SUMO and Alzheimer's disease.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and is the most common cause of dementia in the elderly. Histopathologically, AD features insoluble aggregates of two proteins in the brain, amyloid-β (Aβ) and the microtubule-associated protein tau, both of which have been linked to the small ubiquitin-like modifier (SUMO). A large body of research has elucidated many of the molecular and cellular pathways that underlie AD, including those involving the abnormal Aβ and tau aggregates. However, a full understanding of the etiology and pathogenesis of the disease has remained elusive. Consequently, there are currently no effective therapeutic options that can modify the disease progression and slow or stop the decline of cognitive functioning. As part of the effort to address this lacking, there needs a better understanding of the signaling pathways that become impaired under AD pathology, including the regulatory mechanisms that normally control those networks. One such mechanism involves SUMOylation, which is a post-translational modification (PTM) that is involved in regulating many aspects of cell biology and has also been found to have several critical neuron-specific roles. Early studies have indicated that the SUMO system is likely altered with AD-type pathology, which may impact Aβ levels and tau aggregation. Although still a relatively unexplored topic, SUMOylation will likely emerge as a significant factor in AD pathogenesis in ways which may be somewhat analogous to other regulatory PTMs such as phosphorylation. Thus, in addition to the upstream effects on tau and Aβ processing, there may also be downstream effects mediated by Aβ aggregates or other AD-related factors on SUMO-regulated signaling pathways. Multiple proteins that have functions relevant to AD pathology have been identified as SUMO substrates, including those involved in synaptic physiology, mitochondrial dynamics, and inflammatory signaling. Ongoing studies will determine how these SUMO-regulated functions in neurons and glial cells may be impacted by Aβ and AD pathology. Here, we present a review of the current literature on the involvement of SUMO in AD, as well as an overview of the SUMOylated proteins and pathways that are potentially dysregulated with AD pathogenesis.


Exercise-induced ST segment elevation 2 weeks after uncomplicated myocardial infarction: contributing factors and prognostic significance.
To define the prevalence and clinical significance of exercise-induced ST segment elevation during predischarge treadmill testing after uncomplicated acute myocardial infarction confirmed by serum MB creatine kinase (CK) activity, 241 consecutive patients were prospectively investigated with quantitative exercise thallium-201 scintigraphy, rest radionuclide ventriculography and coronary angiography at 10 +/- 3 days. All patients received customary care, and in none was thrombolytic therapy or emergency coronary angioplasty employed. Eighty-two patients (34%) had exercise-induced ST segment elevation of greater than or equal to 1 mm above rest baseline. These patients were similar to the 159 patients without this finding with respect to history of prior infarction, the Norris coronary prognostic index, exercise duration, metabolic equivalents (METs) achieved and peak heart rate-blood pressure product. The frequency of inducible myocardial ischemia and extent of angiographic coronary disease was also comparable in the two groups. Findings associated with larger infarct size and transmural extent of infarction were more common in patients with exercise-induced ST segment elevation than in those without, including higher peak CK values (1,235 +/- 1,037 versus 942 +/- 915 mumol/min per liter, p less than 0.026), lower left ventricular ejection fraction (43 +/- 12 versus 51 +/- 10%, p less than 0.001), a higher prevalence of pathologic Q waves in greater than or equal to 2 contiguous infarct-related leads (80 versus 55%, p less than 0.001), more persistent thallium-201 defects (2.2 +/- 1.1 versus 1.4 +/- 1.1, p less than 0.001), abnormally increased lung uptake of thallium (33 versus 18%, p less than 0.01) and a greater number of akinetic or dyskinetic segments (3.2 +/- 2.5 versus 1.4 +/- 1.9, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)


Production of colony-stimulating factor 1 by T cells: possible involvement in their interaction with antigen-presenting cells.
Colony-stimulating factor 1 (CSF-1) is required for the growth and differentiation of mononuclear phagocytes, and is also involved in modulating various activities in mature cells. We report herein that T-cell lines produce 4.6 and 1.5 kb mRNA species of CSF-1, and express the CSF-1 protein on their outer membranes, as determined by immunofluorescence staining with anti-CSF-1 antibodies. The CSF-1 protein is biologically active. Interested by the possible immunoregulatory function of CSF-1, we assessed its effect in an assay of antigen presentation to the T cell lines. We found that anti-CSF-1 antibodies inhibited T-cell stimulation. Moreover, soluble CSF-1 could not overcome this inhibition, but exerted a significant inhibitory activity on the interaction between T cells and antigen-presenting cells leading to T-cell activation and proliferation in vitro. Based on these observations we propose that T-cell CSF-1 may be involved in the interaction of these cells with CSF-1 receptor bearing antigen-presenting cells.


FPPS: Fast Profiling of Protease Specificity.
Profiling of protease specificity is crucial for characterization of these important enzymes that play numerous roles in health and disease. In the past, several proteomic methods have been developed that enable profiling of protease specificities. Although able to identify thousands of protease cleavage events, these degradomics approaches are often time consuming and methodologically challenging, which limits their application to specialized proteomic groups or the laboratories that initially introduced them. The FPPS approach described here (i.e., fast proteomic profiling of protease specificity) is simple and straightforward and produces reliable results comparable to other more elaborate procedures. It employs labeling the novel N-termini generated by the protease under investigation and subsequent peptide fractionation on SAX-C18 Stage Tips. The procedure can be performed in 2 days, does not require peptide enrichment steps, and can thus be implemented in any proteomic laboratory.


Plasma-Soluble Biomarkers for Fibrodysplasia Ossificans Progressiva (FOP) Reflect Acute and Chronic Inflammatory States.
Fibrodysplasia ossificans progressiva (FOP) is a progressive, debilitating genetic disease in which skeletal muscle and connective tissue is episodically replaced by heterotopic bone. Discovery of surrogate biomarkers of disease (genotype)-related and flare-up-associated activity of FOP in a readily accessible matrix, such as plasma, would facilitate an understanding of the complex pathophysiology of FOP, aid patient care, and provide a valuable tool for the development and monitoring of potential therapeutics. In a case-control study, using a carefully collected and curated set of plasma samples from 40 FOP patients with the classic ACVR1R206H mutation and 40 age- and sex-matched controls, we report the identification of disease-related and flare-up-associated biomarkers of FOP using a multiplex analysis of 113 plasma-soluble analytes. Adiponectin (implicated in hypoxia, inflammation, and heterotopic ossification) as well as tenascin-C (an endogenous activator of innate immune signaling through the TLR4 pathway and a substrate for kallikrein-7) were highly correlated with FOP genotype, while kallikrein-7 was highly correlated with acute flare-up status. Plasma-soluble biomarkers for FOP support a flare-up-related acute inflammatory phase of disease activity superimposed on a genotypic background of chronic inflammation. © 2021 American Society for Bone and Mineral Research (ASBMR).


MiR-96 promotes apoptosis of nucleus pulpous cells by targeting FRS2.
This study aimed to investigate the molecular mechanism by which microRNA (miR)-96 regulates the progression of intervertebral disc degeneration (IDD). The expression of miR-96 in normal intervertebral discs and in IDD was detected by performing reverse transcription-quantitative PCR. CCK8 assay was applied to examine the proliferation of nucleus pulpous (NP) cells and flow cytometry was used to evaluate the cell apoptosis and cell cycle profile. In addition, the immunofluorescence analysis was employed to detect cell proliferation. The expressions of proteins were assessed by western blot analysis. TargetScan and miRDB were used to predict the target genes of miR-96. The results indicated that miR-96 expression was upregulated in IDD compared with normal intervertebral discs. Overexpression of miR-96 could significantly inhibit the proliferation of NP cells via inducing apoptosis and G1 arrest. In addition, fibroblast growth factor receptor substrate 2 (FRS2) was identified as the target of miR-96 and overexpression of FRS2 could revere the effect of miR-96 mimics in NP cells. Therefore, these findings demonstrated that miR-96 plays a critical role during the progression of IDD and miR-96 may serve as a target for the treatment of IDD.


Transferred metal gate to 2D semiconductors for sub-1 V operation and near ideal subthreshold slope.
Ultrathin two-dimensional (2D) semiconductors are regarded as a potential channel material for low-power transistors with small subthreshold swing and low leakage current. However, their dangling bond–free surface makes it extremely difficult to deposit gate dielectrics with high-quality interface in metal-oxide-semiconductor (MOS) field-effect transistors (FETs). Here, we demonstrate a low-temperature process to transfer metal gate to 2D MoS2 for high-quality interface. By excluding extrinsic doping to MoS2 and increasing contact distance, the high–barrier height Pt-MoS2 Schottky junction replaces the commonly used MOS capacitor and eliminates the use of gate dielectrics. The MoS2 transferred metal gate (TMG) FETs exhibit sub-1 V operation voltage and a subthreshold slope close to thermal limit (60 mV/dec), owing to intrinsically high junction capacitance and the high-quality interface. The TMG and back gate enable logic functions in a single transistor with small footprint.


Behavioral desensitization to nicotine is enhanced differentially by ethanol in long-sleep and short-sleep mice.
In order to assess the anticonvulsant potency of ethanol, male and female long-sleep (LS) and short-sleep (SS) mice were pretreated with ethanol 7.5 min prior to challenge with an ED80 dose of nicotine (LS: 4.25 mg/kg; SS: 6.25 mg/kg). LS mice were more sensitive to the anticonvulsant effects of ethanol than were SS mice. In order to assess the effect of ethanol on the nicotine-induced behavioral desensitization to nicotine observed previously in these mice, animals were pretreated with saline, nonanticonvulsant doses of ethanol (0.25 g/kg, 0.75 g/kg or 1.5 g/kg), a subseizure-producing dose of nicotine (2.0 mg/kg) or a combination of these two drugs 15 or 30 min prior to nicotine challenge. Ethanol enhanced the nicotine-induced behavioral desensitization in both mouse lines; however, this effect was seen at lower ethanol doses and was more pronounced in LS mice. Ethanol pretreatment did not affect brain nicotine concentrations; therefore, the ethanol effect probably involves changes in brain sensitivity to nicotine.


Staining of cerebellar cortex granular layer interneurons with natural dye of Madder.
The objective of the present study was an investigation of root Rubia Tinctorum (Madder) as a natural dye to identification of granular layer interneurons of the rat cerebellum. Seven to ten micrometre sections were collected from the cerebellum and stained only with Madder for 2, 24 and 48 h. Other sections were stained with Madder then with hematoxyllin, cresyl violet, eosin, light green. Microscopic identification of cells was performed based on cell morphology, reaction and binding of with the dye. All data were expressed as mean ± SD in and significance was set at p ≤0.05. Madder with alum as mordant resulted a deep red staining of interneurons. Unipolar brush cells (UBCs) were observed with a cell body diameter intermediate between granule and Golgi cells in the superficial layer of the granular layer. Golgi cells were identified almost as large as Purkinje cells with irregular rounded or polygonal morphology. Lugaro cells were observed as spindle-shaped cells adjacent to Purkinje layer. Results of the present study showed that mader could stain granular layer interneurons in cerebellum cortex of rat.


Virtual screening, ADMET profiling, molecular docking and dynamics approaches to search for potent selective natural molecules based inhibitors against metallothionein-III to study Alzheimer's disease.
Metallothionein-III (MT-III) displays neuro-inhibitory activity and is involved in the repair of neuronal damage. An altered expression level of MT-III suggests that it could be a mitigating factor in Alzheimer's disease (AD) neuronal dysfunction. Currently there are limited marketed drugs available against MT-III. The inhibitors are mostly pseudo-peptide based with limited ADMET. In our present study, available database InterBioScreen (natural compounds) was screened out for MT-III. Pharmacodynamics and pharmacokinetic studies were performed. Molecular docking and simulations of top hit molecules were performed to study complex stability. Study reveals potent selective molecules that interact and form hydrogen bonds with amino acids Ser-6 and Lys-22 are common to established melatonin inhibitors for MT-III. These include DMHMIO, MCA B and s27533 derivatives. The ADMET profiling was better with comparable interaction energy values. It includes properties like blood brain barrier, hepatotoxicity, druggability, mutagenicity and carcinogenicity. Molecular dynamics studies were performed to validate our findings.


Combined operation for myasthenia gravis and coronary artery disease.
A 57-year-old man with ocular myasthenia gravis was admitted to our hospital because of acute respiratory insufficiency associated with myasthenic crisis. He had a history of unstable angina indicated percutaneous coronary artery angioplasty. He was diagnosed with generalized nonthymomatous myasthenia gravis and a triple vessel coronary artery disease. We conducted a simultaneous surgical intervention, including extended thymectomy and coronary artery bypass grafting, using a standard cardiopulmonary bypass via median sternotomy. The patient had already been immunocompromised at surgery for having diabetes, and postoperative long-term steroid therapy. In this rare and special condition, a meticulous overall therapeutic strategy was needed in order to avoid myasthenic crisis and prepare for the worst case scenario of mediastinitis.


Comparison of different models for the testing of pilocarpine eyedrops using conventional eyedrops and a novel depot formulation (nanoparticles).
An objective in the development of ophthalmic formulations is the use of in vitro or animal models that closely resemble the clinical situation. For this reason, experiments with conventional pilocarpine nitrate eyedrops and a depot formulation of pilocarpine nitrate sorbed to poly (butylcyanoacrylate) nanoparticles were carried out. In vitro, the diffusion of pilocarpine through bovine cornea was measured using Edelhauser cells. In vivo, the rabbit aqueous humor concentration of pilocarpine and miosis were determined after application of the above formulations. In addition, intraocular pressure was measured. Since pilocarpine has little influence on intraocular pressure in healthy rabbits, the pressure had to be increased artificially. Three models were employed that are described in the literature, namely, the betamethasone model, the alpha-chymotrypsin model, and the water-loading model. Pilocarpine could be loaded onto nanoparticles by 15% but was rapidly released from the nanoparticles based on the bovine corneal experiment. Nanoparticles only enhanced the aqueous humor concentration at 30 min; this increase, however, led to a considerably extended period of miosis as well as a reduction in intraocular pressure. The duration of the action and the intensity of the response were different among the three models tested. According to the present results, the betamethasone model seems to represent the best correlation to the clinical situation.


Mammalian oocyte maturation: model systems and their physiological relevance.
Maturation of mammalian oocytes is studied mainly in two dissimilar in vitro models: isolated oocytes maturing spontaneously in culture, and hormone-induced maturation of follicle-enclosed oocytes. In this discussion the following aspects of maturation in vitro in the two aforementioned models were compared: timing of germinal vesicle breakdown (GVB), involvement of cyclic nucleotides, protein synthesis and divalent cations. A third approach to the study of oocyte maturation in vitro, namely oocyte co-culture with follicular constituents was adopted in order to test the role of follicular components in the control of the resumption of meiosis. Such studies demonstrated an inhibitory action of granulosa cells, granulosa cell-conditioned medium and of follicular fluid upon the spontaneous maturation of the co-cultured oocytes. Furthermore, addition of LH to co-cultures of oocytes and granulosa cells induced resumption of meiosis. Although oocytes obtained by spontaneous or by hormone-induced maturation cannot be distinguished morphologically, the developmental potential of oocytes matured spontaneously has been questioned, at least in some species. Furthermore, analysis of the kinetics of spontaneous maturation suggests that oocytes dislodged from their follicles escape physiologic mechanisms ensuring meiotic arrest and skip some of the regulatory steps involved in the normal hormonal triggering of maturation. Oocyte co-culture with granulosa cells offers a close approximation to physiological conditions in that meiotic maturation depends on hormonal stimulation, while the system permits the application of separate treatments to the oocyte-cumulus complex and granulosa cells. As in any in vitro system, critical evaluation is required to discriminate between artifacts inherent in the model and physiological processes.


Standardizing the classification of gastric cancer patients with limited and adequate number of retrieved lymph nodes: an externally validated approach using real-world data.
Currently, there is no formal consensus regarding a standard classification for gastric cancer (GC) patients with < 16 retrieved lymph nodes (rLNs). Here, this study aimed to validate a practical lymph node (LN) staging strategy to homogenize the nodal classification of GC cohorts comprising of both < 16 (Limited set) and ≥ 16 (Adequate set) rLNs. All patients in this study underwent R0 gastrectomy. The overall survival (OS) difference between the Limited and Adequate set from a large Chinese multicenter dataset was analyzed. Using the 8th American Joint Committee on Cancer (AJCC) pathological nodal classification (pN) for GC as base, a modified nodal classification (N') resembling similar analogy as the 8th AJCC pN classification was developed. The performance of the proposed and 8th AJCC GC subgroups was compared and validated using the Surveillance, Epidemiology, and End Results (SEER) dataset comprising of 10,208 multi-ethnic GC cases. Significant difference in OS between the Limited and Adequate set (corresponding N0-N3a) using the 8th AJCC system was observed but the OS of N0limited vs. N1adequate, N1limited vs. N2adequate, N2limited vs. N3aadequate, and N3alimited vs. N3badequate subgroups was almost similar in the Chinese dataset. Therefore, we formulated an N' classification whereby only the nodal subgroups of the Limited set, except for pT1N0M0 cases as they underwent less extensive surgeries (D1 or D1 + gastrectomy), were re-classified to one higher nodal subgroup, while those of the Adequate set remained unchanged (N'0 = N0adequate + pT1N0M0limited, N'1 = N1adequate + N0limited (excluding pT1N0M0limited), N'2 = N2adequate + N1limited, N'3a = N3aadequate + N2limited, and N'3b = N3badequate + N3alimited). This N' classification demonstrated less heterogeneity in OS between the Limited and Adequate subgroups. Further analyses demonstrated superior statistical performance of the pTN'M system over the 8th AJCC edition and was successfully validated using the SEER dataset. The proposed nodal staging strategy was successfully validated in large multi-ethnic GC datasets and represents a practical approach for homogenizing the classification of GC cohorts comprising of patients with < 16 and ≥ 16 rLNs.


Firearm Injury Prevention Advocacy: Lessons Learned and Future Directions.
Injuries and deaths due to firearms in children and young adults is a public health crisis in the United States. Pediatric clinicians are powerful advocates to reduce harm due to firearms. By forming coalitions with legislators on a bipartisan basis, working with government relations teams in the hospitals, and partnering with community allies and stakeholders, pediatric clinicians can work to enact legislation and influence policies at the individual, state, and national levels. This can include advocacy for strengthening Child Access Prevention Laws and firearm safer storage campaigns.


Performance of artificial intelligence for the detection of pathological myopia from colour fundus images: a systematic review and meta-analysis.
Pathological myopia (PM) is a major cause of worldwide blindness and represents a serious threat to eye health globally. Artificial intelligence (AI)-based methods are gaining traction in ophthalmology as highly sensitive and specific tools for screening and diagnosis of many eye diseases. However, there is currently a lack of high-quality evidence for their use in the diagnosis of PM. A systematic review and meta-analysis of studies evaluating the diagnostic performance of AI-based tools in PM was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance. Five electronic databases were searched, results were assessed against the inclusion criteria and a quality assessment was conducted for included studies. Model sensitivity and specificity were pooled using the DerSimonian and Laird (random-effects) model. Subgroup analysis and meta-regression were performed. Of 1021 citations identified, 17 studies were included in the systematic review and 11 studies, evaluating 165,787 eyes, were included in the meta-analysis. The area under the summary receiver operator curve (SROC) was 0.9905. The pooled sensitivity was 95.9% [95.5%-96.2%], and the overall pooled specificity was 96.5% [96.3%-96.6%]. The pooled diagnostic odds ratio (DOR) for detection of PM was 841.26 [418.37-1691.61]. This systematic review and meta-analysis provides robust early evidence that AI-based, particularly deep-learning based, diagnostic tools are a highly specific and sensitive modality for the detection of PM. There is potential for such tools to be incorporated into ophthalmic public health screening programmes, particularly in resource-poor areas with a substantial prevalence of high myopia.


Facial wound management.
This article presents an overview of facial wound management, beginning with a brief review of basic anatomy of the head and face as it relates to wound care. Basic wound management is discussed, and techniques for repairing specific cosmetically high-risk areas of the face, particularly the eyes, lips, and ears, are reviewed. Also described are the proper techniques for the management of an auricular hematoma.


A variable stoichiometry model for pH homeostasis in bacteria.
The composition of the proton-motive force of a hypothetical bacterial cell of wide pH tolerance is analyzed according to a model whereby the electron transport chain and various proton-linked sodium and potassium ion transporting modes are responsible for the development of the membrane potential and the chemical potentials of the three cations. Simultaneous use of two or more modes employing the same metal cation, but at a different stoichiometric ratio with respect to protons, produces nonintegral stoichiometry; the modes could represent either different devices or different states of a single device. Cycling of the cation, driven by proton-motive force, results. The relative conductances of the various modes are postulated to be pH-dependent. The pattern of potentials that results is qualitatively in accord with current knowledge and may reflect the mechanism of pH homeostasis in bacteria. The membrane potential is outwardly directed (positive inside) at extremely acid pH, becoming inwardly directed as the pH increases; the pH gradient across the membrane is large and inwardly directed (alkaline inside) at acid pH, becoming smaller and eventually inverting at alkaline pH values; the transmembrane potassium gradient is outwardly directed (high concentration inside) at all pH values; the transmembrane sodium gradient is inwardly directed at all pH values, following the pH gradient from acid through neutral pH, but then diverging at alkaline pH.


Getting Through the Crisis Together: Do Friendships Contribute to University Students' Resilience During the COVID-19 Pandemic?
Social contacts and social support represent resources that contribute to resilience. However, the COVID-19 pandemic and the associated measures, including contact restrictions, posed challenges for young adults' social networks, in particular for their friendships. Employing a mixed-method approach, we investigated the pandemic's effects on friendships and their role in successfully navigating the crisis. We combined a qualitative approach based on narratives and in-depth interviews and a quantitative approach based on online surveys focusing on university students in Austria. Longitudinal data collections allowed investigating changes and developments as the pandemic progressed. Results indicate profound challenges for participants' friendships and difficulties in both building new and maintaining existing friendships. This also impaired the provision of social support by friends, scattering participants' social resources and diminishing their resilience rather than strengthening it. Altogether, the results of this longitudinal study suggest a lasting negative effect of the pandemic on friendships for students.


Transfer of regulatory T cells into abortion-prone mice promotes the expansion of uterine mast cells and normalizes early pregnancy angiogenesis.
Implantation of the fertilized egg depends on the coordinated interplay of cells and molecules that prepare the uterus for this important event. In particular, regulatory T cells (Tregs) are key regulators as their ablation hinders implantation by rendering the uterus hostile for the embryo. In addition, the adoptive transfer of Tregs can avoid early abortion in mouse models. However, it is still not defined which mechanisms underlie Treg function during this early period. Cells of the innate immune system have been reported to support implantation, in part by promoting angiogenesis. In particular, uterine mast cells (uMCs) emerge as novel players at the fetal-maternal interface. Here, we studied whether the positive action of Tregs is based on the expansion of uMCs and the promotion of angiogenesis. We observed that abortion-prone mice have insufficient numbers of uMCs that could be corrected by the adoptive transfer of Tregs. This in turn positively influenced the remodeling of spiral arteries and placenta development as well as the levels of soluble fms-like tyrosine kinase 1 (sFlt-1). Our data suggest an interplay between Tregs and uMCs that is relevant for the changes required at the feto-maternal interface for the normal development of pregnancy.


Braking impulse and muscle activation during unplanned gait termination in human subjects with parkinsonism.
Persons with parkinsonism (PD) are known to have difficulty with both rapid force production and declination, and may not be able to adjust force levels during bimanual tasks in the upper extremity. We proposed that these deficits might underlie the problems experienced by those with PD when attempting to rapidly terminate locomotor activity. Rapid gait termination requires concomitant increases in braking impulse and decreases in propulsion impulse. We hypothesized that those with PD would be less able to modulate muscle activity and the associated braking impulse during gait termination. Muscular activity of soleus, tibialis anterior and gluteus medius, and braking impulse were compared between a group of subjects with PD and age and gender matched control subjects. Subjects with PD had similar patterns of muscular activation to control subjects although at dramatically reduced levels of amplitude. Consequently, PD subjects were unable to generate sufficient net braking impulse under time-critical conditions.


GABA receptor molecules of insects.
Receptors for 4-aminobutyric acid (GABA) have been identified in both central and peripheral nervous systems of several invertebrate phyla. To date, much of the information derived from physiological and biochemical studies on insect GABA receptors relates to GABA-gated chloride channels that show some similarities with vertebrate GABAA receptors. Like their vertebrate central nervous system (CNS) counterparts, agonist activation of such insect GABA receptors leads to a rapid, picrotoxin-sensitive increase in chloride ion conductance across the cell membrane. In insects, responses to GABA can be modulated by certain benzodiazepines and barbiturates. However, recent studies have detected a number of striking pharmacological differences between GABA-gated chloride channels of insects and vertebrates. Receptor binding, electrophysiological and 36Cl- flux assays have indicated that many insect receptors of this type are insensitive to the vertebrate GABAA antagonists bicuculline and pitrazepin. Benzodiazepine binding sites coupled to insect GABA receptors display a pharmacological profile distinct from that of corresponding sites in vertebrate CNS. Receptor binding studies have also demonstrated differences between convulsant binding sites of insect and vertebrate receptors. Insect GABA receptor molecules are important target sites for several chemically-distinct classes of insecticidally-active molecules. By characterizing these pharmacological properties in detail, it may prove possible to exploit differences between vertebrate and insect GABA receptors in the rational design of novel, more selective pest control agents. The recent application of the powerful techniques of molecular biology has revealed a diversity of vertebrate GABAA receptor subunits and their respective isoforms that can assemble in vivo to form a multiplicity of receptor subtypes. Molecular cloning of insect GABA receptor subunits will not only enhance our understanding of invertebrate neurotransmitter receptor diversity but will also permit the precise identification of the sites of action of pest control agents.


Retinotopic organization in the dorsal lateral geniculate nucleus of the tammar wallaby (Macropus eugenii).
Electrophysiological recordings were made from 187 single cells in the tammar wallaby (Macropus eugenii) dorsal lateral geniculate nucleus (LGNd). The results show that it is topographically organized such that the superior visual field is represented dorsally, the inferior field is represented ventrally, the nasal visual field is represented caudally, and the temporal visual field is represented rostrally. The visual field of one eye ranges from -30 degrees nasal to +179 degrees temporal in azimuth and +73 degrees superior to -49 degrees inferior in elevation. Ganglion cells that had receptive field positions between -9 degrees and +179 degrees projected to the contralateral LGNd while the ganglion cells that projected to the ipsilateral LGNd had visual fields from 0 to +30 degrees. The binocular visual field extends 60 degrees in azimuth. This representation in the LGNd is expanded relative to the monocular representation. There is also an increased representation of the horizon in the temporal field corresponding to the visual streak of retinal ganglion cells. The binocular visual field is located where contralateral and ipsilateral laminae are shown to interdigitate by proline autoradiography. There are nine eye-specific laminae in the LGNd. Four receive afferents from the contralateral eye and five receive afferents from the ipsilateral eye. The lines of isoelevation are perpendicular to the coronal plane of section while the lines of isoazimuth are nearly parallel to the coronal plane. The lines of projection representing one visual direction are inferred to be perpendicular to the tangent of curvature of the laminae as in the LGNd of other mammals. The majority of cells (85%) recorded had on- or off-centre responses. On- and off-centre responses were not apparently segregated in the LGNd but segregation may not have been revealed by the single-unit recording technique.


Comparative immunological recognition of proteins from New Guinea "C" dengue virus type 2 prototype and from a dengue virus type 2 strain isolated in the State of Rio de Janeiro, Brazil.
The protein profiles of the New Guinea "C" dengue virus type 2 (DENV-2)prototype and those of a Brazilian DENV-2 isolated in the State of Rio de Janeiro in 1995 were compared. SDS-PAGE analysis showed that the virus from Rio de Janeiro expresses NS5 (93.0 kDa), NS3 (66.8 kDa) E (62.4 kDa) and NS1 (41.2 kDa) proteins differently from the New Guinea "C" virus. The immunoblot revealed specificity and antigenicity for the NS3 protein from DENV-2 Rio de Janeiro mainly in primary infections, convalescent cases, and in secondary infections in both cases and only antigenicity for E and NS1 proteins for both viruses in primary and secondary infections.


Dorsolateral medullary ischemic infarction causing autonomic dysfunction and headache: a case report.
Stroke can present, among other signs, with headache. Here, we describe the case of a man suffering from severe orbitary pain and autonomic dysfunction secondary to dorsolateral medullary ischemia. The anatomical relationship between lesion and symptomatology could be an indirect sign of hypothalamospinal tract involvement in the genesis of autonomic dysfunction and headache resembling a trigeminal autonomic cephalalgia.


TatAc, the third TatA subunit of Bacillus subtilis, can form active twin-arginine translocases with the TatCd and TatCy subunits.
Two independent twin-arginine translocases (Tat) for protein secretion were previously identified in the Gram-positive bacterium Bacillus subtilis. These consist of the TatAd-TatCd and TatAy-TatCy subunits. The function of a third TatA subunit named TatAc was unknown. Here, we show that TatAc can form active protein translocases with TatCd and TatCy.


Heart rate-dependent atrioventricular nodal conduction and the effects of calcium channel blocking drugs: comparison of verapamil and nifedipine.
We compared the effects of the calcium channel blocking drugs verapamil and nifedipine on atrioventricular (AV) nodal function by His bundle electrocardiography in 24 pigs. AV nodal conduction time was decreased 16% by nifedipine (0.1 mg/kg + 3 micrograms/kg/min; p less than 0.05) and increased 20% by verapamil (0.2 mg/kg + 10 micrograms/kg/min; p less than 0.05). Pretreatment with a beta-adrenoceptor blocking agent (metoprolol, 0.4 mg/kg) prevented the decrease in AV nodal conduction time by nifedipine. Vasodilatation alone (nitroprusside, 20 micrograms/kg/min) produced a 16% decrease in AV nodal conduction time and a 19% decrease in cycle length. Before any of the drugs was given, AV nodal conduction time correlated negatively with the heart rate (rho = -0.65; p less than 0.001; n = 24). beta-Adrenoceptor blockade (metoprolol, 0.4 mg/kg) resulted in a 13% increase in cycle length and an 8% increase in AV nodal conduction time. These results indicate that, even with high concentrations, the effect of nifedipine on the AV node in vivo is primarily a facilitation caused by a baroreceptor reflex. In contrast, verapamil causes a depression of the AV node without such an increase in sympathetic tone.


Asymmetric membrane capsules for osmotic drug delivery. I. Development of a manufacturing process.
This paper describes a novel non-disintegrating polymeric capsule and a manual and a semi-automatic process developed for its manufacture. The capsule wall was made by a phase inversion process in which the membrane structure was precipitated on stainless steel mold pins by dipping the mold pins into a coating solution containing a polymer-solvent-nonsolvent system followed by dipping into a quench solution. The resulting asymmetric membrane wall was composed of a thin dense region supported on a thicker porous region. The asymmetric membrane capsules can be filled with a blend of the active agent and excipients for use in osmotically modulated controlled drug delivery applications.


Inhibition of inflammatory reactions in 2,4-Dinitrochlorobenzene induced Nc/Nga atopic dermatitis mice by non-thermal plasma.
Non-thermal plasma (NTP) has recently been introduced and reported as a novel tool with a range of medicinal and biological roles. Although many studies using NTP have been performed, none has investigated the direct relationship between NTP and immune responses yet. Especially, the effects of NTP on atopic dermatitis (AD) were not been explored. Here, NTP was tested whether it controls immune reactions of AD. NTP treatment was administered to pro-inflammatory cytokine-stimulated keratinocytes and DNCB (2,4-Dinitrochlorobenzene)-induced atopic dermatitis mice, then the immune reactions of cells and skin tissues were monitored. Cells treated with NTP showed decreased expression levels of CCL11, CCL13, and CCL17 along with down-regulation of NF-κB activity. Repeated administration of NTP to AD-induced mice reduced the numbers of mast cells and eosinophils, IgE, CCL17, IFNγ levels, and inhibited NF-κB activity in the skin lesion. Furthermore, combined treatment with NTP and 1% hydrocortisone cream significantly decreased the immune responses of AD than that with either of these two treatments individually. Overall, this study revealed that NTP significantly inhibits several immune reactions of AD by regulating NF-κB activity. Therefore, NTP could be useful to suppress the exaggerated immune reactions in severe skin inflammatory diseases such as AD.


Terbutaline modulation of human allergic skin reactions.
Terbutaline, a preferential beta 2-adrenergic agonist, has been shown to inhibit allergen-induced histamine release in vitro. In contrast, orally administered therapeutic doses of terbutaline do not inhibit antigen-induced wheal and flare reactions. We studied the effects of local terbutaline on antigen-induced whealing response, histamine release, cellular inflammatory response, and ultramicroscopic mast cell changes in antigen-challenged skin sites in ragweed-sensitive subjects. Results showed that ragweed challenge significantly induced increased histamine release in all subjects. In contrast, no such histamine release was observed at sites challenged with antigen in the presence of terbutaline. Thus locally applied terbutaline in nontoxic doses modulates mediator release in certain allergic reactions.


Mechanisms of atrial tachyarrhythmia induction in a canine model of autonomic tone fluctuation.
The purpose of this study was to investigate the effect of cholinergic modulation in the presence of increased adrenergic tone (i. e., autonomic fluctuation) on atrial tachyarrhythmia (AT) induction. High-resolution optical mapping was used to measure action potentials from the left atrium in isolated arterially perfused canine atrial preparations. Optical recordings were made in the presence of isoproterenol during electrical stimulation of a fat pad at the right pulmonary veinatrial junction (Group I, n = 6), during electrical stimulation of a fat pad locating the superior vena cava contacted by the right pulmonary artery (Group II, n = 4), and during acetylcholine (ACh; Group III, n = 4) infusion. In the presence of isoproterenol,each of the three different transitory cholinergic interventions induced spontaneous AT in all preparations. In Group I, AT induced from the right atrium was sustained. However, AT induced from the left atrium was not sustained (RRB) in Group I. In Groups II and III, AT induced from the left atrium as well as the right atrium were also sustained (BAF-AT). The A1A2 coupling interval was shorter when BAF-AT was induced than it was when RRB was induced. Mean cycle length of repetitive focal excitation was shorter during the initiation of BAF-AT compared to RRB. Isochrone maps during the initiation of AT demonstrated a macroreentry with lines of conduction block following a single extrasystole (27 %) and focal repetitive excitation (73 %). These results suggest that transitory cholinergic activation in the presence of increased adrenergic drive in the left atrium causes a single premature extrasystole with a short coupling interval and a focal repetitive excitation with a short cycle length, which favors the generation of AT originating from the left atrium.


Patient-Centered Core Impact Sets: What They are and Why We Need Them.
A quote attributed to Mark Twain states, "What gets us into trouble is not what we don't know. It's what we know for sure that just ain't so." The growing focus on patient centricity has revealed a misalignment between what patients report as important to them about their disease and/or treatment, and the data collected in research and care. Decisions across healthcare are made using an evidence base most stakeholders acknowledge is inadequate. Patients might report that what is important to them are everyday life impacts, concepts that can be very different from the more typical clinical outcomes we often track. In this paper, we encourage expanding current thinking to all "impacts," not only health outcomes, but also the other equally (and sometimes more important) concerns patients report as important to them. We propose that a patient-centered core impact set be developed for each disease or condition of interest, and/or subpopulation of patients. A patient-centered core impact set begins with gathering from patients and caregivers an inventory of all impacts disease and treatments have on a patient's (and carers' and families') life. Then, through a formal prioritization process, a core set of impacts is derived, inclusive of but extending beyond relevant health outcomes. We offer several recommendations on how to move the goal of a patient-centered core impact set forward through collaboration, leadership, and establishment of a patient-centered core impact set development blueprint with supporting tools.


Functional mapping of the activity of the R region in the human T-cell leukemia virus type I long terminal repeat to increase gene expression.
We previously demonstrated the activity of the R fragment in the long terminal repeat of human T-cell leukemia virus type I for elevation of the level of gene expression. In this study, the fragment was deleted with BAL31 nuclease to determine its functional domain. Series of the shortened R fragments were linked to the simian virus 40 promoter unit, which regulated expression of a reporter gene. Examination with the R fragments deleted from the 5' and 3' ends showed that borders of the functional domain were mapped within nucleotide positions 458 to 473 for the 5' end and nucleotide positions 559 to 594 for the 3' end, respectively. Thus we conclude that a 136-base-pair fragment corresponding to the second half of the R region was sufficient to allow elevation of the level of gene expression.


Generation and functional evaluation of novel monoclonal antibodies targeting glycosylated human stem cell factor.
Human stem cell factor (hSCF) is an early-acting growth factor that promotes proliferation, differentiation, migration, and survival in several tissues. It plays a crucial role in hematopoiesis, gametogenesis, melanogenesis, intestinal motility, and in development and recovery of nervous and cardiovascular systems. Potential therapeutic applications comprise anemia treatment, mobilization of hematopoietic stem/progenitor cells to peripheral blood, and increasing gene transduction efficiency for gene therapy. Developing new tools to characterize recombinant hSCF in most native-like form as possible is crucial to understand the complexity of its in vivo functions and for improving its biotechnological applications. The soluble domain of hSCF was expressed in HEK293 cells. Highly purified rhSCF showed great molecular mass variability due to the presence of N- and O-linked carbohydrates, and it presented a 2.5-fold increase on proliferative activity compared to bacteria-derived hSCF. Three hybridoma clones producing monoclonal antibodies (mAbs) with high specificity for the glycoprotein were obtained. 1C4 and 2D3 mAbs were able to detect bacteria-derived and glycosylated rhSCF and demonstrated to be excellent candidates to develop a sandwich ELISA assay for rhSCF quantification, with detection limits of 0.18 and 0.07 ng/ml, respectively. Interestingly, 1A10 mAb only recognized glycosylated rhSCF, suggesting that sugar moieties might be involved in epitope recognition. 1A10 mAb showed the highest binding affinity, and it constituted the best candidate for immunodetection of the entire set rhSCF glycoforms in western blot assays, and for intracellular cytokine staining. Our work shows that combining glycosylated rhSCF expression with hybridoma technology is a powerful strategy to obtain specific suitable immunochemical assays and thus improve glycoprotein-producing bioprocesses. KEY POINTS: • Soluble glycosylated human SCF exerted improved proliferative activity on UT-7 cells. • Three mAbs with high specificity targeting glycosylated human SCF were obtained. • mAbs applications comprise sandwich ELISA, western blot, and immunofluorescence assays.


A novel dominant COL11A1 mutation in a child with Stickler syndrome type II is associated with recurrent fractures.
This case describes a child with blindness, recurrent low-impact fractures, low bone mass, and intermittent joint pain who was found to have a novel missense mutation in COL11A1, consistent with Stickler syndrome type II. The case illustrates the phenotypic variability of the syndrome, which may include increased fragility in childhood. Stickler syndrome type II is an autosomal dominant disorder caused by mutations in the gene that encodes the type XI collagen chain α1 (COL11A1). Manifestations include craniofacial dysmorphology and ocular abnormalities that may lead to blindness, hearing loss, and skeletal anomalies that range from joint pain and arthritis to scoliosis and hypermobility. Herein, we describe a child who carried the presumed diagnosis of osteoporosis-pseudoglioma syndrome because of the combined findings of recurrent low-impact fractures due to low bone mass and blindness. The child also suffered from joint pain but had no facial dysmorphism or hearing loss. Targeted sequencing and deletion analysis of the LRP5, COL1A1, and COL1A2 genes failed to identify any mutations, and whole exome sequence analysis revealed a novel missense mutation (c.3032C>A:p.P1011Q) in COL11A1, consistent with Stickler type II. This case highlights the phenotypic variability of Stickler type II, broadens the list of differential diagnosis of increased bone fragility in childhood, and highlights utility of unbiased genetic testing towards establishing the correct diagnosis in children with frequent fractures.


Muscle-sparing posterolateral thoracotomy.
We have developed a technique for posterolateral thoracotomy that allows adequate exposure for most thoracic operations, yet spares both the latissimus dorsi and serratus anterior muscles. Postoperative pain is decreased, functional recovery is improved, and patients can frequently be discharged earlier from the hospital. Although the time for opening is slightly prolonged, closing time is less and the incision can easily be converted to the standard muscle-splitting approach if more room is required.


Use of Remifentanil in a Novel Clinical Paradigm to Characterize Onset and Duration of Opioid Blockade by Samidorphan, a Potent μ-Receptor Antagonist.
A novel clinical study design was used to evaluate the blockade of a selective short-acting μ-opioid agonist (remifentanil) in 24 opioid-experienced subjects. Samidorphan (3-carboxamido-4-hydroxynaltrexone) is a novel opioid modulator with μ-antagonist properties. Objective (pupil diameter) and subjective (visual analog scale) responses to repeated remifentanil and saline infusion challenges were assessed after single oral administration of placebo (day 1) and samidorphan (day 2). Complete blockade persisted with samidorphan for 24 hours for pupil miosis and 48 hours for the drug liking visual analog scale. Samidorphan effects persisted beyond measurable samidorphan exposure (t½ = 7 hours). Samidorphan was associated with complete blockade of remifentanil, and the duration supports daily administration. This study used a novel approach with multiple administrations of remifentanil to successfully demonstrate a durable effect with samidorphan and a rapid and potent blockade of physiological and subjective μ-opioid effects.


Maleimide-Based Chemical Proteomics for Quantitative Analysis of Cysteine Reactivity.
Cysteine is the most intrinsically nucleophilic residue in proteins and serves as a mediator against increasing reactive oxygen species (ROS) via reversible thiol oxidation. Despite the importance of cysteine oxidation in understanding biological stress response, cysteine sites most reactive toward ROS remain largely unknown and are a major analytical challenge. Herein, a chemical proteomic method to quantify site-specific cysteine reactivity using a maleimide-activated, thiol-reactive probe (N-propargylmaleimide, NPM) is described. Implementation of a gel-based approach via conjugation of rhodamine-azide to NPM-labeled cysteine residues by copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry allowed simple and highly sensitive fluorescence profiling. Relative quantification of >1500 unique cysteine sites from greater than 800 proteins was achieved by conjugating dialkoxydiphenylsilane (DADPS) biotin-azide by the CuAAC reaction and subsequently performing biotin-streptavidin affinity purification and mass-spectrometry-based proteomics. Taken together, this work defines a novel role for the NPM probe in chemical proteomics and presents a robust method for determination of cysteine reactivity during oxidative stress response.


Radioisotopic quantitation in microtitration plates by an autofluorographic method.
An autofluorographic record of drug titrations in microtitration plates has been obtained using cultures labelled with [35s] methionine after treatment with cytostatic drugs. By adding scintillation fluid directly to each culture well of the microtitration plate, and then centrifuging the evaporate the toluene and leave a flat even film of fluor, in situ scintillation is produced. When X-ray film is exposed to the plate the scintillation of individual wells is recorded as spots on the film. These may be interpreted by eye or by scanning densitometry.


Sleepiness and sleep in elderly persons with tinnitus.
The aim of this study was to evaluate the relation of tinnitus to sleep and daytime sleepiness (DS) in a group of elderly men and women. A questionnaire survey was undertaken among 10,216 elderly subjects in northern Sweden. The mean (+/-s.d.) ages of the men and women were 73.0+/-6.0 and 72.6+/-6.7 years, respectively. Tinnitus was reported by 14.9% of the men and 12.0% of the women. The relative number with tinnitus was not related to age in men, but increased with age in women. Poor sleep was reported by 14.4% of the men and 27.9% of the women. Among subjects with tinnitus poor sleep and frequent waking were more common in both sexes, while difficulties in falling asleep after awakening at night were reported more often by women. DS was more common in subjects with tinnitus and the frequency was even more increased in those with both tinnitus and poor sleep. There was no further increase in DS in men and women on sleep medication. Thus, DS in elderly persons with tinnitus may due both to tiring effect of the annoying sound itself but also the negative effect by tinnitus on sleep.


In vitro comparison of polymerisation kinetics and the micro-mechanical properties of low and high viscosity giomers and RBC materials.
The study aims to characterise a low and high viscosity giomer bulk fill resin restorative with established low and high viscosity resin-based composite (RBC) restoratives at simulated clinical relevant specimen depths. The irradiance of a light curing unit (Bluephase 20i) was measured on a laboratory-grade spectrometer at distances up to 10mm from the light tip (in 1mm increments). Polymerization kinetics (real-time decrease of CC double bond and degree of cure, DC) and micro-mechanical properties (Vickers hardness/HV; Depth of cure/DOC; Indentation modulus/E) were assessed at varying specimen depths (0.1-6mm in 100μm steps for E, DOC and HV and 0.1, 2, 4 and 6mm for DC) for a 20s irradiation. One and two-way ANOVA (α=0.05) were performed. The parameter material has a significant (p<0.001) effect on DC (ηP(2)=0.839), HV (ηP(2)=0.683), and E (ηP(2)=0.536), whereas the specimen depth influenced only DC (ηP(2)=0.584) but not HV (p=0.093) or E (p=0.133). The polymerisation kinetic could be described by an exponential sum function, distinguishing between the gel and the glass phase. The hardness drop out was lower than 20%, indicated a depth of cure of 6mm for all materials. The low and high viscosity giomer bulk-fill restoratives fulfil the requirements of bulk-fill placement, since under the analysed irradiation conditions an adequate depth of cure of >4mm was identified. Variation of DC with specimen depth was low, with little variation at specimen depths of <4mm. The micro-mechanical properties of the giomer materials were higher compared with the conventional RBC materials.


Molecular composition and regulation of the Nox family NAD(P)H oxidases.
Reactive oxygen species (ROS) are conventionally regarded as inevitable deleterious by-products in aerobic metabolism with a few exceptions such as their significant role in host defense. The phagocyte NADPH oxidase, dormant in resting cells, becomes activated during phagocytosis to deliberately produce superoxide, a precursor of other microbicidal ROS, thereby playing a crucial role in killing pathogens. The catalytic center of this oxidase is the membrane-integrated protein gp91(phox), tightly complexed with p22(phox), and its activation requires the association with p47(phox), p67(phox), and the small GTPase Rac, which normally reside in the cytoplasm. Since recent discovery of non-phagocytic gp91(phox)-related enzymes of the NAD(P)H oxidase (Nox) family--seven homologues identified in humans--deliberate ROS production has been increasingly recognized as important components of various cellular events. Here, we describe a current view on the molecular composition and post-translational regulation of Nox-family oxidases in animals.


Activities of extract and constituents of Banisteriopsis caapi relevant to parkinsonism.
Dopamine deficiency is characteristic of Parkinson's disease (PD) and treatments aim at elevating levels by administration of its precursor L-dihydroxyphenylalanine (L-DOPA), or inhibiting monoamine oxidases (MAOs), thus preventing its breakdown. Reports of improvements in PD patients treated with Banisteriopsis caapi extracts stimulated investigation of B. caapi stem extract and its two ingredients, harmine and harmaline for these activities. Tests for MAO inhibition using liver homogenate showed that extract and harmaline showed a concentration-dependent inhibition of MAO A (IC(50) 1.24 microg/ml and IC(50) 4.54 nM, respectively) but had little effect on MAO B activity. The extract at 2.5 mg/ml caused a highly significant increase in release of [3H]dopamine from rat striatal slices, as did 200 microM harmine and 6 microM harmaline. In both these experiments, the amount of harmine present could not account for the total activity of the extract. The ability of harmine and harmaline to stimulate dopamine release is a novel finding. These results give some basis to the reputed usefulness of B. caapi stem extract in the treatment of PD.


HspB3, the most deviating of the six known human small heat shock proteins.
From the alignment of 14 EST clones, the cDNA sequence of a novel human small heat shock protein (sHsp), called HspB3, could be deduced. The 3' part of the HspB3 cDNA is 99% identical to that of the previously reported HspL27 cDNA (W.Y. Lam, S.K. Wing Tsui, P.T. Law, S.C. Luk, K.P. Fung, C.Y. Lee, M.M. Waye, Isolation and characterization of a human heart cDNA encoding a new member of the small heat shock protein family-HSPL27, Biochim. Biophys. Acta 1314 (1996) 120-124). We argue that the HspB3 cDNA sequence is a corrected version of the HspL27 cDNA. The HspB3 cDNA is 742 bp long and contains an open reading frame specifying a polypeptide of 150 amino acid residues. Among the six known human sHsps it is evident that HspB3 is the most deviating one, having a unique N-terminal domain and essentially lacking a C-terminal extension. Northern blot analysis shows that in smooth muscle tissue the cDNA hybridizes with mRNA of about 0.9 kb.


Effect of Heliogeophysical and Atmospheric Factors on the Degree of Synchronization of Ultradian Rhythms of Body Temperature in Mice.
In a long-term (8 months) study, we examined the degree of synchronization of ultradian body temperature oscillations of two isolated groups of mice kept under constant dim illumination. In most cases, the periods of increased activity accompanied by rapid elevation of body temperature coincided in these groups of mice, but in some days, no significant synchronization between the examined parameters was observed. Analysis of the effects of environmental factors on the degree of synchronization of ultradian rhythms in mice revealed association of this parameter with the dynamics of atmospheric pressure (AtmP) and to a lesser extent with the vertical component of interplanetary magnetic field Bz. The loss in synchronicity of ultradian rhythms of mouse activity occurred after a rapid drop of AtmP or during pronounced negative Bz. Therefore, these factors can be viewed as desynchronizers of the biological ultradian rhythms.


Echocardiographic evaluation of segmental wall motion early and late after thrombolytic therapy in acute myocardial infarction: the Western Washington Tissue Plasminogen Activator Emergency Room Trial.
In 92 acute myocardial infarction (AMI) patients treated with tissue plasminogen activator 2.3 +/- 1.2 hours after the onset of chest pain, echocardiography was performed at 11 +/- 14 hours (early) and, in 49 patients, again at 13 +/- 7 weeks (late). Infarct location and the left ventricular wall motion score index--the average score (normal = 1, hypokinetic = 2, akinetic = 3, dyskinetic = 4) for 20 segments--were determined by 2 observers unaware of clinical, angiographic or electrocardiographic data. Concordance between noninvasive infarct location by electrocardiography or echocardiography and infarct-related artery at angiography 4 +/- 2 days later (n = 85) was 76 and 81%, respectively. The early wall motion score index was worse for anterior (1.8 +/- 0.4) versus inferior (1.3 +/- 0.2, p less than 0.0001) or posterior-lateral (1.6 +/- 0.2, p = 0.0003) infarcts. Overall, the wall motion score index improved from early to late echocardiography (n = 49, 1.5 +/- 0.3 to 1.3 +/- 0.3, p = 0.0008). However, improvement was confined to those with time to treatment less than or equal to 2 hours (n = 22, 1.4 +/- 0.3 to 1.2 +/- 0.2, p less than 0.0001), and evidence of reperfusion at angiography (n = 38, 1.5 +/- 0.3 to 1.2 +/- 0.3, p less than 0.0001). The decrease in the wall motion score index was related to a decrease in the number of adjacent involved segments (5.5 +/- 3.0 to 3.7 +/- 3.9/patient, p = 0.0006). Thus, echocardiography early after AMI identifies infarct location. Improvement in regional wall motion is seen after early treatment with intravenous tissue plasminogen activator.


Numerical evaluation of the use of vegetation as a shelterbelt for enhancing the wind and thermal comfort in peripheral and lateral-type skygardens in highrise buildings.
Skygardens or skycourts are a unique architectural intervention in the built environment, enhancing the social, economic, and environmental values of the building. It allows occupants to connect and experience outdoor freshness within a semi-enclosed environment. However, skygardens located on a highrise building may generate intense wind gusts, endangering the safety of occupants. Using a validated computational fluid dynamics model, this study investigates the potential of various vegetative barriers or shelterbelts in attenuating the high wind speeds encountered in such spaces and the impact on wind and thermal comfort. Three skygarden configurations were investigated with and without vegetative barriers, simplified and modelled as porous zones, and their effect was studied on the velocity and temperature profile at the occupants' level. The results indicate that while hedges and trees can offer resistance to airflow, trees provide higher temperature reduction. However, a combination of vegetative and geometrical barriers provides the most optimal condition in the skygarden. The study has identified the importance of assessing wind attenuation characteristics of tree plantations on highrise skygarden, and the results can be used in designing intervention strategies. Moreover, vegetation can attenuate pollutants and mitigate poor air quality by surface deposition, and future studies should investigate in that direction. The Appendix is available in the online version of this article at 10.1007/s12273-022-0943-7.


Arbaprostil's [15(R)-15-methyl PGE2] effects on intrauterine pressure in the nonpregnant and pregnant human female--a report of four clinical trials.
Four clinical trials evaluating arbaprostil's effects on the human uterus are reported. The initial two trials measured intrauterine pressures in nonpregnant and pregnant human females following arbaprostil doses of 10, 25, and/or 50 mcg. No statistical differences were found at any dosage level in either study for average uterine resting pressures, average peak pressures, the number of contractions or Montevideo units. Subsequently, two trials determined the abortifacient potential of arbaprostil in pregnant women during the first trimester. The first utilized total daily doses of 400 and 800 mcgs. while the second used total daily doses of 1200 and 1600 mcgs. Vaginal spotting was noted in one woman receiving 400 mcgs, three receiving 1200 mcgs. and in two receiving 1600 mcgs. One episode of moderate bleeding was seen in the latter study. Based on these studies, arbaprostil exhibits little potential for inducing abortifacient activity at these dosages in these patient populations.


The Policies for the Disclosure of Funding and Conflict of Interest in Surgery Journals: A Cross-Sectional Survey.
Industry through its funding of research and through its relationships with study authors can influence the results of research. Most journals have policies for reporting funding and disclosing conflict of interest (COI) to mitigate the influence of industry on research. The objective of this study is to assess the policies of surgery journals for the reporting of funding and the disclosure of COI. We described the prevalence and characteristics of funding and COI policies of journals indexed under "Surgery" in the Journal Citation Reports. We extracted data from publicly available information and through simulation of manuscript submission. Of the 186 eligible journals, 171 (92%) had policies for reporting of funding. None of the policies described procedures to deal with non-reporting or underreporting of funding. Of the 186 journals, 183 (99%) had a policy for disclosure of COI. All journals with a COI policy required disclosure of financial interest, while 96 (52%) required the disclosure of non-financial interests. Only 24 (13%) policies described how non-disclosure of COI affects the editorial process, and none described procedures to verify COI disclosure. Of the policies that required disclosing COI, 94 (51%) also required reporting the source of financial COI. Most journals have policies for reporting of funding and disclosure of financial COI. However, many do not have clear policies for disclosing non-financial COI. Major limitations in the policies include the lack of processes for the verification of disclosed interests and for dealing with underreporting of funding and of COI.


IL-1α Counteract TGF-β Regulated Genes and Pathways in Human Fibroblasts.
Dysregulated wound healing is commonly associated with excessive fibrosis. Connective tissue growth factor (CTGF/CCN2) is characteristically overexpressed in fibrotic diseases and stimulated by transforming growth factor-β (TGF-β) in dermal fibroblasts. We previously showed that interleukin-1 (IL-1α) counteracts TGF-β-stimulated CTGF mRNA and protein expression in these cells. The aim of this study was to explore the effects of IL-1α on further genes and pathways in TGF-β regulated fibroblasts. Transcriptional microarray and multiple comparison analysis showed that the antagonizing effects of IL-1α was much more prominent than the synergistic effects, both with respect to number of genes and extent of changes in gene expression. Moreover, comparing canonical pathways by gene set enrichment analysis and the Ingenuity Pathway Analysis tool revealed that IL-1α counteracted TGF-β in the top six most confident pathways regulated by both cytokines. Interferon and IL-1 signaling, as well as two pathways involved in apoptosis signaling were suppressed by TGF-β and activated by IL-1α. Pathways involving actin remodeling and focal adhesion dynamics were activated by TGF-β and suppressed by IL-1α. Analyzing upstream regulators in part corroborate the comparison of canonical pathways and added cell cycle regulators as another functional group regulated by IL-1α. Finally, gene set enrichment analysis of fibrosis-related genes indicated that IL-1 moderately counteracts the collective effect of TGF-β on these genes. Microarray results were validated by qPCR. Taken together, the results indicate prominent antagonistic effects of IL-1α on TGF-β regulated interferon signaling, as well as on a wide variety of other genes and pathways in fibroblasts. J. Cell. Biochem. 117: 1622-1632, 2016. © 2015 Wiley Periodicals, Inc.


Leukotriene C4 synthase is a novel PPARγ target gene, and leukotriene C4 and D4 activate adipogenesis through cysteinyl LT1 receptors in adipocytes.
Leukotriene (LT) C4 synthase (LTC4S) catalyzes the conversion from LTA4 to LTC4, which is a proinflammatory lipid mediator in asthma and other inflammatory diseases. LTC4 is metabolized to LTD4 and LTE4, all of which are known as cysteinyl (Cys) LTs and exert physiological functions through CysLT receptors. LTC4S is expressed in adipocytes. However, the function of CysLTs and the regulatory mechanism in adipocytes remain unclear. In this study, we investigated the expression of LTC4S and production of CysLTs in murine adipocyte 3T3-L1 cells and their underlying regulatory mechanisms. Expression of LTC4S and production of LTC4 and CysLTs increased during adipogenesis, whereas siRNA-mediated suppression of LTC4S expression repressed adipogenesis by reducing adipogenic gene expression. The CysLT1 receptor, one of the two LTC4 receptors, was expressed in adipocytes. LTC4 and LTD4 increased the intracellular triglyceride levels and adipogenic gene expression, and their enhancement was suppressed by co-treatment with pranlukast, a CysLT1 receptor antagonist. Moreover, the expression profiles of LTC4S gene/protein during adipogenesis resembled those of peroxisome proliferator-activated receptor (PPAR) γ. LTC4S expression was further upregulated by treatment with troglitazone, a PPARγ agonist. Promoter-luciferase and chromatin immunoprecipitation assays showed that PPARγ directly bound to the PPAR response element of the LTC4S gene promoter in adipocytes. These results indicate that the LTC4S gene expression was enhanced by PPARγ, and LTC4 and LTD4 activated adipogenesis through CysLT1 receptors in 3T3-L1 cells. Thus, LTC4S and CysLT1 receptors are novel potential targets for the treatment of obesity.


Oncologists' confidence in knowledge of fertility issues for young women with cancer.
We sought to identify factors associated with greater cancer-related fertility knowledge in a national survey of oncologists. We surveyed 344 oncologists from a sampling pool drawn randomly from the AMA Masterfile. We conducted multiple linear regression to determine the relationship between confidence in knowledge and oncologists' characteristics. Respondents' average age was 48.5, and 75.3% were male. The average confidence in knowledge summary score was 23.8 (SD 6.4, range 8-40). In multivariable regression, confidence was higher among oncologists with more information resources, a sense of responsibility to discuss fertility issues and among gynecologic oncologists vs. other oncology specialties. Physician age, gender, and practice setting were not associated with fertility-related knowledge. Oncologists lack confidence in their knowledge of fertility issues in young women with breast cancer. Increasing professional responsibility to discuss fertility and greater information access could improve the depth and breadth of education regarding fertility issues among oncologists and their young patients.


All-optical microwave bandpass filter with negative coefficients based on a phase modulator and linearly chirped fiber Bragg gratings.
A novel all-optical microwave bandpass filter with negative coefficients is presented. Positive and negative coefficients are obtained through conversion from phase modulation to intensity modulation by passing the phase-modulated optical carriers through chirped fiber Bragg gratings having group-delay responses with positive and negative slopes. A two-tap transversal microwave filter with one negative coefficient is experimentally implemented.


Genistein-induced neuronal differentiation is associated with activation of extracellular signal-regulated kinases and upregulation of p21 and N-cadherin.
Neuronal differentiation in the mammalian CNS is driven by multiple events. When treated with retinoic acid (RA), hNTera-2 (NT-2) cells undergo postmitotic neuronal differentiation. Here, we show that a prolonged exposure of NT-2 cells with non-cytotoxic doses of genistein, a protein tyrosine kinase (PTK) inhibitor, induced differentiation of NT-2 cells. Additionally, genistein enhanced RA-induced neuronal differentiation by increasing the activation of extracellular signal-related kinase 1/2 (ERK1/2) via phosphorylation at Thr183 and Tyr185 in 3-7 days. Meanwhile, genistein also upregulated N-cadherin and p21 (a Cdk inhibitor), but downregulated proliferating cell nuclear antigen protein (PCNA). MEK1/2 inhibitors, such as PD98059 and U0126, reduced RA-induced ERK1/2 activity, but could not block the genistein effects. Our observations indicate that genistein-induced neuronal differentiation is not dependent of the MEK-ERK signaling cascade. Instead, genistein-upregulated ERK activation is likely due to this chemical's direct effect on chromosome and gene transcription, rather than its inhibition on tyrosine kinases. Failure of inhibition of ERK1/2 activation by the MEK1/2 inhibitors PD98059 and U0126 suggests presence of an unknown activator for ERK1/2 in neuronal cells.


Clinical and imaging modality factors impacting radiological interpretation of breast screening in young women with neurofibromatosis type 1.
Young women with Neurofibromatosis type 1 (NF1) have a high risk of developing breast cancer and poorer survival following breast cancer diagnosis. International guidelines recommend commencing breast screening between 30 and 35 years; however, the optimal screening modality is unestablished, and previous reports suggest that breast imaging may be complicated by the presence of intramammary and cutaneous neurofibromas (cNFs). The aim of this study was to explore potential barriers to implementation of breast screening for young women with NF1.Twenty-seven women (30-47 years) with NF1 completed breast screening with breast MRI, mammogram and breast ultrasound. Nineteen probably benign/suspicious lesions were detected across 14 women. Despite the presence of breast cNFs, initial biopsy rate for participants with NF1 (37%), were comparable to a BRCA pathogenic variant (PV) cohort (25%) (P = 0.311). No cancers or intramammary neurofibromas were identified. Most participants (89%) returned for second round screening.The presence of cNF did not affect clinician confidence in 3D mammogram interpretation, although increasing breast density, frequently seen in young women, impeded confidence for 2D and 3D mammogram. Moderate or marked background parenchymal enhancement on MRI was higher in the NF1 cohort (70.4%) than BRCA PV carriers (47.3%), which is an independent risk factor for breast cancer.Breast MRI was the preferred mode of screening over mammogram, as the majority (85%) with NF1 demonstrated breast density (BI-RADS 3C/4D), which hinders mammogram interpretation. For those with high breast density and high cNF breast coverage, 3D rather than 2D mammogram is preferred, if MRI is unavailable.


Comparision of biological and genomic characteristics of five virulent bacteriophages against Enterobacter hormaechei.
Enterobacter hormaechei is a zoonotic bacteria that may cause respiratory diseases in animals and neonatal sepsis in humans. Bacteriophages are increasingly considered as potential biocontrol agents to control pathogens in the food industry. In this study, five E. hormaechei virulent phages, named as Ehp-YZU08, Ehp-YZU10, Ehp-YZU9-1, Ehp-YZU9-2 and Ehp-YZU9-3, were isolated from sewage in China and analyzed for their biological and whole-genome characteristics, and a comparative genomic analysis was performed to study the functional genes and phylogenetic evolution of phages. The results showed that four of the phage strains belong to the Podoviridae family and one belongs to the Myoviridae family. The burst sizes were 70-283 PFU/cell after a latent period of 5-40 min. Phages were able to survive in a pH range of 5-10 and resist temperatures up to 60 °C for 60 min. The sequencing results showed that the full length of the genomes of the five phages ranged from 39,502 to 173,418 bp. Each phage contained multiple genes related to phage replication, and genes related to bacterial virulence or drug resistance were not found. The five phages belonged to three different groups by a construction of a phylogenetic tree, and the significant genetic evolutionary distance from each E. hormaechei phage was observed. The inhibition assay showed that all five phages could completely inhibit the growth of E. hormaechei at 37 °C within 8 h, suggesting that the phages in this study have great potential for the development of biocontrol agents against E. hormaechei in the food industry.


Trends in Procedure Type, Morbidity and In-Hospital Outcomes of Patients with Peripheral Artery Disease: Data from the Brazilian Public Health System.
The prevalence of peripheral artery disease (PAD) is rising worldwide, with considerable impact on health care systems. We aimed to characterize the trends in therapeutic procedures and outcomes of PAD in the Brazilian Public Health System Database (DataSUS) between 2008 and 2012. The number of hospitalizations remained stable from 2008 to 2012, although there was a significant change in the proportions of treatment modalities. In 2008, surgical revascularization (SR) = 8,001 (29%), endovascular revascularization (EVR) = 3,207 (11%), and clinical treatment (CT) = 16,887 (60%); and in 2012, SR = 7,882 (28%), EVR = 5,044 (18%), and CT = 15,225 (54%); P < 0.001, a 57% increase in EVR, and 9.8% decrease in CT. Total costs raised 37% (US $18.2-24.9 million, P < 0.001), with a marked 92% increase in EVR costs (US $5.1-9.8 million), compared with SR (11%) and CT (30%). Mortality decreased for EVR (2.0-1.4%, P = 0.048), increased for CT (5.1-5.8%, P = 0.002) and remained stable for SR. A nonsignificant increase was observed in total mortality (5.7-5.9%, P = NS). Our analysis depicts the high-PAD mortality in Brazil emphasizing the need of preventing and controlling cardiovascular risk factors. The impact of PAD in costs increased, mainly because of costs related to EVR.


Paracetamol 325 mg/tramadol 37.5 mg effect on pain during needle electromyography: a double-blind crossover clinical trial.
Needle insertion during electromyography (EMG) may cause varying levels of pain that could lead to inaccurate assessment and premature termination of the procedure. The aim of this study is to compare paracetamol 325 mg/tramadol 37.5 mg with placebo in relieving pain before EMG. This is a randomized, crossover, placebo-controlled, double-blind clinical trial; forty-four healthy individuals, including 27 males with a mean age of 35.3 years (range 18-59 years), entered this study. The needles were inserted unilaterally 2 h after administration of two analgesic tablets of paracetamol 325 mg/tramadol 37.5 mg or two placebo tablets. The pain was scored through a 100-mm visual analog scale (VAS) immediately and 2 h after the procedure. The side effects were also recorded. Within a week, the procedure was repeated on the other upper limb, changing the treatment and placebo. The immediate and 2-h VAS scores were notably lower after administration of treatment compared to placebo (immediate pain: 17.5 ± 12.8 vs. 32.1 ± 16.0, P < 0.001; and 2-h pain: 1.6 ± 5.6 vs. 5.8 ± 7.9, P = 0. 002). There was a higher prevalence of side effects when treatment was used (48 vs. 9 %, P < 0.001). Although most symptoms were mild, transient and resolved without medical interventions, on one occasion a volunteer experienced brief loss of consciousness and one subject had severe vertigo that required hospitalization and fluid therapy. Paracetamol 325 mg/tramadol 37.5 mg administration prior to EMG could effectively alleviate pain. Further application of this medication in patients with neuromuscular disorders would warrant additional clinical trials, particularly considering the adverse events.


Associations of adipose and muscle tissue parameters at colorectal cancer diagnosis with long-term health-related quality of life.
Increased visceral adiposity (visceral obesity) and muscle wasting (sarcopenia) at colorectal cancer (CRC) diagnosis, quantified by computed tomography (CT) image analysis, have been unfavorably associated with short-term clinical outcomes and survival, but associations with long-term health-related quality of life (HRQoL) have not been investigated. We studied associations of visceral adiposity, muscle fat infiltration, muscle mass, and sarcopenia at CRC diagnosis with HRQoL 2-10 years post-diagnosis. A cross-sectional study was conducted in 104 stage I‒III CRC survivors, diagnosed at Maastricht University Medical Center+, the Netherlands (2002-2010). Diagnostic CT images at the level of the third lumbar vertebra were analyzed to retrospectively determine visceral adipose tissue area (cm2); intermuscular adipose tissue area (cm2) and mean muscle attenuation (Hounsfield units) as measures of muscle fat infiltration; and skeletal muscle index (SMI, cm2/m2) as measure of muscle mass and for determining sarcopenia. Participants showed a large variation in body composition parameters at CRC diagnosis with a mean visceral adipose tissue area of 136.1 cm2 (standard deviation: 93.4) and SMI of 47.8 cm2/m2 (7.2); 47% was classified as being viscerally obese, and 32% as sarcopenic. In multivariable linear regression models, associations of the body composition parameters with long-term global quality of life, physical, role and social functioning, disability, fatigue, and distress were not significant, and observed mean differences were below predefined minimal important differences. Although visceral obesity and sarcopenia are relatively common at CRC diagnosis, we found no significant associations of these parameters with long-term HRQoL in stage I-III CRC survivors.


Crosstalk between Thyroid Carcinoma and Tumor-Correlated Immune Cells in the Tumor Microenvironment.
Thyroid cancer (TC) is the most common malignancy in the endocrine system. Although most TC can achieve a desirable prognosis, some refractory thyroid carcinomas, including radioiodine-refractory differentiated thyroid cancer, as well as anaplastic thyroid carcinoma, face a myriad of difficulties in clinical treatment. These types of tumors contribute to the majority of TC deaths due to limited initial therapy, recurrence, and metastasis of the tumor and tumor resistance to current clinically targeted drugs, which ultimately lead to treatment failure. At present, a growing number of studies have demonstrated crosstalk between TC and tumor-associated immune cells, which affects tumor deterioration and metastasis through distinct signal transduction or receptor activation. Current immunotherapy focuses primarily on cutting off the interaction between tumor cells and immune cells. Since the advent of immunotherapy, scholars have discovered targets for TC immunotherapy, which also provides new strategies for TC treatment. This review methodically and intensively summarizes the current understanding and mechanism of the crosstalk between distinct types of TC and immune cells, as well as potential immunotherapy strategies and clinical research results in the area of the tumor immune microenvironment. We aim to explore the current research advances to formulate better individualized treatment strategies for TC patients and to provide clues and references for the study of potential immune checkpoints and the development of immunotherapy technologies.


Induction and increase of HLA-DR antigen expression by immune interferon on ML-3 cell line enhances the anti-HLA-DR immunotoxin activity.
In order to evaluate the impact of induction and increase target antigen expression on immunotoxin potency, we measured the potentiating effect of recombinant immune interferon-gamma (rIFN-gamma) on the cytotoxicity of an anti HLA-DR ricin A-chain immunotoxin (2G5 RTA-IT) on the myeloid cell line ML-3. After 48 h of incubation with rIFN-gamma (500 U/ml) the percentage of 2G5-positive cells increased from 40% to 79%, and the 2G5 mean density was enhanced by 10-fold (11,000 versus 110,000 molecules/cell). Concurrently, rIFN-gamma pretreatment induced a dramatic improvement of 2G5 RTA-IT dose-effect cytotoxicity, as well as immunotoxin cytotoxicity kinetics. When 2G5 RTA-IT was used at the optimal dose of 10(-8)M (the maximum dose which avoided non-specific ricin A-chain cytotoxicity), the immunotoxin-induced cell kill increased with the percentage of DR-positive ML-3 cells according to a similar linear-logarithmic function of rIFN-gamma concentration. Moreover, in the same range of rIFN-gamma concentrations, the killing values and the percentage of DR-positive ML-3 cells were similar if not identical. These findings imply that the enhancement of 2G5 RTA-IT cytotoxicity by rIFN-gamma is mainly related to the rIFN-gamma 2G5 antigen induction on HLA-DR negative cells when immunotoxin was used at 10(-8) M. Furthermore, 2G5 RTA-IT dose-effect cytotoxicity on DR-expressing ML-3 cells, when used at lower concentrations, was also increased by rIFN-gamma in a dose-dependent manner. This result suggests that for immunotoxin concentrations close to the limiting membrane saturation dose (10(-10)M), rIFN-gamma may not solely act by inducing HLA-DR expression on DR-negative ML-3 subpopulation but also by increasing individual cellular DR density on DR expressing ML-3 cells. Finally, our study showed that immunotoxin potency on malignant cell populations which display an heterogeneous antigen expression, could be greatly improved by the use of rIFN-gamma.


Yeast galactose permease is related to yeast and mammalian glucose transporters.
We have cloned and sequenced the GAL2 gene of Saccharomyces cerevisiae, which encodes galactose permease. The GAL2 protein is related to the yeast glucose transporter encoded by the SNF3 gene, and also to mammalian and bacterial sugar permeases. Like the other members of this protein family, GAL2 has twelve hydrophobic segments that are separated by loops of charged amino acids. A comparison of different members of this protein family shows that those parts of the polypeptides thought to be on the cytoplasmic side of the cell membrane, are more conserved than other parts of the molecules.


Chymotrypsinogen D, a new zymogen from porcine pancreas with proelastolytic activity.
During the purification of propancreatopeptidase E, a proATEEase activity is always copurified. The proelastolytic and proesterolytic activities can be separated on a hydroxylapatite column. The zymogen with potential ATEEase activity has a basic isoelectric point, can be activated by trypsin, and can hydrolyse elastin and ATEE but not ATAME. Its molecular weight is about 26,500 and the NH2-terminal sequence indicates clearly that it belongs to the chymotrypsinogen family, but that it is not chymotrypsinogen A, B, or C. We call it chymotrypsinogen D. Although both pancreatopeptidase E and chymotrypsin D can hydrolyse elastin, the synthetic substrate ATAME is attacked only by pancreatopeptidase E. Therefore, the peptide bonds in elastin cleaved by these two enzymes should be different.


Novel biomarkers in amniotic fluid for early assessment of intraamniotic infection.
Intra-amniotic infection/inflammation (IAI) is associated with preterm birth, short and long-term adverse clinical outcomes and oxidative stress. The diagnosis of IAI is based on histological and clinical findings; however, often these results are unspecific. Therefore, efforts have been directed towards validating reliable methods for patients lacking overt clinical symptoms. In this study, amniotic fluid (AF) samples were prospectively collected from 23 women grouped into two categories (with or without IAI) following clinical, microbiological and histological criteria. AFs were analyzed using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) for the determination of the following biomarkers: oxidized and nitrated tyrosines (Tyr), 8-hydroxy-2'-deoxyguanosine (8OHdG), oxidized glutathione (GSSG) and glutathione sulfonamide (GSA). 3-NO2-Tyrosine (3NO2-Tyr) and GSSG concentrations in AF were not identified as significantly relevant biomarkers in the presence of IAI. However, inflammatory biomarkers such as GSA (p=0.002) and 3-Chloro-Tyrosine [3Cl-Tyr (p=0.049)], and oxidative stress biomarker 8OHdG (p=0.021) were significantly increased in AF with IAI as compared to normal controls. Biomarkers of inflammation and oxidative stress determined in AF samples could represent a new approach towards an early diagnosis of IAI and subsequent chorioamnionitis in the clinical setting.


A novel anti-HIV active integrase inhibitor with a favorable in vitro cytochrome P450 and uridine 5'-diphospho-glucuronosyltransferase metabolism profile.
Research efforts on the human immunodeficiency virus (HIV) integrase have resulted in two approved drugs. However, co-infection of HIV with Mycobacterium tuberculosis and other microbial and viral agents has introduced added complications to this pandemic, requiring favorable drug-drug interaction profiles for antiviral therapeutics targeting HIV. Cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) are pivotal determining factors in the occurrence of adverse drug-drug interactions. For this reason, it is important that anti-HIV agents, such as integrase inhibitors, possess favorable profiles with respect to CYP and UGT. We have discovered a novel HIV integrase inhibitor (compound 1) that exhibits low nM antiviral activity against a diverse set of HIV-1 isolates, and against HIV-2 and the simian immunodeficiency virus (SIV). Compound 1 displays low in vitro cytotoxicity and its resistance and related drug susceptibility profiles are favorable. Data from in vitro studies revealed that compound 1 was not a substrate for UGT isoforms and that it was not an inhibitor or activator of key CYP isozymes.


Economic burden of refractory chronic spontaneous urticaria on Kuwait's health system.
Chronic spontaneous urticaria (CSU) is a common problem worldwide. We evaluated the direct medical costs of treating patients with refractory CSU and the budget effect of omalizumab use in these patients in Kuwait. The prevalence of CSU was estimated using the Delphi method. Medical records of patients with refractory CSU in Kuwait were reviewed. Costs were calculated from a health system perspective. One-way sensitivity analyses were conducted on the price and utilization of each cost component. Before omalizumab use, the total direct costs of treating 1,293 patients with refractory CSU were estimated to be USD 3,650,733 per year. This estimation was principally generated by outpatient visits. After omalizumab use, the cost was sensitive to price variation and estimated to be USD 15,828,612 per year. All other direct costs were reduced. The economic burden of refractory CSU in Kuwait is high. Omalizumab use is costly, but its administration reduces all other direct costs.


Near-Infrared Upconversion Mesoporous Tin Oxide Bio-Photocatalyst for H2O2-Activatable O2-Generating Magnetic Targeting Synergetic Treatment.
Tumor hypoxia compromises the therapeutic efficacy of oxygen (O2)-dependent treatment methods as the endogenous O2 levels have an important influence on the production of reaction oxygen species. Herein, a synergistic multifunctional mesoporous Fe@Sn-UCNPs bio-photocatalytic nanoplatform is provided to comprehensively realize endogenous hydrogen peroxide (H2O2)-activatable, self-supplied O2, photothermal performance, and near-infrared-mediated magnetic targeting PDT/PTT simultaneously for relieving tumor hypoxia. Such a nanoplatform is constructed by encapsulating magnetic Fe3O4 with lanthanide-ion-doped mesoporous tin oxide upconversion nanoparticles and further modified with phosphorylated serine and poly(ethylene glycol) for enhancing the biocompatibility and solubility. The nanoparticles can be activated by endogenous H2O2 and in situ generated O2 to relieve hypoxia through catalytic reaction. Therefore, H2O2-responsive/O2-evolving nanoparticles can elevate the O2 level in the tumor site for an apparently enhanced PDT effect in vitro and in vivo. What is more, Fe@Sn-UCNPs demonstrate enhanced photothermal conversion efficiency based on the special nanostructure and much more circuit loops for electron transitions between Fe3O4 and Sn-UCNPs, and the electronic structure of Fe@Sn-UCNPs was calculated. In addition, such Fe@Sn-UCNPs also exhibit multimodality imaging performance (including photothermal, magnetic resonance, and computed tomography imaging) for monitoring and tracking the in vivo tumor therapeutic process. This work provides novel insight into the smart Fe@Sn-UCNPs as an "all-in-one" theranostic nanosystem for cancer therapy.


DDCNet: Deep Dilated Convolutional Neural Network for Dense Prediction.
Dense pixel matching problems such as optical flow and disparity estimation are among the most challenging tasks in computer vision. Recently, several deep learning methods designed for these problems have been successful. A sufficiently larger effective receptive field (ERF) and a higher resolution of spatial features within a network are essential for providing higher-resolution dense estimates. In this work, we present a systemic approach to design network architectures that can provide a larger receptive field while maintaining a higher spatial feature resolution. To achieve a larger ERF, we utilized dilated convolutional layers. By aggressively increasing dilation rates in the deeper layers, we were able to achieve a sufficiently larger ERF with a significantly fewer number of trainable parameters. We used optical flow estimation problem as the primary benchmark to illustrate our network design strategy. The benchmark results (Sintel, KITTI, and Middlebury) indicate that our compact networks can achieve comparable performance in the class of lightweight networks.


Emerging Role of RNA m5C Modification in Cardiovascular Diseases.
Epitranscriptomics is the emerging field of research that comprises the study of epigenetics changes in RNAs. Progressing development in the field of epigenetics has helped to manage and comprehend human diseases. RNA methylation regulates all aspects of RNA functions, which are involved in the pathogenesis of human diseases. Interestingly, RNA m5C methylation is significantly linked to various types of human disease, including cardiovascular diseases (CVD). The m5C methylation is controlled by m5C regulatory proteins, which act as methyltransferase, demethyltransferase, and RNA-binding protein. Dysregulated expression in m5C regulatory proteins is significantly associated with cardiovascular disease, and these regulatory proteins have crucial roles in biological and cellular functions. This review is mainly focused on the role of RNA m5C modification in CVD and mitochondrial dysfunction. Thus, m5C will contribute to discovering the new diagnostic marker and therapeutic target for CVD.


Effect of a multimedia-assisted informed consent procedure on the information gain, satisfaction, and anxiety of cataract surgery patients.
To assess whether a multimedia-assisted preoperative informed consent procedure has an effect on patients' knowledge concerning cataract surgery, satisfaction with the informed consent process, and reduction in anxiety levels. Hietzing Hospital, Vienna, Austria. Prospective randomized controlled clinical trial. Patients participated in an informed consent procedure for age-related cataract surgery that included the standard approach only (reading the information brochure and having a standardized face-to-face discussion) or supplemented with a computer-animated video. The main outcome was information retention assessed by a questionnaire. Further outcome measures used were the State-Trait Anxiety Inventory, the Visual Function-14 score, and an assessment of satisfaction. The study included 123 patients (64 in standard-only group; 59 in computer-animated video group). Both groups scored well on the questionnaire; however, patients who watched the video performed better (82% retention versus 72%) (P = .002). Scores tended to decrease with increasing age (r = -0.25, P = .005); however, this decrease was smaller in the group that watched the video. Both groups had elevated anxiety levels (means in video group: anxiety concerning the current situation [S-anxiety] = 63.8 ± 9.6 [SD], general tendency toward anxiety [T-anxiety] = 65.5 ± 7.9; means in control group: S-anxiety = 61.9 ± 10.3, T-anxiety = 66.2 ± 7.8). A high level of information retention was achieved using an informed consent procedure consisting of an information brochure and a standardized face-to-face discussion. A further increase in information retention was achieved, even with increasing patient age, by adding a multimedia presentation. No author has a financial or proprietary interest in any material or method mentioned.


Insulin-Like Growth Factor I Produces an Antidepressant-Like Effect and Elicits N-Methyl-D-Aspartate Receptor Independent Long-Term Potentiation of Synaptic Transmission in Medial Prefrontal Cortex and Hippocampus.
Growth factors play an important role in regulating neurogenesis and synapse formation and may be involved in regulating the antidepressant response to conventional antidepressants. To date, Insulin-like growth factor I (IGFI) is the only growth factor that has shown antidepressant properties in human clinical trials. However, its mechanism of action remains unclear. The antidepressant-like effect of a single IV dose of IGFI was determined using a chronic unpredictable stress paradigm in the rat Porsolt, sucrose preference, novelty-induced hypophagia, and ultrasonic vocalization models. The dependence of the medial prefrontal cortex for these effects was determined by direct medial prefrontal cortex injection followed by Porsolt testing as well as IGFI receptor activation in the medial prefrontal cortex following an optimal IV antidepressant-like dose of IGFI. The effect of IGFI on synaptic transmission and long-term potentiation (LTP) of synaptic strength was assessed in the hippocampus and medial prefrontal cortex. The dependence of these effects on IGFI and AMPA receptor activation and protein synthesis were also determined. IGFI produced a rapid-acting and long-lasting antidepressant-like effect in each of the depression models. These effects were blocked by IGFI and AMPA receptor antagonists, and medial prefrontal cortex was localized. IGFI robustly increased synaptic strength in the hippocampus and medial prefrontal cortex and these effects were IGFI receptor and protein synthesis-dependent but N-methyl-d-aspartate receptor independent. IGFI also robustly facilitated hippocampal metaplasticity 24 hours postdosing. These data support the conclusion that the antidepressant-like effects of IGFI are mediated by a persistent, LTP-like enhancement of synaptic strength requiring both IGFIR activation and ongoing protein synthesis.