Autophagy and neuroprotection in astrocytes exposed to 6-hydroxydopamine is negatively regulated by NQO2: relevance to Parkinson's disease.
Dopaminergic degeneration is a central feature of Parkinson's disease (PD), but glial dysfunction may accelerate or trigger neuronal death. In fact, astrocytes play a key role in the maintenance of the blood-brain barrier and detoxification. 6-hydroxydopamine (6OHDA) is used to induce PD in rodent models due to its specific toxicity to dopaminergic neurons, but its effect on astrocytes has been poorly investigated. Here, we show that 6OHDA dose-dependently impairs autophagy in human U373 cells and primary murine astrocytes in the absence of cell death. LC3II downregulation was observed 6 to 48 h after treatment. Interestingly, 6OHDA enhanced NRH:quinone oxidoreductase 2 (NQO2) expression and activity in U373 cells, even if 6OHDA turned out not to be its substrate. Autophagic flux was restored by inhibition of NQO2 with S29434, which correlated with a partial reduction in oxidative stress in response to 6OHDA in human and murine astrocytes. NQO2 inhibition also increased the neuroprotective capability of U373 cells, since S29434 protected dopaminergic SHSY5Y cells from 6OHDA-induced cell death when cocultured with astrocytes. The toxic effects of 6OHDA on autophagy were attenuated by silencing NQO2 in human cells and primary astrocytes from NQO2-/- mice. Finally, the analysis of Gene Expression Omnibus datasets showed elevated NQO2 gene expression in the blood cells of early-stage PD patients. These data support a toxifying function of NQO2 in dopaminergic degeneration via negative regulation of autophagy and neuroprotection in astrocytes, suggesting a potential pharmacological target in PD.


[Acute psychotic disorder associated with vigabatrin].
Vigabatrin, a drug mainly used in the treatment of therapy-resistant epilepsy, has been associated to a large range of adverse effects, including acute psychotic disorders. The authors report the case of a 44-year-old patient with drug-resistant temporal lobe epilepsy that developed an acute psychotic episode about three weeks after initiating medication with vigabatrin. After the withdrawal of vigabatrin and the addition of an antipsychotic drug, the clinical picture improved promptly and the patient was discharged within a short period of time. The authors discuss the patient's diagnosis, the possible mechanisms of vigabatrin-associated psychosis and the therapeutic approach, stressing the questions that concern vigabatrin prescription and withdrawal.


Improved one-year survival after acute myocardial infarction in Icelandbetween 1986 and 1996.
During the last decade the treatment of patients with acute myocardial infarction (AMI) has changed dramatically. In order to evaluate the overall impact of these changes on mortality and morbidity, we collected data on all patients hospitalized for AMI in Reykjavik, Iceland, during the calendar years of 1986 and 1996. Demographical characteristics of AMI patients did not change significantly between study periods. One-year mortality decreased from 26.3 to 19.7% (p < 0.05). Patients discharged with aspirin or beta-antagonists as well as those who received thrombolytic therapy had decreased 1-year mortality both years. Patients discharged with diuretics, digoxin or antiarrhythmics had increased 1-year mortality. We conclude that the 25% reduction in 1-year mortality is partially due to changes in therapy.


Defective lamin A-Rb signaling in Hutchinson-Gilford Progeria Syndrome and reversal by farnesyltransferase inhibition.
Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare premature aging disorder caused by a de novo heterozygous point mutation G608G (GGC>GGT) within exon 11 of LMNA gene encoding A-type nuclear lamins. This mutation elicits an internal deletion of 50 amino acids in the carboxyl-terminus of prelamin A. The truncated protein, progerin, retains a farnesylated cysteine at its carboxyl terminus, a modification involved in HGPS pathogenesis. Inhibition of protein farnesylation has been shown to improve abnormal nuclear morphology and phenotype in cellular and animal models of HGPS. We analyzed global gene expression changes in fibroblasts from human subjects with HGPS and found that a lamin A-Rb signaling network is a major defective regulatory axis. Treatment of fibroblasts with a protein farnesyltransferase inhibitor reversed the gene expression defects. Our study identifies Rb as a key factor in HGPS pathogenesis and suggests that its modulation could ameliorate premature aging and possibly complications of physiological aging.


Isolation of tobacco DNA segments with plant promoter activity.
We constructed a promoter probe vector, pGVL120, to isolate plant DNA segments with promoter activity in tobacco. Plant nuclear DNA Sau3A fragments were inserted in front of the npt-II sequence, and a mixture of recombinant plasmids was mobilized to Agrobacterium sp. and used to transform tobacco protoplasts. By kanamycin selection, transformed plant cell lines containing NPT-II T-DNAs were isolated. Eight of these cell lines were regenerated and analyzed for the levels of NPT-II activity in stem, root, midrib, and leaf. These levels demonstrated novel regulation patterns in each isolate. One cell line, T20, was analyzed in detail and found to contain four different T-DNAs. One of the recloned T-DNAs, T20-2, contains an insert of 401 base pairs in front of the NPT-II sequence, and by reintroducing this T-DNA into plant cells we could demonstrate that this insert provides a promoter sequence. The NPT-II enzyme activity under the control of the P20 promoter is especially high in stem and root, but low in leaf and callus, both in the originally isolated T20 plant and in independently isolated transformants with the T20-2 T-DNA.


Reductive dechlorination of 1, 2-dichloroethane using anaerobic sequencing batch reactor (ASBR).
The objective of this research was to study the dechlorination of 1,2-dichloroethane (1,2-DCA) in a synthetic wastewater with lab-scale anaerobic sequencing batch (ASBR) reactors. Anaerobic sludge was used as a biocatalyst. Sodium acetate and dextrose served as the main methanogenic substrate. Experimental studies were conducted at wide-range of volumetric (0.25-1.25 g COD/L.d) and specific (0.0362-0.181 g COD/ g VSS.d) loading rates and influent wastewater CODs (500-2500 mg/L). During 266 days of reactor operation, the mixed culture degraded 1,2 dichloroethane at concentrations of up to 50 mg/L, with an HRT of 48 hrs. No chlorinated intermediates or residues were found. 1,2-DCA degradation resulted in ethene and ethane formation. Acetate was the most effective electron donor for dechlorination, although, dextrose was also effective, but to a lesser extent. The mixed culture degraded 1,2 Dichloroethane in the temperature range of 28+/-4 degrees C, with the pH range of 7.25 to 7.95. The 1,2-DCA removal rates achieved, and the safe nature of the end products, signify the anaerobic sequencing batch (ASBR) reactor technology for practical decontamination of waters containing such types of organochlorines. The COD removal efficiencies were in the range of 95 to 98% depending on volumetric and specific loading rates applied.


(Di-2-pyridyl-amine)-(methanol)sulfato-copper(II).
The title complex, [Cu(SO(4))(C(10)H(9)N(3))(CH(3)OH)], is a mononuclear species with the Cu(II) ion in a Jahn-Teller-distorted '4 + 1' square-pyramidal geometry. The basal plane is defined by the pyridyl N-atom donors of the bipyridyl-amine (bpa) ligand and two O-atom donors of the sulfate ligand. The coordination geometry is completed by the axial coordination of a methanol O-atom donor. The axial bond length displays the usual elongation: Cu-O(axial) = 2.168 (2), Cu-O(basal) = 2.016 (2) (average) and Cu-N(basal) = 1.951 (3) Å (average). In the crystal structure, the complex mol-ecules are linked through N-H⋯O and O-H⋯O hydrogen bonds into chains along [100].


[Diabetic cardiac autonomic neuropathy].
Cardiac autonomic neuropathy (CAN) is a common complication of diabetes mellitus, which is associated with a higher risk of morbidity and mortality. It can be detected by analyzing spontaneous (Holter) or provoked (Ewing's test battery) changes in heart rate and arterial blood pressure. Baroreflex gain is a specific index of great interest. Our laboratory has acquired a large experience in the assessment of CAN in diabetic patients. We use the Finapres, a device that allows continuous noninvasive monitoring of blood pressure and heart rate, and a special and discriminative active orthostatic manoeuvre, the "squatting" test (standing-squatting-standing).


Is Europe 'giving in to baby markets?' Reproductive tourism in Europe and the gradual erosion of existing legal limits to reproductive markets.
The main question in this article is how national legal orders in Europe, given their often restrictive laws on reproductive markets and assisted reproductive technologies (ARTs), are currently responding and should respond to reproductive tourism, in light of the fact that access to foreign reproductive markets seems to be making these national laws 'merely symbolic'. Although many national governments have finally managed after many years of political and legal struggles to establish a carefully balanced legal framework for the regulation of these often ethically and religiously sensitive matters, ironically reproductive travel seems to be turning national reproductive laws into a dead letter. Currently, as a reaction to these developments, new legal strategies are being proposed and explored. Within the European context, the view is gaining ground that laws that curb international reproductive markets and their accompanying streams of fertility tourism have become ineffective, meaningless, and even harmful. As a result, a certain tendency towards tolerance of reproductive markets and reproductive travel can be detected in both politics and academia. According to this line of reasoning, restrictive and prohibitive legislation should be replaced by more pragmatic policies that take the realities of reproductive markets as a starting point. From this perspective, the legal restrictions within the country of origin, rather than the lack of regulation in the country of destination, should be regarded as the core of the problem. As a result, an increasing number of scholars and policy makers are arguing for more lenient national policies towards ARTs, hoping to thereby remove the main incentive for aspiring parents to resort to foreign reproductive services. This emerging pragmatic strategy of tolerance towards reproductive tourism and international reproductive markets rests on three arguments, which are each critically examined in this article. Although these arguments offer valuable insights, several disadvantages and weaknesses tend to be overlooked. The critical examination of these pragmatic arguments is followed by a plea for a more positive understanding and recognition of the symbolic dimensions of reproductive legislation. It is argued that ART laws also have an important communicative, expressive and anthropological meaning and function, which surpass these laws' practical effectiveness. Alternatively, policies based on the pragmatic tolerance of reproductive markets show significant shortcomings, which also need to be taken into consideration by national governments when evaluating existing ART laws.


Effects of spatial and temporal resolution on cardiovascular magnetic resonance feature tracking measurements using a simple realistic numerical phantom.
To develop a single-slice numerical phantom with known myocardial motion, at several temporal and in-plane spatial resolutions, for testing and comparison of Cardiovascular Magnetic Resonance (CMR) feature tracking (FT) software. The phantom was developed based on CMR acquisitions of one volunteer (acquired cine, tagging cine, T1 map, T2 map, proton density weighted image). The numerical MRI simulator JEMRIS was used, and the phantom was generated at several in-plane spatial resolutions (1.4 × 1.4 mm2 to 3.0 × 3.0 mm2) and temporal resolutions (20 to 40 cardiac phases). Two feature tracking software packages were tested: Medical Image Tracking Toolbox (MITT) and two versions of cvi42 (v5.3.8 and v5.13.7). The effect of resolution on strain results was investigated with reference to ground-truth radial and circumferential strain. Peak radial strain was consistently undermeasured more for cvi42 v5.13.7 than for v5.3.8. Increased pixel size produced a trend of increased difference from ground-truth peak strain, with the largest changes for cvi42 obtained using v5.13.7 between 1.4 × 1.4 mm2 and 3.0 × 3.0 mm2, at 9.17 percentage points (radial) and 8.42 percentage points (circumferential). The results corroborate the presence of intervendor differences in feature tracking results and show the magnitude of strain differences between software versions. This study shows how temporal and in-plane spatial resolution can affect feature tracking with reference to the ground-truth strain of a numerical phantom. Results reaffirm the need for numerical phantom development for the validation and testing of FT software.


Syntaphilin Regulates Neutrophil Migration in Cancer.
Pathologically activated neutrophils (PMN) with immunosuppressive activity, which are termed myeloid-derived suppressor cells (PMN-MDSC), play a critical role in regulating tumor progression. These cells have been implicated in promoting tumor metastases by contributing to premetastatic niche formation. This effect was facilitated by enhanced spontaneous migration of PMN from bone marrow to the premetastatic niches during the early-stage of cancer development. The molecular mechanisms underpinning this phenomenon remained unclear. In this study, we found that syntaphilin (SNPH), a cytoskeletal protein previously known for anchoring mitochondria to the microtubule in neurons and tumor cells, could regulate migration of PMN. Expression of SNPH was decreased in PMN from tumor-bearing mice and patients with cancer as compared with PMN from tumor-free mice and healthy donors, respectively. In Snph-knockout (SNPH-KO) mice, spontaneous migration of PMN was increased and the mice showed increased metastasis. Mechanistically, in SNPH-KO mice, the speed and distance travelled by mitochondria in PMN was increased, rates of oxidative phosphorylation and glycolysis were elevated, and generation of adenosine was increased. Thus, our study reveals a molecular mechanism regulating increased migratory activity of PMN during cancer progression and suggests a novel therapeutic targeting opportunity.


Quantifying the Nearly Random Microheterogeneity of Aqueous tert-Butyl Alcohol Solutions Using Vibrational Spectroscopy.
The microheterogeneous structure of aqueous tert-butyl alcohol (TBA) solutions is quantified by combining experimental, simulations, and theoretical results. Experimental Raman multivariate curve resolution (Raman-MCR) C-H frequency shift measurements are compared with predictions obtained using combined quantum mechanical and effective fragment potential (QM/EFP) calculations, as well as with molecular dynamics (MD), random mixture (RM), and finite lattice (FL) predictions. The results indicate that the microheterogeneous aggregation in aqueous TBA solutions is slightly less than that predicted by MD simulations performed using either CHARMM generalized force field (CGenFF) or optimized parameters for liquid simulations all atom (OPLS-AA) force fields but slightly more than that in a self-avoiding RM of TBA-like molecules. The results imply that the onset of microheterogeneity in aqueous solutions occurs when solute contact free energies are about an order of magnitude smaller than thermal fluctuations, thus suggesting a fundamental bound of relevance to biological self-assembly.


Impact on plant productivity under low-fertility sandy soil in arid environment by revitalization of lentil roots.
Lentil is one of the essential legume crops, which provides protein for humans and animals. This legume can improve soil fertility through nitrogen fixation, which is imperative in low-fertility soils. The growth and productivity of lentil could be enhanced through improving nutrition and root revitalization. Therefore, the objective of this study was to assess the impact of root activator (RA) and phosphorus (P) application on morphological, physiological, agronomic, and quality traits of lentil under newly reclaimed low-fertility sandy soil in an arid environment. The RA was applied at four levels of 0 (RA0-untreated control), 1.25 (RA1), 2.5 (RA2), and 3.75 (RA3) l ha-1. RA contained 9% potassium humate, 1,600 ppm indole butyric acid, 200 ppm gibberellic acid, and 200 ppm naphthalene acetic acid. The recommended rate of phosphorus (P) fertilization in the newly reclaimed low-fertility sandy soil (75 kg P2O5 ha-1) was applied, and its amount was increased and decreased by 25 kg P2O5 ha-1 vs. non-added control. Thus, P rates were applied at four rates 0 (P0; control), 50 (P1), 75 (P2), and 100 (P3) kg phosphorus pentoxide (P2O5) ha-1. Our results revealed that treated lentil plants with the high levels of both treatments (RA3 and P3) exhibited superiority in root measurements (root length, total number of nodules plant-1, number of active nodules plant-1, dry weights of active nodules, and total root), nitrogenase activity, chlorophyll a and b, carotenoids, yield traits, and seed proteins and carbohydrates. However, the recommended P level (75 kg P2O5 ha-1, P2) under the high level of RA (3.75 l ha-1, RA3) displayed non-significant differences in yield traits (plant height, 1,000-seed weight, seed yield ha-1) and quality traits (protein and carbohydrate) with the high P level (100 kg P2O5 ha-1, P3). Accordingly, its recommended economically and environmentally to use this coapplication of RA3 and P3 in low-fertility soil for better lentil growth, and seed yield and quality.


A five-year analysis of the incidence of glomerulonephritis at Cairo University Hospital-Egypt.
Our study aimed to obtain a comprehensive review of the incidence of biopsy-proven glomerulonephritis (GN) at the Cairo University Hospitals, Egypt, over the last five years. We analyzed the clinical and pathological data of all renal biopsy samples that were performed during the period from July 2003 to July 2008. Renal biopsy samples of 924 patients were referred for pathological assessment during the period of the study [437 male and 487 female patients; their mean age was 26.5 ± 14.6 years (range: 2.5-71 years)]. Focal segmental glomerulo-nephritis was the most frequent cause of primary GN (21.21%), followed by mesangial proliferative GN (18.93%), diffuse proliferative GN (13.96%), focal proliferative GN (12.77%) and membranous GN (10.93%). The results could be explained by the high incidence of lupus nephritis among the study subjects as well as the relatively young age of the study group.


The regulation of transmitter expression in postembryonic lineages in the moth Manduca sexta. II. Role of cell lineage and birth order.
The expression of GABA is restricted to the progeny of only six of the 24 identified postembryonic lineages in the thoracic ganglia of the tobacco hornworm, Manduca sexta (Witten and Truman, 1991). It is colocalized with a peptide similar to molluscan small cardioactive peptide B (SCPB) in some of the neurons in two of the six lineages. By combining chemical ablation of the neuroblasts at specific larval stages with birth dating of the progeny, we tested whether the expression of GABA and the SCPB-like peptide was determined strictly by cell lineage or involved cellular interactions among the members of individual clonal groups. Chemical ablation of the six specific neuroblasts that produced the GABA-positive neurons (E, K, M, N, T, and X) or of the two that produced the GABA + SCPB-like-immunoreactive neurons (K, M) prior to the generation of their lineages resulted in the loss of these immunoreactivities. These results suggest that regulation between lineages did not occur. Ablation of the K and M neuroblasts after they had produced a small portion of their lineages had no effect on the expression of GABA, but did affect the pattern of the SCPB-like immunoreactivity. Combining birth-dating techniques with transmitter immunocytochemistry revealed that it was the position in the birth order and not interactions among the clonally related neurons that influenced the peptidergic phenotype. These results suggest that cell lineage is involved in establishing the GABAergic phenotype and that both cell lineage and birth order influence the determination of the peptidergic phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)


Variations in the clinical course of submacular hemorrhage.
To assess variations in the clinical course of submacular hemorrhages. We reviewed fundus photography charts taken of patients during a 27-month period. Thirty-one eyes of 31 patients with submacular hemorrhages under the foveal avascular zone were reviewed. In 20 of the eyes, the underlying etiology was age-related macular degeneration (ARMD). The other 11 eyes had various underlying conditions, including macroaneurysms (two), presumed ocular histoplasmosis syndrome (two), trauma (one), Valsalva's retinopathy (one), idiopathic central serous choroidopathy (one), diabetic retinopathy (two), central retinal vein occlusion (one), and choroidal rupture (one). Of the eyes with ARMD (mean follow-up, 29 months), eight (40%) of 20 showed an improvement in visual acuity (> or = 2 Snellen lines), six (30%) of 20 had a final visual acuity of 20/80 or better, and three (15%) had a final visual acuity of 20/40 or better (range, 20/25 to 20/80). Of the eyes without ARMD (mean follow-up, 29 months), five (45) of 11 had an improvement in visual acuity and five (45%) of 11 attained a final visual acuity of 20/40 or better (range, 20/20 to 20/40). The best predictive factor for poor final visual acuity was the presence of a subretinal neovascular membrane. Patients with submacular hemorrhage may have spontaneous improvement in visual acuity without surgery. Patients without subretinal neovascular membranes had a better visual improvement rate.


Improving recognition of anxiety and depression in rheumatoid arthritis: a qualitative study in a community clinic.
Comorbid anxiety and depression are common in patients with rheumatoid arthritis (RA) but are often under-recognised and treated, contributing to worse outcomes. National Institute for Health and Care Excellence (NICE) recommends that patients with RA should be offered a holistic annual review, including an assessment of mood. To explore patients' perspectives of anxiety and depression in RA and preferences for disclosure and management of mood problems. Qualitative interview study with patients recruited from a nurse-led RA annual review clinic in the Midlands, England. Patients attending the clinic who scored ≥3 on the case-finding questions (PHQ-2 and GAD-2) were invited for interview. Data were analysed thematically using principles of constant comparison. Participants recognised a connection between their RA and mood, though this was perceived variably. Some lacked candidacy for care, normalising their mood problems. Fear of stigmatisation, a lack of time, and the perception that clinicians prioritise physical over mental health problems recursively affected help-seeking. Good communication and continuity of care were perceived to be integral to disclosure of mood problems. Participants expressed a preference for psychological therapies, though they reported problems accessing care. Some perceived medication to be offered as a 'quick fix' and feared potential drug interactions. Prior experiences can lead patients with RA and comorbid anxiety and depression to feel they lack candidacy for care. Provision of equal priority to mental and physical health problems by GPs and improved continuity of care could help disclosure of mood concerns. Facilitation of access to psychological therapies could improve outcomes for both mental and physical health problems.


Acetylation: a novel link between double-strand break repair and autophagy.
Histone deacetylase (HDAC) inhibitors are clinically relevant because they are used as anticancer drugs. Recent evidence sheds light on an intriguing connection among the DNA damage response (DDR), protein acetylation, and autophagy. HDAC inhibitors have been shown to counteract key steps in the cellular response to double-strand break formation by affecting checkpoint activation, homologous recombination-mediated repair of DNA lesions, and stability of crucial enzymes involved in resection of DNA ends. The degradation of the resection factors depends on autophagy, which plays a detrimental role when cells are in a hyperacetylated state and experience treatment with radiomimetic anticancer drugs. Future work will be required to further investigate the mechanisms underlying the link between acetylation, autophagy, and the DDR, as well as the significance of mTORC1 inhibitors, which are potent inducers of autophagy that are now used in cancer treatment.


A porous sodium polyacrylate-grafted chitosan xerogel for severe hemorrhage control synthesized from one-pot reaction.
Controlling severe hemorrhages remains a challenge. Successful hemorrhage control depends on the speed and quality of blood clot formation. Fast deprivation of water from blood leads to the concentration of blood cells and coagulation factors and thus triggers blood clot formation. This inspired us to develop a new hemostatic material. In this study, we grafted sodium polyacrylate (SPA) onto the backbone of chitosan (CTS) and crosslinked with methacrylic anhydride-modified polyethylene glycol (MAAPEG) to provide a flexible and elastic inter-chain connection between SPA and CTS chains in the presence of a blowing agent to achieve a porous structure. By a simple one-pot reaction, we fabricated a soft, elastic porous xerogel sponge that could reach maximum water absorbency of 180 in less than 200 seconds. This SPA-co-chitosan xerogel sponge demonstrated superior hemostatic properties in thromboelastography (TEG®) test and in a rabbit lethal extremity arterial bleeding model as compared to zeolite granules, kaolin gauze, and chitosan granules. Furthermore, this hemostat worked as a whole to transfer external pressure to the bleeding area and was adhesive to wet wound tissue to seal the bleeding site. In general, the SPA-co-CTS sponge demonstrates a fast and powerful hemostatic effect both in vitro and in vivo, which is superior over the existing commercial products. It might be a promising first-aid device for severe hemorrhage control.


Colorimetric one-tube nested PCR for detection of Trichomonas vaginalis in vaginal discharge.
A colorimetric one-tube nested PCR was developed for the detection of Trichomonas vaginalis in clinical vaginal discharge specimens. A family of 650-bp specific DNA repeats from the T. vaginalis genome was targeted. There was no cross-reaction with human DNA or other infectious agents, including Pentatrichomonas hominis and Giardia lamblia. The colorimetric assay was applied as an adjunct to nested PCR for semiquantitative determination of T. vaginalis DNA at levels corresponding to 1 to 1,000 parasites. PCR of samples prepared by a rapid boiling method was as sensitive and specific as PCR of samples prepared by the standard DNA extraction method: the equivalent of one T. vaginalis organism in 20 microliters of vaginal discharge could be detected. The colorimetric nested PCR was compared with wet mount and culture for the detection of T. vaginalis. A total of 378 clinical vaginal discharge specimens from symptomatic patients were examined; 31 patients were positive for T. vaginalis both by culture and by nested PCR. However, only 17 of these 31 patients were positive by wet mount examination. In addition, of 113 asymptomatic patients, 9 were positive for T. vaginalis by nested PCR. Of these nine PCR-positive patients, only two were also positive both by wet mount and by culture, four patients were positive by culture but negative by wet mount, and three patients were negative both by wet mount and by culture. No specimens negative by nested PCR were positive by wet mount or by culture. The three asymptomatic patients with PCR-positive but wet mount- and culture-negative samples were subsequently found to have T. vaginalis infection after repeated and prolonged culture was performed. This colorimetric nested PCR was very sensitive compared with culture for the diagnosis of vaginal trichomoniasis, especially asymptomatic T. vaginalis infection. It is also simple, specific, rapid, and semiquantitative.


Diagnostic Accuracy of Rapid Ultrasound in Shock (RUSH) Exam; A Systematic Review and Meta-analysis.
To perform a diagnostic accuracy of the rapid ultrasound in shock (RUSH) to diagnose the etiology of undifferentiated shock in patients presenting to the emergency department (ED). We searched the Medline via PubMed, Scopus, and ISI Web of Knowledge till July 2017. Two independent reviewers screened studies for eligibility. Our study analysis is planned in accordance with the guidelines for meta-analysis of diagnostic studies. In the systematic search, of 397 references, 295 were excluded on the basis of the title and abstract. For the remaining 102 articles, the full text was retrieved and critically reviewed. After the selection process, five papers were included. The pooled estimate of all data showed that the RUSH protocol exhibited high sensitivity (0.87, 95% Confidence Interval (CI): 0.80-0.92, I2 = 46.7%) and specificity (0.98, 95% C. I.: 0.96-0.99, I2 = 30.8%). The AUC for SROC, a global measure of the RUSH protocol performance, was 0.98 ± 0.01, indicates the high accuracy of the test. Positive and negative likelihood ratios reported from the studies ranged from 9.83 to 51.32 and 0.04 to 0.33, respectively. The pooled estimate of all data showed that the RUSH protocol exhibited high positive likelihood ratio (19.19, 95% C. I.: 11.49-32.06, I2 = 14.1%) and low negative likelihood ratio (0.23, 95% C. I.: 0.15-0.34, I2 = 18.4%). This meta-analysis suggests that RUSH protocol has generally good role to distinguish the states of shock in patients with undifferentiated shock referred to the emergency department.


Children in the household and risk of severe COVID-19 during the first three waves of the pandemic: a prospective registry-based cohort study of 1.5 million Swedish men.
To investigate whether Swedish men living with children had elevated risk for severe COVID-19 or infection with SARS-CoV-2 during the first three waves of the pandemic. Prospective registry-based cohort study. 1 557 061 Swedish men undergoing military conscription between 1968 and 2005 at a mean age of 18.3 (SD 0.73) years. Infection with SARS-CoV-2 and hospitalisation due to COVID-19 from March 2020 to September 2021. There was a protective association between preschool children at home and hospitalisation due to COVID-19 during the first and third waves compared with only older or no children at all, with ORs (95% CIs) 0.63 (0.46 to 0.88) and 0.75 (0.68 to 0.94) respectively. No association was observed for living with children 6-12 years old, but for 13-17 years old, the risk increased. Age in 2020 did not explain these associations. Further adjustment for socioeconomic and health factors did not attenuate the results. Exposure to preschool children also had a protective association with testing positive with SARS-CoV-2, with or without hospitalisation, OR=0.91 (95% CI 0.89 to 0.93), while living with children of other ages was associated with increased odds of infection. Cohabiting with preschool children was associated with reduced risk for severe COVID-19. Living with school-age children between 6 and 12 years had no association with severe COVID-19, but sharing the household with teenagers and young adults was associated with elevated risk. Our results are of special interest since preschools and compulsory schools (age 6-15 years) in Sweden did not close in 2020.


Covid-19 Vaccine Effectiveness in New York State.
Population-based data from the United States on the effectiveness of the three coronavirus disease 2019 (Covid-19) vaccines currently authorized by the Food and Drug Administration are limited. Whether declines in effectiveness are due to waning immunity, the B.1.617.2 (delta) variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or other causes is unknown. We used data for 8,690,825 adults in New York State to assess the effectiveness of the BNT162b2, mRNA-1273, and Ad26.COV2.S vaccines against laboratory-confirmed Covid-19 and hospitalization with Covid-19 (i.e., Covid-19 diagnosed at or after admission). We compared cohorts defined according to vaccine product received, age, and month of full vaccination with age-specific unvaccinated cohorts by linking statewide testing, hospital, and vaccine registry databases. We assessed vaccine effectiveness against Covid-19 from May 1 through September 3, 2021, and against hospitalization with Covid-19 from May 1 through August 31, 2021. There were 150,865 cases of Covid-19 and 14,477 hospitalizations with Covid-19. During the week of May 1, 2021, when the delta variant made up 1.8% of the circulating variants, the median vaccine effectiveness against Covid-19 was 91.3% (range, 84.1 to 97.0) for BNT162b2, 96.9% (range, 93.7 to 98.0) for mRNA-1273, and 86.6% (range, 77.8 to 89.7) for Ad26.COV2.S. Subsequently, effectiveness declined contemporaneously in all cohorts, from a median of 93.4% (range, 77.8 to 98.0) during the week of May 1 to a nadir of 73.5% (range, 13.8 to 90.0) around July 10, when the prevalence of the delta variant was 85.3%. By the week of August 28, when the prevalence of the delta variant was 99.6%, the effectiveness was 74.2% (range, 63.4 to 86.8). Effectiveness against hospitalization with Covid-19 among adults 18 to 64 years of age remained almost exclusively greater than 86%, with no apparent time trend. Effectiveness declined from May through August among persons 65 years of age or older who had received BNT162b2 (from 94.8 to 88.6%) or mRNA-1273 (from 97.1 to 93.7%). The effectiveness of Ad26.COV2.S was lower than that of the other vaccines, with no trend observed over time (range, 80.0 to 90.6%). The effectiveness of the three vaccines against Covid-19 declined after the delta variant became predominant. The effectiveness against hospitalization remained high, with modest declines limited to BNT162b2 and mRNA-1273 recipients 65 years of age or older.


Exosomal long non-coding RNAs in glioblastoma.
Glioblastoma multiforme (GBM) is the most prevalent primary tumor found in the central nervous system, accounting for 70% of all adult brain tumors. The median overall survival rate is one year post-diagnosis with treatment, and only four months without treatment. Current GBM diagnostic methods, such as magnetic resonance imaging (MRI), surgery, and brain biopsies, have limitations. These include difficulty distinguishing between tumor recurrence and post-surgical necrotic regions, and operative risks associated with obtaining histological samples through direct surgery or biopsies. Consequently, there is a need for rapid, inexpensive, and minimally invasive techniques for early diagnosis and improved subsequent treatment. Research has shown that tumor-derived exosomes containing various long non-coding RNAs (lncRNAs) play critical regulatory roles in immunomodulation, cancer metastasis, cancer development, and drug resistance in GBM. They regulate genes that enhance cancer growth and progression and alter the expression of several key signaling pathways. Due to the specificity and sensitivity of exosomal lncRNAs, they have the potential to be used as biomarkers for early diagnosis and prognosis, as well as to monitor a patient's response to chemotherapy for GBM. In this review, we discuss the role of exosomal lncRNAs in the pathogenesis of GBM and their potential clinical applications for early diagnosis.


A Narrative Synthesis of Women's Out-of-Body Experiences During Childbirth.
Some women have a dissociated, out-of-body experience (OBE) during childbirth, which may be described as seeing the body from above or floating above the body. This review examines this phenomenon using narratives from women who have experienced intrapartum OBEs. A narrative synthesis of qualitative research was employed to systematically synthesize OBE narratives from existing studies. Strict inclusion and exclusion criteria were applied. The included papers were critiqued by 2 of the authors to determine the appropriateness of the narrative synthesis method, procedural transparency, and soundness of the interpretive approach. Women experiencing OBEs during labor and birth report a disembodied state in the presence of stress or trauma. Three forms of OBEs are described: floating above the scene, remaining close to the scene, or full separation of a body part from the main body. Women had clear recall of OBEs, describing the experience and point of occurrence. Women who reported OBEs had experienced current or previous traumatic childbirth, or trauma in a non-birth situation. OBEs as prosaic experiences were not identified. OBEs are part of the lived experience of some women giving birth. The OBEs in this review were trauma related with some women disclosing previous posttraumatic stress disorder (PTSD). It is not evident whether there is a connection between PTSD and OBEs at present, and OBEs may serve as a potential coping mechanism in the presence of trauma. Clinicians should legitimize women's disclosure of OBEs and explore and ascertain their impact, either as a normal coping mechanism or a precursor to perinatal mental illness. Research into the function of OBEs and any relationship to PTSD may assist in early interventions for childbearing women.


In vitro lysis of tumor cells by antibody and complement: detection of antibody with low cytotoxic reactivity.
The factors affecting the in vitro lysis of PARA-7 tumor cells mediated by antibody and complement were examined with the use of the 51Cr-release assay. The addition of immune syngeneic hamster antisera (HA) to 51Cr-labeled PARA-7 target cells 30 minutes before the addition of guinea pig complement (GPC) failed to produce significant levels of lysis. Similarly, the addition of rabbit anti-PARA-7 serum (RAS) 30 minutes prior to the addition of GPC resulted in low levels of lysis. Longer incubations in the presence of RAS, but not RAS and GPC, increased levels of lysis. Extended incubation in the presence of RAS increased the amount of antibody bound to the target cells. This increase did not appear to be due to the expression of additional antigen, because the increase occurred at 4 degrees C and was not sensitive to inhibitors of protein synthesis. The inability to obtain increased levels of lysis by extended incubation in the presence of both RAS and GPC appeared to be due to the inhibitory effects of GPC on the interaction of antibody and antigen. Similar inhibitory effects could be produced by inactivated GPC and various other substances. When extended incubations in the presence of antiserum were used for the reexamination of the cytolytic activity of syngeneic immune HA, significant lysis was detectable.


Computerised Decision Support Systems for the management of freshwater radioecological emergencies: assessment of the state-of-the-art with respect to the experiences and needs of end-users.
Assessment of the environmental and radiological consequences of a nuclear accident requires the management of a great deal of data and information as well as the use of predictive models. Computerised Decision Support Systems (CDSS) are essential tools for this kind of complex assessment and for assisting experts with a rational decision process. The present work focuses on the assessment of the main features of selected state-of-the-art CDSS for off-site management of freshwater ecosystems contaminated by radionuclides. This study involved both developers and end-users of the assessed CDSS and was based on practical customisation exercises, installation and application of the decision systems. Potential end-users can benefit from the availability of several ready-to-use CDSS that allow one to run different kinds of models aimed at predicting the behaviour of radionuclides in aquatic ecosystems, evaluating doses to humans, assessing the effectiveness of different kinds of environmental management interventions and ranking these interventions, accounting for their social, economic and environmental impacts. As a result of the present assessment, the importance of CDSS "integration" became apparent: in many circumstances, different CDSS can be used as complementary tools for the decision-making process. The results of this assessment can also be useful for the future development and improvement of the CDSS.


Caregiver acceptance of adverse effects and use of cholinesterase inhibitors in Alzheimer's disease.
Caregivers play a determining role in choosing treatments for persons with Alzheimer's disease. The objective of this study was to examine caregivers' willingness to have persons with Alzheimer's disease continue taking cholinesterase inhibitors in the event that any 1 of 11 adverse effects was to occur. Data were gathered via postal questionnaire from 375 caregivers in Montreal. Sixty-four per cent of caregivers responded ( n = 201), and most (> or =59%) were willing to continue treatment if persons with Alzheimer's disease suffered from weight loss or loss of appetite. However, most (> or =53%) were not willing to continue treatment in the event of headache, dizziness, nausea, diarrhea, vomiting, drop in blood pressure, insomnia, muscle cramps, or stomach bleeding. The use of cholinesterase inhibitors by persons with Alzheimer's disease was positively associated with caregivers' willingness to accept greater numbers of adverse effects (adjusted relative risk = 1.97; 95% CI = 1.11 to 3.61). Caregivers appear to make a risk-benefit assessment when they decide whether or not care-recipients should continue pharmacotherapy in the event of adverse effects.


Contribution of synchronized atrial systole to left ventricular contraction in the newborn pig heart.
Synchronized atrial contraction may be much more important in the newborn, who has a faster heart rate and a less compliant ventricle, than in the adult. We therefore investigated the extent by which synchronized atrioventricular contraction contributes to cardiac output and cardiac work in a neonatal circulation, and whether this effect can be fully explained by the Starling mechanism. In neonatal piglets, left ventricular pressure and volume (conductance catheter) were measured during atrial and ventricular pacing. By manipulating preload during atrial pacing, end-systolic pressure and volume, stroke work, and dP/dtmax were compared at the same end-diastolic volume as indices of contractility. Finally, end-diastolic pressure-volume relationships were assessed to investigate the validity of using end-diastolic pressure as an indicator of preload. We found a significant contribution of synchronized atrial contraction; cardiac output increased 27% when pacing mode was switched form ventricular to atrial. The mechanism by which this was achieved is entirely the enhancement of ventricular filling and thus the Starling effect; contractility was unaffected by pacing mode. This large and important effect can be explained by slowed relaxation (compared with the adult ventricle), which impairs passive filling during the ventricular relaxation phase, and makes active filling during atrial contraction more important. In addition, we found that the use of end-diastolic pressure as an indicator of preload, instead of end-diastolic volume, leads to serious misinterpretations, due to not only the nonlinearity of this relationship, but also the possible shifts in this relationship with certain interventions.


Particle scale dynamics in granular impact.
We perform an experimental study of granular impact, where intruders strike 2D beds of photoelastic disks from above. High-speed video captures the intruder dynamics and the local granular force response, allowing investigation of grain-scale mechanisms in this process. We observe rich acoustic behavior at the leading edge of the intruder, strongly fluctuating in space and time, and we show that this acoustic activity controls the intruder deceleration, including large force fluctuations at short time scales. The average intruder dynamics match previous studies using empirical force laws, suggesting a new microscopic picture, where acoustic energy is carried away and dissipated.


Pre-stimulus sensorimotor rhythms influence brain-computer interface classification performance.
The influence of pre-stimulus ongoing brain activity on post-stimulus task performance has recently been analyzed in several studies. While pre-stimulus activity in the parieto-occipital area has been exhaustively investigated with congruent results, less is known about the sensorimotor areas, for which studies reported inconsistent findings. In this work, the topic is addressed in a brain-computer interface (BCI) setting based on modulations of sensorimotor rhythms (SMR). The goal is to assess whether and how pre-stimulus SMR activity influences the successive task execution quality and consequently the classification performance. Grand average data of 23 participants performing right and left hand motor imagery were analyzed. Trials were separated into two groups depending on the SMR amplitude in the 1000 ms interval preceding the cue, and classification by common spatial patterns (CSPs) preprocessing and linear discriminant analysis (LDA) was carried out in the post-stimulus time interval, i.e., during the task execution. The correlation between trial group and classification performance was assessed by an analysis of variance. As a result of this analysis, trials with higher SMR amplitude in the 1000 ms interval preceding the cue yielded significantly better classification performance than trials with lower amplitude. A further investigation of brain activity patterns revealed that this increase in accuracy is mainly due to the persistence of a higher SMR amplitude over the ipsilateral hemisphere. Our findings support the idea that exploiting information about the ongoing SMR might be the key to boosting performance in future SMR-BCI experiments and motor related tasks in general.


Retinoblastoma: Etiology, Modeling, and Treatment.
Retinoblastoma is a retinal cancer that is initiated in response to biallelic loss of RB1 in almost all cases, together with other genetic/epigenetic changes culminating in the development of cancer. RB1 deficiency makes the retinoblastoma cell-of-origin extremely susceptible to cancerous transformation, and the tumor cell-of-origin appears to depend on the developmental stage and species. These are important to establish reliable preclinical models to study the disease and develop therapies. Although retinoblastoma is the most curable pediatric cancer with a high survival rate, advanced tumors limit globe salvage and are often associated with high-risk histopathological features predictive of dissemination. The advent of chemotherapy has improved treatment outcomes, which is effective for globe preservation with new routes of targeted drug delivery. However, molecularly targeted therapeutics with more effectiveness and less toxicity are needed. Here, we review the current knowledge concerning retinoblastoma genesis with particular attention to the genomic and transcriptomic landscapes with correlations to clinicopathological characteristics, as well as the retinoblastoma cell-of-origin and current disease models. We further discuss current treatments, clinicopathological correlations, which assist in guiding treatment and may facilitate globe preservation, and finally we discuss targeted therapeutics for future treatments.


Probing Microplasticity in Small-Scale FCC Crystals via Dynamic Mechanical Analysis.
In small-scale metallic systems, collective dislocation activity has been correlated with size effects in strength and with a steplike plastic response under uniaxial compression and tension. Yielding and plastic flow in these samples is often accompanied by the emergence of multiple dislocation avalanches. Dislocations might be active preyield, but their activity typically cannot be discerned because of the inherent instrumental noise in detecting equipment. We apply alternate current load perturbations via dynamic mechanical analysis during quasistatic uniaxial compression experiments on single crystalline Cu nanopillars with diameters of 500 nm and compute dynamic moduli at frequencies 0.1, 0.3, 1, and 10 Hz under progressively higher static loads until yielding. By tracking the collective aspects of the oscillatory stress-strain-time series in multiple samples, we observe an evolving dissipative component of the dislocation network response that signifies the transition from elastic behavior to dislocation avalanches in the globally preyield regime. We postulate that microplasticity, which is associated with the combination of dislocation avalanches and slow viscoplastic relaxations, is the cause of the dependency of dynamic modulus on the driving rate and the quasistatic stress. We construct a continuum mesoscopic dislocation dynamics model to compute the frequency response of stress over strain and obtain a consistent agreement with experimental observations. The results of our experiments and simulations present a pathway to discern and quantify correlated dislocation activity in the preyield regime of deforming crystals.


Comparative genomic analysis of strong biofilm-forming Klebsiella pneumoniae isolates uncovers novel ISEcp1-mediated chromosomal integration of a full plasmid-like sequence.
The goal of the current study was to elucidate the genomic background of biofilm formation in Klebsiella pneumoniae. Clinical isolates were screened for biofilm formation using the crystal violet assay. Antimicrobial resistance (AMR) profiles were assessed by disk diffusion and broth microdilution tests. Biofilm formation was correlated to virulence and resistance genes screened by PCR. Draft genomes of three isolates that form strong biofilm were generated by Illumina sequencing. Only the siderophore-coding gene iutA was significantly associated with more pronounced biofilm formation. ST1399-KL43-O1/O2v1 and ST11-KL15-O4 were assigned to the multidrug-resistant strain K21 and the extensively drug-resistant strain K237, respectively. ST1999-KL38-O12 was assigned to K57. Correlated with CRISPR/Cas distribution, more plasmid replicons and prophage sequences were identified in K21 and K237 compared to K57. The acquired AMR genes (blaOXA-48, rmtF, aac(6')-Ib and qnrB) and (blaNDM-1, blaCTX-M, aph(3')-VI, qnrS, and aac(6')-Ib-cr) were found in K237 and K21, respectively. The latter showed a novel ISEcp1-mediated chromosomal integration of replicon type IncM1 plasmid-like structure harboring blaCTX-M-14 and aph(3')-VI that uniquely interrupted rcsC. The plasmid-mediated heavy metal resistance genes merACDEPRT and arsABCDR were spotted in K21, which also exclusively carried the acquired virulence genes mrkABCDF and the hypervirulence-associated genes iucABCD-iutA, and rmpA/A2. Pangenome analysis revealed NTUH-K2044 accessory genes most frequently shared with K21. While less virulent to Galleria mellonella than ST1999 (K57), the strong biofilm former, multidrug-resistant, NDM-producer K. pneumoniae K21 (ST1399-KL43-O1/O2v1) carries a novel chromosomally integrated plasmid-like structure and hypervirulence-associated genes and represents a serious threat to countries in the area.


Physically adjusted neutral detergent fiber system for lactating dairy cow rations. I: Deriving equations that identify factors that influence effectiveness of fiber.
Physically effective neutral detergent fiber (peNDF) is the fraction of neutral detergent fiber (NDF) that stimulates chewing activity and contributes to the floating mat of large particles in the rumen. Multiplying dietary NDF by particle size has been used as an estimate of peNDF. In re-evaluating the concept of peNDF, we compared the use of peNDF as dietary NDF × particle size with the use of individual NDF and particle size descriptors (physically adjusted NDF; paNDF) when used with other physical and chemical diet descriptors to predict dry matter (DM) intake (DMI), rumination time, and ruminal pH in lactating dairy cows. The purpose is to ultimately use these equations to estimate diet adequacy to maintain ruminal conditions. Each response variable had 8 models in a 2 (peNDF, paNDF) × 2 (diet, diet and ruminal factors) × 2 (DM, as fed basis) factorial arrangement. Particle size descriptors were those determined with the Penn State Particle Separator. Treatment means (n = 241) from 60 publications were used in backward elimination multiple regression to derive models of response variables. When available, peNDF terms entered equations. Models containing peNDF terms had similar or lower unadjusted concordance correlation coefficients (an indicator of similar or lower accuracy and precision) than did models without peNDF terms. The peNDF models for rumen pH did not differ substantially from paNDF models. This suggests that peNDF can account for some variation in ruminal pH; however, overt advantages of peNDF were not apparent. Significant variables that entered the models included estimated mean particle size; as fed or DM proportions retained on 19- and 8-mm sieves of the Penn State Particle Separator; DMI; dietary concentrations of forage; forage NDF; CP; starch; NDF; rumen-degraded starch and rumen-degraded NDF; and the interaction terms of starch × mean particle size, acid detergent fiber/NDF, and rumination time/DMI. Many dietary factors beyond particle size and NDF were identified as influencing the response variables. In conclusion, these results appear to justify the development of a modeling approach to integrate individual physical and chemical factors to predict effects on factors affecting rumen conditions.


Capacity assessment and spatial analysis of cervical cancer services in The Gambia.
Cervical cancer is the most common cancer and the leading cause of cancer-related death in Gambian women. The Gambian Ministry of Health is striving to improve access to screening, diagnostic, and treatment services for cervical cancer, but comprehensive data on currently available services is limited making it challenging to appropriately prioritize the ideal next steps for expanding care. This study aims to describe the current services available for the prevention, screening, and treatment of cervical cancer in The Gambia and provide suggestions for expanding geographic access to care. A survey aimed at assessing the availability of key cervical cancer-related services was developed and then administered in person by research assistants to all secondary and tertiary health facilities (HFs) in The Gambia. ArcGIS Pro Software and 2020 LandScan population density raster were used to visualize and quantify geographic access to care. Survey results were compared with published targets outlined by the Gambian Ministry of Health in the "Strategic Plan for the Prevention and Control of Cervical Cancer in The Gambia: 2016-2020." One hundred and two HFs were surveyed including 12 hospitals, 3 major health centers, 56 minor health centers, and 31 medical centers/clinics. Seventy-eight of these HFs provided some form of cervical cancer-related service. HPV vaccination was available in all health regions. Two-thirds of the population lived within 10 km of a HF that offered screening for cervical cancer and half lived within 10 km of a HF that offered treatment for precancerous lesions. Ten HFs offered hysterectomy, but nine were located in the same region. Two HFs offered limited chemotherapy. Radiotherapy was not available. If all major health centers and hospitals started offering visual inspection with acetic acid and cryotherapy, 86.1% of the population would live within 25 km of a HF with both services. Geographic access to cervical cancer screening, and precancer treatment is relatively widespread across The Gambia, but targeted expansion in line with the country's "Strategic Plan" would improve access for central and eastern Gambia. The availability of treatment services for invasive cancer is limited, and establishing radiotherapy in the country should continue to be prioritized.


Increased mortality and dysregulated cytokine production in tumor necrosis factor receptor 1-deficient mice following systemic Klebsiella pneumoniae infection.
A significant clinical complication of pulmonary infections with Klebsiella pneumoniae is peripheral blood dissemination, resulting in a systemic infection concurrent with the localized pulmonary infection. In this context, little is known about the role of tumor necrosis factor receptor 1 (TNFR1)-mediated innate immune responses during systemic Klebsiella infections. Mice lacking TNFR1 were significantly more susceptible to Klebsiella-induced mortality following intravenous inoculation. Bacterial clearance was impaired in TNFR1-deficient mice at early times following infection. Unexpectedly, bacterial burdens at the onset of mortality (days 2 to 3 postinfection) were not higher in mice lacking TNFR1. However, elevated production of liver-associated proinflammatory cytokines (interleukin-12, tumor necrosis factor alpha [TNF-alpha[, and gamma interferon [IFN-gamma]) and chemokines (MIP-1 alpha, MIP-2, and MCP-1) was observed within the first 24 h of infection. Additionally, excessive plasma-associated IFN-gamma was also observed late in the course of infection (day 3). Spleen cells from day-3 infected TNFR1-deficient mice secreted markedly enhanced levels of IFN-gamma when cultured in vitro. Additionally, there was a marked increase in the total number of activated lymphocyte subsets as indicated by CD69 upregulation. A notable exception was the sharp decrease in the frequency of splenic NK T cells in infected TNFR1 knockout (KO) mice. Anti-TNF-alpha therapy in TNFR1 KO mice significantly reduced chemokine production and liver injury. Combined, these data indicate a dysregulated antibacterial host response following intravenous Klebsiella infection in the absence of TNFR1 signaling, resulting in heightened cytokine production and hyperactivation of specific splenic lymphocyte subsets.


Poor Outcomes of Pediatric Acute Compartment Syndrome in the Setting of Extracorporeal Membrane Oxygenation: A Multicenter Case Series.
Acute compartment syndrome (ACS) is a well-described condition that merits emergent surgical decompression. Peripheral arterial cannulation can increase the likelihood of ACS in patients requiring extracorporeal membranous oxygen (ECMO). Comorbidities in these critically ill patients may portend negative consequences of decompressive fasciotomy. This study investigated the clinical short-term and mid-term outcomes in pediatric patients with ECMO-associated ACS. This is a retrospective case series at 3 pediatric hospitals from 2006 to 2019, including children ages 0 to 19 years who underwent peripheral arterial cannulation and developed ACS. Eighteen patients developed ACS after receiving peripheral cannulation ECMO. Mean time to diagnosis after cannulation was 63.1 hours. All patients were diagnosed clinically; the most common findings were tight compartments, swelling, and loss of peripheral pulses. Eight patients (44%) died due to underlying illness. Treating physicians decided against decompression for 5 patients due to their underlying illness, instability, and concern for infection. Thirteen patients (72%) underwent decompressive fasciotomies. Ten surgical patients required subsequent surgeries and 6 (33%) developed surgical site infections. Of the 7 surviving surgical patients, 4 (57%) required extremity amputations and 4 had lower extremity neurological deficits on follow-up. Two of 3 nonsurgical patients (66%) had functional lower extremity motor deficits on follow-up. No surviving nonoperative patients developed infections or required amputations. ACS on ECMO is associated with high rates of complications including neurologic deficits, infection, and amputation. Patients treated nonoperatively avoided complications such as infection and amputation, but had more functional neurological deficits than surgical patients. Orthopaedic surgeons should consider the high morbidity of compartment release in these critically ill patients and, with critical care teams, assess whether the potential benefits of surgery outweigh expected risks. Level IV.


Evaluation of chlamydiazyme enzyme immunoassay for detection of Chlamydia trachomatis in urine specimens from men.
Paired first-voided urine and urethral swab specimens were collected from 540 men attending sexually transmitted disease clinics in three geographic locations. Urine specimens were tested for the presence of Chlamydia trachomatis by commercial enzyme immunoassay (Chlamydiazyme), and the results were compared with those of urethral swab cultures. Overall prevalence of urethral C. trachomatis by culture was 14%, and the Chlamydiazyme assay had an overall sensitivity of 83%, a specificity of 96%, a positive predictive value of 76%, and a negative predictive value of 97%. Sensitivity was greater (94%) in those culture-positive samples with a high antigen load (> or = 20 inclusion-forming units per coverslip) than those with a lower antigen load (68%). Assay of urine specimens from men attending sexually transmitted disease clinics by Chlamydiazyme appears to be a reliable, noninvasive method of detection of C. trachomatis infection, and further evaluation of its performance in asymptomatic and low-prevalence populations is indicated.


Fractures and bone health monitoring in boys with Duchenne muscular dystrophy managed within the Scottish Muscle Network.
There are limited reports of radiologically confirmed fractures and bone health monitoring in with Duchenne muscular dystrophy. We performed a retrospective study of 91 boys, with a median age of 11.0 years, who are currently managed in Scotland with the aim to assess the frequency of radiologically confirmed fractures and report on bone health monitoring in relation to International Care Consensus Guidance. Of these boys, 59 (65%) were receiving glucocorticoid (GC) therapy and 23 (25%) had received previous treatment. Of those currently on GC, 37 (63%) had an assessment of bone mineral density and none had routine imaging for vertebral fractures during the study period. Of the 91 boys, 44 (48%) had sustained at least one symptomatic radiographically confirmed fracture. The probability of sustaining a first symptomatic fracture was 50% by 12.8 years old (95%CI: 12.1, 13.6). The most common sites for non-vertebral fracture were the femur and tibia. In this review of boys with DMD, almost half had sustained at least one radiologically confirmed symptomatic fracture. There is a need for standardized bone health monitoring in DMD that includes routine imaging of the spine to identify vertebral fractures, given the persistence of insult to the skeleton in these boys.


A beta-helical antifreeze protein isoform with increased activity. Structural and functional insights.
The insect spruce budworm (Choristoneura fumiferana)(Cf) produces a number of isoforms of its highly active antifreeze protein (CfAFP). Although most of the CfAFP isoforms are in the 9-kDa range, isoforms containing a 30- or 31-amino acid insertion have also been identified. Here we describe the functional and structural analysis of a selected long isoform, CfAFP-501. X-ray crystal structure determination reveals that the 31-amino acid insertion found in CfAFP-501 forms two additional loops within its highly regular beta-helical structure. This effectively extends the area of the two-dimensional Thr array and ice-binding surface of the protein. The larger isoform has 3 times the thermal hysteresis activity of the 9-kDa CfAFP-337. As well, a deletion of the 31-amino acid insertion within CfAFP-501 to form CfAFP-501-Delta-2-loop, results in a protein with reduced activity similar to the shorter CfAFP isoforms. Thus, the enhanced antifreeze activity of CfAFP-501 is directly correlated to the length of its beta-helical structure and hence the size of its ice-binding face.


Signal acquisition and analysis for cortical control of neuroprosthetics.
Work in cortically controlled neuroprosthetic systems has concentrated on decoding natural behaviors from neural activity, with the idea that if the behavior could be fully decoded it could be duplicated using an artificial system. Initial estimates from this approach suggested that a high-fidelity signal comprised of many hundreds of neurons would be required to control a neuroprosthetic system successfully. However, recent studies are showing hints that these systems can be controlled effectively using only a few tens of neurons. Attempting to decode the pre-existing relationship between neural activity and natural behavior is not nearly as important as choosing a decoding scheme that can be more readily deployed and trained to generate the desired actions of the artificial system. These artificial systems need not resemble or behave similarly to any natural biological system. Effective matching of discrete and continuous neural command signals to appropriately configured device functions will enable effective control of both natural and abstract artificial systems using compatible thought processes.


Assessment of kainate toxicity using contrast enhanced magnetic resonance imaging.
The purpose of this study was to test the capability of contrast enhanced magnetic resonance imaging (MRI) in assessing lesion formation in rat brain after systemic (i.v.) administration of kainate. MRI was performed with T1-weighted spin echo sequence before and after the administration of kainate and contrast media. Contrast media used were based on paramagnetic gadolinium (III) ion: Gd-DTPA (gadoliniumdiethylenetriaminepentaacetic acid) and prototype agents for blood-pool enhancement. Gadomer-17 and polylysine-Gd-DTPA. Enhancement of lesion rims and other brain tissue abnormalities due to kainate with Gd-DTPA, Gadomer-17 and polylysine-Gd-DTPA were observed mainly in the region of hippocampus and in the areas not protected by the blood-brain-barrier (BBB).


An unexpected cause of dysphagia: pleural mesothelioma.
Malignant mesothelioma usually originates from the pleura or peritoneum, and has a poor prognosis. The incidence of this type of tumor is increasing worldwide, which is probably a result of occupational or environmental exposure to asbestos. In 90% dyspnea, chest pain or a combination of both are usually the initial symptoms. Dysphagia only occurs in 1.4% and is very rare as the initial symptom. We present the case of a middle-aged patient, in whom the initial symptom was dysphagia, so an endoscopy was performed. This showed extrinsic compression of the esophagus that was demonstrated when performing the chest X-ray, in which it was revealed a posterior mediastinal mass surrounding the esophagus concentrically without mucosal invasion.


Clinical implications of velocity vector imaging-based two dimensional strain imaging for the evaluation of left ventricular systolic functions.
Two-dimensional (2D) echocardiography is the most common imaging modality used to assess left ventricular (LV) myocardial function. Although the studies revealed useful conclusions, there are some limitations with the conventional measurement of ejection fraction. Two dimensional (2D) strain imaging is newer echocardiographic technique which is utilized for the evaluation of quantitative regional ventricular functions. Velocity vector imaging based- 2D strain imaging is the most recent technology with a few advantages sourced by its software. This review introduces a novel 2D strain imaging technology, explains its fundamental concepts and discusses clinical applications with all the major advantages and limitations.


Preliminary Development and Testing of C595 Radioimmunoconjugates for Targeting MUC1 Cancer Epitopes in Pancreatic Ductal Adenocarcinoma.
Mucin 1 is a transmembrane glycoprotein which overexpresses cancer-specific epitopes (MUC1-CE) on pancreatic ductal adenocarcinoma (PDAC) cells. As PDAC is a low survival and highly aggressive malignancy, developing radioimmunoconjugates capable of targeting MUC1-CE could lead to improvements in PDAC outcomes. The aim of this study was to develop and perform preliminary testing of diagnostic and therapeutic radioimmunoconjugates for PDAC using an anti-MUC1 antibody, C595. Firstly, p-SCN-Bn-DOTA was conjugated to the C595 antibody to form a DOTA-C595 immunoconjugate. The stability and binding affinity of the DOTA-C595 conjugate was evaluated using mass spectrometry and ELISA. DOTA-C595 was radiolabelled to Copper-64, Lutetium-177, Gallium-68 and Technetium-99m to form novel radioimmunoconjugates. Cell binding assays were performed in PANC-1 (strong MUC1-CE expression) and AsPC-1 (weak MUC1-CE expression) cell lines using 64Cu-DOTA-C595 and 177Lu-DOTA-C595. An optimal molar ratio of 4:1 DOTA groups per C595 molecule was obtained from the conjugation process. DOTA-C595 labelled to Copper-64, Lutetium-177, and Technetium-99m with high efficiency, although the Gallium-68 labelling was low. 177Lu-DOTA-C595 demonstrated high cellular binding to the PANC-1 cell lines which was significantly greater than AsPC-1 binding at concentrations exceeding 100 nM (p < 0.05). 64Cu-DOTA-C595 showed similar binding to the PANC-1 and AsPC-1 cells with no significant differences observed between cell lines (p > 0.05). The high cellular binding of 177Lu-DOTA-C595 to MUC1-CE positive cell lines suggests promise as a therapeutic radioimmunoconjugate against PDAC while further work is required to harness the potential of 64Cu-DOTA-C595 as a diagnostic radioimmunoconjugate.


NONAN GaitPrint: An IMU gait database of healthy young adults.
An ongoing thrust of research focused on human gait pertains to identifying individuals based on gait patterns. However, no existing gait database supports modeling efforts to assess gait patterns unique to individuals. Hence, we introduce the Nonlinear Analysis Core (NONAN) GaitPrint database containing whole body kinematics and foot placement during self-paced overground walking on a 200-meter looping indoor track. Noraxon Ultium MotionTM inertial measurement unit (IMU) sensors sampled the motion of 35 healthy young adults (19-35 years old; 18 men and 17 women; mean ± 1 s.d. age: 24.6 ± 2.7 years; height: 1.73 ± 0.78 m; body mass: 72.44 ± 15.04 kg) over 18 4-min trials across two days. Continuous variables include acceleration, velocity, position, and the acceleration, velocity, position, orientation, and rotational velocity of each corresponding body segment, and the angle of each respective joint. The discrete variables include an exhaustive set of gait parameters derived from the spatiotemporal dynamics of foot placement. We technically validate our data using continuous relative phase, Lyapunov exponent, and Hurst exponent-nonlinear metrics quantifying different aspects of healthy human gait.


Serotonergic control of the hippocampus via local inhibitory interneurons.
Information flow and processing in hippocampal neuronal networks is determined by a wide range of inhibitory mechanisms [e.g., feedforward or feedback, gamma-aminobutyrate (GABA) A or B receptor-mediated, perisomatic shunting, or distal dendritic inhibition], each subserving specialized functions. These forms of local inhibition are mediated by morphologically and neurochemically well-defined, mostly GABA-containing, interneurons, which control large populations of principal cells through their extensive axonal arborizations. These neurons can serve as ideal targets for subcortical pathways, such as those originating in the septum or raphe, which exercise a global control over hippocampal activity. This intriguing possibility prompted us to study whether the profound effect of the serotonergic raphe-hippocampal pathway is mediated by inhibitory interneurons or whether a direct diffuse action on the principal cells is dominant. We demonstrate that axons of this pathway form multiple synaptic contacts with hippocampal GABAergic interneurons. Interestingly, the serotonergic afferents selectively innervate the somata and dendritic trees of GABAergic neurons that contain the 28-kDa calcium-binding protein calbindin D28K, but never those that contain another calcium-binding protein, parvalbumin. These results show that the mechanism by which the serotonergic pathway may exert a powerful influence on hippocampal function involves the modulation of local inhibitory circuits. Furthermore, the selectivity in the choice of target GABAergic interneurons suggests a strong functional specialization among inhibitory circuits, as well as among the subcortical input pathways originating in the septum and raphe.


Chiral p-wave order in Sr2RuO4.
Shortly after the discovery in 1994 of superconductivity in Sr(2)RuO(4), it was proposed on theoretical grounds that the superconducting state may have chiral p-wave symmetry analogous to the A phase of superfluid (3)He. Substantial experimental evidence has since accumulated in favor of this pairing symmetry, including several interesting recent results related to broken time-reversal symmetry (BTRS) and vortices with half of the usual superconducting flux quantum. Great interest surrounds the possibility of chiral p-wave order in Sr(2)RuO(4), since this state may exhibit topological order analogous to that of a quantum Hall state, and can support such exotic physics as Majorana fermions and non-Abelian winding statistics, which have been proposed as one route to a quantum computer. However, serious discrepancies remain in trying to connect the experimental results to theoretical predictions for chiral p-wave order. In this paper, I review a broad range of experiments on Sr(2)RuO(4) that are sensitive to p-wave pairing, triplet superconductivity and time-reversal symmetry breaking and compare these experiments to each other and to theoretical predictions. In this context, the evidence for triplet pairing is strong, although some puzzles remain. The 'smoking gun' experimental results for chiral p-wave order, those which directly look for evidence of BTRS in the superconducting state of Sr(2)RuO(4), are most perplexing when the results are compared with each other and to theoretical predictions. Consequently, the case for chiral p-wave superconductivity in Sr(2)RuO(4) remains unresolved, suggesting the need to consider either significant modifications to the standard chiral p-wave models or possible alternative pairing symmetries. Recent ideas along these lines are discussed.


Formation of on- and off-pathway intermediates in the folding kinetics of Azotobacter vinelandii apoflavodoxin.
The folding kinetics of the 179-residue Azotobacter vinelandii apoflavodoxin, which has an alpha-beta parallel topology, have been followed by stopped-flow experiments monitored by fluorescence intensity and anisotropy. Single-jump and interrupted refolding experiments show that the refolding kinetics involve four processes yielding native molecules. Interrupted unfolding experiments show that the two slowest folding processes are due to Xaa-Pro peptide bond isomerization in unfolded apoflavodoxin. The denaturant dependence of the folding kinetics is complex. Under strongly unfolding conditions (>2.5 M GuHCl), single exponential kinetics are observed. The slope of the chevron plot changes between 3 and 5 M denaturant, and no additional unfolding process is observed. This reveals the presence of two consecutive transition states on a linear pathway that surround a high-energy on-pathway intermediate. Under refolding conditions, two processes are observed for the folding of apoflavodoxin molecules with native Xaa-Pro peptide bond conformations, which implies the population of an intermediate. The slowest of these two processes becomes faster with increasing denaturant concentration, meaning that an unfolding step is rate-limiting for folding of the majority of apoflavodoxin molecules. It is shown that the intermediate that populates during refolding is off-pathway. The experimental data obtained on apoflavodoxin folding are consistent with the linear folding mechanism I(off) <==> U <==> I(on) <== > N, the off-pathway intermediate being the molten globule one that also populates during equilibrium denaturation of apoflavodoxin. The presence of such on-pathway and off-pathway intermediates in the folding kinetics of alpha-beta parallel proteins is apparently governed by protein topology.


Developing a variation of 3D-QSAR/MD method in drug design.
In continuation of the previous reports on a combination of 3D-quantitative structure-activity relationships (QSAR) with computational molecular dynamics (MD) studies, a new variation of 3D-QSAR/MD method has been employed for drug-design as an alternative or supplementary for the typical experimental methods. The presented method is more cost-effective and less time-consuming than the previous methods and avoids several restrictions of experimental methods, such as validity estimation, and predictability. For this purpose, seven inhibitors for bromodomain (BRD)-containing protein, as an important protein in the development of different types of cancer and responsible for oncogenic rearrangements, have been selected to study of their interactions by docking and MD simulations using molecular mechanics/generalized born surface area (MM/GBSA) method. To build the proposed model, a common variant of 3D-QSAR methods, comparative molecular field analysis has been employed using a dataset of 100 MD-extracted ligand conformations and their corresponding MM/GBSA BRD4-binding energies. The results showed excellent predictability of the generated model for both the training set and test groups. Finally, two new inhibitors were selected among total 4000 designed derivatives (generated through evolutionary techniques) using the proposed 3D-QSAR-MD model. The potentials of these inhibitors were assessed by MD simulations, which showed the higher inhibitory of these compounds than the previous inhibitors. Therefore, this method showed high potentials for acceleration of the procedure of drug design and a basis for joining researchers in computational biology and pharmaceutical sciences.


Lathosterol-to-cholesterol ratio in serum predicts cholesterol-lowering response to plant sterol consumption in a dual-center, randomized, single-blind placebo-controlled trial.
Benefits of plant sterols (PS) for cholesterol lowering are compromised by large variability in efficacy across individuals. High fractional cholesterol synthesis measured by deuterium incorporation has been associated with nonresponse to PS consumption; however, prospective studies that show this association have yet to be conducted. The goal was to test whether the lathosterol-to-cholesterol ratio (L:C ratio), a surrogate marker of endogenous cholesterol synthesis, serves as an a priori predictor of cholesterol lowering in response to PS consumption. Sixty-three mildly hypercholesterolemic adults who were preselected as possessing either high endogenous cholesterol synthesis [HS; n = 24; L:C = 2.03 ± 0.39 μmol/mmol (mean ± SD)] or low endogenous cholesterol synthesis (LS; n = 39; L:C = 0.99 ± 0.28 μmol/mmol) on the basis of baseline L:C consumed 2 g PS/d or a placebo for 28 d with the use of a dual-center, single-blind, randomized crossover design. Plasma lipid and noncholesterol sterol concentrations were measured at the end of each phase. PS consumption lowered total cholesterol (TC; -0.25 ± 0.05 mmol/L; P < 0.0001) and LDL cholesterol (-0.17 ± 0.04 mmol/L; P < 0.0001) overall. Specifically, LS individuals responded to PS treatment with a reduction in TC (-0.40 ± 0.07 mmol/L; P < 0.0001) and LDL cholesterol (-0.29 ± 0.05 mmol/L; P = 0.0002), whereas HS individuals failed to show cholesterol lowering (TC: -0.09 ± 0.09 mmol/L; P = 0.2843; LDL cholesterol: -0.05 ± 0.07 mmol/L; P = 0.4917). The odds of LS participants responding to PS consumption with cholesterol lowering better than the mean cholesterol lowering in all participants were 4.25 (95% CI: 1.242, 14.556; P = 0.0211) for TC and 3.36 (95% CI: 1.112, 10.161; P = 0.0317) for LDL cholesterol, which was higher than for HS participants. The L:C ratio predicts the extent of reduction in circulating TC and LDL cholesterol in response to PS consumption. Cholesterol synthesis assessment may thus have a use in identifying responders and nonresponders to PS therapy.


Indications of strong adaptive population genetic structure in albacore tuna (Thunnus alalunga) in the southwest and central Pacific Ocean.
Albacore tuna (Thunnus alalunga) has a distinctly complex life history in which juveniles and adults separate geographically but at times inhabit the same spaces sequentially. The species also migrates long distances and presumably experiences varied regimes of physical stress over a lifetime. There are, therefore, many opportunities for population structure to arise based on stochastic differences or environmental factors that promote local adaptation. However, with the extent of mobility consistently demonstrated by tagged individuals, there is also a strong argument for panmixia within an ocean basin. It is important to confirm such assumptions from a population genetics standpoint for this species in particular because albacore is one of the principal market tuna species that sustains massive global fisheries and yet is also a slow-growing temperate tuna. Consequently, we used 1,837 neutral SNP loci and 89 loci under potential selection to analyze population genetic structure among five sample groups collected from the western and central South Pacific. We found no evidence to challenge panmixia at neutral loci, but strong indications of structuring at adaptive loci. One population sample, from French Polynesia in 2004, was particularly differentiated. Unfortunately, the current study cannot infer whether the divergence is geographic or temporal, or possibly caused by sample distribution. We encourage future studies to include potentially adaptive loci and to continue fine-scale observations within an ocean basin, and not to assume genome-wide panmixia.


Characterization and biocontrol mechanism of Streptomyces olivoreticuli as a potential biocontrol agent against Rhizoctonia solani.
Rhizoctonia solani is a widespread and devastating plant pathogenic fungus that infects many important crops. This pathogen causes tobacco target spot, a disease that is widespread in many tobacco-growing countries and is destructive to tobacco. To identify antagonistic microorganisms with biocontrol potential against this disease, we isolated Streptomyces strains from forest inter-root soil and screened a promising biocontrol strain, ZZ-21. Based on in vitro antagonism assays, ZZ-21 showed a significant inhibitory effect on R. solani and various other phytopathogens. ZZ-21 was identified as Streptomyces olivoreticuli by its phenotypic, genetic, physiological and biochemical properties. Complete genome sequencing revealed that ZZ-21 harbored numerous antimicrobial biosynthesis gene clusters. ZZ-21 significantly reduced the lesion length in detached inoculated leaf assays and reduced the disease index under greenhouse and field conditions. Based on an in vitro antagonistic assay of ZZ-21 culture, the strain exhibited an antifungal activity against R. solani in a dose-dependent manner. The culture filtrate could impair membrane integrity, possibly through membrane lipid peroxidation. ZZ-21 could secrete multiple extracellular enzymes and siderophores. According to a series of antifungal assays, the extracellular metabolites of ZZ-21 contained antimicrobial bioactive compounds composed of proteins/peptides extracted using ammonium sulfate precipitation, which were stable under stress caused by high temperature and protease K. The EC50 value for ammonium sulfate precipitation was determined to be 21.11 μg/mL in this study. Moreover, the proteins/peptides also exhibited biocontrol ability and were observed to alter the plasma membrane integrity of R. solani which were evaluated by biocontrol efficacy assays on detached tobacco leaves and PI staining. Overall, strain ZZ-21 shows the potential to be developed into a biopesticide against tobacco target spot disease.


Psychosocial adjustment after induced abortion and its explanatory factors among adolescent and adult women.
To compare the depressive symptoms and quality of life (QoL) among adolescents (<20 years) and adult women who have had an abortion and to explore individual, social, relational and decision-making explanatory factors for (mal)adjustment in each group. International findings are not consistent regarding the presence of negative psychosocial outcomes after abortion or about the explanatory factors for occurrence among adolescents and adult women. In this cross-sectional study, 177 adolescents (65.1%) and 95 adult women (34.9%) who underwent abortion were recruited. Data on individual, social, relational and decision-making characteristics, depressive symptoms (Edinburgh Postnatal Depression Scale) and QoL (EUROHIS-QOL-8) were collected through self-report questionnaires at 16 healthcare services that provide abortion. Although adolescents are not at greater risk of maladjustment than adult women, abortion may be an emotionally significant event for both age groups. Regarding adolescents, feelings of being pressured into abortion and lower satisfaction with the abortion decision were significantly associated with depressive symptoms and lower QoL. Lower support from the mother was also associated with lower QoL. With regard to adult women, lower satisfaction with the abortion decision was significantly associated with depressive symptoms. None of variables was significantly associated with QoL. Our results suggest that adolescents are not at greater risk of psychosocial maladjustment than are adult women. Factors from different ecological contexts and specific factors depending on age group should be considered in preventive interventions for (mal)adjustment after abortion.


Selection of microcarrier diameter for the cultivation of mammalian cells on microcarriers.
The kinetics of mammalian cell growth in a microcarrier culture are affected by the distribution of cells on microcarriers. It has been shown previously that a critical cell number per microcarrier is required for the growth of FS-4 cells on microcarriers. It is advantageous to alter the cell distribution on microcarriers to allow for a larger fraction of microcarriers to acquire enough cells to initiate normal growth. This can be achieved by selecting the diameter of the microcarriers employed. It has also been shown previously that the critical cell number could be reduced by choosing a better culture medium to support low density growth. However, even if all cells inoculated into a culture are capable of growing to confluence, it is still necessary to select the microcarrier diameter ration ally to improve the growth kinetics. The method of selecting the microcarrier diameter is discussed. By employing a improved medium as well as using microcarriers of selected diameter, the multiplication ratio was in creased to 15- to 16-fold for FS-4 cells, as opposed to 3- to 4-fold typically obtained in a batch culture.


Performance of novel kidney biomarkers in preclinical toxicity studies.
The kidney is one of the main targets of drug toxicity, but early detection of renal damage is often difficult. As part of the InnoMed PredTox project, a collaborative effort aimed at assessing the value of combining omics technologies with conventional toxicology methods for improved preclinical safety assessment, we evaluated the performance of a panel of novel kidney biomarkers in preclinical toxicity studies. Rats were treated with a reference nephrotoxin or one of several proprietary compounds that were dropped from drug development in part due to renal toxicity. Animals were dosed at two dose levels for 1, 3, and 14 days. Putative kidney markers, including kidney injury molecule-1 (Kim-1), lipocalin-2 (Lcn2), clusterin, and tissue inhibitor of metalloproteinases-1, were analyzed in kidney and urine using quantitative real-time PCR, ELISA, and immunohistochemistry. Changes in gene/protein expression generally correlated well with renal histopathological alterations and were frequently detected at earlier time points or at lower doses than the traditional clinical parameters blood urea nitrogen and serum creatinine. Urinary Kim-1 and clusterin reflected changes in gene/protein expression and histopathological alterations in the target organ in the absence of functional changes. This confirms clusterin and Kim-1 as early and sensitive, noninvasive markers of renal injury. Although Lcn2 did not appear to be specific for kidney toxicity, its rapid response to inflammation and tissue damage in general may suggest its utility in routine toxicity testing.


Long-Term Neurological Consequences Related to Boxing and American Football: A Review of the Literature.
The long-term effects of repetitive head trauma on the brain have often been studied in boxers and American football players. The medical literature on this topic was reviewed in order to compare the findings related to boxing with those related to football. The evidence gathered from this review indicates that there are significant differences between the clinical and neuropathological descriptions of the chronic brain damage reported in retired boxers compared to those reported in retired football players. Differing biomechanics of head impacts in the two sports may help explain the different clinical and neuropathological consequences of participation in boxing versus football.


Facilitators, barriers and ethical values related to the coordination of return-to-work among employees on sick leave due to common mental disorders: a protocol for a qualitative study (the CORE-project).
Diagnoses related to common mental disorders such as anxiety, depression, adjustment disorders and stress-related disorders are one of the leading causes of long-term sick leave for both women and men in Organisation for Economic Co-operation and Development countries. To increase the rate of return-to-work workplace involvement in a coordinated return-to-work process has been included in recent best practice guidelines. This form of cooperation is a complex process, involving political structures and a wide range of stakeholders. The study's first aim is to describe facilitators and barriers to the coordination of return-to-work from the perspectives of: (A) employees on sick leave due to common mental disorders, (B) employers, (C) rehabilitation coordinators, (D) physicians and (E) other stakeholders. The second aim is to identify ethical issues that arise in the coordination of return-to-work and analyse how these can be resolved. The study has a qualitative design using interviews with employees on sick leave due to common mental disorders, employers, rehabilitation coordinators, physicians and other stakeholders. The study is conducted in the Swedish primary healthcare. Employees, employers and rehabilitation coordinators are recruited via primary healthcare centres. Rehabilitation coordinators receive information about the study and those who consent to participation are asked to recruit employees and employers. Interview guides have been developed from the consolidated framework for implementation research and ethical values and norms found in Swedish healthcare, social services and workplace legislation. Data will be analysed with qualitative content analysis reflecting manifest and latent content, and ethical issues will be analysed by means of reflective equilibrium methodology. The study was approved by the Regional Ethical Review Board in Stockholm, Sweden (Reg.no 2018/677-31/2 and 2018/2119-32). The findings will be disseminated through publication in scientific journals, social media, seminars and national and international conferences.


Flexible and practical modeling of animal telemetry data: hidden Markov models and extensions.
We discuss hidden Markov-type models for fitting a variety of multistate random walks to wildlife movement data. Discrete-time hidden Markov models (HMMs) achieve considerable computational gains by focusing on observations that are regularly spaced in time, and for which the measurement error is negligible. These conditions are often met, in particular for data related to terrestrial animals, so that a likelihood-based HMM approach is feasible. We describe a number of extensions of HMMs for animal movement modeling, including more flexible state transition models and individual random effects (fitted in a non-Bayesian framework). In particular we consider so-called hidden semi-Markov models, which may substantially improve the goodness of fit and provide important insights into the behavioral state switching dynamics. To showcase the expediency of these methods, we consider an application of a hierarchical hidden semi-Markov model to multiple bison movement paths.


Targeting the Bacterial Cytoskeleton of the Burkholderia cepacia Complex for Antimicrobial Development: A Cautionary Tale.
Burkholderia cepacia complex (BCC) bacteria are a group of opportunistic pathogens that cause severe lung infections in cystic fibrosis (CF). Treatment of BCC infections is difficult, due to the inherent and acquired multidrug resistance of BCC. There is a pressing need to find new bacterial targets for antimicrobials. Here, we demonstrate that the novel compound Q22, which is related to the bacterial cytoskeleton destabilising compound A22, can reduce the growth rate and inhibit growth of BCC bacteria. We further analysed the phenotypic effects of Q22 treatment on BCC virulence traits, to assess its feasibility as an antimicrobial. BCC bacteria were grown in the presence of Q22 with a broad phenotypic analysis, including resistance to H₂O₂-induced oxidative stress, changes in the inflammatory potential of cell surface components, and in-vivo drug toxicity studies. The influence of the Q22 treatment on inflammatory potential was measured by monitoring the cytokine responses of BCC whole cell lysates, purified lipopolysaccharide, and purified peptidoglycan extracted from bacterial cultures grown in the presence or absence of Q22 in differentiated THP-1 cells. BCC bacteria grown in the presence of Q22 displayed varying levels of resistance to H₂O₂-induced oxidative stress, with some strains showing increased resistance after treatment. There was strain-to-strain variation in the pro-inflammatory ability of bacterial lysates to elicit TNFα and IL-1β from human myeloid cells. Despite minimal toxicity previously shown in vitro with primary CF cell lines, in-vivo studies demonstrated Q22 toxicity in both zebrafish and mouse infection models. In summary, destabilisation of the bacterial cytoskeleton in BCC, using compounds such as Q22, led to increased virulence-related traits in vitro. These changes appear to vary depending on strain and BCC species. Future development of antimicrobials targeting the BCC bacterial cytoskeleton may be hampered if such effects translate into the in-vivo environment of the CF infection.


The promise of CaMKII inhibition for heart disease: preventing heart failure and arrhythmias.
Calcium-calmodulin-dependent protein kinase II (CaMKII) has emerged as a central mediator of cardiac stress responses which may serve several critical roles in the regulation of cardiac rhythm, cardiac contractility and growth. Sustained and excessive activation of CaMKII during cardiac disease has, however, been linked to arrhythmias, and maladaptive cardiac remodeling, eventually leading to heart failure (HF) and sudden cardiac death. In the current review, the authors describe the unique structural and biochemical properties of CaMKII and focus on its physiological effects in cardiomyocytes. Furthermore, they provide evidence for a role of CaMKII in cardiac pathologies, including arrhythmogenesis, myocardial ischemia and HF development. The authors conclude by discussing the potential for CaMKII as a target for inhibition in heart disease. CaMKII provides a promising nodal point for intervention that may allow simultaneous prevention of HF progression and development of arrhythmias. For future studies and drug development there is a strong rationale for the development of more specific CaMKII inhibitors. In addition, an improved understanding of the differential roles of CaMKII subtypes is required.


BmPxt1 mediated immune response by regulating PGE2 in silkworm, Bombyx mori.
Prostaglandins (PGs) mediates the immune response of insects to multiple stimuli. Mammalian cyclooxygenase (COXs) is a key enzyme in the synthesis of PGs, and peroxinectin (Pxt) may have similar functions in some sequenced insect genomes. As a representative of Lepidoptera, the silkworm also contains PGs, but its synthetic pathway is not clear. We cloned a full-length cDNA encoding a Pxt, designated as BmPxt1, from silkworm. Sequence alignment analysis showed that the protein encoded by BmPxt1 has a conserved domain similar to Pxts, and its catalytic site is shared with the Pxt of Manduca sexta, which also produces PGs. The expression of BmPxt1 gene was the highest in the hemocytes and was induced by Nuclear Polyhedrosis Virus (NPV) challenge in the detected tissues. Moreover, we found that dsPxt1 treatment deficiency down-regulated BmPxt1 transcript levels and efficiently inhibiting hemocyte-spreading and nodule formation in silkworm. Hemocyte-spreading, nodule formation, phenoloxidase (PO) and AMP genes (attacin, defencin and moricin) were also inhibited by aspirin, a COX inhibitor. Treatment by PGE2 but not arachidonic acid (AA) rescued the immunosuppression; PGs concentrations was also inhibited by aspirin. PGE2, but not AA, treatment rescued the PGs concentrations. The COX inhibitor, aspirin, impaired the innate immune response including nodulation, encapsulation, and melanization in silkworm, while PGE2, but not arachidonic acid (AA), partially reversed these effects of aspirin. Recombinant BmsPxt1 significantly induced PO activation in larvae hemolymph, PGs concentrations and encapsulation of agarose beads. Injection of recombinant BmsPxt1 into larvae resulted in increased transcript levels of AMP genes. Our results confirmed that BmPxt1 was involved in the synthesis of PGs in the innate immune response of silkworm larvae, and provided new information for the role of BmsPxt1 secreted by silkworm in activating PO and antimicrobial peptides.