Identification of French Guiana anopheline mosquitoes by MALDI-TOF MS profiling using protein signatures from two body parts.
In French Guiana, the malaria, a parasitic infection transmitted by Anopheline mosquitoes, remains a disease of public health importance. To prevent malaria transmission, the main effective way remains Anopheles control. For an effective control, accurate Anopheles species identification is indispensable to distinguish malaria vectors from non-vectors. Although, morphological and molecular methods are largely used, an innovative tool, based on protein pattern comparisons, the Matrix Assisted Laser Desorption / Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) profiling, emerged this last decade for arthropod identification. However, the limited mosquito fauna diversity of reference MS spectra remains one of the main drawback for its large usage. The aim of the present study was then to create and to share reference MS spectra for the identification of French Guiana Anopheline species. A total of eight distinct Anopheles species, among which four are malaria vectors, were collected in 6 areas. To improve Anopheles identification, two body parts, legs and thoraxes, were independently submitted to MS for the creation of respective reference MS spectra database (DB). This study underlined that double checking by MS enhanced the Anopheles identification confidence and rate of reliable classification. The sharing of this reference MS spectra DB should make easier Anopheles species monitoring in endemic malaria area to help malaria vector control or elimination programs.


The influence of Pleistocene climatic changes and ocean currents on the phylogeography of the southern African barnacle, Tetraclita serrata (Thoracica; Cirripedia).
The evolutionary effects of glacial periods are poorly understood for Southern Hemisphere marine intertidal species, particularly obligatory sessile organisms. We examined this by assessing the phylogeographic patterns of the southern African volcano barnacle, Tetraclita serrata, a dominant species on rocky intertidal shores. Restricted gene flow in some geographical areas was hypothesized based on oceanic circulation patterns and known biogeographic regions. Barnacle population genetic structure was investigated using the mitochondrial cytochrome oxidase subunit 1 (COI) region for 410 individuals sampled from 20 localities spanning the South African coast. The mtDNA data were augmented by generating nuclear internal transcribed spacer 1 (ITS1) sequences from a subset of samples. Phylogenetic and population genetic analyses of mitochondrial DNA data reveal two distinct clades with mostly sympatric distributions, whereas nuclear analyses reveal only a single lineage. Shallow, but significant structure (0.0041-0.0065, P<0.01) was detected for the mtDNA data set, with the south-west African region identified as harbouring the highest levels of genetic diversity. Gene flow analyses on the mtDNA data show that individuals sampled in south-western localities experience gene flow primarily in the direction of the Benguela Current, while south and eastern localities experience bi-directional gene flow, suggesting an influence of both the inshore currents and the offshore Agulhas Current in the larval distribution of T. serrata. The mtDNA haplotype network, Bayesian Skyline Plots, mismatch distributions and time since expansion indicate that T. serrata population numbers were not severely affected by the Last Glacial Maximum (LGM), unlike other southern African marine species. The processes resulting in the two morphologically cryptic mtDNA lineages may be the result of a recent historical allopatric event followed by secondary contact or could reflect selective pressures due to differing environmental conditions.


Quality assessment of fluconazole capsules and oral suspensions compounded by pharmacies located in the United States.
OBJECTIVE To evaluate pharmaceutical characteristics (strength or concentration, accuracy, and precision), physical properties, and bacterial contamination of fluconazole compounded products. SAMPLE Fluconazole compounded products (30- and 240-mg capsules; 30- and 100-mg/mL oral suspensions) from 4 US veterinary compounding pharmacies. PROCEDURES Fluconazole compounded products were ordered 3 times from each of 4 pharmacies at 7- or 10-day intervals. Generic fluconazole products (50- and 200-mg tablets; 10- and 40-mg/mL oral suspensions) served as references. Compounded products were evaluated at the time of receipt; suspensions also were evaluated 3 months later and at beyond-use dates. Evaluations included assessments of strength (concentration), accuracy, precision, physical properties, and bacterial contamination. Acceptable accuracy was defined as within ± 10% of the labeled strength (concentration) and acceptable precision as within ± 10%. Fluconazole was quantified by use of high-performance liquid chromatography. RESULTS Physical characteristics of compounded products differed among pharmacies. Aerobic bacterial cultures yielded negative results. Capsules (30 and 240 mg) had acceptable accuracy (median, 96.3%; range, 87.3% to 135.2%) and precision (mean ± SD, 7.4 ± 6.0%). Suspensions (30 and 100 mg/mL) had poor accuracy (median, 73.8%; range, 53.9% to 95.2%) and precision (mean ± SD, 15.0 ± 6.9%). Accuracy and precision were significantly better for capsules than for suspensions. CONCLUSIONS AND CLINICAL RELEVANCE Fluconazole compounded products, particularly suspensions, differed in pharmaceutical and physical qualities. Studies to evaluate the impact of inconsistent quality on bioavailability or clinical efficacy of compounded fluconazole products are indicated, and each study should include data on the quality of the compounded product evaluated.


Damages and Expected Deaths Due to Excess NOx Emissions from 2009 to 2015 Volkswagen Diesel Vehicles.
We estimate the damages and expected deaths in the United States due to excess emissions of NOx from 2009 to 2015 Volkswagen diesel vehicles. Using data on vehicle registrations and a model of pollution transport and valuation, we estimate excess damages of $430 million and 46 excess expected deaths. Accounting for uncertainty about emissions gives a range for damages from $350 million to $500 million, and a range for excess expected deaths from 40 to 52. Our estimates incorporate significant local heterogeneity: for example, Minneapolis has the highest damages despite having fewer noncompliant vehicles than 13 other cities. Our estimated damages greatly exceed possible benefits from reduced CO2 emissions due to increased fuel economy.


Blood pressure reactivity at onset of mental stress determines sympathetic vascular response in young adults.
We have previously shown in young males that the rate of rise in blood pressure (BP) at the onset of mental stress determines whether or not muscle sympathetic nerve activity (MSNA) has a role in driving the pressor response. The aim of this study was to investigate these interactions in young females. BP and MSNA were recorded continuously in 19 females and 21 males during 2-min mental stressors (mental arithmetic and Stroop test). Physical stressor tasks (cold pressor, handgrip exercise, postexercise ischemia) were also performed. During the first minute of mental arithmetic, the rate of rise in mean arterial pressure (MAP) was significantly greater in negative responders (mean decrease in MSNA) compared with positive responders (mean increase in MSNA) in both males (1.9 ± 0.7 vs. 0.7 ± 0.3 mmHg/sec) and females (1.0 ± 0.3 vs. 0.5 ± 0.2 mmHg/sec). For the Stroop test, there was no significant difference in the rate of the rise in BP between positive and negative responders (P > 0.05). However, peak changes in MAP were significantly greater in negative responders compared with positive responders in both males (22 ± 6 vs. 13 ± 3 mmHg) and females (12 ± 2 vs. 6 ± 1 mmHg). Sympathetic baroreflex sensitivity was greater in negative responders and may contribute to the fall in MSNA experienced by these individuals during mental stress. During physical stressors there were consistent increases in BP and MSNA in males and females. The findings suggest that, in both males and females, BP reactivity at the onset of mental stress dictates whether or not there is an increase or decrease in MSNA.


Degenerative Cervical Myelopathy: Clinical Presentation, Assessment, and Natural History.
Degenerative cervical myelopathy (DCM) is a leading cause of spinal cord injury and a major contributor to morbidity resulting from narrowing of the spinal canal due to osteoarthritic changes. This narrowing produces chronic spinal cord compression and neurologic disability with a variety of symptoms ranging from mild numbness in the upper extremities to quadriparesis and incontinence. Clinicians from all specialties should be familiar with the early signs and symptoms of this prevalent condition to prevent gradual neurologic compromise through surgical consultation, where appropriate. The purpose of this review is to familiarize medical practitioners with the pathophysiology, common presentations, diagnosis, and management (conservative and surgical) for DCM to develop informed discussions with patients and recognize those in need of early surgical referral to prevent severe neurologic deterioration.


[Biomolecular markers in renal adenocarcinoma].
To review the literature and analyze the main contributions in molecular markers in renal adenocarcinoma. We reviewed the literature over the last 10 years on molecular markers in renal adenocarcinoma (Medline 1991-2001). Outstanding papers published before 1991, included in the references of the selected articles, were also reviewed. A large number of biomolecular markers have been studied in renal adenocarcinoma with results that are often contradictory. Some proteins have been associated with different histopathological parameters and with tumor prognosis, although their clinical importance has yet to be established. Although the traditional prognostic factors, such as tumor grade and stage, provide important information on the outcome of renal adenocarcinoma, they are insufficient to predict the clinical behavior of this tumor type with absolute certainty. The foregoing has prompted the study of a variety of biomolecular markers that might predict the biological behavior of the tumor and identify the patients at a higher risk for tumor recurrence or death from the tumor. Despite the promising results obtained with biomolecular markers in renal adenocarcinoma, further studies are warranted to determine the prognostic value of these markers.


Let-7a promotes periodontal bone regeneration of bone marrow mesenchymal stem cell aggregates via the Fas/FasL-autophagy pathway.
Periodontal bone regeneration using bone marrow mesenchymal stem cell (BMMSC) transplantation is a promising method; however, the method for osteogenic differentiation of BMMSCs needs to be improved. In this research, we sought to identify the roles of let-7a in the osteogenesis of BMMSCs and to provide a potential method for periodontal bone regeneration. Our previous study revealed that Fas/FasL is a target of let-7a. In this study, we demonstrated that let-7a overexpression significantly enhanced BMMSC-CAs osteogenesis both in vitro and in vivo. Mechanistically, upregulation of Fas/FasL using the rfas/rfaslg plasmid obstructed the osteogenesis of BMMSCs by inhibiting autophagy. Furthermore, we confirmed that overexpression of let-7a activated autophagy and alleviated the inhibited osteogenesis by the autophagy inhibitor 3-MA and the rfas/rfaslg plasmid of BMMSCs. In general, our findings showed that let-7a promoted the osteogenesis of BMMSCs through the Fas/FasL-autophagy pathway, suggesting that the application of let-7a in BMMSC-CAs based periodontal bone regeneration could be a promising strategy.


The optimal management of patients on oral anticoagulation undergoing coronary artery stenting. The 10th Anniversary Overview.
Even 10 years after the first appearance in the literature of articles reporting on the management of patients on oral anticoagulation (OAC) undergoing percutaneous coronary intervention with stent (PCI-S), this issue is still controversial. Nonetheless, some guidance for the everyday management of this patient subset, accounting for about 5-8 % of all patients referred for PCI-S, has been developed. In general, a period of triple therapy (TT) of OAC, with either vitamin K-antagonists (VKA) or non-vitamin K-antagonist oral anticoagulants (NOAC), aspirin, and clopidogrel is warranted, followed by the combination of OAC, and a single antiplatelet agent for up to 12 months, and then OAC alone. The duration of the initial period of TT is dependent on the individual risk of thromboembolism, and bleeding, as well as the clinical context in which PCI-S is performed (elective vs acute coronary syndrome), and the type of stent implanted (bare-metal vs drug-eluting). In this article, we aim to provide a comprehensive, at-a-glance, overview of the management strategies, which are currently suggested for the peri-procedural, medium-term, and long-term periods following PCI-S in OAC patients. While acknowledging that most of the evidence has been obtained from patients on OAC because of atrial fibrillation, and with warfarin being the most frequently used VKA, we refer in this overview to the whole population of OAC patients undergoing PCI-S. We refer to the whole population of patients on OAC undergoing PCI-S also when OAC is carried out with NOAC rather than VKA, pointing out, when appropriate, the particular management issues.


Chronic kidney disease as a coronary disease equivalent--a comparison with diabetes over a decade.
Whether chronic kidney disease (CKD) should also be considered a coronary disease equivalent like diabetes is not clear. Veterans with and without diabetes and with and without CKD were prospectively recruited. A competing Cox regression model was used to describe the risk of myocardial infarction (MI) in the two groups (CKD and diabetes) over a decade of follow-up. The incidence rate of MI in those without CKD was 0.047/yr and in those with CKD was 0.206/yr. Multivariate adjustment revealed the incident rate ratio for MI in CKD as 3.5 and for diabetes mellitus as 2.5. The cumulative incidence for MI was influenced by CKD and diabetes. CKD was associated with a subhazard ratio for MI of 3.74; in contrast, diabetes was associated with a subhazard ratio for MI of 2.6. For the outcome of all-cause mortality, after multivariate adjustment, CKD was associated with a hazard ratio (HR) of 1.86, which was similar to the HR of 2.27 for prevalent coronary artery disease. The HR for diabetes was NS at 1.35. CKD is associated with a risk of death similar to that of established coronary artery disease and higher than that of diabetes mellitus. CKD is associated with a risk of MI that is at least as much as that from diabetes mellitus. Among veterans, CKD appears to be a coronary disease equivalent.


[Raised levels of circulating endothelial cells in systemic sclerosis].
Circulating endothelial cells (CECs) have been described in different conditions with vascular injury. Vascular abnormalities play a key role in the pathogenesis of Systemic Sclerosis (SSc). The aim of our study was to look for the presence of CECs in SSc patients and to evaluate their clinical significance. We studied 52 SSc patients and 40 healthy controls (HC). Five-parameter, 3-color flow cytometry was performed with a FACScan. CECs were defined as CD45 negative, CD31 and P1H12 positive, and activated CECs as CD45 negative and P1H12, CD62, or CD106 positive. Total and activated CEC counts were significantly higher in SSc patients when compared with HC and positively correlated with disease activity score. We found a significant association between CECs and disease activity; as regard with organ involvement, CEC number correlate with the severity of pulmonary hypertension. Raised counts of CECs may represent direct evidence of active vascular disease in SSc as regard as visceral involvement, the association between CECs and pulmonary hypertension suggest a relevant role for CECs as a marker of prominent endothelial involvement.


Quantification of monosaccharides through multiple-reaction monitoring liquid chromatography/mass spectrometry using an aminopropyl column.
A simple, sensitive, and reproducible quantitative liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was designed for the simultaneous quantification of monosaccharides derived from glycoprotein and blood serum using a multiple-reaction monitoring (MRM) approach. Sialic acids and neutral monosaccharides were efficiently separated using an amino-bonded silica phase column. Neutral monosaccharide molecules were detected as their aldol acetate anion adducts [M + CH(3)CO(2)](-) using electrospray ionization in negative ion MRM mode, while sialic acids were detected as deprotonated ions [M-H](-). The new method did not require a reduction step, and exhibited very high sensitivity to carbohydrates with limits of detection of 1 pg for the sugars studied. The linearity of the described approach spanned over three orders of magnitude (pg to ng). The method was validated for monosaccharides originating from N-linked glycans attached to glycoproteins and glycoproteins found in human blood serum. The method effectively quantified monosaccharides originating from as little as 1 microg of glycoprotein and 5 microL of blood serum. The method was robust, reproducible, and highly sensitive. It did not require reduction, derivatization or postcolumn addition of reagents.


Compartmental analysis of cerebrospinal fluid transfer and absorption in simulated hydrocephalus.
A mathematical model of the cerebrospinal fluid (CSF) flow dynamics found in hydrocephalic infants with myelomeningocele lesions was constructed using criteria obtained from analogous clinical situations where 125I-labelled and 131I-labelled ortho-iodobenzoyl-amino-acetic acid (hippuran) had been employed to measure CSF flow dynamics. The quantitative results from this study allowed clinical data to be assessed and the importance of various CSF transfer mechanisms to be discussed. Our mathematical model indicates that the majority of radiopharmaceutical passes from the cerebral reservoir (the ventricles) into the blood. Experimental evidence indicates that the principal mechanism responsible for this movement is the bulk flow of CSF between its sites of production in the choroid plexus and absorption by the arachnoid villi.


Acupuncture for infertility: is it an effective therapy?
Acupuncture has been used to treat infertility extensively, including ovulatory dysfunction, in vitro fertilization and embryo transfer (IVF-ET), and male infertility. This review summarizes the recent studies which investigated the role of acupuncture in infertility. In conclusion, most of the existing studies suggest a positive effect of acupuncture in infertility treatment. Firstly, acupuncture may improve ovulation by modulating the central and peripheral nervous systems, the neuroendocrine and endocrine systems, the ovarian blood flow, and metabolism. Secondly, acupuncture can improve the outcome of IVF-ET, and the mechanisms may be related to the increased uterine blood flow, inhibited uterine motility, and the anesis of depression, anxiety and stress. Its effect on modulating immune function also suggests helpfulness in improving the outcome of IVF-ET. Finally, the studies suggest that acupuncture plays a positive role in male infertility, the mechanism of which is not yet clear. Even though a positive effect of acupuncture in infertility has been found, well-designed multi-center, prospective randomized controlled studies are still needed to provide more reliable and valid scientific evidence. Furthermore, it is urgent and necessary to clarify the mechanism of acupuncture for infertility.


PD-L1 is a direct target of cancer-FOXP3 in pancreatic ductal adenocarcinoma (PDAC), and combined immunotherapy with antibodies against PD-L1 and CCL5 is effective in the treatment of PDAC.
High expression of PD-L1 marks the poor prognosis of pancreatic ductal adenocarcinomas (PDAC). However, the regulatory mechanism of PD-L1 remains elusive. We recently reported that cancer Forkhead box protein 3 (Cancer-FOXP3 or C-FOXP3) promoted immune evasion of PDAC by recruiting Treg cells into PDAC via upregulation of CCL5. In this study, we confirmed that PD-L1 was overexpressed in PDAC samples from two independent cohorts of patients with radical resection. Moreover, C-FOXP3 was colocalized and correlated with the expression of PD-L1 in tumor cells at the mRNA and protein levels, and this finding was confirmed by the The Cancer Genome Atlas (TCGA) database. Chromatin immunoprecipitation (ChIP) revealed that C-FOXP3 directly bound to the promoter region of PD-L1 in pancreatic cancer cells. Furthermore, overexpression of C-FOXP3 activated the luciferase reporter gene under the control of the PD-L1 promoter. However, mutation of the binding motif-a completely reversed the luciferase activity. In addition, C-FOXP3-induced upregulation of PD-L1 effectively inhibited the activity of CD8+ T cells. Based on our recent finding that the CCL-5 antibody achieved a better response to PDAC models with high C-FOXP3 levels, we further demonstrated that the PD-L1 antibody strengthened the antitumor effect of CCL-5 blockade in xenograft and orthotopic mouse models with high C-FOXP3 levels. In conclusion, C-FOXP3 directly activates PD-L1 and represents a core transcription factor that mediates the immune escape of PDAC. Combined blockade of PD-L1 and CCL-5 may provide an effective therapy for patients with PDAC that have high C-FOXP3 levels.


Clinical expression, but not disease outcome, may vary according to age at disease onset in psoriatic spondylitis.
To investigate whether the clinical expression and disease outcome in psoriatic spondylitis (PsS) may vary according to age at disease onset. This study included 70 patients from a unique outpatient spondylitis clinic followed on a regular basis with a standard protocol. Patients were diagnosed with PsS according to ESSG criteria plus radiographic sacroiliitis (SI). Outcome parameters included: disease activity, functional evaluation, radiological damage, mobility restriction, and enthesitis score. Patients were divided into those with disease onset before 40 years (young-onset PsS) and those with onset over this age (late-onset PsS). Clinical features and outcome parameters were compared between groups. There were 44 men and 26 women. Thirty-nine (M:F ratio 1.8) patients had disease onset before 40 years and 31 (M:F ratio 1.6) over this age. HLA-B27 correlated with PsS susceptibility (34% vs 7%, RR 6.4, p<0.0004), but it was found over-represented in young-onset PsS compared to late-onset cases (51% vs 13%, p=0.001). Young-onset cases tended to have a higher frequency of family history (26% vs 13%), bilateral SI (62% vs 29%, p=0.013), isolated axial pattern (31% vs 13%), and enthesitis (54% vs 29%, p=0.09). In late-onset PsS there was a higher frequency of unilateral SI (71% vs 38%, p=0.013), polyarthritis (45% vs 23%, p=0.022), and silent axial disease (32% vs 10%, p=0.022). Outcome parameters were similar between groups. Clinical picture but not outcome parameters, varies according to age at disease onset in PsS. The correlation between HLA-B27 and young-onset PsS supports the notion that disease susceptibility and disease expression are not driven by the same gene in this entity.


Penetrating keratoplasty for pseudophakic corneal edema with exchange of intraocular lenses.
We studied one eye in each of 25 consecutive patients with pseudophakic corneal edema. Each patient underwent a penetrating keratoplasty with exchange of intraocular lenses and was followed up for 12 to 38 months (mean, 18.7 months). The corneal graft remained clear in 22 (88%) eyes, but only eight eyes (32%) had acuity of 20/40 or better; nine eyes (36%) manifested cystoid macular edema, and six eyes (24%) had degenerative maculopathy. Elevated intraocular pressure was present in 12 eyes after surgery, with three eyes manifesting visual field loss; in all eyes the condition was controlled medically. Peripheral anterior synechiae appeared postoperatively in two eyes. We now treat severe cases of pseudophakic corneal edema with a penetrating keratoplasty, meticulous anterior vitrectomy, gonioplasty, iridoplasty, and exchange of intraocular lenses, employing a flexible-loop anterior chamber lens or a posterior chamber lens sutured to the iris.


Substrate recognition by Escherichia coli MutY using substrate analogs.
The Escherichia coli adenine glycosylase MutY is involved in the repair of 7,8-dihydro-8-oxo-2"-deoxyguanosine (OG):A and G:A mispairs in DNA. Our approach toward understanding recognition and processing of DNA damage by MutY has been to use substrate analogs that retain the recognition properties of the substrate mispair but are resistant to the glycosylase activity of MutY. This approach provides stable MutY-DNA complexes that are amenable to structural and biochemical characterization. In this work, the interaction of MutY with the 2"-deoxyadenosine analogs 2"-deoxy-2"-fluoroadenosine (FA), 2"-deoxyaristeromycin (R) and 2"-deoxyformycin A (F) was investigated. MutY binds to duplexes containing the FA, R or F analogs opposite G and OG within DNA with high affinity; however, no enzymatic processing of these duplexes is observed. The specific nature of the interaction of MutY with an OG:FA duplex was demonstrated by MPE-Fe(II) hydroxyl radical footprinting experiments which showed a nine base pair region of protection by MutY surrounding the mispair. DMS footprinting experiments with an OG:A duplex revealed that a specific G residue located on the OG-containing strand was protected from DMS in the presence of MutY. In contrast, a G residue flanking the substrate analogs R, F or FA was observed to be hypersensitive to DMS in the presence of MutY. These results suggest a major conformational change in the DNA helix upon binding of MutY that exposes the substrate analog-containing strand. This finding is consistent with a nucleotide flipping mechanism for damage recognition by MutY. This work demonstrates that duplex substrates for MutY containing FA, R or F instead of A are excellent substrate mimics that may be used to provide insight into the recognition by MutY of damaged and mismatched base pairs within DNA.


New challenges in HIV care: prevention among HIV-infected patients.
The HIV-infected population has been understudied and underserved with respect to risk reduction and prevention interventions. Increases in high-risk sex practices and sexually transmitted diseases (STDs) have prompted considerable concern and have led to initiatives to implement routine STD screening and risk reduction counseling among the HIV-infected population. Available evidence indicates that risk reduction counseling can be effective. Improved attention to risk reduction counseling in the HIV medical care setting in needed, and efforts to improve access and maintain linkage to care must be increased. This article summarizes a presentation given by Carlos del Rio, MD, at the March 2003 International AIDS Society-USA course in Atlanta.


Mating induces an immune response and developmental switch in the Drosophila oviduct.
Mating triggers physiological and behavioral changes in females. To understand how females effect these changes, we used microarray, proteomic, and comparative analyses to characterize gene expression in oviducts of mated and unmated Drosophila females. The transition from non-egg laying to egg laying elicits a distinct molecular profile in the oviduct. Immune-related transcripts and proteins involved in muscle and polarized epithelial function increase, whereas cell growth and differentiation-related genes are down-regulated. Our combined results indicate that mating triggers molecular and biochemical changes that mediate progression from a "poised" state to a mature, functional stage.


Effects of melatonin on ischemic spinal cord injury caused by aortic cross clamping in rabbits.
Spinal cord injury remains a devastating complication of thoracic and thoracoabdominal aortic operations. We aimed to investigate neuro-protective role of melatonin administered to rabbits before ischemia against ischemia-reperfusion (IR) injury. Occlusion of the abdominal aorta was applied to adult rabbits, followed by removal of aortic clamp and reperfusion. The abdominal aortas of New Zealand White albino rabbits (n = 18) were occluded for 30 minutes. Experimental groups were as follows: control group (sham operation group, n =10), Ischemia/reperfusion group (I/R) (n = 10) undergoing occlusion but receiving no pharmacologic intervention, Melatonin-treated group (n = 8) receiving 10mg/kg melatonin intravenously 10 minutes before ischemia. Neurologic status was assessed at 6, 24, and 48 hours after the operation. Spinal cords were harvested for histopathologic and biochemical analyses. Melatonin-treated animals had better neurologic function than those of the I/R group. Decreased tissue and serum malondialdehyde (MDA) levels and increased tissue and serum glutathione (GSH) levels were observed in melatonin-treated group (p<0.05). In the same group tissue and serum nitrate levels were decreased (p<0.05). Histopathologic analyses demonstrated typical morphologic changes characteristic of necrosis in I/R group. Melatonin attenuated ischemia-induced necrosis. Melatonin administration may significantly reduce the incidence of spinal cord injury following temporary aortic occlusion.


Analysis of the functions of glycoproteins E and I and their promoters during VZV replication in vitro and in skin and T-cell xenografts in the SCID mouse model of VZV pathogenesis.
The two VZV glycoproteins, gE and gI, are encoded by genes that are designated open reading frames, ORF67 and ORF68, located in the short unique region of the VZV genome. These proteins have homologs in the other alphaherpesviruses. Like their homologues, VZV gE and gI exhibit prominent co-localization in infected cells and form heterodimers. However, VZV gE is much larger than its homologues because it has a unique N-terminal domain, consisting of 188 amino acids that are not present in these other gene products. VZV gE also differs from the related gE proteins, in that it is essential for viral replication. Targeted mutations of gE that are compatible with VZV replication in cultured cells have varying phenotypes in skin and T-cell xenografts in the SCID mouse model of VZV pathogenesis in vivo. While gI is dispensable for growth in cultured cells in vitro, this glycoprotein is essential for VZV infection of differentiated human skin and T cells in vivo. The promoter regions of gE and gI are regulated by the cellular transactivator, specificity protein factor 1 (Sp1) in combination with the major VZV transactivator in reporter construct experiments and some Sp1 promoter elements are important for VZV virulence in vivo. Further analysis of VZV gE and gI functions and their interactions with other viral and host cell proteins are important areas for studies of VZV replication and pathogenesis.


Unexpected mode of engagement between enterovirus 71 and its receptor SCARB2.
Enterovirus 71 (EV71) is a common cause of hand, foot and mouth disease-a disease endemic especially in the Asia-Pacific region1. Scavenger receptor class B member 2 (SCARB2) is the major receptor of EV71, as well as several other enteroviruses responsible for hand, foot and mouth disease, and plays a key role in cell entry2. The isolated structures of EV71 and SCARB2 are known3-6, but how they interact to initiate infection is not. Here, we report the EV71-SCARB2 complex structure determined at 3.4 Å resolution using cryo-electron microscopy. This reveals that SCARB2 binds EV71 on the southern rim of the canyon, rather than across the canyon, as predicted3,7,8. Helices 152-163 (α5) and 183-193 (α7) of SCARB2 and the viral protein 1 (VP1) GH and VP2 EF loops of EV71 dominate the interaction, suggesting an allosteric mechanism by which receptor binding might facilitate the low-pH uncoating of the virus in the endosome/lysosome. Remarkably, many residues within the binding footprint are not conserved across SCARB2-dependent enteroviruses; however, a conserved proline and glycine seem to be key residues. Thus, although the virus maintains antigenic variability even within the receptor-binding footprint, the identification of binding 'hot spots' may facilitate the design of receptor mimic therapeutics less likely to quickly generate resistance.


Urinary incontinence: prevalence, need for treatment, and effectiveness of intervention by nurse.
To measure the unmet need of patients with regular urinary incontinence (incontinence twice or more a month) treatable by a nurse. Self completed postal questionnaire and randomised controlled trial of assessment and intervention by a nurse. One urban and one rural general practice in Somerset. 7300 adults randomly selected from 10,300 aged 35 and over on the combined practice lists. 515 women and 185 men with regular incontinence were offered assessment and treatment, of whom 134 women and 49 men had no intervention for three months (historical controls). They then joined the assessment and treatment programme. Four sessions of pelvic floor exercises and bladder retraining supervised by non-specialist nurse who had taken a three week course on assessing and treating uncomplicated incontinence. Number of patients desiring treatment; self reported cure, improvement, or deterioration in continence after three months. The questionnaire achieved a 79% response. Validated responses showed a prevalence of 4.4% in men and 16.4% in women aged 35-64. 315 (45%) of the 700 patients offered assessment refused it and seven had moved away or died, 64 men and 41 women were referred to their general practitioner. 197 of 292 treated women (68%) reported cure or improvement compared with seven (5%) of controls. 22 of the 86 men desiring treatment were suitable for intervention by the nurse. Seventeen were cured or improved compared with none of the men in the control group. About half the people with regular urinary incontinence took up the offer of treatment (9.2% of women and 3.4% of men in the study population). This condition can be effectively managed by a nurse with limited training.


Phase 2 study of rituximab in the treatment of cladribine-failed patients with hairy cell leukemia.
Hairy cell leukemia (HCL) is an indolent B-cell neoplasm, strongly expressing CD20. Despite initial very high response rates following cladribine, many patients (pts) ultimately relapse. Having relapsed after prior treatment with cladribine, 24 HCL pts (21 male, 3 female) with a median age of 53.5 years were treated with rituximab at 375 mg/m2 intravenously weekly for 4 weeks. Of the pts, 3 (13%) achieved complete remissions and 3 (13%), partial responses. Thus, 6 (25%) of 24 pts achieved a response following rituximab. At a median follow-up of 14.6 months, 2 responders have relapsed; median time to relapse was not yet reached. The only grade III or IV toxicities demonstrated were culture-negative febrile neutropenia, transient and reversible disseminated intravascular coagulation related to rituximab administration, and a diverticular abscess, each in single patients. Of 18 nonresponders, 9 pts subsequently received other treatments; 5 pts were retreated with cladribine, 3 underwent splenectomy, and 1 received pentostatin. Follow-up data are available on 7 of these 9 patients; all 7 patients achieved improvements in hematologic parameters. Rituximab, administered at this dose and schedule, has only modest single-agent activity in cladribine-failed HCL patients when compared with other agents active in this disease.


Pathogen reduction in minimally managed composting of bovine manure.
Spread of manure pathogens is of considerable concern due to use of manure for land application. In this study, the effects of four static pile treatment options for bovine manure on die-off of a generic Escherichia coli, E. coli O157:H7 surrogate, Salmonella Senftenberg, Salm. Typhimurium, and Listeria monocytogenes were evaluated. Bovine manure spiked with these bacteria were placed in cassettes at the top, middle, and bottom sections of four static pile treatments that reflect minimal changes in pile construction with and without straw. Temperatures were monitored continuously during the 28 day self-heating period. E. coli and salmonellae were reduced from 8 to 9 log10 CFU g(-1) to undetectable levels (<1.77 log10 MPN g(-1)) at 25-30 cm depths within 7 days in all pile sections except for the manure-only pile in which 3-4 logs of reduction were obtained. No L. monocytogenes initially present at 6.62 log10 CFU g(-1) were recovered from straw-amended piles after 14 days, in contrast with manure-only treatment in which this pathogen was recovered even at 28 days. Decline of target bacterial populations corresponded to exposure to temperatures above 45°C for more than 3 days and amendments of manure with straw to increase thermophilic zones. Use of straw to increase aeration, self-heating capacity, and heat retention in manure piles provides producers a minimal management option for composting that enhances pathogen die-off and thereby reduces risk of environmental spread when manure is applied to land.


Putative Serine Protease Effectors of Clavibacter michiganensis Induce a Hypersensitive Response in the Apoplast of Nicotiana Species.
Clavibacter michiganensis subspp. michiganensis and sepedonicus cause diseases on solanaceous crops. The genomes of both subspecies encode members of the pat-1 family of putative serine proteases known to function in virulence on host plants and induction of hypersensitive responses (HR) on nonhosts. One gene of this family in C. michiganensis subsp. sepedonicus, chp-7, is required for triggering HR in Nicotiana tabacum. Here, further investigation revealed that mutation of the putative catalytic serine residue at position 232 to threonine abolished the HR induction activity of Chp-7, suggesting that enzymatic activity is required. Purified Chp-7 triggered an HR in N. tabacum leaves in the absence of the pathogen, indicating Chp-7 itself is the HR elicitor from C. michiganensis subsp. sepedonicus. Ectopic expression of chp-7 constructs in N. tabacum leaves revealed that Chp-7 targeted to the apoplast triggered an HR while cytoplasmic Chp-7 did not, indicating that Chp-7 induces the HR in the apoplast of N. tabacum leaves. Chp-7 also induced HR in N. sylvestris, a progenitor of N. tabacum, but not in other Nicotiana species tested. ChpG, a related protein from C. michiganensis subsp. michiganensis, also triggered HR in N. tabacum and N. sylvestris. Unlike Chp-7, ChpG triggered HR in N. clevelandii and N. glutinosa.


Alkylation of intracellular and extracellular DNA by dimethylnitrosamine following activation by isolated rat hepatocytes.
Freshly prepared rat hepatocytes isolated by perfusion with collagenase were able to metabolize microM concentrations of dimethylnitrosamine to a methylating agent. The methylation of hepatocyte DNA in this system was complete within 2 hr, and after this time, the content of O6-methylguanine in the DNA declined, showing that the repair system for this product was active in the isolated hepatocytes. When extracellular calf thymus DNA was added to the incubated hepatocytes, this also became methylated. Methylation of this DNA was not due to cell lysis releasing activating enzymes into the medium, showing that the methylating species formed by the hepatocytes from dimethylnitrosamine is sufficiency stable to pass out of the cell in substantial amounts. These results support the possibility that alkylation of liver cells would not be confined to those cells metabolizing dimethylnitrosamine but could be extended to those cells which are in close proximity to the activating cells. These cells could include nonparenchymal cells which are known to be targets for the carcinogenic action of dimethylnitrosamine.


Assessing the Impact of Anthropic Pressures on Aquatic Macroinvertebrates: A Functional Trait Approach in the Irtysh River Watershed.
Little is known about how changes in the biodiversity and functional traits of macroinvertebrates in rivers respond to the responses of anthropic pressures and their driving factors. Macroinvertebrates were sampled at 17 sites in the Irtysh River Basin and classified macroinvertebrates into 10 traits and 38 categories between May and August 2022. Then, we performed R-mode linked to Q-mode (RLQ) analysis and calculated functional richness, evenness, divergence, and Rao's quadratic entropy (RaoQ) for each site and community-weighted means for each trait category. Our results indicated that there were pronounced alterations in species variability in the urban region. Functional divergence indicated fierce competition among species and considerable niche overlap in the urban region. Functional evenness indicated that species abundance distribution and interspecific functional distance were not uniform in the urban region. Functional richness indicated that the urban region was the strongest region in terms of niche occupation, resource utilization, and buffering capacity for environmental fluctuations. Rao's quadratic entropy showed that the trait difference of macroinvertebrates was the largest in all regions, which was caused by the gradient environmental difference. Research has revealed that urbanization significantly influences the evolutionary trajectory of macroinvertebrate fauna, culminating in an upsurge in pollution-tolerant species and a convergence of functional traits. We recommend strengthening the control of urban and industrial pollution and wise planning and management of land and water resources to mitigate the impact of anthropogenic destruction on habitat fragmentation in the Irtysh River Basin.


Measurable residual disease in multiple myeloma and light chain amyloidosis: more than meets the eye.
The emergence of highly effective multiple myeloma (MM) treatments may bring cure within reach and highlights the need for highly sensitive measurable residual disease (MRD) techniques to replace conventional response assessments. MRD is being incorporated as an endpoint in an increasing number of studies and had been repeatedly shown to be both a predictive marker of response to treatment and a prognostic marker for future relapse. However, those results should be cautiously interpreted due to non-uniform reporting and the need for longer follow up to assess for sustained MRD negativity. This review aims to critically analyze the key MRD aspects including the current evidence supporting the use of MRD in clinical practice and the pitfalls of the various methods used to assess MRD. The utility of MRD for light chain (AL) amyloidosis will also be discussed.


Evolution of floral meristem identity genes. Analysis of Lolium temulentum genes related to APETALA1 and LEAFY of Arabidopsis.
Flowering (inflorescence formation) of the grass Lolium temulentum is strictly regulated, occurring rapidly on exposure to a single long day (LD). During floral induction, L. temulentum differs significantly from dicot species such as Arabidopsis in the expression, at the shoot apex, of two APETALA1 (AP1)-like genes, LtMADS1 and LtMADS2, and of L. temulentum LEAFY (LtLFY). As shown by in situ hybridization, LtMADS1 and LtMADS2 are expressed in the vegetative shoot apical meristem, but expression increases strongly within 30 h of LD floral induction. Later in floral development, LtMADS1 and LtMADS2 are expressed within spikelet and floret meristems and in the glume and lemma primordia. It is interesting that LtLFY is detected quite late (about 12 d after LD induction) within the spikelet meristems, glumes, and lemma primordia. These patterns contrast with Arabidopsis, where LFY and AP1 are consecutively activated early during flower formation. LtMADS2, when expressed in transgenic Arabidopsis plants under the control of the AP1 promoter, could partially complement the organ number defect of the severe ap1-15 mutant allele, confirming a close relationship between LtMADS2 and AP1.


Effects of in ovo exposure of white leghorn chicken, common pheasant, and Japanese quail to 2,3,7,8-tetrachlorodibenzo-p-dioxin and two chlorinated dibenzofurans on CYP1A induction.
In birds, activation of the aryl hydrocarbon receptor (AhR) by some polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) results in induction of cytochrome P4501A (CYP1A) expression. This response has been useful for predicting relative sensitivity of birds to dioxin-like compounds. To further investigate species-sensitivity to dioxins and dioxin-like compounds induction of cytochrome P450 1A4 and 1A5 (CYP1A4 and CYP1A5) mRNA and ethoxyresorufin O-deethylase (EROD) activity were quantified in liver of posthatch white leghorn chicken, common pheasant, and Japanese quail exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), or 2,3,7,8-tetrachlorodibenzofuran (TCDF) via air cell injection. The rank-order of sensitivity of TCDD- and TCDF-exposed birds, based on CYP1A, was chicken>pheasant>quail. Based on CYP1A5 mRNA expression and EROD induction, the order of sensitivity of PeCDF-exposed birds was identical to that for TCDD and TCDF. However, based on CYP1A4 mRNA expression the rank-order was pheasant>chicken>quail. When comparing the potency of the three compounds in each species, based on CYP1A4 mRNA expression, TCDD was the most potent compound in chicken. However, PeCDF was equally potent to TCDD in quail and was more potent than TCDD in pheasant. These results suggest that quantitative real-time polymerase chain reaction (Q-PCR) analysis of CYP1A expression, particularly CYP1A4 mRNA expression, may be a more sensitive biomarker of exposure than analysis of EROD induction, especially in less responsive avian species. Based on these findings future risk assessments should consider the sensitivity of the species inhabiting a site and the congeners of concern that are present.


Decreased expression of antioxidant enzymes in the conjunctival epithelium of dry eye (Sjögren's syndrome) and its possible contribution to the development of ocular surface oxidative injuries.
Previous studies have described elevated lipid peroxidase, myeloperoxidase and xanthine oxidoreductase/xanthine oxidase levels on the ocular surface of patients suffering from autoimmune dry eye (Sjögren's syndrome, SS). Reactive oxygen species generated by various enzymatic systems may be dangerous to the eye if they are not sufficiently cleaved by antioxidants. Because antioxidants have not been investigated in dry eye, the aim of this study was to examine the expression of antioxidant enzymes that cleave reactive oxygen species and play a key role in antioxidant protection. Conjunctival epithelial cells of dry eye (SS) patients were obtained by the method of impression cytology using Millicell membranes. Normal eyes served as controls. In the conjunctival epithelium superoxide dismutase, catalase and glutathione peroxidase were examined immunohistochemically. The enzyme expression levels were determined by image analysis and statistical evaluation. In contrast to normal eyes, where antioxidant enzymes were highly expressed in the conjunctival epithelium, in dry eye their expression was much less pronounced in correlation with the increasing severity of dry eye symptoms. Our study suggests that the decreased expression of antioxidant enzymes in dry eye disease (SS) contributes to the development of anterior eye surface oxidative injuries.


Ultrasound-guided tendon fenestration.
A potential treatment for chronic tendinosis or tendinopathy is percutaneous ultrasound-guided tendon fenestration, also termed dry needling or tenotomy. This procedure involves gently passing a needle through the abnormal tendon multiple times to change a chronic degenerative process into an acute condition that is more likely to heal. This article reviews the literature on tendon fenestration and describes the technical aspects of this procedure including postprocedural considerations. Although peer-reviewed literature on this topic is limited, studies to date have shown that ultrasound-guided tendon fenestration can improve patient symptoms. Several other percutaneous treatments for tendinopathy that include prolotherapy, autologous whole-blood injection, and autologous platelet-rich plasma injection are often performed in conjunction with fenestration. It is currently unknown if these other percutaneous procedures have any benefit over ultrasound-guided tendon fenestration alone.


Is there a gender gap in clinical neurosciences? A cross-sectional analysis of female participation in academic neurology, neurosurgery, and psychiatry.
Gender equality or the lack thereof is a constantly recurring theme. Here, we sought to provide an overview of the status with respect to the participation and leadership of female doctors in clinical neuroscience analyzing different disciplines (neurosurgery, neurology and psychiatry). A total of 1910 articles published in six representative journals (07-12/2020) were reviewed. Of these, 1327 were original research papers, 145 invited publications and 303 letters/comments. Out of a total of 15,080 authors, 4365 (29%) were women. The percentage of female authors was found to differ significantly between the different specialties (19% in neurosurgery, 39% in neurology and 45% in psychiatry). Women were last authors in 9.5% of the papers in neurosurgery, 29% in neurology and 39% in psychiatry Based on these findings, it can be concluded that gender disparity in academic neuroscience is quite conspicuous. Our review seeks to address the reasons behind this phenomenon in the context of new publications as well as various cultural and historical underpinnings.


Important roles of brain-specific carnitine palmitoyltransferase and ceramide metabolism in leptin hypothalamic control of feeding.
Brain-specific carnitine palmitoyltransferase-1 (CPT-1c) is implicated in CNS control of food intake. In this article, we explore the role of hypothalamic CPT-1c in leptin's anorexigenic actions. We first show that adenoviral overexpression of CPT-1c in hypothalamic arcuate nucleus of rats increases food intake and concomitantly up-regulates orexigenic neuropeptide Y (NPY) and Bsx (a transcription factor of NPY). Then, we demonstrate that this overexpression antagonizes the anorectic actions induced by central leptin or compound cerulenin (an inhibitor of fatty acid synthase). The overexpression of CPT-1c also blocks leptin-induced down-regulations of NPY and Bsx. Furthermore, the anorectic actions of central leptin or cerulenin are impaired in mice with brain CPT-1c deleted. Both anorectic effects require elevated levels of hypothalamic arcuate nucleus (Arc) malonyl-CoA, a fatty acid-metabolism intermediate that has emerged as a mediator in hypothalamic control of food intake. Thus, these data suggest that CPT-1c is implicated in malonyl-CoA action in leptin's hypothalamic anorectic signaling pathways. Moreover, ceramide metabolism appears to play a role in leptin's central control of feeding. Leptin treatment decreases Arc ceramide levels, with the decrease being important in leptin-induced anorectic actions and down-regulations of NPY and Bsx. Of interest, our data indicate that leptin impacts ceramide metabolism through malonyl-CoA and CPT-1c, and ceramide de novo biosynthesis acts downstream of both malonyl-CoA and CPT-1c in mediating their effects on feeding and expressions of NPY and Bsx. In summary, we provide insights into the important roles of malonyl-CoA, CPT-1c, and ceramide metabolism in leptin's hypothalamic signaling pathways.


The association between attention deficit/hyperactivity disorder and internet addiction: a systematic review and meta-analysis.
This study aimed to analyze the association between Attention Deficit/Hyperactivity Disorder (ADHD) and Internet addiction (IA). A systematic literature search was performed in four online databases in total including CENTRAL, EMBASE, PubMed and PsychINFO. Observational studies (case-control, cross-sectional and cohort studies) measuring the correlation between IA and ADHD were screened for eligibility. Two independent reviewers screened each article according to the predetermined inclusion criteria. A total of 15 studies (2 cohort studies and 13 cross-sectional studies) met our inclusion criteria and were included in the quantitative synthesis. Meta-analysis was conducted using RevMan 5.3 software. A moderate association between IA and ADHD was found. Individuals with IA were associated with more severe symptoms of ADHD, including the combined total symptom score, inattention score and hyperactivity/impulsivity score. Males were associated with IA, whereas there was no significant correlation between age and IA. IA was positively associated with ADHD among adolescents and young adults. Clinicians and parents should pay more attention to the symptoms of ADHD in individuals with IA, and the monitoring of Internet use of patients suffering from ADHD is also necessary. Longitudinal studies controlling for baseline mental health are needed.


The effects of strain heterology on the epidemiology of equine influenza in a vaccinated population.
We assess the effects of strain heterology (strains that are immunologically similar but not identical) on equine influenza in a vaccinated population. Using data relating to individual animals, for both homologous and heterologous vaccinees, we estimate distributions for the latent and infectious periods, quantify the risk of becoming infected in terms of the quantity of cross-reactive antibodies to a key surface protein of the virus (haemagglutinin) and estimate the probability of excreting virus (i.e. becoming infectious) given that infection has occurred. The data suggest that the infectious period, the risk of becoming infected (for a given vaccine-induced level of cross-reactive antibodies) and the probability of excreting virus are increased for heterologously vaccinated animals when compared with homologously vaccinated animals. The data are used to parameterize a modified susceptible, exposed, infectious and recovered/resistant (SEIR) model, which shows that these relatively small differences combine to have a large effect at the population level, where populations of heterologous vaccinees face a significantly increased risk of an epidemic occurring.


67,000 years of coastal engagement at Panga ya Saidi, eastern Africa.
The antiquity and nature of coastal resource procurement is central to understanding human evolution and adaptations to complex environments. It has become increasingly apparent in global archaeological studies that the timing, characteristics, and trajectories of coastal resource use are highly variable. Within Africa, discussions of these issues have largely been based on the archaeological record from the south and northeast of the continent, with little evidence from eastern coastal areas leaving significant spatial and temporal gaps in our knowledge. Here, we present data from Panga ya Saidi, a limestone cave complex located 15 km from the modern Kenyan coast, which represents the first long-term sequence of coastal engagement from eastern Africa. Rather than attempting to distinguish between coastal resource use and coastal adaptations, we focus on coastal engagement as a means of characterising human relationships with marine environments and resources from this inland location. We use aquatic mollusc data spanning the past 67,000 years to document shifts in the acquisition, transportation, and discard of these materials, to better understand long-term trends in coastal engagement. Our results show pulses of coastal engagement beginning with low-intensity symbolism, and culminating in the consistent low-level transport of marine and freshwater food resources, emphasising a diverse relationship through time. Panga ya Saidi has the oldest stratified evidence of marine engagement in eastern Africa, and is the only site in Africa which documents coastal resources from the Late Pleistocene through the Holocene, highlighting the potential archaeological importance of peri-coastal sites to debates about marine resource relationships.


Surgical management of melanoma in situ on chronically sun-damaged skin.
Lentigo maligna (LM) commonly presents as a slow-growing pigmented macular lesion in chronically sun-damaged skin and may progress to invasive melanoma. Many regard it as a subtype of melanoma in situ (MIS), and surgical excision remains the preferred treatment, but standard 5-mm surgical margins recommended for typical MIS are often insufficient for LM due to its indistinct borders both clinically and histologically. A search of the literature was conducted to review specialized surgical techniques for the treatment of LM, focusing on methods that employ total peripheral margin assessment prior to definitive closure, using either frozen or permanent histologic sections. Many investigators have reported surgical modalities utilizing permanent sections for margin control, including variations of the "square" procedure and "perimeter" technique. Recurrence rates are low with these methods, but only short-term data have been reported. Similarly, several studies have demonstrated the efficacy of Mohs micrographic surgery (MMS) for treatment of MIS, with recurrence rates generally less than 1% over 3 to 5 years of follow-up. Many investigators have had success with immunohistochemical stains to identify melanocytes on frozen sections, aiding margin assessment in MMS. Compared to standard excision, methods that employ surgical margin control offer superior cure rates for LM and should be utilized when available. Total peripheral margin assessment using staged excisions and permanent sections is a simple and effective alternative to MMS for institutions that lack the resources for intraoperative frozen section analysis.


Walking as an Opportunity for Cardiovascular Disease Prevention.
Cardiovascular disease (CVD) is the leading cause of death in the United States, and increasing physical activity can help prevent and manage disease. Walking is an easy way for most adults to be more active and may help people at risk for CVD avoid inactivity, increase their physical activity levels, and improve their cardiovascular health. To guide efforts that promote walking for CVD prevention and management, we estimated the prevalence of walking among US adults by CVD risk status. Nationally representative data on walking from participants (N = 29,742) in the 2015 National Health Interview Survey Cancer Control Supplement were analyzed. We estimated prevalence of walking (ie, any, transportation, and leisure) overall and by CVD status. We defined CVD status as either not having CVD and not at risk for CVD; being at risk for CVD (overweight or having obesity plus 1 or more additional risk factors); or having CVD. We defined additional risk factors as diabetes, high cholesterol, or hypertension. Odds ratios were estimated by using logistic regression models adjusted for respondent characteristics. Prevalence of any walking decreased with increasing CVD risk (no CVD/not at risk, 66.6%; at risk: overweight or has obesity with 1 risk factor, 63.0%; with 2 risk factors, 59.5%; with 3 risk factors, 53.6%; has CVD, 50.2%). After adjusting for respondent characteristics, the odds of any walking and leisure walking decreased with increasing CVD risk. However, CVD risk was not associated with walking for transportation. Promoting walking may be a way to help adults avoid inactivity and encourage an active lifestyle for CVD prevention and management.


Physical and structural changes in liquid whole egg treated with high-intensity pulsed electric fields.
Liquid whole egg (LWE) is currently pasteurized through the application of heat; however, this treatment entails deleterious effects against some of the functional and technological properties of the product. In this study, the effect of high-intensity pulsed electric fields (HIPEF) processing (field strength: 19, 32, and 37 kV/cm) was compared to the traditional heat pasteurization (66 °C for 4.5 min). Different physical and structural characteristics of LWE, subjected or not to homogenization, were evaluated and compared, having the untreated LWE as a reference. Thermal treatment caused an increase in the viscosity of LWE, especially in nonhomogenized samples. HIPEF treatments did not modify the original color of LWE, whereas thermally treated samples developed an opaque appearance. LWE treated at 19 and 32 kV/cm exhibited a similar foaming capacity as fresh untreated egg, whereas thermal processing and PEF treatments of 37 kV/cm caused a substantial decrease in the foaming capacity of untreated liquid egg. Regarding the microstructure, the lipoprotein matrix appeared to be less affected by the HIPEF than by heat treatment if compared to the control. In addition, heat pasteurization had a significant impact on both the water-soluble protein content of the LWE samples (19.5% to 23.6% decrease) and the mechanical properties of the egg gels (up to 21.3% and 14.5% increase in hardness and cohesiveness, respectively). On the other hand, these parameters were not substantially affected in the HIPEF-treated samples. Heat-induced gels obtained from HIPEF-treated samples did not exhibit remarkable differences in the water-holding capacity (WHC) with respect to heat-pasteurized samples. The impact of high-intensity pulsed electric fields (HIPEF) processing on technological properties of liquid-whole egg was investigated and compared to that of thermal processing. Heat treatments cause a severe impact on the foaming capacity, the water-soluble protein content, and the rheological properties of liquid egg samples, whereas HIPEF treatments better preserved the food matrix structure. Microscopic observations support these results, thus suggesting that HIPEF-processing has potential application for the preservation of liquid egg through nonthermal means.


Ischemic preconditioning fails to improve microcirculation but increases apoptotic cell death in experimental pancreas transplantation.
Brief periods of warm ischemia and subsequent short reperfusion before either long-term cold or warm ischemic insult (ischemic preconditioning, IPC) have proven to ameliorate ischemia/reperfusion (I/R) injury in various organs, such as the liver and lung. The aim of this study was to examine the effect of IPC on pancreatic cell apoptosis and microcirculatory impairments in experimental pancreas transplantation. Male Lewis rats served as donors and recipients of heterotopic syngeneic pancreaticoduodenal transplantation. Recipient animals were divided into two experimental groups: group Tx (n=7) received grafts without IPC, group Tx&IPC received grafts with IPC. Animals that had not undergone transplantation but whose pancreata had been exteriorized served as controls (n=5). All pancreatic grafts were preserved in University of Wisconsin solution for 6 h at 4 degrees C. IPC was induced by interruption of the arterial blood flow for 10 min followed by 10 min of reperfusion. One and two hours after reperfusion, graft microcirculation was assessed by means of intravital microscopy (IVM). Rats were immediately killed after the second measurement and DNA breaks of acinar cells were detected by in situ terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate digoxigenin nick end-labelling (TUNEL) assay and gel electrophoresis (laddering). The apoptotic index (AI) was defined as the number of apoptotic cells per high-power field. Analysis of both groups of transplanted grafts showed a significant decrease in functional capillary density (FCD) and a significant increase in leukocyte sticking to postcapillary venules (LAV) at 1 h and 2 h of reperfusion, compared with animals that had not undergone transplantation ( P<0.01). In parallel, AI was significantly increased in transplanted grafts compared to the controls ( P<0.01). Grafts subjected to IPC showed no significant differences, neither for FCD nor LAV, at both time points if compared with grafts of group Tx. However, IPC resulted in a significant increase in AI ( P<0.05). We can conclude that IPC has no effect on pancreatic microcirculation but enhances acinar cell apoptosis in experimental pancreas transplantation. These results indicate that IPC might increase I/R injury after pancreatic cold ischemia.


Comparative effects of n-3, n-6 and n-9 unsaturated fatty acid-rich diet consumption on lupus nephritis, autoantibody production and CD4+ T cell-related gene responses in the autoimmune NZBWF1 mouse.
Mortality from systemic lupus erythematosus (SLE), a prototypical autoimmune disease, correlates with the onset and severity of kidney glomerulonephritis. There are both preclinical and clinical evidence that SLE patients may benefit from consumption of n-3 polyunsaturated fatty acids (PUFA) found in fish oil, but the mechanisms remain unclear. Here we employed the NZBWF1 SLE mouse model to compare the effects of dietary lipids on the onset and severity of autoimmune glomerulonephritis after consuming: 1) n-3 PUFA-rich diet containing docosahexaenoic acid-enriched fish oil (DFO), 2) n-6 PUFA-rich Western-type diet containing corn oil (CRN) or 3) n-9 monounsaturated fatty acid (MUFA)-rich Mediterranean-type diet containing high oleic safflower oil (HOS). Elevated plasma autoantibodies, proteinuria and glomerulonephritis were evident in mice fed either the n-6 PUFA or n-9 MUFA diets, however, all three endpoints were markedly attenuated in mice that consumed the n-3 PUFA diet until 34 wk of age. A focused PCR array was used to relate these findings to the expression of 84 genes associated with CD4+ T cell function in the spleen and kidney both prior to and after the onset of the autoimmune nephritis. n-3 PUFA suppression of autoimmunity in NZBWF1 mice was found to co-occur with a generalized downregulation of CD4+ T cell-related genes in kidney and/or spleen at wk 34. These genes were associated with the inflammatory response, antigen presentation, T cell activation, B cell activation/differentiation and leukocyte recruitment. Quantitative RT-PCR of representative affected genes confirmed that n-3 PUFA consumption was associated with reduced expression of CD80, CTLA-4, IL-10, IL-18, CCL-5, CXCR3, IL-6, TNF-α and osteopontin mRNAs in kidney and/or spleens as compared to mice fed n-6 PUFA or n-9 MUFA diets. Remarkably, many of the genes identified in this study are currently under consideration as biomarkers and/or biotherapeutic targets for SLE and other autoimmune diseases.


Coherence vortices in Mie scattering of statistically stationary partially coherent fields.
Points within a fully coherent complex scalar optical field, where the amplitude is identically zero but the optical phase has a jump discontinuity, have been widely investigated by the singular-optics community. More recent researches have extended the domain of singular optics to include partially coherent fields. For example, in coherence vortices the phase of the two-point spectral degree of coherence of a partially coherent field exhibits vortex structure around a point where the magnitude of the spectral degree of coherence vanishes. We show that the spectral degree of coherence of Mie scattered partially coherent statistically stationary electromagnetic fields exhibits a rich set of coherence vortices in both the internal and external fields. Specifically, we look at Mie scattering of a stationary beam from a dielectric sphere and study the formation of coherence vortices and their evolution with both the properties of the scattering sphere, and of the incident partially coherent beam.


Nurse-physician relationships in ambulatory oncology settings.
The purpose of this study was to explore nurses' perceptions of nurse-physician relationships in ambulatory oncology settings, which are linked to patient safety. This cross-sectional, descriptive study analyzed survey data collected in 2010 from oncology nurses employed in ambulatory settings. The sampling frame was the nurse licensure database in one state in the Southeastern United States. Nurses completed the Practice Environment Scale of the Nursing Work Index (PES-NWI), reported on the quality of care in their setting, and commented on factors that promoted or inhibited high-quality care delivery. Data analysis used three study variables: empirically derived values from the PES-NWI, a scale of nurse-reported quality of care in their setting, and open-text comments about features in their workplace that promoted or hindered high-quality care. After categorizing open-text comments, analysis of variance was used to evaluate differences in PES-NWI subscales by comment category. Chi-square test statistics were calculated to examine differences in overall practice environment and quality of care by comment category. Nurses reported their relationships with physicians as generally favorable. Qualitative findings suggest two themes that influence how nurses characterize their working relationships with physicians: (a) physician behaviors and (b) structural factors. Both PES-NWI scores and quality of care were rated significantly higher by nurses who wrote favorably about physicians. Favorable nurse-physician relationships in ambulatory settings may reflect positive workplaces and promote high-quality care. Consistent with findings from inpatient units, nurse-physician relationships are important to the quality of ambulatory oncology care. Systematic measurement and attention to reported deficits in these relationships may promote higher quality care.


Shadowless-illuminated variable-angle TIRF (siva-TIRF) microscopy for the observation of spatial-temporal dynamics in live cells.
Total-internal-reflection fluorescence (TIRF) microscopy provides high optical-sectioning capability and a good signal-contrast ratio for structures near the surfaces of cells. In recent years, several improvements have been developed, such as variable-angle TIRF (VA-TIRF) and spinning TIRF (sp-TIRF), which permit quantitative image analysis and address non-uniform scattering fringes, respectively. Here, we present a dual-color DMD-based shadowless-illuminated variable-angle TIRF (siva-TIRF) system that provides a uniform illumination field. By adjusting the incidence angle of the illuminating laser on the back focal plane (BFP) of the objective, we can rapidly illuminate biological samples in layers of various thicknesses in TIRF or hollow-cone epi-fluorescence mode. Compared with other methods of accomplishing VA-TIRF/sp-TIRF illumination, our system is simple to build and cost-effective, and it provides optimal multi-plane dual-color images. By showing spatiotemporal correlated movement of clathrin-coated structures with microtubule filaments from various layers of live cells, we demonstrate that cortical microtubules are important spatial regulators of clathrin-coated structures. Moreover, our system can be used to prove superb axial information of three-dimensional movement of structures near the plasma membrane within live cells.


Chimeric antigen-receptor T-cell therapy for hematological malignancies and solid tumors: Clinical data to date, current limitations and perspectives.
Progress in our understanding of basic immunology along with the advent of bioengineering technologies have made possible the production of human T-cells expressing Chimeric Antigen Receptors (CAR T-cells). These CAR T-cells are designed to target specific antigens presented by cancer cells. Once CARs are bound to these antigens, CAR T-cells get activated and can initiate potent anti-tumor effects. We will here overview the bioengineering advances which made possible the clinical application of CAR T-cell therapy. We will review the data to date regarding anti-CD19 CAR T-cell therapy for acute lymphoblastic leukemia, non-Hodgkin lymphomas, and chronic lymphocytic leukemia. Besides CD19, CAR T-cells directed against the B-cell maturation antigen have also shown encouraging results to treat patients with refractory multiple myeloma. The more limited body of clinical research in the field of solid tumors will also be reviewed. Moreover, we will elaborate on the main toxicities of limitations of CAR T-cell therapy, namely cytokine release syndrome and neurotoxicity. While enjoying an undeniable hype, CAR T-cell therapy bears significant limitations. We will conclude by exposing the possible approaches to make CAR T-cells safer and more efficient beyond the CD19 target.


Characterization of the KRN cell transfer model of rheumatoid arthritis (KRN-CTM), a chronic yet synchronized version of the K/BxN mouse.
In this study, a chronic yet synchronized version of the K/BxN mouse, the KRN-cell transfer model (KRN-CTM), was developed and extensively characterized. The transfer of purified splenic KRN T cells into T cell-deficient B6.TCR.Calpha(-/-)H-2(b/g7) mice induced anti-glucose 6-phosphate isomerase antibody-dependent chronic arthritis in 100% of the mice with uniform onset of disease 7 days after T cell transfer. Cellular infiltrations were assessed by whole-ankle transcript microarray, cytokine and chemokine levels, and microscopic and immunohistochemical analyses 7 through 42 days after T cell transfer. Transcripts identified an influx of monocytes/macrophages and neutrophils into the ankles and identified temporal progression of cartilage damage and bone resorption. In both serum and ankle tissue there was a significant elevation in interleukin-6, whereas macrophage inflammatory protein-1 alpha and monocyte chemotactic protein-1 were only elevated in tissue. Microscopic and immunohistochemical analyses revealed a time course for edema, synovial hypertrophy and hyperplasia, infiltration of F4/80-positive monocytes/macrophages and myeloperoxidase-positive neutrophils, destruction of articular cartilage, pannus invasion, bone resorption, extra-articular fibroplasia, and joint ankylosis. The KRN cell transfer model replicates many features of chronic rheumatoid arthritis in humans in a synchronized manner and lends itself to manipulation of adoptively transferred T cells and characterizing specific genes and T cell subsets responsible for rheumatoid arthritis pathogenesis and progression.


Dissection of functional domains of the voltage-dependent Ca2+ channel alpha2delta subunit.
Coexpression of the cloned voltage-dependent Ca2+ channel alpha2delta subunit with the pore-forming alpha1 subunit results in a significant increase in macroscopic current amplitude. To gain insight into the mechanism underlying this interaction, we have examined the regulatory effect of either the alpha2delta complex or the delta subunit on the Ca2+ channel alpha1 subunit. Transient transfection of tsA201 cells with the cardiac L-type alpha1C subunit alone resulted in the expression of inward voltage-activated currents as well as measurable [3H]-PN200-110 binding to membranes from transfected cells. Coexpression of the alpha2delta subunit significantly increased the macroscopic current amplitude, altered the voltage dependence and the kinetics of the current, and enhanced [3H]-PN200-110 binding. Except for the increase in amplitude, coexpression of the delta subunit reproduced entirely the effects of the full-length alpha2delta subunit on the biophysical properties of the alpha1C currents. However, no effect on specific [3H]-PN200-110 binding was observed on delta subunit coexpression. Likewise, profound effects on current kinetics of the neuronal alpha1A subunit were observed on coexpression of the alpha2delta complex in Xenopus oocytes. Furthermore, by using a chimeric strategy, we localized the region involved in this regulation to the transmembrane domain of the delta subunit. These data strongly suggest that the molecular determinants involved in alpha2delta regulation are conserved across L-type and non-L type Ca2+ channels. Taken together, our results indicate that the region of the alpha2delta subunit involved in the modulation of the gating properties of the high voltage-activated calcium channels is localized in the delta domain of the protein. In contrast, the level of membrane expression of functional channels relies on the presence of the alpha2 domain of the alpha2delta complex.


A Pumpless Pediatric Artificial Lung Maintains Function for 72 h Without Systemic Anticoagulation Using the Nitric Oxide Surface Anticoagulation System.
Children with end-stage lung disease are commonly managed with extracorporeal life support (ECLS) as a bridge to lung transplantation. A pumpless artificial lung (MLung) is a portable alternative to ECLS and it allows for ambulation. Both ECLS and pumpless artificial lungs require systemic anticoagulation which is associated with hemorrhagic complications. We tested the MLung with a novel Nitric Oxide (NO) Surface Anticoagulation (NOSA) system, to provide local anticoagulation for 72 h of support in a pediatric-size ovine model. Four mini sheep underwent thoracotomy and cannulation of the pulmonary artery (inflow) and left atrium (outflow), recovered and were monitored for 72hr. The circuit tubing and connectors were coated with the combination of an NO donor (diazeniumdiolated dibutylhexanediamine; DBHD-N2O2) and argatroban. The animals were connected to the MLung and 100 ppm of NO was added to the sweep gas. Systemic hemodynamics, blood chemistry, blood gases, and methemoglobin were collected. Mean device flow was 836 ± 121 mL/min. Device outlet saturation was 97 ± 4%. Pressure drop across the lung was 3.5 ± 1.5 mmHg and resistance was 4.3 ± 1.7 mmHg/L/min. Activated clotting time averaged 170 ± 45s. Methemoglobin was 2.9 ± 0.8%. Platelets declined from 590 ± 101 at baseline to 160 ± 90 at 72 h. NO flux (x10-10 mol/min/cm2) of the NOSA circuit averaged 2.8 ± 0.6 (before study) and 1.9 ± 0.1 (72 h) and across the MLung 18 ± 3 NO flux was delivered. The MLung is a more portable form of ECLS that demonstrates effective gas exchange for 72 h without hemodynamic changes. Additionally, the NOSA system successfully maintained local anticoagulation without evidence of systemic effects.


Characterization of Extracellular Vesicles Secreted in Lentiviral Producing HEK293SF Cell Cultures.
Lentiviral vectors (LVs) are a powerful tool for gene and cell therapy and human embryonic kidney cells (HEK293) have been extensively used as a platform for production of these vectors. Like most cells and cellular tissues, HEK293 cells release extracellular vesicles (EVs). EVs released by cells share similar size, biophysical characteristics and even a biogenesis pathway with cell-produced enveloped viruses, making it a challenge to efficiently separate EVs from LVs. Thus, EVs co-purified with LVs during downstream processing, are considered "impurities" in the context of gene and cell therapy. A greater understanding of EVs co-purifying with LVs is needed to enable improved downstream processing. To that end, EVs from an inducible lentivirus producing cell line were studied under two conditions: non-induced and induced. EVs were identified in both conditions, with their presence confirmed by transmission electron microscopy and Western blot. EV cargos from each condition were then further characterized by a multi-omic approach. Nineteen proteins were identified by mass spectrometry as potential EV markers to differentiate EVs in LV preparations. Lipid composition of EV preparations before and after LV induction showed similar enrichment in phosphatidylserine. RNA cargos in EVs showed enrichment in transcripts involved in viral processes and binding functions. These findings provide insights on the product profile of lentiviral preparations and could support the development of improved separation strategies aimed at removing co-produced EVs.


Linking Hip Disability and Osteoarthritis Outcome Score-Physical Function Short Form and PROMIS Physical Function.
Linking scores on patient-reported outcome measures can enable data aggregation for research, clinical care, and quality. We aimed to link scores on the Hip Disability and Osteoarthritis Outcome Score-Physical Function Short Form (HOOS-PS) and the Patient-reported Outcomes Measurement Information System Physical Function (PROMIS PF). A retrospective study was conducted from 2017 to 2020 evaluating patients with hip osteoarthritis who received routine clinical care from an orthopaedic surgeon. Our sample included 3,382 unique patients with 7,369 pairs of HOOS-PS and PROMIS PF measures completed at a single nonsurgical, preoperative, or postoperative time point. We included one randomly selected time point of scores for each patient in our linking analysis sample. We compared the accuracy of linking using four methods, including equipercentile and item response theory-based approaches. PROMIS PF and HOOS-PS scores were strongly correlated ( r = -0.827 for raw HOOS-PS scores and r = 0.820 for summary HOOS-PS scores). The assumptions were met for equipercentile and item response theory approaches to linking. We selected the item response theory-based Stocking-Lord approach as the optimal crosswalk and estimated item parameters for the HOOS-PS items on the PROMIS metric. A sensitivity analysis demonstrated overall robustness of the crosswalk estimates in nonsurgical, preoperative, and postoperative patients. These crosswalks can be used to convert scores between HOOS-PS and PROMIS PF metric at the group level, which can be valuable for data aggregation. Conversion of individual patient-level data is not recommended secondary to increased risk of error.


Canonical correlation reveals important relations between health locus of control, coping, affect and values.
This article explored advantages of canonical correlation using the Multidimensional Health Locus of Control (MHLC) scales in relation to measures of coping, affect and values. Survey data collected from 659 participants demonstrated significant canonical correlations between the MHLC and synthetic variables representing all three of these constructs. Results verified some previously hypothesized relations (e.g. external health control relates to passive coping) and introduced new findings pertaining to the relations between networks of MHLC variables and networks of the other three constructs (e.g. positive affect relates to collaborative control between self and God regarding health). Canonical correlation promotes greater understanding of relations between health loci of control and other multidimensional variables than can be obtained through simpler analytic strategies.


Prevalence and determinants of cervicovaginal, oral, and anal HPV infection in a population of transgender and gender diverse people assigned female at birth.
HPV causes oral, cervicovaginal, and anogenital cancer, and cervical cancer screening options include HPV testing of a physician-collected sample. Transgender and gender diverse (TGD) people assigned female at birth (AFAB) face discrimination and stigma in many healthcare settings; are believed to be a lower risk for cervical cancer by many physicians; are less likely to be up to date on preventive health care services such as pelvic health exams; and are more likely to have inadequate results from screening tests. Self-sampling options may increase access and participation in HPV testing and cancer screening. We recruited 137 TGD individuals AFAB for an observational study, mailing them a kit to self-collect cervicovaginal, oral, and anal samples at home. We tested samples for HPV genotypes 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73 and 90 using a PCR mass array test. 102 participants completed the study. Among those with valid tests, 8.8% were positive for oral HPV, 30.5% were positive for cervicovaginal HPV, and 39.6% were positive for anal HPV. A large fraction of anal (50.0%) and oral (71.4%) infections were concordant with a cervicovaginal infection of the same type. HPV infection in TGD people AFAB may be just as high, if not higher, than in cisgender women. It is essential that we reduce barriers to cancer screening for TGD populations, such as through the development of a clinically approved self-screening HPV test.


Interaction Between Spironolactone and Natriuretic Peptides in Patients With Heart Failure and Preserved Ejection Fraction: From the TOPCAT Trial.
The aims of this study were to explore the relationship of baseline levels of natriuretic peptides (NPs) with outcomes and to test for an interaction between baseline levels of NPs and the effects spironolactone. Plasma NPs are considered to be helpful in the diagnosis of heart failure (HF) with preserved ejection fraction (HFpEF), and elevated levels are associated with adverse outcomes. Levels of NPs higher than certain cutoffs are often used as inclusion criteria in clinical trials of HFpEF to increase the likelihood that patients have HF and to select patients at higher risk for events. Whether treatments have a differential effect on outcomes across the spectrum of NP levels is unclear. The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) trial randomized patients with HFpEF and either prior hospitalization for HF or elevated natriuretic peptide levels (B-type NP [BNP] ≥100 pg/ml or N-terminal proBNP ≥360 pg/ml) to spironolactone or placebo. Baseline BNP (n = 430) or N-terminal proBNP (n = 257) levels were available in 687 patients enrolled from the Americas in the elevated-NP stratum of TOPCAT. Higher levels of NPs were independently associated with an increased risk for TOPCAT's primary endpoint of cardiovascular mortality, aborted cardiac arrest, or hospitalization for HF when analyzed either continuously or grouped by terciles, adjusting for region of enrollment, age, sex, atrial fibrillation, diabetes, renal function, body mass index, and heart rate. There was a significant interaction between the effect of spironolactone and baseline NP terciles for the primary outcome (p = 0.017), with greater benefit of the drug in the lower compared with higher NP terciles. Similar to the effects of irbesartan in the I-PRESERVE (Irbesartan in Heart Failure With Preserved Ejection Fraction) trial, a greater benefit of spironolactone was observed in the group with lower levels of NPs and overall risk in TOPCAT. Elevated NPs in HFpEF identify patients at higher risk for events but who may be less responsive to treatment. The mechanism of this apparent interaction between disease severity and response to therapy requires further exploration. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]; NCT00094302).


Using information from historical high-throughput screens to predict active compounds.
Modern high-throughput screening (HTS) is a well-established approach for hit finding in drug discovery that is routinely employed in the pharmaceutical industry to screen more than a million compounds within a few weeks. However, as the industry shifts to more disease-relevant but more complex phenotypic screens, the focus has moved to piloting smaller but smarter chemically/biologically diverse subsets followed by an expansion around hit compounds. One standard method for doing this is to train a machine-learning (ML) model with the chemical fingerprints of the tested subset of molecules and then select the next compounds based on the predictions of this model. An alternative approach would be to take advantage of the wealth of bioactivity information contained in older (full-deck) screens using so-called HTS fingerprints, where each element of the fingerprint corresponds to the outcome of a particular assay, as input to machine-learning algorithms. We constructed HTS fingerprints using two collections of data: 93 in-house assays and 95 publicly available assays from PubChem. For each source, an additional set of 51 and 46 assays, respectively, was collected for testing. Three different ML methods, random forest (RF), logistic regression (LR), and naïve Bayes (NB), were investigated for both the HTS fingerprint and a chemical fingerprint, Morgan2. RF was found to be best suited for learning from HTS fingerprints yielding area under the receiver operating characteristic curve (AUC) values >0.8 for 78% of the internal assays and enrichment factors at 5% (EF(5%)) >10 for 55% of the assays. The RF(HTS-fp) generally outperformed the LR trained with Morgan2, which was the best ML method for the chemical fingerprint, for the majority of assays. In addition, HTS fingerprints were found to retrieve more diverse chemotypes. Combining the two models through heterogeneous classifier fusion led to a similar or better performance than the best individual model for all assays. Further validation using a pair of in-house assays and data from a confirmatory screen--including a prospective set of around 2000 compounds selected based on our approach--confirmed the good performance. Thus, the combination of machine-learning with HTS fingerprints and chemical fingerprints utilizes information from both domains and presents a very promising approach for hit expansion, leading to more hits. The source code used with the public data is provided.


[Leukocyte transfusions in the treatment of sepsis].
Leukotransfusion from ordinary donors and those immunized by staphylococcal anatoxin were used in complex treatment of 55 patients in a catabolic phase of different forms of sepsis. It was found that transfusion of leukosuspensions, immune ones in particular, had pronounced immunostimulating, detoxicating, antibacterial and anti-inflammatory effects. A short course of transfusions of allogenic leukocytes can be fulfilled without a selection by the HLA system.


Transplacental transmission: A rare case of Ebola virus transmission.
During the mid-transmission period of the Ebola virus disease (EVD) outbreak in Sierra Leone, a 19-year-old pregnant woman, who was a petty trader in a health facility in Freetown, noticing no fetal movement for the past 3 days, reported to a health facility. Medical history and laboratory testing showed no abnormalities except that she was positive for sickle cell. She was not known to any surveillance team of having any epidemiological link to EVD case. She was induced with oral medications as well as IV infusion. EVD test showed that the fetus was positive to EVD with a high threshold value of 21, while the woman was negative for EVD with a threshold value of 42. The woman was positive to EVD IgG but negative to EVD IgM by ELISA technique. This is a rare EVD case in the period of medium transmission. We conclude that the woman may have come into contact with a low dose of virus not enough to cause a full blown EVD and that her immune system was able to stop the virus from further replication.


Effect of dynamic platelet-to-lymphocyte ratio on the prognosis of patients with esophageal squamous cell carcinoma receiving chemoradiotherapy.
Systemic inflammatory load affects the long-term developmental outcomes in patients with malignancy. The purpose of this study was to investigate the effect of the dynamic levels of platelet-to-lymphocyte ratio (PLR) at different treatment stages on the prognosis of patients with esophageal squamous cell carcinoma (ESCC) undergoing chemoradiotherapy. This study included 168 patients who received chemoradiotherapy between 2012 and 2018. PLR levels at different treatment stages were calculated based on blood test results. The association between PLR and overall survival (OS) was determined using the Kaplan-Meier method and Cox proportional regression models. The cutoff values of PLR before and after treatment of 168 patients with ESCC were 195.7 and 403.6, respectively. The 5-year OS rates of patients in the low and high pre-PLR groups were 42.1% and 21.7%, respectively. The overall 5-year OS rate of all patients was 27.1%. Multivariate analysis results showed that patient age (hazard ratio [HR] = 1.736; 95% confidence interval (CI) = 1.129-2.669; P = .012), alcohol consumption (HR = 1.622; 95%CI = 1.050-2.508; P = .029), T stage (HR = 12.483; 95%CI = 3.719-41.896; P < .001), pre-PLR (HR = 1.716; 95%CI = 1.069-2.756; P = .025), post-PLR (HR = 1.664; 95%CI = 1.106-2.503; P = .015) were independent factors of the prognosis of patients with ESCC. PLR at different treatment stages can be used to effectively evaluate the prognosis of patients with ESCC undergoing chemoradiotherapy.


Sustained Swimming Speeds of Dolphins.
Observations of fout large groups of dolphins suggest that they are able to swim at a sustained speed of 14 to 18 knots. The blackfish are able to maintain speeds of about 22 knots, and one killer whale seemed able to swim somewhat faster. This implies that the apparent coefficient of surface friction remains approximately constant for dolphins from 6 to 22 ft long, as is the case for rigid bodies.


Antidepressants versus placebo for people with bulimia nervosa.
Bulimia Nervosa (BN) represents an important public health problem and is related to serious morbidity and even mortality. This review attempted to systematically evaluate the use of antidepressant medications compared with placebo for the treatment of bulimia nervosa. The primary objective of this review was to determine whether using antidepressant medications was clinically effective for the treatment of bulimia nervosa. The secondary objectives were:(i) to examine whether there was a differential effect for the various classes/types of antidepressants with regard to effectiveness and tolerability(ii) to test the hypothesis that the effect of antidepressants on bulimic symptoms was independent of its effect on depressive symptoms (1) electronic searches of MEDLINE (1966 to December 2002), EMBASE (1980-December 2002), PsycINFO (to December 2002), LILACS & SCISEARCH (to 2002)(2) the Cochrane Register of Controlled Trials and the Cochrane Depression, Anxiety and Neurosis Group Register - ongoing(3) inspection of the references of all identified trials(4) contact with the pharmaceutical companies and the principal investigator of included trials(5) inspection of the International Journal of Eating Disorders - ongoing every randomised, placebo-controlled trial in which antidepressant medications were compared to placebo to reduce the symptoms of bulimia nervosa in patients of any age or gender.Quality criteria: reports were considered adequate if they were classified as A or B according to the Cochrane Manual. The Jadad scale, with a cut off of 2 points, was applied to check the validity of the above referred criterion but was not used as an inclusion criterion. Data were extracted independently by two reviewers for each included trial. Dichotomous data were evaluated by the relative risk with 95% confidence intervals (CI) around this measure, based on the random effects model; continuous data were evaluated by the standardised mean difference with the 95% CI. NNT was calculated using the inverse of the absolute risk reduction. Currently the review includes 19 trials comparing antidepressants with placebo: 6 trials with TCAs (imipramine, desipramine and amitriptyline), 5 with SSRIs (fluoxetine), 5 with MAOIs (phenelzine, isocarboxazid, moclobemide and brofaromine) and 3 with other classes of drugs (mianserin, trazodone and bupropion). Similar results were obtained in terms of efficacy for these different groups of drugs. The pooled RR for remission of binge episodes was 0.87 (95% CI 0.81-0.93; p<0,001) favouring drugs. The NNT for a mean treatment duration of 8 weeks, taking the non-remission rate in the placebo controls of 92% as a measure of the baseline risk was 9 (95% CI 6 - 16). The RR for clinical improvement, defined as a reduction of 50% or more in binge episodes was 0.63 (95% CI 0.55-0.74) and the NNT for a mean treatment duration of 9 weeks was 4 (95% CI 3 - 6), with a non-improvement rate of 67% in the placebo group. Patients treated with antidepressants were more likely to interrupt prematurely the treatment due to adverse events. Patients treated with TCAs dropped out due to any cause more frequently that patients treated with placebo. The opposite was found for those treated with fluoxetine, suggesting it may be a more acceptable treatment. Independence between antidepressant and anti-bulimic effects could not be evaluated due to incomplete published data. The use of a single antidepressant agent was clinically effective for the treatment of bulimia nervosa when compared to placebo, with an overall greater remission rate but a higher rate of dropouts. No differential effect regarding efficacy and tolerability among the various classes of antidepressants could be demonstrated.


[The action of antifeins with different memory effects on the cAMP-independent protein kinases of brain chromatin].
The two cAMP-independent protein kinases (PK I and PK II) were obtained from neuronal chromatin of rat brain. Nonhistone HMG-proteins were used as phosphorylation substrates. The possibility of antifeines direct action on PK II was revealed. Ethylnorantifeine and its demethylated analogues increased enzyme activity whereas allylnorantifeine decreased it. The action of ethylnorantifeine and its structural analogues were similar to its influence on neuronal RNA-synthesizing activity and long-term memory. The conclusion was made that cAMP-independent PK II may be the target of antifeines action during realization of its mnestic effects.