tissue. It provides an automatic trade-off between noise and resolution, thereby significantly enhancing reconstruction accuracy and eliminating boundary artifacts.


Long-term survival of shiga toxin-producing Escherichia coli O26, O111, and O157 in bovine feces.
Cattle are an important reservoir of Shiga toxin-producing Escherichia coli (STEC) O26, O111, and O157. The fate of these pathogens in bovine feces at 5, 15, and 25 degrees C was examined. The feces of a cow naturally infected with STEC O26:H11 and two STEC-free cows were studied. STEC O26, O111, and O157 were inoculated into bovine feces at 10(1), 10(3), and 10(5) CFU/g. All three pathogens survived at 5 and 25 degrees C for 1 to 4 weeks and at 15 degrees C for 1 to 8 weeks when inoculated at the low concentration. On samples inoculated with the middle and high concentrations, O26, O111, and O157 survived at 25 degrees C for 3 to 12 weeks, at 15 degrees C for 1 to 18 weeks, and at 5 degrees C for 2 to 14 weeks, respectively. Therefore, these pathogens can survive in feces for a long time, especially at 15 degrees C. The surprising long-term survival of STEC O26, O111, and O157 in bovine feces shows that such feces are a potential vehicle for transmitting not only O157 but also O26 and O111 to cattle, food, and the environment. Appropriate handling of bovine feces is emphasized.


15-year outcomes of the JOCRI study (JOCRIED study): a randomised comparison of off-pump and on-pump multiple arterial coronary revascularisation.
The Japanese Off-Pump Coronary Revascularization Investigation (JOCRI) study reported a non-significant difference in early outcomes and graft patency between off-pump coronary artery bypass grafting and on-pump coronary artery bypass grafting in 2005. The JOCRIED study aimed to review the long-term outcomes of the JOCRI study participants. The JOCRIED study enrolled 123 of the JOCRI study participants completing the clinical follow-up between August 2018 and August 2020; 61 patients in the off-pump group and 62 patients in the on-pump group. The follow-up period was 13.8 ± 2.8 years. The groups were compared regarding mortality, the incidence of major adverse cardiac and cerebrovascular events and repeat revascularisation. The 15-year cumulative survival rate (off-pump vs on-pump, respectively; 77.7% vs 75.3%; p = 0.85), major adverse events-free survival rate (62.5% vs 55.6%; p = 0.27) and repeat revascularisation-free rate (84.8% vs 78.0%; p = 0.16) were not significantly different between the two groups. Revascularisation was the most common major adverse events in the JOCRIED participants. Although percutaneous coronary intervention was performed in 8 patients (13%) in the off-pump group and in 14 patients (23%) in the on-pump group (p = 0.23), no patients underwent redo coronary artery bypass grafting. Off-pump coronary artery bypass grafting provides comparable 15-year outcomes to on-pump coronary artery bypass grafting.


Shame and non-disclosure: a study of the emotional isolation of people referred for psychotherapy.
Thirty-four people referred to an NHS psychotherapy department were given a modified form of Oatley and Duncan's (1992) emotion diary which included questions about whether each recorded emotion had been subsequently disclosed to anyone (for example a partner, friend or professional). One week later the diaries were collected and participants interviewed. Interviews focused, among other things, on reasons for nondisclosure of recorded emotional experiences and the relationship between shame and non-disclosure. The results indicated that a majority of the emotional incidents recorded in the diaries were not disclosed (68%). This result contrasts with studies on non-clinical samples in which only approximately 10% of everyday emotions are kept secret. Qualitative analysis of the interview data revealed that participants appeared to be habitual non-disclosers of emotional and personal experiences and that non-disclosure was related to the anticipation of negative interpersonal responses to disclosure (in particular labelling and judging responses) in addition to more self-critical factors including shame. It is suggested that these results add to the existing literature on shame by illustrating the interpersonal effects of shame in a clinical sample.


Fetal and umbilical Doppler ultrasound in normal pregnancy.
One of the main aims of routine antenatal care is to identify the 'at risk' fetus in order to apply clinical interventions which could result in reduced perinatal morbidity and mortality. Doppler ultrasound study of umbilical artery waveforms helps to identify the compromised fetus in 'high-risk' pregnancies and, therefore, deserves assessment as a screening test in 'low-risk' pregnancies. To assess the effects on obstetric practice and pregnancy outcome of routine fetal and umbilical Doppler ultrasound in unselected and low-risk pregnancies. We searched the Cochrane Pregnancy and Childbirth Group Trials Register (May 2010). Randomised and quasi-randomised controlled trials of Doppler ultrasound for the investigation of umbilical and fetal vessels waveforms in unselected pregnancies compared to no Doppler ultrasound. Studies where uterine vessels have been assessed together with fetal and umbilical vessels have been included. Two authors independently assessed the studies for inclusion, assessed risk of bias and carried out data extraction. We included five trials involving 14,185 women. The methodological quality of the trials was generally unclear because of insufficient data included in the reports.Routine fetal and umbilical Doppler ultrasound examination in low-risk or unselected populations did not result in increased antenatal, obstetric and neonatal interventions, and no overall differences were detected for substantive short term clinical outcomes such as perinatal mortality. There is no available evidence to assess the effect on substantive long term outcomes such as childhood neurodevelopment and no data to assess maternal outcomes, particularly psychological effects. Existing evidence does not provide conclusive evidence that the use of routine umbilical artery Doppler ultrasound, or combination of umbilical and uterine artery Doppler ultrasound in low-risk or unselected populations benefits either mother or baby. Future studies should be designed to address small changes in perinatal outcome, and should focus on potentially preventable deaths.


Fine-tuning the LSPR response of gold nanorod-polyaniline core-shell nanoparticles with high photothermal efficiency for cancer cell ablation.
Gold nanorods (GNRs) with suitable aspect ratios have strong localized surface plasmon resonance (LSPR) absorption and scattering in the 650-900 nm near-infrared region, which make them attractive for in vitro or in vivo imaging and photothermal cancer therapy. However, they often suffer from cytotoxicity and instability for practical applications, and therefore need further surface modification to solve these issues. In this study, GNRs coated with biocompatible polyaniline (PANI) were used as a stable and highly efficient photothermal agent for cancer cell ablation. Fine-tuning the LSPR response of the GNR-PANI core-shell nanoparticles via thickness-controlled coating of the PANI nanoshells, optimizes the photothermal conversion efficiency of the agent. As a result of the contributions from the GNR core and PANI shell, the capability of photothermal transduction of the resultant nanoparticles at 808 nm is greatly enhanced. After exposure to a continuous NIR laser at 808 nm for ∼5 min, cancer cells were efficiently ablated requiring only a very low laser flux of 0.6 W cm-2, the lowest value reported to date for plasmonic nanostructures, showing the great potential for photothermal cancer therapy.


Melatonin delivery in solid lipid nanoparticles: prevention of cyclosporine A induced cardiac damage.
Melatonin is a potent antioxidant molecule with a capacity to protect tissues from damage caused by oxidative stress. It reduces cyclosporine A (CsA)-induced cardiotoxicity; this improvement required melatonin's binding to its membrane receptors. This experimental study examined whether melatonin is a useful tool for counteracting CsA-induced apoptosis in the heart of rats. We investigated melatonin's antiapoptotic efficacy in protecting the heart and tested whether this effect was totally dependent on its binding to membrane receptors or also involved radical scavenging. In some animals, solid lipid nanoparticles (SLN) as a melatonin delivery system were used. In one group of rats, melatonin (1 mg/kg/day i.p.) was given concurrently with CsA (15 mg/kg/day s.c.; CsA-MT) for 21 days. In other animals, melatonin loaded in SLN was injected with CsA (CsA-MTSLN). Oxidative stress in heart tissue was estimated using the evaluation of lipid peroxidation and the expression of the isoform of inducible nitric oxide (iNOS). The antiapoptotic effect of melatonin was evaluated using TUNEL staining and Bcl-2 protein family expression. CsA administration produced morphological and biochemical changes in the heart of rats, while melatonin reversed the changes. In particular, since the antiapoptotic melatonin's efficacy is mainly observed when it is loaded in SLN, we suggest that MT1/MT2 pathway is not sufficient for apoptosis antagonism and the additional intracellular effects may be required. Finally, we show that, (i) melatonin significantly reduces CsA cardiotoxicity acting also on apoptotic processes, and (ii) the reduction in CsA-induced cardiotoxicity is mediated mainly by its antioxidant effect.


Factors associated with chest injuries to front seat occupants in frontal impacts.
Objective: Frontal impact chest protection in European cars has been highlighted as an area where possible improvements could be made. The chest is particularly vulnerable in older occupants whose numbers are forecast to increase significantly in the coming decades. This study aimed to provide some direction to areas for possible improvements in frontal crash chest protection.Methods: Real-world crash injury data were interrogated, focusing on cars with current restraint components. The research examined belted front seat occupants in frontal impacts where airbags, pretensioners, and load limiters were present.Results: The chest was the most often injured body region at Abbreviated Injury Scale (AIS) 2+, 3+, and 4+ injury levels. The rate of AIS 2+ and AIS 3+ chest injuries was highest among elderly occupants and lowest among young occupants, and elderly occupants sustained proportionally more severe chest injuries in low/moderate-speed impacts compared to young and middle-aged occupants. However, it should be noted that rates of AIS 2 chest injury were also significantly higher for middle-aged occupants compared to the young. The front passenger seat was shown to be more often associated with significant chest injury than the driver seat. The higher proportion of elderly female occupants was postulated as a reason for this. Skeletal injury was the most frequent type of AIS 2+ chest injury, and the rate of injury for elderly occupants with such injuries was higher than that for young and middle-aged occupants. With the increase in the number of rib fractures, the risk of pulmonary complications and organ injuries tended to increase. The major cause of chest injury was identified as restraining loads transmitted to the chest via the seat belt. The absence of intrusion in the majority of cases suggests an opportunity for the restraint system to better manage the crash pulse, not only for elderly occupants but for those who are middle-aged as well.Conclusions: This study shows the necessity for safety interventions, through new vehicle crashworthiness systems, to improve chest protection, especially for middle-aged and elderly car occupants. Deployment of appropriate injury risk criteria, use of an appropriate dummy thorax, development of a low-energy restraint test, and the development of more adaptive restraints have been discussed as possible solutions to the problem.


Effect of flour extraction rate and baking on thiamine and riboflavin content and antioxidant capacity of traditional rye bread.
The effect of rye flour extraction rates and baking on thiamine and riboflavin content, and antioxidant capacity of traditional rye bread were studied and compared with white wheat flour. The content of thiamine was higher (10.9%) in rye dough formulated with dark rye flour (F-100%; extraction rate of 100%) than in rye dough formulated with brown rye flour (F-92%; extraction rate of 92%) that was similar to dough made with wheat flour. The riboflavin content in rye dough made from flour F-100% was also higher (16%) than in dough formulated with flour F-92%, and both provided larger riboflavin content than wheat dough. Baking led to reductions in thiamine of 56% for wheat bread and of 20% for both rye breads; however, this process caused only a 10% decrease in riboflavin for wheat bread and a 30% decrease for rye breads. Trolox equivalent antioxidant capacity, peroxyl radical scavenging capacity, DPPH radical scavenging activity, and Folin-Ciocalteu reducing capacity were higher in rye than in wheat dough and bread. Baking process produced slight changes in antioxidant activity, except for Superoxide Dismutase-like activity where a sharp decrease was observed. Our findings showed that rye breads are an important source of B vitamins and rye breads formulated with dark and brown flours showed better antioxidant properties than wheat bread. Therefore, rye breads should be more widely recommended in human nutrition.


Photocrosslinked DNA nanospheres for drug delivery.
DNA has been employed as both a genetic and a generic material. X-shaped DNA (X-DNA) in particular has four branched arms, providing multivalent functionalities that can allow for simultaneous multiple crosslinking. Here we report the synthesis of four acrylate-functionalized X-DNA monomers that can be further photocrosslinked to form monodisperse and tunable DNA nanospheres. In particular, the size and surface charge of these nanospheres were precisely controlled in a linear fashion, simply by tuning the monomer concentration in the reaction. The morphology and surface properties of the nanospheres were characterized using FT-IR, HPLC, TEM, AFM, zeta potential, and DLS analysis. In vitro studies in mammalian cells revealed that these DNA nanospheres demonstrated significant efficacy in the delivery of doxorubicin. These results highlight the potential of using DNA as material building blocks to design novel nanocarriers with properties tailored for the delivery of drugs in general and DNA/RNA in particular.


[Repetitive sequences of the human genome].
A review of literature data on different families of repetitive sequences of human genome is presented. Both tandemly organized (classical satellite DNA, alpha satellite DNA, "minisatellites" etc.) and interspersed repetitive elements are characterized in detail. Special attention is paid to description of human genome mobile elements.


Effect of dietary energy source on in vitro substrate utilization and insulin sensitivity of muscle and adipose tissues of Angus and Wagyu steers.
Angus (n = 8; 210 kg of BW) and 7/8 Wagyu (n = 8; 174 kg of BW) steers were used to evaluate the effects of dietary energy source on muscle and adipose tissue metabolism and insulin sensitivity. Steers were assigned to either a grain-based (corn) or hay-based (hay) diet and fed to similar final BW. At slaughter, LM and s.c. and i.m. adipose tissue samples were collected. Portions of the LM and adipose tissues were placed immediately in liquid N for later measurement of glycolytic intermediates. Fresh LM and s.c. and i.m. adipose tissues were incubated with [U-(14)C]glucose to assess glucose metabolism in vitro. All in vitro measures were in the presence of 0 or 500 ng/mL of insulin. Also, s.c. and i.m. adipose tissues were incubated with [1-(14)C]acetate to quantify lipid synthesis in vitro. Glucose-6-phosphate and fructose-6-phosphate concentrations were 12.6- and 2.4-fold greater in muscle than in s.c. and i.m. adipose tissues, respectively. Diet did not affect acetate incorporation into fatty acids (P = 0.86). Insulin did not increase conversion of glucose to CO(2), lactate, or total lipid in steers fed hay but caused an increase (per cell) of 97 to 110% in glucose conversion to CO(2), 46 to 54% in glucose conversion to lactate, and 65 to 160% in glucose conversion to total lipid content in adipose tissue from steers fed corn. On a per-cell basis, s.c. adipose tissue had 37% greater glucose oxidation than i.m. adipose (P = 0.04) and 290% greater acetate incorporation into fatty acids than i.m. adipose (P = 0.04). Insulin addition to s.c. adipose tissue from corn-fed steers failed to stimulate glucose incorporation into fatty acids, but exposing i.m. adipose tissue from corn-fed steers to insulin resulted in a 165% increase in glucose incorporation into fatty acids. These results suggest that feeding hay limited both glucose supply and tissue capacity to increase glucose utilization in response to insulin without altering acetate conversion to fatty acids. Because s.c. adipose tissue consistently utilized more acetate and oxidized more glucose than did i.m. adipose, these results suggest that hay-based diets may alter i.m. adipose tissue metabolism with less effect on s.c. adipose tissue.


Immunoglobulin A antibodies to oxidized collagen type II as a potential biomarker for the stratification of spondyloarthritis from rheumatoid arthritis.
The discovery of diseased tissue-specific neoantigens offers the opportunity to develop important disease tissue-specific biomarkers that can help in the prediction, diagnosis, and stratification of diseases. This opportunity is specifically significant for autoimmune diseases where diagnostic biomarkers are not available. Inflammatory autoimmune diseases are commonly associated with local generation of large amounts of reactive oxidants. We have previously identified oxidative post-translationally modified (oxPTM) tissue-specific neoantigens in rheumatoid arthritis (RA) and type 1 diabetes that elicit an immune response. In the current study, we studied the presence and clinical significance of antibodies to oxPTM collagen type II (CII) in patients with spondyloarthritis (SpA). Levels of antibodies specific to native CII and oxPTM-CII were assessed by enzyme-linked immunosorbent assay. Immunoglobulin G (IgG) binding to oxPTM-CII was observed in 52%, 83%, and 28% of serum samples from patients with axial spondyloarthritis (axSpA), RA, and psoriatic arthritis (PsA), respectively. Importantly, while strong IgA anti-oxPTM-CII responses were detected in axSpA and PsA patients, with 47% and 84% respective binders, no IgA anti-oxPTM-CII was detected in RA patients. IgA anti-oxPTM-CII reactivity in axSpA patients treated with biologics was higher and more frequent, with 85% binders compared to 9% binders in patients treated with synthetic disease-modifying anti-rheumatic drugs. Our data imply that SpA and PsA are associated with the presence of antibodies to oxPTM-CII, suggesting that there may be a humoral component that may distinguish patients with SpA from RA. Our approach could be adapted to other diseases, particularly to inflammatory autoimmune diseases.


Longitudinal association between alcohol use and physical activity in US college students: Evidence for directionality.
Objective: To investigate directionality of the association between alcohol use and physical activity in a college student sample, longitudinally across three time points. Participants: A total of 396 undergraduate students from a large university in the United States (62% females) participated in this study. Methods: Self-report data of alcohol use and physical activity were collected at three timepoints with 3-month lags between waves. Random-intercept cross-lagged panel modeling was used to disentangle within- and between-person effects. Results: Despite no significant between-person effects, there were significant cross-lagged paths from alcohol use to vigorous physical activity at the within-person level. Specifically, when individuals consumed more alcohol than normal at earlier timepoints, they reported more subsequent vigorous physical activity at 3-month follow-ups. Conclusion: We provide evidence that alcohol use may positively predict later physical activity in college students over the course of a school year. These findings advance theoretical understanding of how these two health behaviors are linked using sophisticated methods.


The neurovascular basis of processing speed differences in humans: A model-systems approach using multiple sclerosis.
Behavioral studies investigating fundamental cognitive abilities provide evidence that processing speed accounts for large proportions of performance variability between individuals. Processing speed decline is a hallmark feature of the cognitive disruption observed in healthy aging and in demyelinating diseases such as multiple sclerosis (MS), neuromyelitis optica, and Wilson's disease. Despite the wealth of evidence suggesting a central role for processing speed in cognitive decline, the neural mechanisms of this fundamental ability remain unknown. Intact neurovascular coupling, acute localized blood flow increases following neural activity, is essential for optimal neural function. We hypothesized that efficient coupling forms the neural basis of processing speed. Because MS features neural-glial-vascular system disruption, we used it as a model to test this hypothesis. To assess the integrity of the coupling system, we measured blood-oxygen-level-dependent (BOLD) signal in healthy controls (HCs) and MS patients using a 3T MRI scanner while they viewed radial checkerboards that flickered periodically at 8 Hz. To assess processing speed and cognitive function, we administered a battery of neuropsychological tests. While MS patients exhibited reduced ΔBOLD with reductions in processing speed, no such relationships were observed in HCs. To further investigate the mechanisms that underlie ΔBOLD-processing speed relationships, we assessed the physiologic components that constitute ΔBOLD signal (i.e., cerebral blood flow, ΔCBF; cerebral metabolic rate of oxygen, ΔCMRO2; neurovascular coupling ratio) in speed-preserved and -impaired MS patients. While ΔCBF and ΔCMRO2 showed no group-differences, the neurovascular coupling ratio was significantly reduced in speed-impaired MS patients compared to speed-preserved MS patients. Together, these results suggest that neurovascular uncoupling might underlie cognitive slowing in MS and might be the central pathogenic mechanism governing processing speed decline.


Department of Defense influenza and other respiratory disease surveillance during the 2009 pandemic.
The Armed Forces Health Surveillance Center's Division of Global Emerging Infections Surveillance and Response System (AFHSC-GEIS) supports and oversees surveillance for emerging infectious diseases, including respiratory diseases, of importance to the U.S. Department of Defense (DoD). AFHSC-GEIS accomplishes this mission by providing funding and oversight to a global network of partners for respiratory disease surveillance. This report details the system's surveillance activities during 2009, with a focus on efforts in responding to the novel H1N1 Influenza A (A/H1N1) pandemic and contributions to global public health. Active surveillance networks established by AFHSC-GEIS partners resulted in the initial detection of novel A/H1N1 influenza in the U.S. and several other countries, and viruses isolated from these activities were used as seed strains for the 2009 pandemic influenza vaccine. Partners also provided diagnostic laboratory training and capacity building to host nations to assist with the novel A/H1N1 pandemic global response, adapted a Food and Drug Administration-approved assay for use on a ruggedized polymerase chain reaction platform for diagnosing novel A/H1N1 in remote settings, and provided estimates of seasonal vaccine effectiveness against novel A/H1N1 illness. Regular reporting of the system's worldwide surveillance findings to the global public health community enabled leaders to make informed decisions on disease mitigation measures and controls for the 2009 A/H1N1 influenza pandemic. AFHSC-GEIS's support of a global network contributes to DoD's force health protection, while supporting global public health.


Hematological and Mineral Profiles of Reproductive Failure of Exotic Breed Cattle in Payakumbuh, West Sumatra, Indonesia.
Female exotic breed cattle raised by traditional small farms are susceptible to reproductive disturbances that result in failure or delay to produce calves. The present research investigated the hematologic profiles of exotic breed cattle having reproductive troubles versus heifers and pregnant cows raised by small farms. A survey was conducted to identify the reproduction performance of 160 female Simmental cows raised at 15 smallholders in Payakumbuh, West Sumatra, Indonesia. Samples of blood were collected from 15 female Simmentals comprised of three different reproductive statues (heifers, pregnant and reproductive failure, n = 5 animals each). Blood plasma was then separated and analyzed for hematological parameters [hemoglobin (Hb), hematocrit, red and white blood cell, mean corpuscular Hb concentration], total protein and mineral content (Ca, P, Mg, Fe, Mn, Cu and Zn). Samples of fodder feed were collected from 15 farms for determination of dominant species and mineral composition. Data were statistically analyzed in a completely randomized 3×5 design for blood parameters and 4×3 design for forage minerals. About one-third of female cows found to have reproductive problems. Anestrus was found to be the most important causal factor for reproductive failure, followed by postpartum infertility (poor fertilization). The reproductive failure group had significantly lower (p<0.05) Hb levels, hematocrit, red and white blood cell and protein but higher mean corpuscular Hb concentration. Considering the critical levels in the blood and feed, the animals were deficient in protein, Ca, P, Mn and Cu. Anestrus and repeated insemination were found to be the major causes of reproductive disorders in exotic breed cattle under small farm conditions that results in delay or failure to produce calves. Reproductive disturbances in Simmental cows were most likely associated with nutrient deficiencies.


Comparative effectiveness of continuous subcutaneous insulin infusion using insulin analogs and multiple daily injections in pregnant women with diabetes mellitus: a systematic review and meta-analysis.
We systematically reviewed the effectiveness and safety of continuous subcutaneous insulin infusion (CSII) with insulin analogs compared with multiple daily injections (MDI) in pregnant women with diabetes mellitus. We searched Medline®, Embase®, and the Cochrane Central Register of Controlled Trials through May 2013. Studies comparing CSII with MDI in pregnant women with diabetes mellitus were included. Studies using regular insulin CSII were excluded. We conducted meta-analyses where there were two or more comparable studies based on the type of insulin used in the MDI arm. Seven cohort studies of pregnant women with type 1 diabetes reported improvement in hemoglobin A1c (HbA1c) in both groups. Meta-analysis showed no difference in maternal and fetal outcomes for CSII versus MDI. Results were similar when CSII was compared with MDI with insulin analogs or regular insulin. Studies had moderate to high risk bias with incomplete descriptions of study methodology, populations, treatments, follow up, and outcomes. We conclude that observational studies reported similar improvements in HbA1c with CSII and MDI during pregnancy, but evidence was insufficient to rule out possible important differences between CSII and MDI for maternal and fetal outcomes. This highlights the need for future studies to examine the effectiveness and safety of CSII with insulin analogs and MDI in pregnant women with diabetes mellitus.


Case of localized scleroderma successfully treated with bath psoralen and ultraviolet A therapy.
The patient was a 12-year-old girl with linear scleroderma distributed on the right abdomen, dorsal aspect of the right thigh, lower leg and foot. The initial regimen of oral prednisolone and methotrexate, or i.v. methylprednisolone failed in the treatment of the scleroderma. Then bath psoralen and ultraviolet A therapy (bath-PUVA) therapy of 0.2 J-4.0 J/cm(2) daily to total doses 62.8 J/cm(2) combined with oral prednisolone was started. After bath-PUVA therapy, regression of the skin sclerosis was observed, the possible mobile range of the right ankle was increased and histological examination confirmed improvement of the sclerosis. The successful results of bath-PUVA therapy in this case suggest its utility for localized scleroderma.


Response of type illa-j kodak spectroscopic plates to baking in various controlled atmospheres.
A new emulsion with excellent signal-to-noise characteristics has been hypersensitized to speeds practicable for astronomical applications by baking in a controlled nitrogen atmosphere. Important gains are achieved in speed and fog suppression relative to the usual procedure of baking in air.


Temporal trends and factors associated with preterm birth in Chile, 1992-2018.
An analytical study based on Chilean birth records obtained from the Department of Statistics and Health Information (DEIS) was conducted. This study aimed to evaluate temporal trends in preterm births by maternal age in Chile from 1990 to 2018. Results show that the preterm birth rate in 1992 was 5.0% and increased to 7.2% in 2018. The average annual percent change (AAPC) was 1.44. Age groups at the extremes (19 and under and 35 and over) presented the highest rates of preterm birth, both at the beginning and at the end of the study period. The latter group showed a smaller decrease at the beginning (1992 to 1995), with an annual percentage change (APC) of -3.00. The probability of preterm birth in both groups was higher compared to the 20-34 year old group. Although Chile boasts some of the best maternal and child health indicators in the region, repercussions associated with the current postponement of maternity - including preterm birth - must be monitored.


On the Connection Between Language Change and Language Processing.
Previous studies provided evidence for a connection between language processing and language change. We add to these studies with an exploration of the influence of lexical-distributional properties of words in orthographic space, semantic space, and the mapping between orthographic and semantic space on the probability of lexical extinction. Through a binomial linear regression analysis, we investigated the probability of lexical extinction by the first decade of the twenty-first century (2000s) for words that existed in the first decade of the nineteenth-century (1800s) in eight data sets for five languages: English, French, German, Italian, and Spanish. The binomial linear regression analysis revealed that words that are more similar in form to other words are less likely to disappear from a language. By contrast, words that are more similar in meaning to other words are more likely to become extinct. In addition, a more consistent mapping between form and meaning protects a word from lexical extinction. A nonlinear time-to-event analysis furthermore revealed that the position of a word in orthographic and semantic space continues to influence the probability of it disappearing from a language for at least 200 years. Effects of the lexical-distributional properties of words under investigation here have been reported in the language processing literature as well. The results reported here, therefore, fit well with a usage-based approach to language change, which holds that language change is at least to some extent connected to cognitive mechanisms in the human brain.


How are eczema 'flares' defined? A systematic review and recommendation for future studies.
Eczema is an important public health problem due to high prevalence and associated morbidity. As a chronic, relapsing disease, the ability to capture disease flares is important when evaluating treatment success, yet it is unclear how flares should be defined. This study systematically reviews and critically appraises the literature defining flares in eczema, and explores methodological and practical aspects of including eczema flares as outcome measures in trials to inform developing an international consensus definition adding details of our own recent experience. A systematic review was undertaken of flare definitions in prospective intervention studies of eczema published up until 14 February 2013. Data were double-extracted. We pre-specified that important characteristics of a good flare definition should include (i) being feasible to collect and (ii) being recorded at the time flare symptoms were experienced. Three hundred and fourteen papers were identified of which 26 included some description of eczema flares. Overall, 22 different flare definitions were used. Flares were included as the primary outcome in 17 studies (65%). Only four studies (15%) used a patient-reported flare definition. No studies fulfilled all of our pre-specified essential characteristics. No validation studies were identified. The wide variation and lack of validation of flare definitions hampers comparison of findings between studies for this chronic, relapsing disease. None of the currently used definitions seem fit for purpose. Further research should establish which aspects of worsening of disease are most important to patients, and how best to capture these data in a way that is valid, reliable and feasible in all clinical and research settings.


Predictors of poor follow-up after bariatric surgery.
to identify predictive factors of loss of follow-up of patients submitted to Roux-en-Y gastric bypass and sleeve gastrectomy in a 48-month period. we conducted a retrospective, cohort study from January 2010 to December 2012. We analyzed thirteen variables and compared them to loss of follow-up. among the 559 patients studied, there was a great reduction in the frequency (43.8%) of the consultations from the second postoperative year on, with a significant loss in the 4th year (70.8%). In the univariate analysis, only the variable "excess weight" was associated with loss of follow-up. The proportion of overweight (>49.95kg) was higher in the follow-up group with greater loss (>3 absences) (p=0.025). In the logistic regression, patients exposed to a greater excess weight (>49.95kg) presented a two-fold higher risk for loss of follow-up (>3 absences) (OR=2.04, 95% CI 1.15-3.62; p=0.015). In the univariate analysis, at the 48th postoperative month, only the variable "mesoregion of origin" was associated with loss of follow-up (p=0.012). there was a progressive loss of follow-up from the second postoperative year on. Among the factors analyzed, only the variable "excess weight" greater than 49.95kg in the preoperative period was associated with loss of medical-surgical follow-up. In the 48th month of the postoperative period, there was a higher prevalence of loss of medical-surgical follow-up for patients outside the perimeter of the city of Recife (51%, p=0.052).


The Benefits of Streamlined Hip Fracture Management in a Regional Hospital.
Hip fracture is an increasingly common injury in the growing elderly population. The morbidity and mortality associated with this injury can be reduced by minimizing delays to surgical treatment. We describe the impact of a regional hospital service redesign project that utilized the principles of smart simplicity, a management strategy that lays emphasis on collaboration to achieve desired goals. Prior to the redesign, patients with hip fractures were taking an average of 72 hours for surgical treatment. A hip fracture working group was created to examine closely the process of hip fracture care, and a single key performance indicator (KPI) of "surgery within 48 hours" was adopted. This allowed identification of processes that could be clarified and streamlined, with the agreement of relevant stakeholders, in the creation of a new hip fracture pathway. In the first 3 months of the pathway's implementation, 16 of 18 patients had surgery within 48 hours of presentation. In a 6-month follow-up audit after 2 years of implementation, 36 of 39 patients were treated within 48 hours. This was significantly different to the time to surgery seen in the 12 months prior to the redesign (P < .001, Student t test). The mean time to surgery was reduced from 72 hours to 36 hours, a saving in an annual acute bed stay cost of A$152 000. Decreased time to the operating room, the cost savings inherent to this, can be achieved with the introduction of the best standard of care. A redesign that mandates collaboration in achieving a single KPI has allowed a significant culture shift in the treatment of hip fractures in our institution in the months following its institution. Collaborative, multidisciplinary collaboration has facilitated a higher standard of care and demonstrated significant cost benefit.


Thalamic rosette-forming a glioneuronal tumor in an elderly patient: Case report and literature review.
The rosette-forming glioneuronal tumor (RGNT) is a novel type of brain tumor recently listed in the WHO 2007 classification of central nervous system (CNS) tumors. We report the case of a 75-year-old woman harboring a thalamic RGNT with third ventricle dissemination. Age and location make the present case exceptional and which has never previously been reported. A review of the clinical, pathological and radiological features is presented along with the relevant literature.


Online social networks that connect users to physical activity partners: a review and descriptive analysis.
The US Centers for Disease Control and Prevention have identified a lack of encouragement, support, or companionship from family and friends as a major barrier to physical activity. To overcome this barrier, online social networks are now actively leveraging principles of companion social support in novel ways. The aim was to evaluate the functionality, features, and usability of existing online social networks which seek to increase physical activity and fitness among users by connecting them to physical activity partners, not just online, but also face-to-face. In September 2012, we used 3 major databases to identify the website addresses for relevant online social networks. We conducted a Google search using 8 unique keyword combinations: the common keyword "find" coupled with 1 of 4 prefix terms "health," "fitness," "workout," or "physical" coupled with 1 of 2 stem terms "activity partners" or "activity buddies." We also searched 2 prominent technology start-up news sites, TechCrunch and Y Combinator, using 2 unique keyword combinations: the common keyword "find" coupled with 1 of 2 stem terms "activity partners" and "activity buddies." Sites were defined as online social health activity networks if they had the ability to (1) actively find physical activity partners or activities for the user, (2) offer dynamic, real-time tracking or sharing of social activities, and (3) provide virtual profiles to users. We excluded from our analysis sites that were not Web-based, publicly available, in English, or free. Of the 360 initial search results, we identified 13 websites that met our complete criteria of an online social health activity network. Features such as physical activity creation (13/13, 100%) and private messaging (12/13, 92%) appeared almost universally among these websites. However, integration with Web 2.0 technologies such as Facebook and Twitter (9/13, 69%) and the option of direct event joining (8/13, 62%) were not as universally present. Largely absent were more sophisticated features that would enable greater usability, such as interactive engagement prompts (3/13, 23%) and system-created best fit activities (3/13, 23%). Several major online social networks that connect users to physical activity partners currently exist and use standardized features to achieve their goals. Future research is needed to better understand how users utilize these features and how helpful they truly are.


[Morphogenesis of the cranium of Cavia porcellus L. I: Introduction, classification and descriptive part].
The craniogenesis of Cavia porcellus has been investigated in 7 embryos of different ages. From the developmental stage of 36 mm CRL, a reconstruction of the chondrocranium is described. As there is still a gap in the tectum posterius, the foramen magnum is not closed posteriorly. The course of the notochord is retrobasilar at the beginning, more rostrally it runs intrabasilar. After ossification, the place where the notochord enters the basioccipital is marked by a cavity. This cavity is not identical with the posterior basicranial fenestra. The laminae alares build up strong paracondylar processes. The auditory capsule is connected with the occipital region only by the exoccipitocapsular commissure, but there is no supraoccipitocapsular commissure. The fossa subarcuata is pierced by a subarcuate foramen. The very short lamina parietalis is not in contact with the orbital wing as there is no orbitoparietal commissure. The processus recessus divides the perilymphatic foramen into fenestra rotunda and aquaeductus cochleae. The suprafacial commissure arises from the upper margin of the canalicular part of the auditory capsule, but it does not reach the superior surface of the cochlear part at this stage. The tegmen tympani is well developed. The foramen singulare is not yet separated from the inferior acoustic foramen. At the stage of 36 mm CRL there is no septum spirale cartilagineum. Mm. tensor tympani et stapedius are developed in the typical way. The auditory capsule is connected with the basal plate by the anterior basicochlear and the alicochlear commissures. The floor of the orbitotemporal region is incomplete, the temporal wings are small. The alicochlear commissure, the alar process, the anterior basicochlear commissure, and the basal plate surround the carotid foramen, but there is no blood vessel passing through it. The temporal wing is at the beginning of ossification and shows a fissura ovalis for the mandibular nerve. Although the hypophysial canal is still present, there are no structures passing through it. There is no foramen rotundum. The orbital wing is still cartilagineous. The basal plate and the pre- and postoptic roots border the optical foramen. The straight muscles of the eyeball are attached to the ala hypochiasmatica which projects from the postoptic root. The interorbital septum is absent. The ophthalmic artery, which instead of the obliterated internal carotid artery, contributes to the circulus arteriosus cerebri is well developed. There is no orbitonasal commissure . The epiphanial foramina are present.(ABSTRACT TRUNCATED AT 400 WORDS)


Transcriptome analysis identifies genes with enriched expression in the mouse central extended amygdala.
The central extended amygdala (EAc) is an ensemble of highly interconnected limbic structures of the anterior brain, and forms a cellular continuum including the bed nucleus of the stria terminalis (BNST), the central nucleus of the amygdala (CeA) and the nucleus accumbens shell (AcbSh). This neural network is a key site for interactions between brain reward and stress systems, and has been implicated in several aspects of drug abuse. In order to increase our understanding of EAc function at the molecular level, we undertook a genome-wide screen (Affymetrix) to identify genes whose expression is enriched in the mouse EAc. We focused on the less-well known BNST-CeA areas of the EAc, and identified 121 genes that exhibit more than twofold higher expression level in the EAc compared with whole brain. Among these, 43 genes have never been described to be expressed in the EAc. We mapped these genes throughout the brain, using non-radioactive in situ hybridization, and identified eight genes with a unique and distinct rostro-caudal expression pattern along AcbSh, BNST and CeA. Q-PCR analysis performed in brain and peripheral organ tissues indicated that, with the exception of one (Spata13), all these genes are predominantly expressed in brain. These genes encode signaling proteins (Adora2, GPR88, Arpp21 and Rem2), a transcription factor (Limh6) or proteins of unknown function (Rik130, Spata13 and Wfs1). The identification of genes with enriched expression expands our knowledge of EAc at a molecular level, and provides useful information to toward genetic manipulations within the EAc.


Antigenic characterization and analysis of the human immune response to outer membrane protein E of Branhamella catarrhalis.
Outer membrane protein E (OMP E) is a 50-kDa major OMP of Branhamella catarrhalis. Polyclonal antisera and four monoclonal antibodies (MAbs) to OMP E were generated to study its antigenic structure. All antibodies recognized epitopes in all 19 B. catarrhalis strains tested by immunoblot assays. By flow cytometry, it was determined that MAbs 1B3 and 9G10d recognized epitopes which are expressed on the surface of the intact bacterium, while MAbs IC11 and 7C10 recognized epitopes which were buried within the outer membrane. A competitive enzyme-linked immunosorbent assay showed that MAbs 1B3 and 9G10d recognize the same or closely related epitopes. Proteinase K treatment of whole bacterial cells revealed that MAbs 1B3 and 9G10d recognize a surface-exposed epitope located in the 17-kDa region towards the amino terminus of OMP E. The human serum and mucosal antibody responses to OMP E in adults with chronic bronchitis were studied. A majority of these patients had immunoglobulin A to OMP E in sputum supernatants. None of ten adults who experienced lower respiratory tract infections due to B. catarrhalis demonstrated a clear-cut rise in antibody titer to OMP E in serum or sputum supernatant. This study has demonstrated that OMP E has at least one surface-exposed epitope which is highly conserved among strains of B. catarrhalis and which is located in the amino-terminal 184 amino acids of the molecule.


Neurodevelopmental disorders in children exposed in utero to synthetic progestins: analysis from the national cohort of the Hhorages Association.
The medical and scientific communities have not yet fully acknowledged the undesirable effects of the synthetic hormones that have been administered to pregnant women for decades. The somatic effects of in utero exposure to diethylstilbestrol (DES), such as genital malformations, infertility, and cancer, have long been recognized but this has not been the case concerning psychiatric disorders. The progestins used in contraception and hormone replacement therapy are known to affect the adult brain, but no data exist on their effects due to in utero exposure of children. The Hhorages Association, a national patient support group, has assembled a cohort of 1200 women who took synthetic hormones during pregnancy. These women had a combined 1934 children. We obtained full questionnaire responses from 46 women treated with progestins only - and not an estrogenic cocktail - who gave birth to 115 children. Three groups were observed: Group 1 (n = 18): firstborn unexposed children, Group 2 (n = 62): children exposed in utero to synthetic progestins, and Group 3 (n = 35): children born after a previous pregnancy treated with progestins. No psychiatric disorders were reported in Group 1 and the incidence of psychiatric disorders was drastically elevated in Group 2. Our work shows a striking increase in psychiatric disorders among children exposed in utero to progestins and strongly suggests that prenatal exposure is associated with a high risk of psychiatric disorders in adolescence and adulthood, whether accompanied or not by disorders of sex development.


A Neuroendocrine View of ECT.
A neuroendocrine hypothesis to explain the clinical activity of convulsive therapy is described. The hypothesis is based on the diabetes/insulin model and suggests that hypothalamic dysfunction with an insufficiency of a mood-maintaining peptide is the basis for affective disorders. Repeated seizures enhance the production and release of the hypothalamic peptide antidepressin-the active principle that relieves both neuroendocrine and behavioral abnormalities.


Anaerobic methane oxidation in a coastal oxygen minimum zone: spatial and temporal dynamics.
Coastal waters are a major source of marine methane to the atmosphere. Particularly high concentrations of this potent greenhouse gas are found in anoxic waters, but it remains unclear if and to what extent anaerobic methanotrophs mitigate the methane flux. Here we investigate the long-term dynamics in methanotrophic activity and the methanotroph community in the coastal oxygen minimum zone (OMZ) of Golfo Dulce, Costa Rica, combining biogeochemical analyses, experimental incubations and 16S rRNA gene sequencing over 3 consecutive years. Our results demonstrate a stable redox zonation across the years with high concentrations of methane (up to 1.7 μmol L-1 ) in anoxic bottom waters. However, we also measured high activities of anaerobic methane oxidation in the OMZ core (rate constant, k, averaging 30 yr-1 in 2018 and 8 yr-1 in 2019-2020). The OPU3 and Deep Sea-1 clades of the Methylococcales were implicated as conveyors of the activity, peaking in relative abundance 5-25 m below the oxic-anoxic interface and in the deep anoxic water respectively. Although their genetic capacity for anaerobic methane oxidation remains unexplored, their sustained high relative abundance indicates an adaptation of these clades to the anoxic, methane-rich OMZ environment, allowing them to play major roles in mitigating methane fluxes.


Five-year follow-up of early lisuride and levodopa combination therapy versus levodopa monotherapy in de novo Parkinson's disease. The French Lisuride Study Group.
The value of an early initial coadministration of levodopa (L-dopa) and lisuride in Parkinson's disease was the main goal of the present study. Eighty-two patients with recently diagnosed idiopathic Parkinson's disease were randomized into two groups for treatment with L-dopa alone or L-dopa + lisuride. The trial was double-blinded for the first year and open for the following 4 years. Selegiline (10 mg/day b.i.d.) was added in both groups at the end of the first year. Outcome measures were evolution of L-dopa dosage and Unified Parkinson's Disease Rating Scale scores and subscores, and incidence of motor complications. The dropout rate was higher in the L-dopa group (63.4%) than in the combination group. Motor improvement was better (p < 0.01) in the L-dopa + lisuride group. Expected motor complications were rare, moderate and equivalent in the two groups despite a difference in L-dopa dosage (446.7 vs. 387.5 mg/day). Long-term follow-up demonstrated the L-dopa-sparing effect of lisuride (average 1 mg/day), the beneficial effect of early combination therapy on motor status and the paucity of motor complications in both groups.


Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists.
In an effort to improve indole-based CB(2) cannabinoid receptor ligands and also to develop SAR for both the CB(1) and CB(2) receptors, 47 indole derivatives were prepared and their CB(1) and CB(2) receptor affinities were determined. The indole derivatives include 1-propyl- and 1-pentyl-3-(1-naphthoyl)indoles both with and without a 2-methyl substituent. Naphthoyl substituents include 4- and 7-alkyl groups as well as 2-, 4-, 6-, 7-methoxy and 4-ethoxy groups. The effects of these substituents on receptor affinities are discussed and structure-activity relationships are presented. In the course of this work three new highly selective CB(2) receptor agonists were identified, 1-propyl-3-(4-methyl-1-naphthoylindole (JWH-120), 1-propyl-2-methyl-3-(6-methoxy-1-naphthoylindole (JWH-151), and 1-pentyl-3-(2-methoxy-1-naphthoylindole (JWH-267). GTPgammaS assays indicated that JWH-151 is a full agonist at CB(2), while JWH-120 and JWH-267 are partial agonists. Molecular modeling and receptor docking studies were carried out on a set of 3-(4-propyl-1-naphthoyl)indoles, a set of 3-(6-methoxy-1-naphthoyl)indoles and the pair of N-pentyl-3-(2-methoxy-1-naphthoyl)indoles. Docking studies indicated that the CB(1) receptor affinities of these compounds were consistent with their aromatic stacking interactions in the aromatic microdomain of the CB(1) receptor.


The relationship between leaf area growth and biomass accumulation in Arabidopsis thaliana.
Leaf area growth determines the light interception capacity of a crop and is often used as a surrogate for plant growth in high-throughput phenotyping systems. The relationship between leaf area growth and growth in terms of mass will depend on how carbon is partitioned among new leaf area, leaf mass, root mass, reproduction, and respiration. A model of leaf area growth in terms of photosynthetic rate and carbon partitioning to different plant organs was developed and tested with Arabidopsis thaliana L. Heynh. ecotype Columbia (Col-0) and a mutant line, gigantea-2 (gi-2), which develops very large rosettes. Data obtained from growth analysis and gas exchange measurements was used to train a genetic programming algorithm to parameterize and test the above model. The relationship between leaf area and plant biomass was found to be non-linear and variable depending on carbon partitioning. The model output was sensitive to the rate of photosynthesis but more sensitive to the amount of carbon partitioned to growing thicker leaves. The large rosette size of gi-2 relative to that of Col-0 resulted from relatively small differences in partitioning to new leaf area vs. leaf thickness.


Orchestrating liver development.
The liver is a central regulator of metabolism, and liver failure thus constitutes a major health burden. Understanding how this complex organ develops during embryogenesis will yield insights into how liver regeneration can be promoted and how functional liver replacement tissue can be engineered. Recent studies of animal models have identified key signaling pathways and complex tissue interactions that progressively generate liver progenitor cells, differentiated lineages and functional tissues. In addition, progress in understanding how these cells interact, and how transcriptional and signaling programs precisely coordinate liver development, has begun to elucidate the molecular mechanisms underlying this complexity. Here, we review the lineage relationships, signaling pathways and transcriptional programs that orchestrate hepatogenesis.


Glycerol metabolism in the neonatal rat.
1. The possible role of glycerol as a precursor in neonatal gluconeogenesis in the rat was investigated by recording the activities of glycerol kinase and l-glycerol 3-phosphate dehydrogenase in the liver, kidney and other tissues around birth and during the neonatal period. 2. Blood glycerol concentrations in the neonatal rat are high. 3. There is a marked increase after birth in the ability of both liver and kidney slices to convert glycerol into glucose plus glycogen that correlates with the increase in glycerol kinase activity. 4. High hepatic and renal l-glycerol 3-phosphate dehydrogenase activities are also found in the neonatal period. 5. The marked capacity for neonatal gluconeogenesis from glycerol thus demonstrated and the role of glycerol kinase in its control are discussed.


Occupational and environmental lead exposure in Port Harcourt, Nigeria: analysis of its association with renal function indices.
In spite of the high risk of lead exposure in Nigeria, there is a paucity of data on the occupational and environmental burden of lead exposure and its impact on human health especially its nephrotoxic effects. This study aims to assess the degree of occupational and environmental lead exposure in Port Harcourt Nigeria and the relationship between lead exposure and indices of renal function. A cross sectional comparative study of 190 aduIt subjects with occupational lead exposure and 80 matched controls. Blood lead was used as the biomarker of lead exposure. Serum urea, creatinine, uric acid, urine albumin and glomerular filtration rate were the renal function indices measured. Occupationally lead exposed subjects had higher mean blood lead 50.37 +/- 24.58 ug/dI, than controls 41.40 +/- 26.85 ug/dl (p = 0.008). The mean values of serum urea, creatinine and uric acid were significantly higher in study subjects compared to controls 3.06 +/- 0.81 mmol/L vs. 2.7 +/- 0.84 mmol/L (p = 0.002), 87.2 +/- 14.30 umol/L vs. 80.68 +/- 14.70 umol/L (p = 0.001) and 271.93 +/- 71.18 umol/L vs. 231.1 +/- 62.70 umol/L (p = 0.000) respectively. Creatinine clearance was significantly lower in subjects compared to controls 98.86 +/- 21.26 mI/min/1.72m2 vs. 108.18 +/- 25.16 mI/min/1.72m2 (p = 0.002). Blood lead correlated positively only with blood urea [r = .031, r2 = .017, p = .031] and negatively [r = -.144, r2 = .02 1, p = .018] with serum phosphate. The level of environmental and occupational lead exposure in Port Harcourt, Nigeria is high, with occupational lead exposure increasing the risk of lead toxicity and renal function impairment.