Aquatic long-distance dispersal and vicariance shape the evolution of an ostracod species complex (Crustacea) in four major Brazilian floodplains.
Cladogenesis is often driven by the interplay of dispersal and vicariance. The importance of long-distance dispersal in biogeography and speciation is increasingly recognised, but still ill-understood. Here, we study faunal interconnectivity between four large Brazilian floodplains, namely the Amazon, Araguaia, Pantanal (on Paraguay River) and Upper Paraná River floodplains, investigating a species complex of the non-marine ostracod genus Strandesia. We use DNA sequence data from the mitochondrial COI and the nuclear Elongation Factor 1 alpha genes to construct molecular phylogenies and minimum spanning networks, to identify genetic species, analyse biogeographic histories and provide preliminary age estimates of this species complex. The Strandesia species complex includes five morphological and eleven genetic species, which doubles the known diversity in this lineage. The evolutionary history of this species complex appears to comprise sequences of dispersal and vicariance events. Faunal and genetic patterns of connectivity between floodplains in some genetic species are mirrored in modern hydrological connections. This could explain why we find evidence for (aquatic) long-distance dispersal between floodplains, thousands of kilometres apart. Our phylogenetic reconstructions seem to mostly indicate recent dispersal and vicariance events, but the evolution of the present Strandesia species complex could span up to 25 Myr, which by far exceeds the age of the floodplains and the rivers in their current forms.


[Advice on the x-ray positioning of the upper and the lower leg].
Roentgenographic images of the femur and tibia to demonstrate the bones in two true right-angled projections (anteroposterior, lateral view) can be obtained by using a small hydrostatic level with two levels positioned at right angles against each other. By taping the small plastic device to the skin of the leg under examination, rotation of the limb between the two x-ray exposures can be controlled and adjusted to exactly 90 degrees. Compared to other common positioning procedures (rotation of the leg to approximately 90 degrees by the patient; angulation of the x-ray tube to 90 degrees around the leg) this method yields the highest accuracy of adjustment.


Use of immobilised bacteria for the wastewater treatment--examples from the sugar industry.
This work focuses on the implementation of high performance systems to the wastewater treatment of sugar factories. For this purpose, systems with immobilised bacteria were studied. For the hydrolysis of organic matter and denitrification, fluidized bed reactors were used. The nitrification was studied with an airlift reactor system. Both hydrolysis and nitrogen elimination were investigated on laboratory and pilot scales in sugar factories. Although with porous materials higher biomass concentrations are attainable for the hydrolysis (up to 55 kg/m3), for economical reasons sand was used (22.5 kg/m3) for the pilot scale-study. With a pilot-scale reactor (volume 1 m3) the maximum sucrose conversion rate achieved with sand in the first campaign was 52 kg/(m3 d). For the nitrogen elimination on the pilot scale, a system with denitrification and nitrification was combined. The highest performance for the nitrification (reactor volume: 0.68 m3) with pumice as support material was 1.2 kg NH4-N/(m3 d), limiting the whole system. The denitrification rate (reactor volume: 0.12 m3) was four times higher (3.5-5 kg NO3-N/(m3 d). Rules of the modelling of the system are discussed.


An application of Indian public health standard for evaluation of primary health centers of an EAG and a Non-EAG state.
National Rural Health Mission (NRHM) has provided the opportunities to develop a standard for Sub centers, PHCs and CHCs in the country, popularly known as Indian Public Health Standards (IPHS). The study was carried out to find out and compare to what extent the IPHS were followed by the PHCs in the selected districts of both the Empowered Action Group (EAG) state of Assam and non EAG state of Karnataka. It was a Cross sectional observational study conducted during September-October 2008 where the quality of care and services provided in the selected PHCs as per the IPHS norms was assessed. All the PHCs in both the studied districts were rendering the assured services of OPD, 24hrs general emergency service and referral services while 24 hour delivery services were being provided by 80% of the PHCs of the selected districts of both the states. Functional labor rooms were available only in 80% and 90% of the studied PHCs in Assam and Karnataka respectively. Basic laboratory facilities, for routine blood, urine and stool examination were available in 80% of the studied PHCs in the non-EAG state of Karnataka while it was only in 20% of the studied PHCs of the EAG state of Assam. The findings of the present study revealed important deficiencies as per IPHS norms in the studied PHCs of both Assam and Karnataka.


[Improvement in stroke care in a non-urban community hospital--quality of procedures before and after participating in a telemedical stroke network].
Although treatment in a stroke unit has been proven to be effective, most stroke patients in rural areas have no access to it. The community hospital of Ebersberg (Bavaria/Germany) joined the Telemedic Project for Integrative Stroke Care (TEMPiS) in order to optimize the quality of stroke care. This analysis focuses on changes in stroke management using generally accepted indicators for quality of acute stroke treatment. The core elements consisted of the setting up of a stroke ward in the community hospital, continual stroke education and a 24-hour telemedical consultation service offered by stroke centers. Treatment of stroke patients was documented during two 12-months periods before the project was started start (i.e. retrospectively) and during the course of the project (prospectively). In addition, data on fatal outcome and institutionalization of patients who had lived at home before the qualifying event were collected 12 months after stroke onset. There were 299 admissions for stroke or transient ischemic attacks between 1 Nov 2001 and 31 Oct 2002, and 305 between 7 July 2003 and 6 June 2004. Length of in-hospital stay decreased from 12.1 to 9.2 days. More patients (10.3 vs. 1.3%) were transferred to other acute hospitals during the later period. Indicators for stroke care quality improved: numbers of cerebral imaging rose from 56.5% to 96.4%, of duplex sonography of cervical arteries from 43.5 to 72.8 %, of speech therapy from 0% to 50.8% and of occupational therapy from 0 to 33.4%. One year after admission, 18.9% and 17.2%, respectively, of the patients had died, while 10.2% and 6.1% were living in institutions. Participation in the TEMPiS network substantially improved stroke care quality according to national and international guidelines. These improvements may lead to a better prognosis after a stroke.


Safety, tolerance, and pharmacokinetics of cefepime administered intramuscularly to healthy subjects.
Steady state pharmacokinetics, absolute bioavailability, and dose proportionality of cefepime were evaluated in healthy male subjects after single (250, 500, 1000, or 2000 mg) and multiple (1000 mg every 12 hours for 10 days) intramuscular injections. Safety and tolerance were also monitored. High performance liquid chromatography/UV methodology was used to determine cefepime concentrations in plasma and urine. Key pharmacokinetic parameters were determined using noncompartmental methods. Cefepime was absorbed rapidly; mean peak times were 1.0-1.6 hours. Pharmacokinetics were linear over the 250-mg to 2000-mg dose range, with mean total body clearance ranging from 125 to 141 mL/min. The peak plasma concentration and area under the curve increased in a dose-proportional manner. The apparent elimination half-life (2 hours) did not appear to be influenced by dose or by duration of dosing. No accumulation of cefepime was observed during the multiple-dose study. More than 80% of the administered dose was excreted in the urine as unchanged cefepime, and absolute bioavailability after intramuscular dose was 100%. Cefepime was well tolerated. Most subjects experienced none to mild pain and only minimum discomfort at the site of injection.


Temporal variability and correlation with geometric parameters in vasospastic angina: a quantitative angiographic study.
Long-term changes in vasocontractility were examined in 23 coronary segments from 20 patients with variant angina using computer-based quantitative coronary angiography and ergonovine provocation tests repeated at an interval of 42 +/- 14 months. Measurements of vasospasticity at the sites of fixed stenoses were compared with values predicted by an elementary geometric theory based on the assumption that the cross-sectional area of a vessel wall is constant regardless of its state of vasoconstriction. While all patients were symptomatic initially, only 11 remained symptomatic at follow-up. At the initial provocation test, the response was correctly predicted in four segments, was lower than expected in one, and was stronger in 18. At follow-up, only one of the four segments in which the response had been initially predicted correctly again showed the predicted response and the remaining three showed a response weaker than expected; the one segment which was initially hypocontractile remained hypocontractile at follow-up; and of the 18 segments which were initially hypercontractile, 12 exhibited hypercontractility again, four had the predicted value and the remaining two showed hypocontractility. In only one of 23 segments did the geometric theory predict the behaviour of vasospasticity at the site of fixed stenosis on both tests. Vasospastic responsiveness is a dynamic process demonstrating temporal variability and is not directly predicted by geometric theory.


Effect of tDCS on corticomuscular coupling and the brain functional network of stroke patients.
Transcranial direct current stimulation (tDCS) is an emerging brain intervention technique that has gained growing attention in recent years in the rehabilitation area. In this paper, we investigated the efficacy of tDCS in the rehabilitation process of stroke patients, utilizing corticomuscular coupling (CMC) and brain functional network analysis. Specifically, we examined changes in CMC relationships between the treatment and control groups before and after rehabilitation by transfer entropy (TE), and constructed brain functional networks by TE. We further calculated features of the functional networks, including node degree, global efficiency, clustering coefficient, characteristic path length, and small world index. Our results demonstrate that CMC in patients increased significantly after treatment, with greater improvements in the tDCS group, particularly within the beta and gamma bands. In addition, the functional brain network analysis revealed enhanced connectivity between brain regions, improved information processing capacity, and increased transmission efficiency in patients as their condition improved. Notably, treatment with tDCS resulted in more significant improvements than the sham group, with a statistically significant difference observed after rehabilitation treatment (p < 0.05). These findings provide compelling evidence regarding the role of tDCS in the treatment of stroke and highlight the potential of this approach in stroke rehabilitation. The use of tDCS for therapeutic interventions in stroke rehabilitation can significantly improve the coupling of patients' functional brain networks. Also, using Transfer Entropy (TE) as a characteristic of CMC, tDCS was found to significantly enhance patients' TE, i.e. enhanced CMC.


Gadolinium-DTPA-dextran: a macromolecular MR blood pool contrast agent.
Magnetic resonance (MR) imaging blood pool agents offer numerous advantages for vascular and tumor imaging. The purpose of this study was to test gadolinium-diethylenetriaminepentaacetate-dextran ([Gd]DTPA-dextran) as a new water soluble macromolecular blood pool agent for MR imaging. [Gd]DTPA-dextran (187 gadolinium atoms per dextran, molecular weight 165 kD, diameter 17.6 nm) was synthesized. Fifteen anesthetized New Zealand White rabbits with thigh VX2 tumors were scanned in a knee coil at 1.5T. Coronal 3D MR angiographic sequences were obtained before and at several time points up to 72 hours after the intravenous bolus injection of [Gd]DTPA-dextran providing gadolinium at either 0.05 (n = 4) or 0.1 mmol/kg (n = 8) or [Gd]DTPA-bismethylamide (BMA) providing gadolinium at 0.1 mmol/kg (n = 3). Time enhancement curves for aorta, cava, and tumor rim were compared by univariate General Linear Model. Contrast enhancement of cava and aorta relative to a water phantom were significantly greater at all time points after either dose of [Gd]DTPA-dextran than after [Gd]DTPA-BMA (P < 0.01). Tumor rim enhancement was less intense for either dose of [Gd]DTPA-dextran at peak than for [Gd]DTPA-BMA (P < 0.05). Tumor rim enhancement with both doses of [Gd]DTPA-dextran became equivalent to that of [Gd]DTPA-BMA at one hour and was greater at 24 hours (P < 0.05). [Gd]DTPA-dextran is a new macromolecular MR contrast agent that can be synthesized to carry a high density of gadolinium atoms without intra-molecular cross-linking. It provides significantly greater vascular residence time than a conventional gadolinium chelate and shows promise for MR blood pool imaging.


Endodontic management of an aberrant germinated composite odontome: A case report.
To describe the endodontic treatment of a germinated composite odontome with atypical internal anatomy. A 35-year-old male presented with pain in the left mandibular second molar region. Intraoral examination and Cone-Beam Computed Tomography (CBCT) revealed a rare case of a germinated composite odontome with a 3-2-1 Vertucci configuration in the mesial root. Occlusal morphology and mesial root configuration required modifications in methods of isolation and access cavity preparation. Contemporary tools like magnification, ultrasonics and controlled memory rotary files were essential for executing the treatment plan. The tooth was functional at 18 months follow up and radiographs revealed no abnormality.


The Anti-Inflammatory Effects of a New Herbal Formula (WSY-1075) in a Nonbacterial Prostatitis Rat Model.
The aim of this study was to investigate the anti-inflammatory effects of a new herbal formula (WSY-1075) in a nonbacterial prostatitis rat model. Prostatitis was induced in male Wistar rats (n=32) by treatment with 17 beta-estradiol and dihydrotestosterone for 4 weeks. After the induction of prostatitis, the rats were randomly divided into one of four treatment groups: control (n=8), ciprofloxacin (n=8), WSY-1075 (100 mg/kg) (n=8), and WSY-1075 (400 mg/kg) (n=8). After 4 weeks of treatment, the prostatic proinflammatory cytokine (tumor necrosis factor-α, interleukin [IL]-6, and IL-8) levels and histological findings were noted. The ciprofloxacin and WSY-1075 treatment groups showed significantly decreased proinflammatory cytokine levels compared with the control group. Histologically, treatment with ciprofloxacin and WSY-1075 significantly suppressed the severity of prostatitis lesions compared with those in the control group. No differences in the proinflammatory cytokine levels or histologic findings were observed with the dose dependent treatment of WSY-1075. The new herbal formula, WSY-1075, showed effective anti-inflammatory activities in the prostate and may be useful for the clinical treatment of nonbacterial prostatitis. Our findings suggest that WSY-1075 has a beneficial effect on the prevention and treatment of nonbacterial prostatitis.


Neuroprotective activity of a virus-safe nanofiltered human platelet lysate depleted of extracellular vesicles in Parkinson's disease and traumatic brain injury models.
Brain administration of human platelet lysates (HPL) is a potential emerging biotherapy of neurodegenerative and traumatic diseases of the central nervous system. HPLs being prepared from pooled platelet concentrates, thereby increasing viral risks, manufacturing processes should incorporate robust virus-reduction treatments. We evaluated a 19 ± 2-nm virus removal nanofiltration process using hydrophilic regenerated cellulose hollow fibers on the properties of a neuroprotective heat-treated HPL (HPPL). Spiking experiments demonstrated >5.30 log removal of 20-22-nm non-enveloped minute virus of mice-mock particles using an immuno-quantitative polymerase chain reaction assay. The nanofiltered HPPL (NHPPL) contained a range of neurotrophic factors like HPPL. There was >2 log removal of extracellular vesicles (EVs), associated with decreased expression of pro-thrombogenic phosphatidylserine and procoagulant activity. LC-MS/MS proteomics showed that ca. 80% of HPPL proteins, including neurotrophins, cytokines, and antioxidants, were still found in NHPPL, whereas proteins associated with some infections and cancer-associated pathways, pro-coagulation and EVs, were removed. NHPPL maintained intact neuroprotective activity in Lund human mesencephalic dopaminergic neuron model of Parkinson's disease (PD), stimulated the differentiation of SH-SY5Y neuronal cells and showed preserved anti-inflammatory function upon intranasal administration in a mouse model of traumatic brain injury (TBI). Therefore, nanofiltration of HPL is feasible, lowers the viral, prothrombotic and procoagulant risks, and preserves the neuroprotective and anti-inflammatory properties in neuronal pre-clinical models of PD and TBI.


Growth suppression of bacteria by biofilm deterioration using silver nanoparticles with magnetic doping.
Decades of antibiotic use and misuse have generated selective pressure toward the rise of antibiotic-resistant bacteria, which now contaminate our environment and pose a major threat to humanity. According to the evolutionary "Red queen theory", developing new antimicrobial technologies is both urgent and mandatory. While new antibiotics and antibacterial technologies have been developed, most fail to penetrate the biofilm that protects bacteria against external antimicrobial attacks. Hence, new antimicrobial formulations should combine toxicity for bacteria, biofilm permeation ability, biofilm deterioration capability, and tolerability by the organism without renouncing compatibility with a sustainable, low-cost, and scalable production route as well as an acceptable ecological impact after the ineluctable release of the antibacterial compound in the environment. Here, we report on the use of silver nanoparticles (NPs) doped with magnetic elements (Co and Fe) that allow standard silver antibacterial agents to perforate bacterial biofilms through magnetophoretic migration upon the application of an external magnetic field. The method has been proved to be effective in opening micrometric channels and reducing the thicknesses of models of biofilms containing bacteria such as Enterococcus faecalis, Enterobacter cloacae, and Bacillus subtilis. Besides, the NPs increase the membrane lipid peroxidation biomarkers through the formation of reactive oxygen species in E. faecalis, E. cloacae, B. subtilis, and Pseudomonas putida colonies. The NPs are produced using a one-step, scalable, and environmentally low-cost procedure based on laser ablation in a liquid, allowing easy transfer to real-world applications. The antibacterial effectiveness of these magnetic silver NPs may be further optimized by engineering the external magnetic fields and surface conjugation with specific functionalities for biofilm disruption or bactericidal effectiveness.


The Subthalamic Nucleus: Unravelling New Roles and Mechanisms in the Control of Action.
How do we decide what we do? This is the essence of action control, the process of selecting the most appropriate response among multiple possible choices. Suboptimal action control can involve a failure to initiate or adapt actions, or conversely it can involve making actions impulsively. There has been an increasing focus on the specific role of the subthalamic nucleus (STN) in action control. This has been fueled by the clinical relevance of this basal ganglia nucleus as a target for deep brain stimulation (DBS), primarily in Parkinson's disease but also in obsessive-compulsive disorder. The context of DBS has opened windows to study STN function in ways that link neuroscientific and clinical fields closely together, contributing to an exceptionally high level of two-way translation. In this review, we first outline the role of the STN in both motor and nonmotor action control, and then discuss how these functions might be implemented by neuronal activity in the STN. Gaining a better understanding of these topics will not only provide important insights into the neurophysiology of action control but also the pathophysiological mechanisms relevant for several brain disorders and their therapies.


Tradeoffs between immune function and childhood growth among Amazonian forager-horticulturalists.
Immune function is an energetically costly physiological activity that potentially diverts calories away from less immediately essential life tasks. Among developing organisms, the allocation of energy toward immune function may lead to tradeoffs with physical growth, particularly in high-pathogen, low-resource environments. The present study tests this hypothesis across diverse timeframes, branches of immunity, and conditions of energy availability among humans. Using a prospective mixed-longitudinal design, we collected anthropometric and blood immune biomarker data from 261 Amazonian forager-horticulturalist Shuar children (age 4-11 y old). This strategy provided baseline measures of participant stature, s.c. body fat, and humoral and cell-mediated immune activity as well as subsample longitudinal measures of linear growth (1 wk, 3 mo, 20 mo) and acute inflammation. Multilevel analyses demonstrate consistent negative effects of immune function on growth, with children experiencing up to 49% growth reduction during periods of mildly elevated immune activity. The direct energetic nature of these relationships is indicated by (i) the manifestation of biomarker-specific negative immune effects only when examining growth over timeframes capturing active competition for energetic resources, (ii) the exaggerated impact of particularly costly inflammation on growth, and (iii) the ability of children with greater levels of body fat (i.e., energy reserves) to completely avoid the growth-inhibiting effects of acute inflammation. These findings provide evidence for immunologically and temporally diverse body fat-dependent tradeoffs between immune function and growth during childhood. We discuss the implications of this work for understanding human developmental energetics and the biological mechanisms regulating variation in human ontogeny, life history, and health.


Genome-Wide Identification of Key Components of RNA Silencing in Two Phaseolus vulgaris Genotypes of Contrasting Origin and Their Expression Analyses in Response to Fungal Infection.
RNA silencing serves key roles in a multitude of cellular processes, including development, stress responses, metabolism, and maintenance of genome integrity. Dicer, Argonaute (AGO), double-stranded RNA binding (DRB) proteins, RNA-dependent RNA polymerase (RDR), and DNA-dependent RNA polymerases known as Pol IV and Pol V form core components to trigger RNA silencing. Common bean (Phaseolus vulgaris) is an important staple crop worldwide. In this study, we aimed to unravel the components of the RNA-guided silencing pathway in this non-model plant, taking advantage of the availability of two genome assemblies of Andean and Meso-American origin. We identified six PvDCLs, thirteen PvAGOs, 10 PvDRBs, 5 PvRDRs, in both genotypes, suggesting no recent gene amplification or deletion after the gene pool separation. In addition, we identified one PvNRPD1 and one PvNRPE1 encoding the largest subunits of Pol IV and Pol V, respectively. These genes were categorized into subgroups based on phylogenetic analyses. Comprehensive analyses of gene structure, genomic localization, and similarity among these genes were performed. Their expression patterns were investigated by means of expression models in different organs using online data and quantitative RT-PCR after pathogen infection. Several of the candidate genes were up-regulated after infection with the fungus Colletotrichum lindemuthianum.


Ligand modification of UiO-66 with an unusual visible light photocatalytic behavior for RhB degradation.
A series of isostructural UiO-66-X (X = H, NH2, Br, (OH)2, (SH)2) catalysts have been successfully synthesized by modifying different functional groups on the ligand. The effects of the ligand modification of UiO-66 were investigated for their photocatalytic activity of Rhodamine B degradation under visible light. Surprisingly, UiO-66-NH2 and UiO-66-(OH)2 which have narrow bandgaps and excellent visible light absorption do not show outstanding photocatalytic performances compared to UiO-66 and UiO-66-Br. Electrochemical test results indicated that the conduction band potential of UiO-66-X and the separation efficiency of electrons were quite important in these photocatalytic reactions, other than the electronic effect as reported. Similar photocatalytic degradation behaviors were found for Congo red and methyl orange. Herein, we firstly reported different mechanisms of selective degradation in the case of UiO-66, which subverted the previous understanding of photodegradation behavior.


Stereospecific interactions between chiral inorganic nanomaterials and biological systems.
Chirality is ubiquitous in nature and plays mysterious and essential roles in maintaining key biological and physiological processes. As biological systems display high selectivity for chiral biomolecules, chiral bio-nanoscience has become a popular research field during the last decade. Homochirality, as an essential attribute of natural compounds (l-amino acids, d-sugars, etc.), inspired the emergence of synthetic chiral nanomaterials, which in turn impacted their biological functions and fates. This review is a comprehensive overview of the interactions between chiral inorganic nanostructures and biosystems. We start with the recent progress in biocompatible chiral nanomaterials and focus on stereospecific biological interactions ranging from enantioselective reactions in applications such as sensing and catalysis to chirality-dependent controllable manipulation of cell behaviours and finally to enantiopure nanoplatforms for improved disease therapy. We also discuss the current challenges and future potential of these chiral nanotechnologies in biomedicine and bioengineering, provide strategies to overcome these barriers and offer a future perspective.


Readability of Prostate Cancer Information Online: A Cross-Sectional Study.
Reading and understanding health information, both components of health literacy, can influence patient decisions related to disease management. Older adults, the population of males at greatest risk for prostate cancer, may have compromised capacity to understand and use health information. The purpose of this study was to determine the readability of prostate cancer materials on the Internet using five recommended readability tests. Using a cleared Internet browser, a search was conducted for "prostate cancer." The URLs of the first 100 websites in English were recorded to create the sample. The readability scores for each website were determined using an online, recommended service. This service generates five commonly recommended readability tests. All five tests revealed that the majority of websites had difficult readability. There were no significant differences identified between websites with .org, .gov, or .edu extension versus those with .com, .net, or other extension. It is apparent that the Internet is used often as a resource for health-related information. This study demonstrates that the large majority of information available on the Internet about prostate cancer will not be readable for many individuals.


Four-years' experience with dynamic implants with internal port for minimally invasive sinus elevation.
The purpose of this article is to describe long-term results of the dynamic implant valve approach (DIVA) for the dental implant procedures when the implant system with internal ports was used. During 2012 to 2015, 378 titanium-aluminum-vanadium implants (Ti6Al4V ELI; diameter 3.75 mm; length 11.5 and 13 mm) were implanted in 172 patients (one to nine implants per patient) using the DIVA technique. The DIVA implants were used in cases when sinus membrane and/or nasal floor elevation procedures were needed. The condition of the implants was assessed during the follow-up period up to 60 months. Out of 378 inserted implants, 257 implants were inserted in the maxilla with the bone level < 5 mm, and 121 implants were inserted in the maxilla with the bone level > 5 mm. In 357 cases (94.5%), the implantation was totally successful both from objective CBCT clinical and subjective patients' viewpoints. The comparison of complication rates between the cases with the bone level < 5 mm and the cases with the bone level > 5 mm indicated no significant difference (P = .32). Preliminary results that the DIVA simplifies the dental implantation procedure and augmentation treatment were confirmed. The implant with an inner sealing screw can be used in cases with elevation of the maxillary sinus membrane, and simplifies the surgery and secures optimal dental implant placement. This new type of implant simplifies the maintenance phase of implant dentistry and helps to overcome possible complications.


[Repression of catabolites in gram-positive and gram-negative bacteria].
Analyzes the mechanism of catabolite repression of grampositive and gramnegative bacteria. The role of cyclic adenosine monophosphate and CRP protein, forming a complex, is shown. Contribution of ATP kinase to manifestation of the catabolic repression phenomenon in grampositive bacteria is discussed.


Masking a Metal Cast Post and Core Using High Opacity e.max Ceramic Coping: A Case Report.
Advancements in dental biomaterials have led to the introduction and application of ceramic-based restorations in dental practice. Currently, ceramic restorations are used in crowns and fixed partial dentures. The optical properties of ceramic restorations are comparable to natural teeth in terms of light scattering and transmission. However, the translucency of ceramic restorations could be a limitation if cemented over metal posts or severely discolored dentin. Therefore, accomplishing the maximum esthetic outcome mandates adequate management of severely discolored foundation. The patient wanted to improve the esthetic of his anterior teeth. This case report describes a clinical case in which the patient had defective restoration in his upper anterior teeth and base-metal cast post and core in his left lateral incisor (tooth #22). Metal-free full crowns were used in the anterior zone of the maxilla with the help of e.max HO (high opacity) coping to mask the dark core buildup of the base-metal post and core on tooth #22. The color of the substrate was masked completely. The esthetic of the anterior teeth was improved and the patient was highly satisfied with the outcome. e.max HO coping offers clinically acceptable masking ability.


Inhibition of Na+,K(+)-ATPase by flavonoids and their inotropic effect. Investigation of the structure-activity relationship.
The relationship between the structures of 39 natural flavonoids (including flavones, flavonols, flavonones, and isoflavones) and their inhibitory and positive inotropic effects have been found. It is shown that flavonoids considerably inhibit the activity of the purified preparation of pig kidney medulla Na+,K(+)-ATPase with Ki = 1.4-22.2 microM and some of the flavonoids studied exert positive inotropic effect on the papillary muscle. Flavones and flavonols, containing hydroxyl groups inside the phenyl radical in ortho- and vicinal positions, exhibit high inhibitory and positive inotropic effects. The inhibitory and positive inotropic effects of flavonoid glycosides and methoxyflavonoids are less pronounced. The presence of dimethylallyl groups in flavonones leads to the increase in the inhibitory and positive activities. Isoflavones produced virtually no effect on the enzyme and the isolated heart muscle. The effect of quercetin on the structure of Na+,K(+)-ATPase was studied by the fluorescence method.


Functional sites of human PCNA which interact with p21 (Cip1/Waf1), DNA polymerase delta and replication factor C.
PCNA, an eukaryotic DNA sliding clamp interacts with replication factors and the cell cycle protein, p21(Cip1/Waf1) and functions as a molecular switch for DNA elongation. To understand how DNA replication is regulated through PCNA, elucidation of the precise mechanisms of these protein interactions is necessary. Loop-region mutants in which human PCNA sequences were substituted with the corresponding Saccharomyces cerevisiae PCNA regions were prepared. Analysis of their functions, along with previously prepared alanine scanning mutants, demonstrated that some loops interact with DNA polymerase delta (pol delta) and replication factor C (RFC). The p21 binding sites of PCNA, mapped by affinity measurement of the mutant forms, found to be located within a distinct structure of the PCNA monomer, overlap with RFC- and pol delta-interaction sites. Competition between p21 and pol delta or RFC for binding to PCNA results in efficient inhibition of its stimulation of pol delta DNA synthesis and RFC ATPase but not of PCNA loading on DNA by RFC. Semi-saturated amounts of p21 selectively block formation of the active pol delta complex but not the RFC-PCNA complex at 3'-ends of DNA primers. This differential effect may explain the specific inhibition of DNA replication by p21.


Correlations between carotid IMT, factor VIII activity level and metabolic disturbances: a cardio-vascular risk factor in the HIV positive persons.
In the HIV infection, the short time-scale between the HIV-induced cardiovascular events and the onset of antiretroviral therapy elicits a thrombophilic co-factor that worsens the induced atherosclerosis. We compared the factor VIII plasma activity, previously implicated in arterial and venous thrombosis, with a surrogate marker of atherosclerosis, the carotid intima-media thickness, and with the usual atherosclerosis risk factors in 154 HIV infected outpatients. The FVIII plasma activity is significantly associated with the carotid intima-media thickness and, strongly, with blood glucose and triglycerides levels. A raised FVIII plasma activity is an important feature of the metabolic syndrome and a putative co-factor of HAART induced cardiovascular events. Thus the prevention of the HAART-induced cardio-vascular events should probably not be exclusively focused on atherosclerosis but likewise on the thrombus formation process.


Blood-brain barrier defects associated with Rbp9 mutation.
Rbp9 is a Drosophila RNA-binding protein that shares a high level of sequence similarity with Drosophila elav and human Hu proteins. Loss of function alleles of elav are embryonic lethal causing abnormal central nervous system (CNS) development, and Hu is implicated in the development of paraneoplastic neurological syndrome associated with small cell lung cancer. To elucidate the role of Rbp9, we generated Rbp9 mutant flies and examined them for symptoms related to paraneoplastic encephalomyelitis. Although Rbp9 proteins begin to appear from the middle of the pupal period in the cortex of the CNS, the Rbp9 mutants showed no apparent defects in development. However, as the mutant adult flies grew older, they showed reduced locomotor activities and lived only one-half of the life expectancy of wild-type flies. To understand the molecular mechanism underlying this symptom, gene expression profiles in Rbp9 mutants were analyzed and potential target genes were further characterized. Reduced expression of cell adhesion molecules was detected, and defects in the blood-brain barrier (BBB) of Rbp9 mutant brains could be seen. Putative Rbp9-binding sites were found in introns of genes that function in cell adhesion. Therefore, Rbp9 may regulate the splicing of cell adhesion molecules, critical for the formation of the BBB.


Solution structure of the C-terminal domain of TFIIH P44 subunit reveals a novel type of C4C4 ring domain involved in protein-protein interactions.
The human general transcription factor TFIIH is involved in both transcription and DNA nucleotide excision repair. Among the 10 subunits of the complex, p44 subunit plays a crucial role in both mechanisms. Its N-terminal domain interacts with the XPD helicase, whereas its C-terminal domain is involved specifically in the promoter escape activity. By mutating an exposed and non-conserved cysteine residue into a serine, we produced a soluble mutant of p44-(321-395) suitable for solution structure determination. The domain adopts a C4C4 RING domain structure with sequential organization of beta-strands that is related to canonical RING domains by a circular permutation of the beta-sheet elements. Analysis of the molecular surface and mutagenesis experiments suggests that the binding of p44-(321-395) to TFIIH p34 subunit is not mediated by electrostatic interactions and, thus, differs from previously reported interaction mechanisms involving RING domains.


Evidence that defence mechanisms are more related to personality than to symptoms.
The Defense Mechanisms Inventory is one of the more popular instruments for examining hypothetical dynamic mechanisms. It is known to correlate with some measures of personality and mood. We proposed that, as measures of personality and measures of defence mechanisms are considered to have a common origin in early experience, they should be more strongly correlated than measures of mood, given equal power in the measures of the dependent variables. In this connection we report the relationship which were found between scores on the subscales of the Inventory and the Hysteroid/Obsessoid Questionnaire and the Hospital Anxiety and Depression Scale. There was only a weak relationship between anxiety or depression on the one hand and the Defense Mechanisms Inventory on the other. The highest correlation noted in this regard was Pearson's r = .18, p = .065 between anxiety and the scale Turning Against Self (TAS). The Hysteroid/Obsessoid Questionnaire showed a positive relationship between high scores (hysteroid, i.e. extraverted) and the scale TAO (Turning Against the Object) and a negative relationship for the TAS scale (r = -.290, p = .003). Thus the Defense Mechanisms Inventory showed a stronger relationship with personality than with mood.


Fermented soybean foods and diabetes.
The number of patients with type 2 diabetes mellitus is increasing, and its prevention and management are important. One of the factors contributing to the increased incidence of type 2 diabetes mellitus is the change in dietary habits, including a Westernized diet. Fermented foods are foods that are transformed by the action of microorganisms to produce beneficial effects in humans and have been consumed for thousands of years. The production and consumption of fermented soy foods, including natto, miso, douchi, cheonggukjang, doenjang, tempeh, and fermented soy milk, are widespread in Asian countries. This review focuses on fermented soybean foods and summarizes their effects on diabetes. Fermentation increases the content of ingredients originally contained in soybeans and adds new ingredients that are not present in the original soybeans. Recent studies have revealed that fermented soybean food modifies the gut microbiota-related metabolites by modifying dysbiosis. Furthermore, it has been reported that fermented soybean foods have antioxidant, anti-inflammatory, and anti-diabetic effects. In recent years, fermented foods, including fermented soybeans, have shown various beneficial effects. Therefore, it is necessary to continue focusing on the benefits and mechanisms of action of fermented foods.


The importance of age in allocating health care resources: does intervention-type matter?
Recent proposals to reform cost-effectiveness analysis (CEA) by weighting health benefits [(Quality-adjusted life-years) QALYs] by recipients' age are based on studies examining age-related preferences in life-saving contexts. We investigated whether the perceived importance of age in resource allocation decisions differs among intervention-types. 160 individuals were recruited from a cafeteria of a university medical centre and asked to choose between hypothetical health care programmes. Scenario A described two programmes treating life-threatening conditions and Scenario B two programmes providing palliative care. Programmes were identical except in average patient age (35 versus 65). Respondents also directly rated the importance of age for allocating resources for six types of interventions. Responses for the life-saving scenario favoured younger age groups while those for the palliative care scenario showed no age preference. The difference between scenarios was statistically significant. When directly rating the importance of age in allocating treatment resources, people placed greatest importance on age in treating infertility and life-saving, and least importance in treating depression. The importance people place on age as a resource allocation criterion depends on the clinical context. As QALYs serve as a common measure of health benefits for all intervention types, age weighting of QALYs is premature.


Music, families and interaction (MUFASA): a protocol article for an RCT study.
General mental health and interpersonal skills of families are crucial to children's development and future. Research suggests a link between participation in music activities and individuals' own sense of mental health, as well as an effect in objective measures of health such as quality of life, social skills, and rehabilitation of various kinds. However, in Denmark there are not many services for families with school-aged children (7-12 years) that focus on prevention and strengthening family interaction hereby minimising the risk of children not thriving and developing optimally in terms of social and emotional skills and competences. The purpose of this study is to investigate the effect of shared music activities on family interaction, parental stress, and child well-being. The study is a controlled effect study where 40 family dyads from Aalborg and Aarhus are randomized into 4 different groups including music therapy activities, community music, family concerts and a control group. Measurements of family interaction (Assessment of Parent Child Interaction, APCI) and mental health (Parental Stress Scale, PSS, and the Strengths and Difficulties Questionnaire, SDQ) will be made at baseline/pre intervention, at post intervention and a follow-up measurement 12 month after baseline (month 1, 3 and 12) 3 times in total. Furthermore, data about the family dyad's regular participation in music events as part of every-day life at the same measure points (month 1, 3 and 12). Since this is a planned prospective study, results are not yet available, but clinical experience from a feasibility study in 2021 were promising and expected challenges and changes are discussed in the article. Findings of this study will be relevant for all fields where music is applied for families, such as education, mental health, social work and for basic research on the study of music and interaction. Music used as a resource for families is crucial in understanding how different modalities can influence the family interaction including emotional communication and attachment. ISRCTN, ISRCTN17290015, Registered 03 March 2022, https://www.isrctn.com/ISRCTN17290015 DATE AND PROTOCOL VERSION: July 2022, version 1. Protocol is planned to be updated after finalized recruitment during second data collection point and again after the third and last data collection point (see Additional file 1: SPIRIT Checklist).


Olfactory learning without the mushroom bodies: Spiking neural network models of the honeybee lateral antennal lobe tract reveal its capacities in odour memory tasks of varied complexities.
The honeybee olfactory system is a well-established model for understanding functional mechanisms of learning and memory. Olfactory stimuli are first processed in the antennal lobe, and then transferred to the mushroom body and lateral horn through dual pathways termed medial and lateral antennal lobe tracts (m-ALT and l-ALT). Recent studies reported that honeybees can perform elemental learning by associating an odour with a reward signal even after lesions in m-ALT or blocking the mushroom bodies. To test the hypothesis that the lateral pathway (l-ALT) is sufficient for elemental learning, we modelled local computation within glomeruli in antennal lobes with axons of projection neurons connecting to a decision neuron (LHN) in the lateral horn. We show that inhibitory spike-timing dependent plasticity (modelling non-associative plasticity by exposure to different stimuli) in the synapses from local neurons to projection neurons decorrelates the projection neurons' outputs. The strength of the decorrelations is regulated by global inhibitory feedback within antennal lobes to the projection neurons. By additionally modelling octopaminergic modification of synaptic plasticity among local neurons in the antennal lobes and projection neurons to LHN connections, the model can discriminate and generalize olfactory stimuli. Although positive patterning can be accounted for by the l-ALT model, negative patterning requires further processing and mushroom body circuits. Thus, our model explains several-but not all-types of associative olfactory learning and generalization by a few neural layers of odour processing in the l-ALT. As an outcome of the combination between non-associative and associative learning, the modelling approach allows us to link changes in structural organization of honeybees' antennal lobes with their behavioural performances over the course of their life.


[Does pre-emptive analgesia really pre-empt?].
The paper discusses the theoretical background and practical rationale for a concept of pre-emptive analgesia. It gives the results of studying the efficacy of lornoxicam that outstrips the infliction of a surgical injury in different anesthesia modes (combined total and intravenous combined multicomponent anesthesia with epidural block). A hundred thirty-seven patients who had undergone laparoscopic cholecystectomies (Group 1) and expanded interventions for colorectal cancer (Group 2) were examined. The examination provided no evidence for the efficiency of pre-emptive analgesia with lornoxicam during perioperative anesthesia in patients undergone moderately and highly traumatic abdominal interventions.


Absorption and tissue distribution of cholesterol in Manduca sexta.
In Manduca sexta larvae, radioactive free cholesterol is absorbed directly from the midgut into mucosal cells where it is stored both in the free form (87% in males and 93% in females) and esterified form (13% in males and 7% in females). Subsequently, cholesterol is transported to fat body via lipophorin in the hemolymph exclusively in the free form. In fat body, the distribution of cholesterol between the free and esterified form varied significantly between genders and developmental stages. Except for the larval stage, males and females were able to store cholesterol in both free and esterified forms in the fat body and in the adult stage cholesterol ester accounted for more than 75% of the stored cholesterol. Placement of radioactive cholesterol at different locations in the gut-foregut, midgut, and hindgut-demonstrated that the midgut is the site where cholesterol is absorbed and released into the hemolymph. Cholesterol-labeled lipophorin injected into larval hemolymph was cleared from the hemolymph with a half-life of 10.2 h. After 17 h, most of the cleared radioactivity was recovered in the fat body (38%). Arch.


Status and perspectives of biomarker validation for diagnosis, stratification, and treatment.
The aim of this study was to discuss the status of and perspective for biomarker validation in view of the challenges imposed on national healthcare systems due to an increasing number of citizens with chronic diseases and new expensive drugs with effects that are sometimes poorly documented. The demand for a paradigm shift toward stratification of patients or even 'personalized medicine' (PM) is rising, and the implementation of such novel strategies has the potential to increase patient outcomes and cost efficiency of treatments. The implementation of PM depends on relevant and reliable biomarkers correlated to disease states, prognosis, or effect of treatment. Beyond biomarkers of disease, personalized prevention strategies (such as individualized nutrition guidance) are likely to depend on novel biomarkers. We discuss the current status of the use of biomarkers and the need for standardization and integration of biomarkers based on multi-omics approaches. We present representative cases from laboratory medicine, oncology, and nutrition, where present and emerging biomarkers have or may present opportunities for PM or prevention. Biomarkers vary greatly in complexity, from single genomic mutations to metagenomic analyses of the composition of the gut microbiota and comprehensive analyses of metabolites, metabolomics. Using biomarkers for decision-making has previously often relied on measurements of single biomolecules. The current development now moves toward the use of multiple biomarkers requiring the use of machine learning or artificial intelligence. Still, the usefulness of biomarkers is often challenged by suboptimal validation, and the discovery of new biomarkers moves much faster than standardization efforts. To reap the potential benefits of personalization of treatment and prevention, healthcare systems and regulatory authorities need to focus on validation and standardization of biomarkers. There is a great public health need for better understanding of the usefulness, but also limitations, of biomarkers among policy makers, clinicians, and scientists, and efforts securing effective validation are key to the future use of novel sets of complex biomarkers.


Lipid screening and treatment by cardiologists have not improved.
Much effort by the national cholesterol education program (NCEP) and others have been made to induce physicians to screen for and treat lipid abnormalities in patients with coronary heart disease. We measured the effect of these efforts in a single group of cardiovascular specialists. We reviewed 20 percent of applicable patient records from 1987, 1989, and 1994 was performed to identify documented screening (cholesterol levels or lipid profiles) and treatment over 12 months after an index admission for coronary heart disease, along with a survey of physician acquaintance with NCEP guidelines, among the eight cardiovascular physicians. In the 160 patients with angina pectoris or myocardial infarction, total cholesterol levels were determined in 77-95 percent and lipid profiles determined in 2-11 percent. Treatment for cholesterol, greater than 150 mg/dl was initiated in 14-32 percent. These rates did not significantly improve over the study period. Yet, all physicians were acquainted with the NCEP and five of the eight perceived their screening and treatment to be more aggressive in 1994 than in 1987. Lipid screening and treatment by cardiovascular specialists have not improved despite copious supportive literature. Barriers other than lack of knowledge may impede implementation of this effective therapy.


Investigation of the relationship between aircraft noise and community annoyance in China.
A survey of community annoyance induced by aircraft noise exposure was carried out around Hangzhou Xiaoshan International Airport. To investigate the relationship curves between aircraft noise and the percentage of "highly annoyed" persons in China and also to get annoyance threshold of aircraft noise in China. Noise annoyance induced by aircraft noise exposure was assessed by 764 local residents around the airport using the International Commission on Biological Effect of Noise (ICBEN) scale. The status quo of aircraft noise pollution was measured by setting up 39 monitoring points. The interpolation was used to estimate the weighted effective continuous perceived noise levels (LWECPN) in different areas around the airport, and the graph of equal noise level contour was drawn. The membership function was used to calculate the annoyance threshold of aircraft noise. Data were analyzed using SPSS 16.0 and Origin 8.0. The results showed that if LWECPN was 64.3 dB (Ldn was 51.4 dB), then 15% respondents were highly annoyed. If LWECPN was 68.1 dB (Ldn was 55.0 dB), then 25% respondents were highly annoyed. The annoyance threshold of aircraft noise (LWECPN) was 73.7 dB, while the annoyance threshold of a single flight incident instantaneous noise level (LAmax) was 72.9 dB. People around the airport had felt annoyed before the aircraft noise LWECPN reached the standard limit.


Linkage analysis and allelic imbalance in human breast cancer kindreds using microsatellite markers from the short arm of chromosome 3.
Eight Icelandic breast cancer kindreds were subjected to linkage analyses with respect to 28 microsatellite loci dispersed along the short arm of chromosome 3. Breast tumors derived from these kindreds were concurrently scored for allelic imbalance with ten of the markers. Linkage to most markers could be excluded on the basis of negative LOD scores and haplotype analyses, although some moderately positive LOD scores resulted. A high frequency of imbalance in the familial tumors was seen with two of the markers in comparison with results obtained from sporadic material. The highest frequency (68%) of imbalance was detected with the marker D3S1217, which is located on 3p14.2-p14.1. Imbalance at the D3S1211 locus, which is more telomeric (3p24.2-p22), was not significantly elevated in the familial tumors. We suggest that the genetic defect responsible for breast cancer susceptibility in these families either promotes instability in the 3p14.2-p14.1 region or enhances the selective advantage of such changes.


Modification by imidazoles of ocular inflammatory and pressure responses.
Imidazole, given intraperitoneally to rabbits, inhibited the prostaglandin E1-induced (PGE1) elevation of intraocular pressure. The maximum imidaz-le effect occurred at three to six hours after intraperitoneal infection. The prostaglandin E1-induced aqueous humor protein elevation was reduced markedly in the imidazole-pretreated rabbits. Intravenous administration of imidazole also was effective in reducing the intraocular pressure elevation produced by prostaglandin E1. Imidazole pretreatment by subconjunctival, subdermal, or topical routes had no such effect. Imidazole derivatives, 1-methylimidazole and 2-methylimidazole, given intraperitoneally, blocked the effect of PGE1 on intraocular pressure and aqueous humor protein. Imidazole pretreatment also inhibited the elevation of intraocular pressure produced by topical nitrogen mustard, 1 per cent.


Subnormothermic ex vivo liver perfusion is a safe alternative to cold static storage for preserving standard criteria grafts.
We developed a novel technique of subnormothermic ex vivo liver perfusion (SNEVLP) for the storage of liver grafts before transplantation. To test the safety of SNEVLP for the nonextended criteria grafts (standard grafts), we compared it to a control group with minimal cold static storage (CS) time. Heart-beating pig liver retrieval was performed. Grafts were either stored in cold unmodified University of Wisconsin solution (CS-1), in cold University of Wisconsin solution with ex vivo perfusion additives (CS-2), or preserved with a sequence of 3 hours CS and 3 hours SNEVLP (33°C), followed by orthotopic liver transplantation. Liver function tests and histology were investigated. Aspartate aminotransferase (AST) levels during SNEVLP remained stable (54.3 ± 12.6 U/L at 1 hour to 47.0 ± 31.9 U/L at 3 hours). Posttransplantation, SNEVLP versus CS-1 livers had decreased AST levels (peak at day 1, 1081.9 ± 788.5 versus 1546.7 ± 509.3 U/L; P = 0.14; at day 2, 316.7 ± 188.1 versus 948.2 ± 740.9 U/L; P = 0.04) and alkaline phosphatase levels (peak at day 1, 150.4 ± 19.3 versus 203.7 ± 33.6 U/L; P = 0.003). Bilirubin levels were constantly within the physiological range in the SNEVLP group, whereas the CS-1 group presented a large standard deviation, including pathologically increased values. Hyaluronic acid as a marker of endothelial cell (EC) function was markedly improved by SNEVLP during the early posttransplant phase (5 hours posttransplant, 1172.75 ± 598.5 versus 5540.5 ± 2755.4 ng/mL). Peak international normalized ratio was similar between SNEVLP and CS-1 groups after transplantation. Immunohistochemistry for cleaved caspase 3 demonstrated more apoptotic sinusoidal cells in the CS-1 group when compared to SNEVLP grafts 2 hours after reperfusion (19.4 ± 19.5 versus 133.2 ± 48.8 cells/high-power field; P = 0.002). Adding normothermic CS-2 had no impact on liver injury or function after transplantation when compared to CS-1. In conclusion, SNEVLP is safe to use for standard donor grafts and is associated with improved EC and bile duct injury even in grafts with minimal CS time.


History through the eyes of a pandemic.
This review provides a historic perspective of the impact that major pandemics have had on human and their relationship with ophthalmology. The novel coronavirus epidemic is also analyzed, highlighting the relevance of the eye as a possible source of transmission, infection, and prognosis for the disease. Smallpox is suspected to be present for more than 12 000 years. However, trachoma seems to be the first recorded ophthalmological infectious disease. The deadliest pandemics include the bubonic plague, smallpox, and Spanish flu. The CoVID-19 epidemic is still developing and measures need to be implemented to prevent further escalation of the crisis. Understanding the current facts in light of earlier historical evidence may help us prepare better to minimize the spread of infections in the future.


Hemofiltration in sepsis and systemic inflammatory response syndrome: the role of dosing and timing.
The benefit of hemofiltration (HF) as an adjunctive treatment of sepsis or the systemic inflammatory response syndrome (SIRS) in critically ill patients is a subject of severe debate. Firm conclusions on this subject are hampered by the heterogeneity in study populations and HF treatments, and the lack of adequately sized randomized controlled clinical trials. The aim of this review was to determine the importance of ultrafiltration dose and timing on the physiologic and clinical effects of HF in sepsis and SIRS. In addition, we discuss the issue of filter pore size. Literature search was done in Embase and PubMed database for animal and human studies. Animal studies suggest beneficial effects of HF on hemodynamics; gas exchange; sepsis-induced immunoparalysis; histology of gut, lung, and kidney; and (short-term) survival. These effects were more prominent with "very high" ultrafiltrate rates (> or =100 mL/kg per hour) and early initiation of HF (ie, before or very early after the septic challenge). Three small randomized studies and 3 observational studies in patients with sepsis or SIRS show beneficial effects of short-term or pulse HF using very high ultrafiltrate rates and/or early initiation of HF on physiologic endpoints and survival. However, the studies were underpowered for survival. The first observations of high permeability HF (pore size, about 10 nm; in vitro cutoff, 100 kd) are promising, but so far, it has not been sufficiently examined to allow strong conclusions. Human and animal studies suggest that early initiation and high ultrafiltrate volumes are determinants of the beneficial physiologic and clinical effect of HF in sepsis and SIRS. As yet, the evidence in humans is too low to recommend HF as an adjunctive therapy for critically ill patients with sepsis or SIRS. Regarding the many uncertainties about optimal volume (high or very high) and type of membrane, clinical studies should first focus on endpoints as recovery from organ failure and length of treatment before survival studies are started.


Interplay and roles of oxidative stress, toll-like receptor 4 and Nrf2 in trichloroethene-mediated autoimmunity.
Previous studies in MRL+/+ mice suggest involvement of oxidative stress (OS) in trichloroethene (TCE)-mediated autoimmunity. However, molecular mechanisms underlying the autoimmunity remain to be fully elucidated. Even though toll-like receptors (TLRs) and Nuclear factor (erythroid-derived 2)-like2 (Nrf2) pathways are implicated in autoimmune diseases (ADs), interplay of OS, TLR and Nrf2 in TCE-mediated autoimmune response remains unexplored. This study was, therefore, undertaken to clearly establish a link among OS, TLR4 and Nrf2 pathways in TCE-induced autoimmunity. Groups of female MRL+/+ mice were treated with TCE, sulforaphane (SFN, an antioxidant) or TCE + SFN (TCE, 10 mmol/kg, i.p., every 4th day; SFN, 8 mg/kg, i.p., every other day) for 6 weeks. TCE exposure led to greater formation of serum 4-hydroxynonenal (HNE)-protein adducts, HNE-specific circulating immune complexes (CICs) and protein carbonyls which were associated with significant increases in serum antinuclear antibodies (ANAs). Moreover, incubation of splenocytes from TCE-treated mice with HNE-modified proteins resulted in enhanced splenocyte proliferation and cytokine release evidenced by increased expression of cyclin D3, Cyclin-dependent kinase 6 (CDK6) and phospho-pRb as well as increased release of IL-6, TNF-α and INF-γ. More importantly, TCE exposure resulted in increased expression of TLR4, MyD88, IRAK4, NF-kB and reduced expression of Nrf2 and HO-1 in the spleen. Remarkably, SFN supplementation not only attenuated TCE-induced OS, upregulation in TLR4 and NF-kB signaling and downregulation of Nrf2, but also ANA levels. These results, in addition to providing further support to a role of OS, also suggest that an interplay among OS, TLR4 and Nrf2 pathways contributes to TCE-mediated autoimmune response. Attenuation of TCE-mediated autoimmunity by SFN provides an avenue for preventive and/or therapeutic strategies for ADs involving OS.


Description of the Males of Androlaelaps misionalis and Androlaelaps ulysespardinasi (Acari: Parasitiformes: Laelapidae) Parasitic of Sigmondontine Rodents From Northeastern Argentina.
Laelapinae mites are common ectoparasites of small mammals, mainly sigmodontine rodents, but males are not frequent in natural populations. In this study, the morphology of the unknown males of Androlaelaps misionalis Lareschi, 2010 and Androlaelaps ulysespardinasi Lareschi, 2011 are described. The males of these species differ from the male of Androlaelaps rotundus (da Fonseca, 1936), a close species, because of the size and shape of their dorsal shield and the length of paranal and sternal st1 and st2 setae. The males of A. misionalis and A. ulysespardinasi differ in their size, in the distance of j6 setae in the dorsal shield, length of hypostomal seta hyp3, number of accessory setae in holoventral shield, length of postanal and sternal st3 setae, number of opisthogastric setae in unarmed integument lateral to level of coxae IV, and shape of tip of movable digit in the chelicera.


Co-localization of the dihydropyridine receptor and the cyclic AMP-binding subunit of an intrinsic protein kinase to the junctional membrane of the transverse tubules of skeletal muscle.
Junctional transverse tubules (TT) isolated from triads of rabbit skeletal muscle by centrifugation in an ion-free sucrose gradient were compared with membrane subfractions, predominantly derived from the free portion of TT, that had been purified from sarcoplasmic reticulum membrane contaminants by three different methods. The markers used were diagnostic membrane markers and the dihydropyridine (DHP) receptor, which is a specific marker of the junctional membrane of TT. Junctional TT have a high membrane density (Bmax. 60 pmol/mg of protein) of high-affinity (Kd 0.25 nM) DHP-binding sites using [3H]PN200-110 as the specific ligand. When analysed by SDS/PAGE under reducing conditions and by Western blot techniques, the TT were found to contain a concanavalin A-binding 150 kDa glycoprotein which probably corresponds to the alpha 2-subunit of the DHP receptor. This conclusion was supported by correlative immunoblot experiments with a specific antibody. Junctional TT are further distinguished from free TT by the presence of a high number (Bmax. 20 pmol/mg of protein) of [3H]cyclic AMP receptor sites, as determined by the Millipore filtration technique of Gill & Walton [(1974) Methods Enzymol. 38, 376-381]. Use of this method means that the number of receptors may have been underestimated. The TT-bound cyclic AMP receptor was identified as a 55 kDa protein by specific photoaffinity labelling with 8-N3-[3H]cyclic AMP, and had similar phosphorylation properties and apparent molecular mass to the RII form of the regulatory subunit of cyclic AMP-dependent protein kinase. Co-localization of the intrinsic cyclic AMP-dependent protein kinase and of the DHP receptor complex to the junctional membrane of TT supports the hypothesis that the 170 kDa alpha 1-subunit of the receptor is a substrate for the kinase.


Role of glucagon in mediating metabolic effects of epinephrine.
In order to separate direct effects of epinephrine on fuel metabolism from those mediated by glucagon, epinephrine (0.1 microng/kg-min) was infused for 120 min in 18- and 65-h fasted, nonanesthetized baboons with and without a concomitant somatostatin infusion. At both stages of fasting, epinephrine stimulated glucagon, secretion, and this was blocked by somatostatin. At 18 h, with epinephrine alone, glucose rose early and remained elevated throughout the infusion. In the glycogen-depleted 65-h fasted animals, there was attenuation of the early glucose rise, with glucose reaching a maximum level at 100-120 min. With somatostatin blockade of glucagon release in the 18-h fasted animals, a pattern of attenuated early glucose rise similar to that of the 65-h fasted animals occurred. Somatostatin also inhibited this early glycogenolytic response when the epinephrine dose was increased fivefold. The behavior of FFA, glycerol, and beta-hydroxybutyrate was unchanged by the addition of somatostatin to epinephrine at either stage of fasting. Thus, glucagon mediates the early glycogenolytic response to epinephrine, but not the delayed hyperglycemia and probably not the lipolysis.


Uveitis induced in primates by interphotoreceptor retinoid-binding protein.
Interphotoreceptor retinoid-binding protein was found to be highly uveitogenic in primates. All six monkeys immunized with bovine interphotoreceptor retinoid-binding protein developed ocular inflammation. The main clinical changes were sheathing of retinal vessels and deep well-circumscribed yellow-white lesions. Histologic changes in the retina included shortening of the outer segments and foci of inflammation, which extended through all retinal layers. Particularly profound were the choroidal changes, such as severe inflammatory infiltration, which often formed focal granulomas with epithelioid and giant cells. Some granulomas had the structure of Dalen-Fuchs nodules. These structures and other histologic changes in the monkeys closely resemble those in uveitic conditions in humans, such as sympathetic ophthalmia or Vogt-Koyanagi-Harada syndrome. These findings show that antigen that localizes specifically in the retina may initiate an immunopathogenic process affecting mainly the choroid.


Evaluating Behavioral Responses of Selected Stink Bugs (Hemiptera: Pentatomidae) to Spinosad.
Southern green stink bug, Nezara viridula (L.) and redbanded stink bug, Piezodorus guildinii (Westwood) are two of the most important seed sucking pests affecting Louisiana soybean production and rice stink bug, Oebalus pugnax (F.) is an important late season pest in Louisiana rice. Exploration of chemicals that exhibit attraction or repellent activities toward major stink bug species would be beneficial in developing push-pull strategies. Spinosad is a commercially available natural insecticide that may have arrestant, attractant, or phagostimulant properties against stink bugs. To test this, a series of laboratory experiments were conducted to investigate the tactile, olfactory, and feeding responses of these stink bugs toward two commercial spinosad products (Entrust and Tracer) and technical grade spinosad. In tactile assays, female and male redbanded stink bug were arrested by Entrust, Tracer, and technical grade spinosad, whereas only rice stink bug and southern green stink bug males were arrested by Entrust. Y-tube assays revealed no attraction to any of the products by either male or female rice stink bug, redbanded stink bug, or southern green stink bug. In paired (treated or untreated soybean seed) feeding preference experiments, southern green stink bug showed no preference for any treatment, whereas redbanded stink bug fed more on Entrust- and Tracer-treated seed. From these results, spinosad appears to have an arrestant and phagostimulant effect on redbanded stink bug in the laboratory.


A role for oligodendrocytes in the stabilization of optic axon numbers.
Differentiated oligodendrocytes express neurite growth inhibitory proteins at a time when these cells are involved in the myelination of recently formed fiber pathways. As the process of myelination follows the completion of neurite outgrowth and is concurrent with the stabilization of fiber numbers in a pathway, we set out to determine whether myelination and fiber tract stability could be causally related. Myelin formation was prevented in the rat retinofugal pathway by x-irradiating the optic nerves during oligodendrocyte proliferation. Electron microscopic and immunohistochemical analysis of irradiated optic nerves at P15 showed that oligodendrocytes and myelin were virtually absent. Optic fiber numbers were determined at 2 weeks of age throughout the length of normal and x-irradiated nerves. In some cases, normal or irradiation-treated pups were intraocularly injected with FGF 5 d prior to the fiber count in order to promote neurite outgrowth. Axon counts showed that the total fiber number in a myelin-free optic nerve was 10-30% higher than that of a myelinated nerve. Further, fiber numbers fluctuated by as much as 20% along the length of a myelin-free nerve but were relatively constant throughout the length of a myelinated nerve. Treatment of myelinated nerves with fibroblast growth factor (FGF) had no effect on either total fiber numbers or fiber number fluctuation. Conversely, fiber numbers in myelin-free/FGF-treated optic nerves were as much as 40% higher than in normals. Furthermore, total fiber numbers along the length of these nerves fluctuated by up to 34%. These results indicate that, in the absence of myelination, optic fibers are able to form sprouts.(ABSTRACT TRUNCATED AT 250 WORDS)


Temporal dispersion of activation of phospholipase C-beta1 and -gamma isoforms by angiotensin II in vascular smooth muscle cells. Role of alphaq/11, alpha12, and beta gamma G protein subunits.
Activation of phospholipase C (PLC) is one of the earliest events in angiotensin II (Ang II) type 1 (AT1) receptor (R)-mediated signal transduction in vascular smooth muscle cells (VSMCs). The coupling mechanisms of AT1 Rs to PLC, however, are controversial, because both tyrosine phosphorylation of PLC-gamma and G protein-dependent PLC-beta activation pathways have been reported. The expression of PLC-beta1, furthermore, has not been consistently demonstrated in VSMCs. Here we identified the PLC subtypes and subunits of heterotrimeric G proteins involved in AT1 R-PLC coupling using cultured rat VSMCs. Western analysis revealed the expression of PLC-beta1, -gamma1, and -delta1 in VSMCs. Ang II-stimulated inositol trisphosphate (IP3) formation measured at 15 s, which corresponds to the peak response, was significantly inhibited by electroporation of antibodies against PLC-beta1, but not by anti-PLC-gamma and -delta antibodies. Electroporation of anti-Galphaq/11 and -Galpha12 antibodies also showed significant inhibition of the Ang II-induced IP3 generation at 15 s, while anti-Galphai and Galpha13 antibodies were ineffective. Furthermore, in VSMCs electroporated with anti-Gbeta antibody and cells stably transfected with the plasmid encoding the Gbetagamma-binding region of the carboxyl terminus of beta-adrenergic receptor kinase1, the peak Ang II-stimulated PLC activity (at 15 s) was significantly inhibited. The tyrosine kinase inhibitor, genistein, had no effect on the peak response to Ang II stimulation, but significantly inhibited IP3 production after 30 s, a time period which temporally correlated with PLC-gamma tyrosine phosphorylation in response to Ang II. Moreover, electropor-ation of anti-PLC-gamma antibody markedly inhibited the IP3 production measured at 30 s, indicating that tyrosine phosphorylation of PLC-gamma contributes mainly to the later phase of PLC activation. Thus, these results suggest that: 1) AT1 receptors sequentially couple to PLC-beta1 via a heterotrimeric G protein and to PLC-gamma via a downstream tyrosine kinase; 2) the initial AT1 receptor-PLC-beta1 coupling is mediated by Galphaq/11beta gamma and Galpha12 beta gamma; 3) Gbeta gamma acts as a signal transducer for activation of PLC in VSMCs. The sequential coupling of AT1 receptors to PLC-beta1 and PLC-gamma, as well as dual coupling of AT1 receptors to distinct Galpha proteins, suggests a novel mechanism for a temporally controlled, highly organized and convergent Ang II-signaling network in VSMCs.


Formation of cytoplasmic heat shock granules in tomato cell cultures and leaves.
Biochemical and electron microscopic analyses of heat-shocked suspension cultures of Peruvian tomato (Lycopersicon peruvianum) revealed that a considerable part of the dominant small heat shock proteins (hsps) with an Mr of approximately 17,000 are structural proteins of newly forming granular aggregates in the cytoplasm (heat shock granules), whose formation strictly depends on heat shock conditions (37 to 40 degrees C) and the presence or simultaneous synthesis of hsps. However, under certain conditions, e.g., in preinduced cultures maintained at 25 degrees C, hsps also accumulate as soluble proteins without concomitant assembly of heat shock granules. Similar heat shock-induced cytoplasmic aggregates were also observed in other cell cultures and heat-shocked tomato leaves and corn coleoptiles.


Transforming colloidal Cs4PbBr6 nanocrystals with poly(maleic anhydride-alt-1-octadecene) into stable CsPbBr3 perovskite emitters through intermediate heterostructures.
The preparation of strongly emissive CsPbBr3 perovskite nanocrystals with robust surface passivation is a challenge in the field of lead halide perovskite nanomaterials. We report an approach to prepare polymer-capped CsPbBr3 perovskite nanocrystals by reacting oleylammonium/oleate-capped Cs4PbBr6 nanocrystals with poly(maleic anhydride-alt-1-octadecene) (PMAO). PMAO contains succinic anhydride units that are reactive towards the oleylamine species present on the Cs4PbBr6 nanocrystals' surface and produces polysuccinamic acid, which, in turn, triggers the Cs4PbBr6 to CsPbBr3 conversion. The transformation occurs through the formation of Cs4PbBr6-CsPbBr3 heterostructures as intermediates, which are captured because of the mild reactivity of PMAO and are investigated by high-resolution electron microscopy. The Cs4PbBr6-CsPbBr3 heterostructures demonstrate a dual emission at cryogenic temperature with an indication of the energy transfer from Cs4PbBr6 to CsPbBr3. The fully-transformed CsPbBr3 NCs have high photoluminescence quantum yield and enhanced colloidal stability, which we attribute to the adhesion of polysuccinamic acid to the NC surface through its multiple functional groups in place of oleate and alkylammonium ligands. The PMAO-induced transformation of Cs4PbBr6 NCs opens up a strategy for the chemical modification of metal halide NCs initially passivated with nucleophilic amines.


Type I glycogen storage disease: nine years of management with cornstarch.
Long-term effects of cornstarch (CS) therapy on biochemical values and physical growth in children with type I glycogen storage disease (GSD I) were compared to those of children receiving continuous nocturnal nasogastric glucose feedings (CNG). Only patients who had received more than 5 years of dietary therapy (either CS or CNG) were evaluated. Six patients (five female, age 13.5 years +/- 1.3, range 11.7-16.5 years) received CS (1.75-2.5 g/kg, four times daily) and seven patients (five female, age 9.6 +/- 2.5 years, range 7.3-14.8 years) received CNG. Blood glucose, lactate, cholesterol and triglyceride levels were not significantly different between the two methods of treatment. All patients maintained linear growth rates normal for their age. The standard deviation score of height after 6.7 +/- 1.6 years (range 5-9 years) of CS treatment was -1.29 +/- 0.59 and after 8.8 +/- 2.4 years (range 7-14 years) of CNG was -1.24 +/- 0.63. These values did not differ significantly from each other or from the target height, an estimate of genetic potential for height as determined from parental heights. With the exceptions of diarrhea, increased flatulence and excess weight gain, there were no adverse effects of CS after 9 years of treatment. Our data suggests that cornstarch is a simple, effective and safe therapy for GSD I.


Policy options for responding to the growing challenge from obesity in the United Kingdom.
The aim of this study was to map and analyse how key stakeholders evaluated options for dealing with the rising incidence of obesity in the UK, as part of a wider cross-national study in nine European countries. Multi-criteria mapping was used to capture the ways in which different policy options were evaluated by a variety of key stakeholders. 'Positive societal benefits' was among the criteria most often selected by participants to assess the options and was generally considered more important than costs. Of the seven pre-defined options that all participants appraised, those related to increasing opportunities for physical activity received the highest rankings, and fiscal measures the lowest. Educational measures fared best among the remaining 13 discretionary options while technological measures performed poorly. No one option, or group of options, was considered sufficient to address the obesity problem. Rather, a general consensus was evident in support of mutually reinforcing measures related to education, information, healthier food and physical activity. Although obesity policies are currently emerging in these different areas in the UK, there is a need for them to be better coordinated, and for improved surveillance to estimate their effectiveness in reversing the trend in obesity.


Characterization of Schistosoma mansoni antigen-reactive T cell clones that form granulomas in vitro.
Granuloma formation and modulation in schistosomiasis are a consequence of discrete subpopulations of T lymphocytes and the mediators they produce. In the present study, T cell clones reactive to soluble egg antigen (SEA) were developed to analyze the roles of T cells in Schistosoma mansoni egg-induced granuloma formation. In an in vitro granuloma assay, 1 X 10(5) T cells specifically augmented the response of 2 X 10(6) normal spleen cells to SEA-coupled but not purified protein derivative-coupled polyacrylamide beads. In vitro granulomatous responses by individual clones were correlated with their capacity to mediate local delayed-type hypersensitivity reactions in footpad swelling assays. Phenotypic analysis of the seven clones characterized in the present study demonstrated that they were L3T4+, Ly-2.2-. An analysis of supernatants of T cells pulsed with concanavalin A or SEA + antigen-presenting cells was also undertaken in an attempt to correlate in vitro granuloma formation with lymphokine production. Stimulated T cells (but not unstimulated T cells) produced interleukin 2, macrophage activating factor, migration inhibitory factor, and eosinophil stimulation promoter in response to both mitogenic and antigenic stimuli. The results suggest that individual clones of T cells are capable of producing a variety of mediators that influence their ability to activate and to recruit cells into granuloma formation. The model may be useful in the analysis of specific antigens and regulatory interactions and their contribution to granuloma formation.


A binuclear iron-thiolate catalyst for electrochemical hydrogen production in aqueous micellar solution.
The substituted iron-thiolate complex [Fe(2)(μ-bdt)(CO)(4){P(OMe)(3)}(2)] (bdt=benzenedithiolate) is an active catalyst for electrochemical hydrogen production in aqueous sodium dodecyl sulfate solution, with a high apparent rate constant of 4×10(6) M(-1) s(-1). The half-peak potential for catalysis of proton reduction is less negative than -0.6 V versus the standard hydrogen electrode at pH 3. Voltammetric data are consistent with the rate of electrode reaction controlled by diffusion. A mechanism that begins with the rapid protonation of the iron-thiolate catalyst is proposed. The Faradaic efficiency in diluted HCl solutions is close to 100%, but the catalytic activity decayed after about twelve turnovers when electrolysis was carried out in the presence of acetic acid.


Regeneration of amputated zebrafish fin rays from de novo osteoblasts.
Determining the cellular source of new skeletal elements is critical for understanding appendage regeneration in amphibians and fish. Recent lineage-tracing studies indicated that zebrafish fin ray bone regenerates through the dedifferentiation and proliferation of spared osteoblasts, with limited if any contribution from other cell types. Here, we examined the requirement for this mechanism by using genetic ablation techniques to destroy virtually all skeletal osteoblasts in adult zebrafish fins. Animals survived this injury and restored the osteoblast population within 2 weeks. Moreover, amputated fins depleted of osteoblasts regenerated new fin ray structures at rates indistinguishable from fins possessing a resident osteoblast population. Inducible genetic fate mapping confirmed that new bone cells do not arise from dedifferentiated osteoblasts under these conditions. Our findings demonstrate diversity in the cellular origins of appendage bone and reveal that de novo osteoblasts can fully support the regeneration of amputated zebrafish fins.


Prescribing of potentially harmful drugs to patients admitted to hospital after head injury.
Fundamental studies in laboratory animals show that certain drugs influence behavioural recovery after brain injury. Although some drugs have the potential to enhance recovery, others may be detrimental. The purpose of the present study was to determine how often these potentially detrimental drugs are used in the management of patients with traumatic brain injury. The medical records of 100 patients with head trauma admitted to a university hospital during one year were reviewed and the frequencies of medication prescriptions during the stay in hospital were recorded. Only 14% of patients with head injury were taking medications at the time of injury. All of the patients were prescribed medications during their stay in hospital. Seventy two per cent of the patients received one or a combination of the drugs (neuroleptics and other central dopamine receptor antagonists, benzodiazepines, and the anticonvulsants phenytoin and phenobarbitone) that animal studies suggest may impair recovery. Until the true impact of these classes of drugs on the recovery process is better understood, care should be exercised in their use.


Factors Associated With In-Hospital Death Among Pneumonia Patients in US Hospitals From 2016~2019.
Pneumonia is one of the leading causes of hospital admission in the United States with a global health burden of about 6.8 million hospitalizations and 1.1 million deaths in patients over 65 years old in 2015. This study aimed to identify possible patient and hospital-related risk factors for in-hospital pneumonia death across US hospitals. The National Inpatient Sample (NIS) was used to identify nationwide pneumonia patients (n=374 766, weighted n=1 873 828) from 2016 to 2019. We examined the characteristics of the study sample and their association with in-hospital death. Multivariate survey logistic regression models were used to identify risk factors. During the study periods, in-hospital death rates continuously decreased (2.45% in 2016 to 2.19% in 2019). Descriptive statistics showed that patient and hospital factors had varied in-hospital death rates. Survey logistic regression results suggested that male, very low income, non-Medicare, government hospitals, rural hospitals, and specific hospital regions were associated with higher in-hospital death rates than their reference groups. Socioeconomic factors, including income and insurance, are associated with pneumonia mortality. Census region, hospital ownership, and rural location are also related to in-hospital mortality. Such findings in underserved, impoverished, and rural areas to identify possible health disparities.


MiR-34a Inhibits Cell Proliferation and Induces Apoptosis in Human Nasopharyngeal Carcinoma by Targeting lncRNA MCM3AP-AS1.
MCM3AP-AS1 has been characterized as an oncogenic lncRNA in several types of cancer, while its role in nasopharyngeal carcinoma (NPC) is unknown. This study aimed to investigate the role of MCM3AP-AS1 in NPC. Paired NPC tissues and non-tumor tissues were collected from 55 NPC patients. Expression of MCM3AP-AS1 and miR-34a in paired tissues was analyzed by RT-qPCR. Interactions between MCM3AP-AS1 and miR-34a were analyzed by overexpression experiments. The roles of MCM3AP-AS1 and miR-34a in regulating NPC cell proliferation and apoptosis were explored by cell proliferation assay and cell apoptosis assay, respectively. Our bioinformatics analysis showed that MCM3AP-AS1 may be targeted by miR-34a, which is a well-studied tumor suppressor miRNA. In this study, we showed that miR-34a was downregulated and MCM3AP-AS1 was upregulated in NPC. An inverse correlation between the expression of MCM3AP-AS1 and miR-34a was found across NPC tissue samples. High expression level of MCM3AP-AS1 and low levels of miR-34a in NPC tissues predicted the poor survival. In NPC cells, overexpression of MCM3AP-AS1 did not affect the expression of miR34a, while overexpression of miR-34a led to downregulated MCM3AP-AS1. Cell proliferation and apoptosis assay showed that overexpression of miR-34a reduced the enhancing effects of overexpressing MCM3AP-AS1 on cell proliferation and the inhibitory effects on cell apoptosis. MiR-34a inhibits cell proliferation and induces apoptosis in human NPC by targeting MCM3AP-AS1.


Heritability of ocular component dimensions in mice phenotyped using depth-enhanced swept source optical coherence tomography.
The range of genetic and genomic resources available makes the mouse a powerful model for the genetic dissection of complex traits. Because accurate, high-throughput phenotypic characterisation is crucial to the success of such endeavours, we recently developed an optical coherence tomography (OCT) system with extended depth range scanning capability for measuring ocular component dimensions in mice. In order to test whether the accuracy and reproducibility of our OCT system was sufficient for gene mapping studies, we carried out an experiment designed to estimate the heritability of mouse ocular component dimensions. High-resolution, two dimensional tomograms were obtained for both eyes of 11 pairs of 8 week-old outbred MF1 mice. Subsequently, images were obtained when their offspring were aged 8 weeks. Biometric data were extracted after image segmentation, reconstruction of the geometric shape of each surface, and calculation of intraocular distances. The repeatability of measurements was evaluated for 12 mice scanned on consecutive days. Heritability estimates were calculated using variance components analysis. Sets of tomograms took ∼2 s to acquire. Biometric data could be obtained for 98% of the 130 eyes scanned. The 95% limits of repeatability ranged from ±6 to ±16 μm for the axial ocular component dimensions. The heritability of the axial ocular components was 0.6-0.8, except for corneal thickness, which had a heritability not significantly different from zero. In conclusion, axial ocular component dimensions are highly heritable in mice, as they are in humans. OCT with extended depth range scanning can be used to rapidly phenotype individual mice with sufficient accuracy and precision to permit gene mapping studies.


Nonhuman Primate Models of Respiratory Disease: Past, Present, and Future.
The respiratory system consists of an integrated network of organs and structures that primarily function for gas exchange. In mammals, oxygen and carbon dioxide are transmitted through a complex respiratory tract, consisting of the nasal passages, pharynx, larynx, and lung. Exposure to ambient air throughout the lifespan imposes vulnerability of the respiratory system to environmental challenges that can contribute toward development of disease. The importance of the respiratory system to human health is supported by statistics from the Centers for Disease Control and Prevention; in 2015, chronic lower respiratory diseases were the third leading cause of death in the United States. In light of the significant mortality associated with respiratory conditions that afflict all ages of the human population, this review will focus on basic and preclinical research conducted in nonhuman primate models of respiratory disease. In comparison with other laboratory animals, the nonhuman primate lung most closely resembles the human lung in structure, physiology, and mucosal immune mechanisms. Studies defining the influence of inhaled microbes, pollutants, or allergens on the nonhuman primate lung have provided insight on disease pathogenesis, with the potential for elucidation of molecular targets leading to new treatment modalities. Vaccine trials in nonhuman primates have been crucial for confirmation of safety and protective efficacy against infectious diseases of the lung in a laboratory animal model that recapitulates pathology observed in humans. In looking to the future, nonhuman primate models of respiratory diseases will continue to be instrumental for translating biomedical research for improvement of human health.


UK National Audit of Early Syphilis Management. Clinics audit: screening for and management of early syphilis.
Data were provided by 131 clinics, and 56% of cases were managed in clinics in the London regions in 2003. Three clinics (2%) do not routinely screen new patients for syphilis, and 28 clinics (21%) do not routinely screen 'rebook' patients who have had a new partner. More than 80% of clinics routinely conduct cardiovascular and neurological examinations, although chest radiography is only performed by 50% of clinics and lumbar puncture by 13%. Only 19 (14%) clinics indicated not routinely using the recommended procaine penicillin G (PPG) regimen or one- or two-dose benzathine penicillin G (BPG) regimens for early syphilis, with 57% providing two doses of BPG 2.4 g, 40% providing PPG 750 mg for 10 days, and 15% providing one dose of BPG 2.4 g. Only seven clinics (5%) indicated that they provided treatment for early syphilis with PPG that is inferior to that recommended in the national guidelines. Only 18 clinics specified using the recommended dose and duration (or in excess of this) of PPG for neurosyphilis for cases with HIV infection. Provision for management of severe penicillin reaction is good, although few patients are desensitized. All clinics report that contact tracing for early syphilis is provided, and is mainly the responsibility of health advisers. Compared with auditing outcomes, audit of management policies overestimated performance in contact tracing and provision of dark ground microscopy.


Strategies for success in creating an effective multihospital health-system pharmacy and therapeutics committee.
Lessons learned from the creation of a multihospital health-system formulary management and pharmacy and therapeutics (P&T) committee are described. A health system can create and implement a multihospital system formulary and P&T committee to provide evidence-based medications for ideal healthcare. The formulary and P&T process should be multidisciplinary and include adequate representation from system hospitals. The aim of a system formulary and P&T committee is standardization; however, the system should allow flexibility for differences. Key points for a successful multihospital system formulary and P&T committee are patience, collaboration, resilience, and communication. When establishing a multihospital health-system formulary and P&T committee, the needs of individual hospitals are crucial. A designated member of the pharmacy department needs to centrally coordinate and manage formulary requests, medication reviews and monographs, meeting agendas and minutes, and a summary of decisions for implementation. It is imperative to create a timeline for formulary reviews to set expectations, as well as a process for formulary appeals. Collaboration across the various hospitals is critical for successful formulary standardization. When implementing a health-system P&T committee or standardizing a formulary system, it is important to be patient and give local sites time to make practice changes. Evidence-based data and rationale must be provided to all sites to support formulary changes. Finally, there must be multidisciplinary collaboration. There are several options for formulary structures and P&T committees in a health system. Potential strengths and barriers should be evaluated before selecting a formulary management process.


High-resolution characterization of Toxoplasma gondii transcriptome with a massive parallel sequencing method.
For the last couple of years, a method that permits the collection of precise positional information of transcriptional start sites (TSSs) together with digital information of the gene-expression levels in a high-throughput manner was established. We applied this novel method, 'tss-seq', to elucidate the transcriptome of tachyzoites of the Toxoplasma gondii, which resulted in the identification of 124,000 TSSs, and they were clustered into 10,000 transcription regions (TRs) with a statistics-based analysis. The TRs and annotated ORFs were paired, resulting in the identification of 30% of the TRs and 40% of the ORFs without their counterparts, which predicted undiscovered genes and stage-specific transcriptions, respectively. The massive data for TSSs make it possible to execute the first systematic analysis of the T. gondii core promoter structure, and the information showed that T. gondii utilized an initiator-like motif for their transcription in the major and novel motif, the downstream thymidine cluster, which was similar to the Y patch observed in plants. This encyclopaedic analysis also suggested that the TATA box, and the other well-known core promoter elements were hardly utilized.


Topological Model for the Search of New Antibacterial Drugs. 158 Theoretical Candidates.
In this paper, molecular topology was used to develop a mathematical model capable of classifying compounds according to their antibacterial activity. Topological indices were used as structural descriptors and their relation to antibacterial activity was determined by applying linear discriminant analysis (LDA) on a group of quinolones, widely used nowadays because of their broad spectrum of activity, well tolerance profile and advantageous pharmacokinetic properties. The topological model of activity obtained included two discriminant functions, selected by a combination of various statistical paremeters such as Fisher-Snedecor F and Wilk's lambda, and allows the reliable prediction of antibacterial activity in any organic compound. After a virtual pharmacological screening on a library of 6375 compounds, the model has selected 263 as active compounds, from which 40% have proven antibacterial activity. The results obtained clearly reveal the high efficiency of molecular topology for the prediction of pharmacological activities. These models are very helpful in the discovery of new applications of natural and synthetic molecules with different chemical or biological properties. Therefore, we finally present 158 strong candidates to be developed as novel antibacterials.