Transcript profiling distinguishes complete treatment responders with locally advanced cervical cancer.
Cervical cancer (CC) mortality is a major public health concern since it is the second cause of cancer-related deaths among women. Patients diagnosed with locally advanced CC (LACC) have an important rate of recurrence and treatment failure. Conventional treatment for LACC is based on chemotherapy and radiotherapy; however, up to 40% of patients will not respond to conventional treatment; hence, we searched for a prognostic gene signature able to discriminate patients who do not respond to the conventional treatment employed to treat LACC. Tumor biopsies were profiled with genome-wide high-density expression microarrays. Class prediction was performed in tumor tissues and the resultant gene signature was validated by quantitative reverse transcription-polymerase chain reaction. A 27-predictive gene profile was identified through its association with pathologic response. The 27-gene profile was validated in an independent set of patients and was able to distinguish between patients diagnosed as no response versus complete response. Gene expression analysis revealed two distinct groups of tumors diagnosed as LACC. Our findings could provide a strategy to select patients who would benefit from neoadjuvant radiochemotherapy-based treatment.


Microfluidic devices for studying coagulation biology.
The ability to study the behavior of cells, proteins, and cell-cell or cell-protein interactions under dynamic forces such as shear stress under fluid flow, provides a more accurate understanding of the physiopathology of hemostasis. This review touches upon the traditional methods for studying blood coagulation and platelet aggregation and provides an overview on cellular and protein response to shear stress. We also elaborate on the biological aspects of how cells recognize mechanical forces and convert them into biochemical signals that can drive various signaling pathways. We give a detailed description of the various types of microfluidic devices that are employed to study the complex processes of platelet aggregation and blood coagulation under flow conditions as well as to investigate endothelial shear-response. We also highlight works mimicking artificial vessels as platforms to study the mechanisms of coagulation, and finish our review by describing anticipated clinical uses of microfluidics devices and their standardization.


Dual functional activity of semaphorin 3B is required for positioning the anterior commissure.
Chemorepulsion by semaphorins plays a critical role during the development of neuronal projections. Although semaphorin-induced chemoattraction has been reported in vitro, the contribution of this activity to axon pathfinding is still unclear. Using genetic and culture models, we provide evidence that both attraction and repulsion by Sema3B, a secreted semaphorin, are critical for the positioning of a major brain commissural projection, the anterior commissure (AC). NrCAM, an immunoglobulin superfamily adhesion molecule of the L1 subfamily, associates with neuropilin-2 and is a component of a receptor complex for Sema3B and Sema3F. Finally, we show that activation of the FAK/Src signaling cascade distinguishes Sema3B-mediated attractive from repulsive axonal responses of neurons forming the AC, revealing a mechanism underlying the dual activity of this guidance cue.


Knowledge Levels of Kindergarten Teachers About Skin Cancer, Sun Protection Behaviors, and Affecting Factors.
The aim of this study was to determine the knowledge level of kindergarten teachers regarding skin cancer, the sun protection behaviors they exhibit for themselves/their students, and the affecting factors. This descriptive study was carried out in the Mediterranean region in a province located by the sea. The universe of the study consisted of 181 teachers working in kindergartens, and data were collected from the 81% who agreed to participate in the study. The mean Skin Cancer and Sun Knowledge Scale of the teachers was 12.50 ± 3.27 (range 0-25) and the mean Sun Protection Behavior Scale score was 24.78 ± 6.26 (range 8-40). When the Sun Protection Behavior Scale sub-dimensions were analyzed, the teachers' mean score of refraining from the sun was 13.02 ± 2.02, sunscreen use was 9.88 ± 4.46, and hat use was 5.13 ± 2.52. Significant positive correlations were found between the teachers' knowledge scores and refraining from the sun (r = 0.222; p = 0.007) and sunscreen use (r = 0.243; p = 0.003). The least used sun protection practice of the teachers regarding the students was wearing sunglasses (64.8%) and the most used practice was remaining in the shade (75.9%). The level of teachers' knowledge about skin cancer and sun protection and their behavior regarding sun protection for themselves were moderate, but the sun protection behaviors they use for their students were inadequate. Thus, educational programs about sun exposure are needed in schools and non-formal education institutions.


A Mathematical Study to Control Visceral Leishmaniasis: An Application to South Sudan.
In this manuscript, we propose and analyze a compartmental model of visceral leishmaniasis (VL). We model the human population with six compartments including asymptomatic, symptomatic and PKDL-infected, animal population as second host and sandfly population as the vector. Furthermore, the non-adult stage of the sandfly population is introduced in the system, which was not considered before in the literature. We show that the increase in the number of host of sandfly population generates a backward bifurcation. Thus, multiple hosts will cause disease persistence even if the basic reproduction number ([Formula: see text]) is below unity. We perform a sensitivity analysis of important model parameters with respect to some epidemiologically significant responses. We validate our model by calibrating it to weekly VL incidence data from South Sudan for the year 2013. We perform cost-effectiveness analysis on different interventions: treatment, non-adult control, adult control and their different layered combinations based on their implementation cost (in USD) and case reduction. We also use a global sensitivity analysis technique to understand the effect of important parameters of our model on the implementation cost of different controls. This cost-effectiveness study and cost-sensitivity analysis are relatively new in existing literature of this disease.


Movement Path Tortuosity Predicts Compliance With Therapeutic Behavioral Prompts in Patients With Traumatic Brain Injury.
Rehabilitation of patients with traumatic brain injury typically includes therapeutic prompts for keeping appointments and adhering to medication regimens. Level of cognitive impairment may significantly affect a traumatic brain injury victim's ability to benefit from text-based prompting. We tested the hypothesis that spatial disorientation as measured by movement path tortuosity during ambulation would be associated with poorer compliance with automated prompts by veterans actively being treated for traumatic brain injury. Clinical polytrauma center. Ten (1 female) veteran patients mean age = 35.4 (SD = 12.4) years. Small group correlational study without random assignment. Fractal Dimension, a measure of movement path tortuosity derived from a GPS logging device used to record casual outdoor ambulation at the start of the study. Compliance with smart home machine-generated therapeutic prompts received during rehabilitation at the James A. Haley Veterans Administration Hospital Polytrauma Transitional Rehabilitation Program. A patient was compliant with a prompt if they transited from where the prompt was presented to the prescribed destination (both within the Polytrauma Transitional Rehabilitation Program) within 30 minutes. Noncompliance was failure to appear at the destination within the allotted time. Fractal dimension was significantly inversely related to overall prompt compliance (r = -0.603, n = 10, P = .032; 1-tailed). The findings support the hypothesis that increased spatial disorientation adversely impacts compliance with automated prompts throughout therapy. The results are consistent with previous studies linking elevated path tortuosity to cognitive impairment and increased risk for falls in assisted living facility residents.


Methylene blue for intractable pain from oral mucositis related to cancer treatment: a randomized phase 2 clinical trial.
Oral mucositis (OM) in patients receiving cancer therapy is thus far not well managed with standard approaches. We aimed to assess the safety and effectiveness of methylene blue (MB) oral rinse for OM pain in patients receiving cancer therapy. In this randomized, single-blind phase 2 clinical trial, patients were randomized to one of four arms: MB 0.025%+conventional therapy (CTx) (n = 15), MB 0.05%+CTx (n = 14), MB 0.1%+CTx (n = 15), or CTx alone (n = 16). Intervention groups received MB oral rinse every 6 h for 2 days with outcomes measured at days 1-2; safety was evaluated up to 30 days. The primary outcome measured change in the pain numeric rating scale (0-10) from baseline to day 2. Secondary outcome measured change in oral function burden scores from baseline to day 2, World Health Organization OM grades, morphine equivalent daily doses, and adverse events. The trial was registered with ClinicalTrials.gov ID: NCT03469284. Sixty patients (mean age 43, range 22-62 years) completed the study. Compared with those who received CTx alone, those who received MB had a significant reduction of pain scores at day 2 of treatment (mean ± SD); 0.025%: 5.2 ± 2.9, 0.05%: 4.5 ± 2.9, 0.1%: 5.15 ± 2.6) and reduction of oral function burden scores (0.025%: 2.5 ± 1.55, 0.05%: 2.8 ± 1.7, 0.1%: 2.9 ± 1.60). No serious adverse events were noted, but eight patients reported burning sensation of the oral cavity with the first dose, and this caused one patient to discontinue therapy. MB oral rinse showed significant pain reduction and improved oral functioning with minimal adverse effects. ClinicalTrials.gov ID: NCT03469284.


Insulin potentiates bradykinin-induced inositol 1,4,5-triphosphate in neonatal rat cardiomyocytes.
This study investigated whether cross-talk between insulin and the bradykinin receptor exists to modulate bradykinin-induced increase in inositol 1,4,5-triphosphate (IP3) in neonatal rat cardiomyocytes. Treatment of the cultures with 1, 2, and 20 nM of insulin for 90 min before adding bradykinin increased the IP3 response to the same bradykinin dose to 372.0 +/- 17.8, 413.7 +/- 17.7, and 457.3 +/- 18.2 pmol/mg protein, respectively. Tyrphostine A23 and genistein (tyrosine kinase inhibitors) decreased the bradykinin (10 nM)-induced IP3 production potentiated by 2 nM insulin from 400.7 +/- 19.4 pmol/mg protein to 297.3 +/- 42.4 and 314.3 +/- 37.5 pmol/mg protein, respectively. Administration of 100 nM N-(6-aminohexyl)-5-chloro-naphthalenesulfonamide (W7, a calmodulin antagonist) significantly increased the bradykinin (10 nM)-induced IP3 production from 311.7 +/- 13.0 pmol/mg protein in the absence of insulin to 457.8 +/- 19.9, 578.2 +/- 25.9, and 665.2 +/- 16.0 pmol/mg protein in the presence of 1, 2, and 20 nM insulin, respectively. These results demonstrate that cross-talk between the insulin receptor and the bradykinin signaling system may exist in neonatal rat cardiomyocytes. Tyrosine kinase appears to play an important role in the cross-talking. Calmodulin controls the IP3 response to bradykinin by a negative feedback mechanism.


Characterization of the repetitive DNA elements in the genome of fish lymphocystis disease viruses.
The complete DNA nucleotide sequence of the repetitive DNA elements in the genome of fish lymphocystis disease virus (FLDV) isolated from two different species (flounder and dab) was determined. The size of these repetitive DNA elements was found to be 1413 bp which corresponds to the DNA sequences of the 5' terminus of the EcoRI DNA fragment B (0.034 to 0.052 m.u.) and to the EcoRI DNA fragment M (0.718 to 0.736 m.u.) of the FLDV genome causing lymphocystis disease in flounder and plaice. The degree of DNA nucleotide homology between both regions was found to be 99%. The repetitive DNA element in the genome of FLDV isolated from other fish species (dab) was identified and is located within the EcoRI DNA fragment B and J of the viral genome. The DNA nucleotide sequence of one duplicate of this repetition (EcoRI DNA fragment J) was determined (1410 bp) and compared to the DNA nucleotide sequences of the repetitive DNA elements of the genome of FLDV isolated from flounder. It was found that the repetitive DNA elements of the genome of FLDV derived from two different fish species are highly conserved and possess a degree of DNA sequence homology of 94%. The DNA sequences of each strand of the individual repetitive element possess one open reading frame.


Fibromatosis in vertical rectus abdominis myocutaneous flap imitating tumor recurrence after surgery for locally advanced rectal cancer: case report.
Abdominoperineal excision is performed in patients with locally advanced, low rectal carcinoma. Reconstruction of the dorsal vagina and perineum using the vertical rectus abdominis myocutaneous flap following extensive surgery results in favorable surgical outcome and quality of life. However, the rectus abdominis muscle, as part of the anterior abdominal wall, may develop fibrous lesions also as a transplant. A 39-year-old female patient with low rectal cancer and extensive colorectal polyposis was treated with neoadjuvant chemoradiotherapy followed by colectomy and abdominoperineal excision with resection of the dorsal vaginal wall and subsequent reconstruction of the perineum using the vertical rectus abdominis myocutaneous flap. At the 6-month follow-up, a suspected 2 × 2 cm tumor recurrence was detected in the transposed tissue and was subsequently surgically removed. Histologic examination concluded with fibromatosis. Genetic testing revealed a known disease-causing mutation in the adenomatous polyposis coli gene, confirming the diagnosis of familial adenomatous polyposis. Fibromatosis may affect the anterior abdominal wall, that is the rectus abdominis muscle, at the primary site or may develop in the muscle after its transposition into the perineum at pelvic reconstruction. Fibromatosis in the muscle flap after pelvic reconstruction may present a difficult diagnostic challenge for the multidisciplinary team.


Spheroidization of Nickel Powder and Coating with Carbon Layer through Laser Heating.
We developed a simple and efficient process, laser heating of nickel powder in ethanol, to produce carbon-encapsulated nickel microspheres. Long-pulse-width laser heated nickel powder suspended in pure ethanol into liquid droplets. In turn, the latter droplets became sphere-like, pyrolyzed surrounding ethanol and dissolved the produced carbon atoms. Because of their lower solubility in solid nickel, excess carbon atoms were then expelled from the metal core after solidification, thus forming graphite-like shells on the laser-modified Ni spheres. Hence, after pyrolysis the transformation of carbon was found to follow the dissolution-precipitation mechanism. The produced carbon-encapsulated nickel microspheres exhibited higher oxidation resistance compared with the initial nickel powder, while keeping their magnetic properties essentially unchanged.


Do carbenes have a "hidden" carbon(0) character? Revisiting the electronic structure of 2,2'-bipyridyl carbene.
Density functional calculations predict that 2,2'-bipyridyl carbenes have some degree of "hidden" carbon(0) character. This is supported by very high second proton affinity values and bond dissociation energies (BDEs) for the dissociation of one AuCl and one Ni(CO)(2) molecule from [(AuCl)(2)(2,2'-bipyridyl carbene)] and [{Ni(CO)(2)}(2)(2,2'-bipyridyl carbene)]. An Arduengo type carbene also showed significant BDE values for gem-dimetallation, thus indicating the possible existence of carbon(0) character. All of the dimetallated derivatives showed metallophilic interactions.


High-performance liquid chromatographic determination of 6-amidino-2-naphthyl [4-(4,5-dihydro-1H-imidazol-2-yl) amino]benzoate dimethanesulphonate and its metabolites in biological fluids.
6-Amidino-2-naphthyl [4-(4,5-dihydro-1H-imidazol-2-yl) amino]benzoate dimethanesulphonate has been developed for the therapy of pancreatitis. A reversed-phase high-performance liquid chromatographic assay of the levels of this drug and its metabolites in biological fluids was investigated. Fluorescence detection with post-column alkaline degradation was used for the determination of the intact drug and the amidinonaphthol moiety metabolite, and ultraviolet detection at 254 nm was used to determine the levels of the benzoic acid moiety metabolite. Satisfactory recoveries and variabilities of the intact drug and its metabolites from biological fluids were obtained. The detection limits for the intact drug and amidinonaphthol were 0.5 ng/ml at a signal-to-noise ratio of 12 in plasma and 10 ng/ml at a signal-to-noise ratio of 32 in urine and homogenized faeces, and those of benzoic acid were 5 ng/ml at a signal-to-noise ratio of 3 in plasma and 50 ng/ml at a signal-to-noise ratio of 7 in urine and homogenized faeces.


Nitric oxide does not mediate the neurotrophic effects of excitatory amino acids in cultured cerebellar granule neurons.
Excitatory amino acids, such as N-methyl-D-aspartate (NMDA) and kainate, promote neuritogenesis and viability in primary cultures of cerebellar granule cells. In view of the recent demonstration that excitatory amino acids activate the synthesis of nitric oxide, the present study examined a potential role of nitric oxide in mediating the neurotrophic effects of excitatory amino acids. NMDA enhanced the viability of 8-day-old cerebellar granule cell cultures in a concentration-dependent fashion, whereas kainate showed a concentration-dependent biphasic effect. A specific inhibitor of nitric oxide synthase, NG-nitroarginine (0.5 mM), did not antagonize the neurotrophic effects of NMDA (0.5 mM) or kainate (0.05 mM). The concentration of NG-nitroarginine was sufficient to inhibit NMDA or kainate stimulated nitric oxide synthesis and was stable in the culture media throughout the 8-day culture period. Using a specific chemiluminescence detection method, endogenous nitric oxide was directly measured in the headspace gas phase of homogenized cultured cerebellar granule cells, and was not detected when homogenates were incubated with NG-nitroarginine (0.5 mM). Furthermore, addition of a nitric oxide precursor, S-nitroso-N-acetylpenicillamine (1-200 microM), was not neurotrophic, but rather, was neurotoxic in granule cells. These findings indicate that nitric oxide is not a neurotrophic factor in primary cultures of cerebellar granule cells.


Congener specific determination of toxaphene residues in fish liver oil using gas chromatography coupled to ion trap MS/MS.
A new approach to the determination of six toxaphene congeners in edible stuff has been accomplished. The analytical procedure presented in this paper involves a single-step cleanup process prior to the analysis. A solution containing three (13)C labelled polychlorinated biphenyls was used as internal standard and tetrachloronaphtalene was used as injection standard. The analytical technique used was gas chromatography coupled to ion trap mass spectrometry detector in MS/MS mode. The parameters affecting the successive fragmentations were discussed and optimized. The limits of detection ranged from 2 to 49pg microl(-1). The toxaphene congeners were determined in two different fish liver oil pills sold in Spain as a supplementary vitamin support.


Smash and DASH with Cas9.
DeRisi and colleagues present a creative application for Cas9 in vitro, using it to deplete unwanted sequence from DNA libraries. It seems plausible that the in vitro use of CRISPR/Cas9 has unrealized potential to revolutionize the practice of molecular biology well beyond genome editing.


A technique for prevention of port complications after laparoscopic adjustable silicone gastric banding.
Laparoscopic adjustable gastric banding is a safe and effective treatment method for morbid obesity. Injection port dislocation, tube perforation and access port infection are generally classified among the minor complications, although they can require a reoperation at the port-site or even at the level of the band which may have to be removed. We designed a technique to fix the port, that can avoid unnecessary complications. The port is sutured onto a polyprophlene mesh, which is then cut into shape and attached to the rectus fascia in the left hypochondrium with a Tacker stapling device. From February 2000 to January 2001, 25 patients (BMI 35-60) were operated using this technique. No injection port dislocation, tube perforation or access port infection has been found in these patients. With the larger surface area by which the port is attached to the fascia, a stable position of the port is obtained and dislocation avoided. Multiple failed attempts at port access, with resulting risk of infection, are avoided. Due to port stability, risk of incidental tube perforation is reduced. Moreover, a considerable gain of time is obtained compared with the classical suturing of the port.


[Removable partial denture principles applied to indirect bonded fixed partial denture in posterior teeth].
The authors present a clinical case of adhesive prosthesis on posterior teeth, where it is proposed an alternative technique based upon the retentive principles of removable parcial prosthesis, diminishing the elimination of enamel.


Melatonin alleviates aluminum toxicity by regulating aluminum-responsive and nonresponsive pathways in hickory.
Aluminum (Al) toxicity is a significant constraint on agricultural productivity worldwide. Melatonin (MT) has been shown to alleviate Al toxicity in plants; however, the underlying mechanisms remain largely unknown. Here, we employed a combination of physiological and molecular biology techniques to examine the role of MT in mitigating Al toxicity of hickory. We found that MT decreased the contents of cell wall pectin, hemicellulose, Al, and Al-induced massive reactive oxygen species accumulation in the roots of hickory. Transcriptomic analysis revealed that MT may alleviate root tip Al stress by regulating Al-responsive and nonresponsive pathways. Co-expression regulatory network and dual-luciferase receptor assays revealed that transcription factors, CcC3H12 and CcAZF2, responded to MT and significantly activated the expression of two cell wall pectin-related genes, CcPME61 and CcGAE6, respectively. Further, yeast one-hybrid and electrophoretic mobility shift assay (EMSA) assays verified that CcC3H12 and CcAZF2 regulated CcPME61 and CcGAE6, respectively, by directly binding to their promoters. Overexpression of CcPME61 enhanced the Al sensitivity of Arabidopsis thaliana. Our results indicate that MT can improve Al tolerance of hickory via multiple pathways, which provides a new perspective for the study of the mechanism of MT in alleviating abiotic stress.


Different methylation of the TNF-alpha promoter in cortex and substantia nigra: Implications for selective neuronal vulnerability.
Increasing evidence has linked inflammatory processes to neurodegenerative disorders, including Alzheimer's and Parkinson's disease (PD). Tumor necrosis factor alpha (TNF-alpha) is a key inflammatory cytokine and several studies linked increased TNF-alpha to dopaminergic cell death in PD. The TNF-alpha promoter sequence contains several CpG dinucleotides located within or next to transcription factor binding sites. To test the hypothesis whether the methylation state of the TNF-alpha promoter contributes to increased expression of TNF-alpha in PD we compared DNA from different brain regions (substantia nigra pars compacta (SNpc) and cortex) of PD patients and neurologically healthy, age and sex matched controls by bisulfite sequencing of the TNF-alpha promoter region. The TNF-alpha promoter DNA from SNpc was significantly less methylated in comparison to DNA from cortex; however both in PD patients and controls. Although there was a tendency for hypomethylation in PD, our analysis of the 10 CpGs in the TNF-alpha core promoter region (-258 to -35 relative to the TSS) revealed no particular pattern in PD patients compared to control and identified no particular hypomethylated position in cortex or SNpc DNA. Electrophoretic mobility shift and luciferase reporter assays showed that methylation of specific solitary CpG in the TNF-alpha promoter resulted in reduced binding of the transcription factors AP-2 and Sp1, respectively, and suppressed TNF-alpha promoter activity. The brain region specific methylation state of solitary CpG in the TNF-alpha promoter thus determines transcription factor binding efficacy and TNF-alpha expression. A lesser degree of methylation of the TNF-alpha promoter in SNpc cells could underlie the increased susceptibility of dopaminergic neurons to TNF-alpha mediated inflammatory reactions.


Nonlinear effects and effect modification at the participant-level in IPD meta-analysis part 1: analysis methods are often substandard.
To review analysis methods used for linear effect modification (LEM), nonlinear covariate-outcome associations (NL) and nonlinear effect modification (NLEM) at the participant-level in individual participant data meta-analysis (IPDMA). We searched Medline, Embase, Web of Science, Scopus, PsycINFO and the Cochrane Library to identify IPDMA of randomized controlled trials (PROSPERO CRD42019126768). We investigated if and how IPDMA examined LEM, NL and NLEM, including whether aggregation bias was addressed and if power was considered. We screened 6,466 records, randomly sampled 207 and identified 100 IPDMA of LEM, NL or NLEM. Power for LEM was calculated a priori in 3 IPDMA. Of 100 IPDMA, 94 analyzed LEM, 4 NLEM and 8 NL. One-stage models were favoured for all three (56%, 100%, 50%, respectively). Two-stage models were used in 15%, 0% and 25% of IPDMA with unclear descriptions in 30%, 0% and 25%, respectively. Only 12% of one-stage LEM and NLEM IPDMA provided sufficient detail to confirm they had addressed aggregation bias. Investigation of effect modification at the participant-level is common in IPDMA projects, but methods are often open to bias or lack detailed descriptions. Nonlinearity of continuous covariates and power of IPDMA are rarely assessed.


Critique of the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST): flaws in CREST and its interpretation.
The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) has been used to support the equivalence of carotid artery stenting (CAS) and carotid endarterectomy (CEA) in the treatment of carotid stenosis in both symptomatic and asymptomatic patients. This inclusion of two different forms of the disease decreased the power and significance of the CREST results and weakened the trial. Other flaws in CREST were the equal weighting of mostly minor myocardial infarctions (MIs) with strokes and death in the peri-procedural, composite 'end' point, but not in the 4-year, long-term 'end' point. Although CAS was associated with 50% fewer peri-procedural MIs compared with CEA, there were >2.5-fold more MIs after CAS than CEA at 4 years. The 4-year MI rate, however, was not a component of the primary 'end' point. Additionally, although the initial CREST report indicated that there was no difference in the outcomes of CAS and CEA according to symptomatic status or sex, subsequent subgroup analyses showed that CAS was associated with significantly higher stroke and death rates than CEA in symptomatic patients, in females and in individuals ≥ 65 years of age. The present article will examine these and other flaws and the details of CREST's results derived from the trial's preplanned subanalyses to show why the claims that CREST demonstrates equivalence of the two therapeutic procedures are unjustified.


Glaucocalyxin A induces apoptosis in human leukemia HL-60 cells through mitochondria-mediated death pathway.
Glaucocalyxin A (GLA) is a biologically active ent-kauranoid diterpenoid isolated from Rabdosia japonica var. glaucocalyx, a traditional Chinese medicinal herb, which has been shown to inhibit tumor cell proliferation. However, the mechanism underlying GLA-induced cytotoxicity remains unclear. In this study, we focused on the effect of GLA induction on apoptosis, the mitochondria-mediated death pathway and the accumulation of reactive oxygen species (ROS) in human leukemia cells (HL-60). GLA could induce a dose-dependent apoptosis in HL-60 cells as characterized by cell morphology, DNA fragmentation, activation of caspase-3, -9 and an increased expression ratio of Bax/Bcl-2. The mitochondrial membrane potential (Δψ(m)) loss and cytochrome c release from mitochondria to cytosol were observed during the induction. Moreover, GLA caused a time- and dose-dependent elevation of intracellular ROS level in HL-60 cells, and N-acetyl-l-cysteine (NAC, a well-known antioxidant) could block GLA-induced ROS generation and apoptosis. These data suggest that GLA induces apoptosis in HL-60 cells through ROS-dependent mitochondrial dysfunction pathway.


Effects of intraocular tetrodotoxin on the development of the retinocollicular pathway in the Syrian hamster.
The developing uncrossed retinocollicular projection in the Syrian hamster undergoes a characteristic set of changes during the first 2 postnatal weeks. The retinal fibres, which initially project across the whole superior colliculus, withdraw from the caudal part and their terminals become clustered into deep, discrete clumps rostrally. Coincident with these afferent changes, there is substantial retinal ganglion cell death. To examine whether neuronal activity plays a role in these changes, we made daily injections of the sodium channel blocker tetrodotoxin (TTX) into one or both eyes from postnatal day 2 or 4 up to day 12. Following TTX treatment, the uncrossed terminals retracted on schedule from the caudal and superficial parts of the superior colliculus and came to lie, as normal, in the deep layers rostrally. Within the rostral superior colliculus, however, the uncrossed terminals from TTX-injected eyes lost their characteristic patchy distribution and were arranged diffusely. When only one eye received TTX injections, this inhibiting effect on terminal segregation was seen only in the projections from the TTX-treated eye. The effect of TTX treatment on terminal segregation was much less severe than that of unilateral enucleation, after which uncrossed terminals persis throughout the entire superior colliculus. TTX injections appeared to have little effect on overall ganglion cell death since the total number of ganglion cells in the crossed projection from TTX-treated eyes was similar to that in normal eyes. However, the relative distribution of uncrossed cells in temporal and nasal retina was altered. In eyes that received TTX injections, the proportion of uncrossed cells in nasal retina was about 1.6 times that in normal animals and was close to the proportion seen in unilaterally enucleated animals. This increase in the treated eye occurred whether one or both eyes were injected with TTX. We conclude that neuronal activity plays a role in the segregation of uncrossed terminals into discrete clumps in rostral colliculus and in the preferential elimination of uncrossed cells from the nasal retina. The inactive uncrossed projections from TTX-treated eyes showed the greatest degree of disruption. The extent of the disruption was similar whether the crossed input from the other eye was active or inactive. This suggests that the activity-drive interactions between ganglion cells within one eye are more significant than those between the two eyes in shaping the final form of the uncrossed retinocollicular projection.


Convergence of distinct signaling pathways on synaptic scaling to trigger rapid antidepressant action.
Ketamine is a noncompetitive glutamatergic N-methyl-d-aspartate receptor (NMDAR) antagonist that exerts rapid antidepressant effects. Preclinical studies identify eukaryotic elongation factor 2 kinase (eEF2K) signaling as essential for the rapid antidepressant action of ketamine. Here, we combine genetic, electrophysiological, and pharmacological strategies to investigate the role of eEF2K in synaptic function and find that acute, but not chronic, inhibition of eEF2K activity induces rapid synaptic scaling in the hippocampus. Retinoic acid (RA) signaling also elicits a similar form of rapid synaptic scaling in the hippocampus, which we observe is independent of eEF2K functioni. The RA signaling pathway is not required for ketamine-mediated antidepressant action; however, direct activation of the retinoic acid receptor α (RARα) evokes rapid antidepressant action resembling ketamine. Our findings show that ketamine and RARα activation independently elicit a similar form of multiplicative synaptic scaling that is causal for rapid antidepressant action.


Machine learning in laryngeal cancer: A pilot study to predict oncological outcomes and the role of adverse features.
Laryngeal carcinoma (LC) remains a significant economic and emotional problem to the healthcare system and severe social morbidity. New tools as Machine Learning could allow clinicians to develop accurate and reproducible treatments. This study aims to evaluate the performance of a ML-algorithm in predicting 1- and 3-year overall survival (OS) in a cohort of patients surgical treated for LC. Moreover, the impact of different adverse features on prognosis will be investigated. Data was collected on oncological FU of 132 patients. A retrospective review was performed to create a dataset of 23 variables for each patient. The decision-tree algorithm is highly effective in predicting the prognosis, with a 95% accuracy in predicting the 1-year survival and 82.5% in 3-year survival; The measured AUC area is 0.886 at 1-year Test and 0.871 at 3-years Test. The measured AUC area is 0.917 at 1-year Training set and 0.964 at 3-years Training set. Factors that affected 1yOS are: LNR, type of surgery, and subsite. The most significant variables at 3yOS are: number of metastasis, perineural invasion and Grading. The integration of ML in medical practices could revolutionize our approach on cancer pathology.


Injuries among Slovenian physical education teachers: a cross-sectional study.
A cross-sectional study was carried out to examine the frequency and types of serious injuries in physical educators throughout their professional career, in relation to their gender, age and teaching level, certain factors causing the injuries and the consequences of those injuries on their working ability. The subjects (n = 468) answered a self-administered questionnaire. In men, one group's higher frequency of injuries was 1.8 (95% CI [1.26, 2.57]) times higher than in women. Every year in age increased the odds for moving into a group with a higher frequency of injuries by 7.6% (95% CI [1.06, 1.10]). The most common injuries for both genders were lower limb injuries. The most common cause of injury was the teacher's own mistake. Over 60% of teachers had to modify their teaching after an injury. It is necessary to further explore preventive strategies to reduce injuries in these workers.


Naphthalene metabolism in Nocardia otitidiscaviarum strain TSH1, a moderately thermophilic microorganism.
The thermophilic bacterium Nocardia otitidiscaviarum strain TSH1, originally isolated in our laboratory from a petroindustrial wastewater contaminated soil in Iran, grows at 50 degrees C on a broad range of hydrocarbons. Transformation of naphthalene by strain TSH1 which is able to use this two ring-polycyclic aromatic hydrocarbon (PAH) as a sole source of carbon and energy was investigated. The metabolic pathway was elucidated by identifying metabolites, biotransformation studies and monitoring enzyme activities in cell-free extracts. The identification of metabolites suggests that strain TSH1 initiates its attack on naphthalene by dioxygenation at its C-1 and C-2 positions to give 1,2-dihydro-1,2-dihydroxynaphthalene. The intermediate 2-hydroxycinnamic acid, characteristic of the meta-cleavage of the resulting diol was identified in the acidic extract. Apart from typical metabolites of naphthalene degradation known from mesophiles, benzoic acid was identified as an intermediate for the naphthalene pathway of this Nocardia strain. Neither phthalic acid nor salicylic acid metabolites were detected in culture extracts. Enzymatic experiments with cell extract showed the catechol 1,2-dioxygenase activity while transformation of phthalic acid and protocatechuic acid was not observed. The results of enzyme activity assays and identification of benzoic acid in culture extract provide strong indications that further degradation goes through benzoate and beta-ketoadipate pathway. Our results indicate that naphthalene degradation by thermophilic N. otitidiscaviarum strain TSH1 differs from the known pathways found for the thermophilic Bacillus thermoleovorans Hamburg 2 and mesophilic bacteria.


Comparison of Outcomes of Surgical Treatment for Ossification of the Posterior Longitudinal Ligament Versus Other Forms of Degenerative Cervical Myelopathy: Results from the Prospective, Multicenter AOSpine CSM-International Study of 479 Patients.
Degenerative cervical myelopathy (DCM) is an all-encompassing term that includes cervical spondylotic myelopathy (CSM), ossification of the posterior longitudinal ligament (OPLL), and other spinal abnormalities that cause cervical cord compression. It is unclear whether surgery is equally effective and safe for patients with OPLL as it is for those with other forms of DCM. The purpose of this study was to compare surgical outcomes of patients with OPLL and those with other forms of DCM. Four hundred and seventy-nine patients with symptomatic DCM were prospectively enrolled in the CSM-International study at sixteen sites. Patients' functional status was evaluated using the modified Japanese Orthopaedic Association scale (mJOA) and the Nurick score. Quality of life was assessed using patient-reported outcome measures, including the Neck Disability Index (NDI) and the Short Form (SF)-36. Postoperative functional and quality-of-life outcomes were assessed at two years of follow-up, and scores were compared between patients with and without OPLL. Of 479 patients, 135 (28.2%) had radiographic evidence of OPLL, and 344 (71.8%) had other forms of DCM. The two groups did not differ significantly in demographics, surgical approach, or baseline myelopathy severity. Patients with OPLL achieved similar functional outcomes by two years following surgery compared with patients with other forms of DCM. With respect to quality of life, the NDI and most of the subscales of the SF-36 were not different between the two diagnostic groups. There was a higher risk of perioperative complications in the OPLL group (p = 0.054), although this relationship did not reach statistical significance. Rates of neurological complications did not differ significantly between diagnostic groups. Surgical decompression for the treatment of OPLL resulted in improvements in functional status and quality of life comparable to those seen in patients with other forms of DCM. Patients with OPLL were at a higher risk of perioperative complications than patients with other forms of DCM.


Prenatal diagnosis of an XXY foetal karyotype in a woman with a previous 21-trisomic child.
Prenatal chromosome analysis revealed that a 34-year-old, gravida 2 mother was pregnant with a XXY foetus. She had previously given birth to a 21-trisomic boy with another spouse. Both parental karyotypes were normal, but a high frequency of associations between satellited chromosomes was observed in maternal lymphocytes. The possibility that increased satellite associations may predispose to aneuploidy in the offspring is discussed. The finding of normal testicular histology in the aborted XXY foetus provides evidence that the characteristic XXY testicular dysgenetic lesions are likely to occur not earlier than in the late prenatal period.


Bilateral vestibulopathy and disabling vertigo: A CARE case series.
The term bilateral vestibulopathy (BV) was recently defined by the Bárány Society. Loss of otolith function was not included in their criteria. Although spontaneous progression to complete bilateral impairment of vestibular function is expected, it is unlikely that patients with advanced BV will continue to present episodes of intense vertigo. Here, following CARE case report guidelines, we report the case of patients meeting the criteria for BV and still disabled by vertigo. Three patients evaluated in our department meeting the Bárány criteria for definite BV but still complaining of disabling rotatory vertigo were included. All underwent clinical and instrumental vestibular examination. The observations are reported. In case of BV, the conservation of a stable otolithic reference frame could allow patients to optimize postural strategy. It would be useful to revisit a classification of BV by stages, by introducing an evaluation of otolithic function and postural control for possible subsequent vestibular implantation.


High cadmium accumulation among humans and primates: comparison across various mammalian species--a study from Japan.
The majority of existing literature reports that cadmium (Cd) is toxic to humans and most living organisms. This paper reports the results of our study that measured Cd levels in the livers and kidneys of humans and other 50 mammalian species under normal conditions in Japan. The study tests the differences in the Cd concentrations across different mammalian species and sexes. Our results revealed that (1) there is a strong correlation between the Cd levels in the livers and kidneys across all examined species, (2) humans exhibit the highest Cd accumulation level in both organs, (3) primates also show a high Cd concentration at a level close to humans, (4) mice and rats show low Cd levels in both organs, indicating that humans accumulate about a few thousand times more Cd than mice and rats, and (5) the Cd concentration of female mammals is more than double of males for both organs. Our results indicate that these cross-sex as well as cross-species discrepancies cannot be explained by the difference in daily Cd intake. While further research is necessary to determine any potential role of Cd accumulation, we speculate that Cd plays some physiological function in the renal cortex of humans and primates.


Dispersive solid phase extraction combined with solidification of floating organic drop-liquid-liquid microextraction using in situ formation of deep eutectic solvent for extraction of phytosterols from edible oil samples.
In this study, a dispersive solid phase extraction method was combined with solidification of floating organic drop-liquid-liquid microextraction based on in situ synthesis of deep eutectic solvent. It was used for the extraction of some phytosterols from edible oil samples. The extracted analytes were quantified by gas chromatography-mass spectrometry. In this procedure, the sample lipids are saponified with sodium hydroxide and then the analytes are adsorbed onto an octadecylsilane sorbent. After that the analytes are desorbed from the sorbent with ethanol as an elution solvent and the eluant is diluted with deionized water to obtain a homogenous solution. Then, a few amounts of choline chloride and n-butyric acid are dissolved in the solution and transferred into a water batch adjusted at 75 ⁰C for 5 min. During this period Choline chloride and n-butyric acid form a deep eutectic solvent (extraction solvent) dispersed in whole parts of the solution. The obtained cloudy solution is placed into an ice bath. The extraction solvent is collected and solidified on the top of the solution. Finally, it is removed and allows melted at room temperature and an aliquat of the solution is injected into the separation system. Validation of the method showed that limits of detection and quantification were in the ranges of 0.52-1.6 and 1.7-5.6 ng mL-1, respectively. Enrichment factors and extraction recoveries of the analytes ranged from 312 to 375 and 75-90%, respectively. The method had a proper percision with relative standard deviations less than ≤8.2% for intra- (n = 6) and inter-day (n = 6) precisions at a concentration of 15 ng mL-1 of each analyte. Finally the method was successfully used for determination of the analytes in some edible oil samples.


Newborn bloodspot screening policy framework for Australia.
The aim of newborn bloodspot screening (NBS) is to identify rare genetic and non-genetic conditions in children soon after birth in order to commence therapies that prevent the development of progressive, serious, and irreversible disabilities. Universal NBS programmes have been implemented in most countries, with minor adaptations to target conditions most relevant to the local healthcare environment. In this article, we describe the initiatives of international and Australian governments to develop policies to address the expansion of NBS in their healthcare systems. We have reviewed published public policies and literature to formulate recommendations based on clinical, social, legal, and ethical principles to inform a national governance and policy framework for Australia. Australian policy makers have been slow to develop a coordinated plan. While the experience from other governments can guide our national policy, there are specific areas that require further consideration by Australian health experts. Key reforms involve the separation of policy and operational activities, multidisciplinary decision-making and oversight by the Australian Health Ministers' Advisory Council for policy direction. A formal national policy framework will guide the coordination of NBS services that can adapt to the needs of Australian children and families.


Gene-pseudogene evolution: a probabilistic approach.
Over the last decade, methods have been developed for the reconstruction of gene trees that take into account the species tree. Many of these methods have been based on the probabilistic duplication-loss model, which describes how a gene-tree evolves over a species-tree with respect to duplication and losses, as well as extension of this model, e.g., the DLRS (Duplication, Loss, Rate and Sequence evolution) model that also includes sequence evolution under relaxed molecular clock. A disjoint, almost as recent, and very important line of research has been focused on non protein-coding, but yet, functional DNA. For instance, DNA sequences being pseudogenes in the sense that they are not translated, may still be transcribed and the thereby produced RNA may be functional.


Impact of hepatitis B immunization strategies on infection rates in Italy: a deterministic computer simulation.
The impact of different immunization strategies on hepatitis B infection rates in Italy over a 20 year period is simulated by the means of a simple deterministic mathematical model. The anticipated effect of vaccination of health workers only, of newborns from HBsAg+ mothers, of all newborns, of the entire population are simulated. Immunization of newborns from HBsAg+ mothers is by far the strategy with the greater effectiveness per unit cost.


Efficient whole brain transduction by systemic infusion of minimally purified AAV-PHP.eB.
Adeno-associated virus (AAV) vectors have excellent properties as gene transfer vehicles. The recent development of AAV-PHP.eB, highly BBB-permeable capsid variant of AAV serotype 9, has opened up systemic application for whole brain transduction. To attain high transduction efficacy, much efforts have been paid to purify AAV vectors using gradient centrifugation or column chromatography. These methods are time-consuming, cost substantially and require expensive equipment. We propose a simple purification method for the production of systemically applicable AAV-PHP.eB targeting the brain. The new method, which we named minimal purification (MP) method, requires only 2 steps: removal of cell debris using a syringe filter and concentration using a disposable ultrafiltration device. The MP method yielded 2 times more AAV-PHP.eB than the standard ultracentrifuge purification (UCP) method. Intravenous injection of AAV-PHP.eB prepared using the MP method caused robust whole brain transduction without overt toxicity on the liver and kidney. Moreover, we found almost no difference in cellular density and morphology of brain microglia between control mice and mice treated systemically with the MP viral solution, suggesting no influence of the viral injection on brain immunity. The new method, which requires only a benchtop centrifuge and takes only 2-4 h to obtain a ready-to-use viral solution, is much less expensive than the existing UCP method, and can avoid cumbersome and time-consuming purification processes. This simplified method further expands the use of AAV vectors in the neuroscience community.


Eosinophilic Granulomatosis with Polyangiitis: Clinical Pathology Conference and Review.
Eosinophilic granulomatosis with polyangiitis (EGPA) (formerly Churg-Strauss syndrome) is a small vessel vasculitis associated with asthma and eosinophilia. Despite its rarity, continuous gains are being made in understanding the disease with knowledge advancements regarding its epidemiology, heterogeneous clinical manifestations, management, and outcomes. Large knowledge gaps remain, however, particularly surrounding pathophysiologic and diagnostic uncertainties. There is still an incomplete understanding of the interplay between the eosinophilic and vasculitic processes that are features of disease pathogenesis. EGPA is also a conceptually difficult disorder given its dual categorization with hypereosinophilic syndromes and systemic vasculitides and the absence of a biomarker that can reliably distinguish between the two. In addition, recent evidence points to distinct, but partly overlapping, disease phenotypes, yet there is insufficient understanding to inform phenotype-tailored therapies. EGPA also remains a diagnostic challenge in part because asthma may be the primary or predominant manifestation for years, and the chronic corticosteroid requirement may mask other disease features. Efforts are ongoing to better elucidate pathophysiologic mechanisms, resolve classification issues, better characterize disease manifestations, and further clarify disease subcategorization, all of which will translate into better diagnosis and treatment with the possibility of specifically adapted therapies.


Calcium Release Deficiency Syndrome: A New Inherited Arrhythmia Syndrome.
Calcium release deficiency syndrome (CRDS) is a newly described form of inherited arrhythmia caused by damaging loss-of-function variants in the cardiac ryanodine receptor (RyR2). Unlike the prototypical RyR2 gain-of-function channelopathy, known as catecholaminergic polymorphic ventricular tachycardia, patients with CRDS are predisposed to sudden death usually in the absence of any electrical abnormalities at rest or during stress electrocardiography. This makes diagnosis incredibly challenging, however, an invasive electrophysiologic test appears to be effective in unmasking the phenotype, called the long-burst, long-pause, short-coupled ventricular extra-stimulus protocol. Optimal therapies for patients with CRDS remain unestablished, although flecainide appears to be a promising candidate drug.


Circular dichroism studies of dihydrofolate reductase from a methotrexate-resistant strain of Escherichia coli B, MB 1428: ternary complexes.
Circular dichroism has been used to monitor the binding of pyridine nucleotide cofactors to enzyme-folate analog complexes of dihydrofolate reductase from Escherichia coli B (MB 1428). The enzyme binds one molar equivalent of many folate analogs and two molar equivalents of several pyridine nucleotide cofactors. The apo-enzyme has very low optical activity. The binding of folate analogs including folate, dihydrofolate, methotrexate, trimethoprim and pyrimethamine induce large Cotton effects. Pyridine nucleotides when bound to the enzyme-folate analog complexes also induce new optically active bands; all the effects being due to the first molar equivalent of cofactor bound. NADPH and NADP+ induce very similar bands when bound to the enzyme-methotrexate complex suggesting that the geometry of the complexes formed are very similar. The oxidized and reduced cofactor likewise have similar effects on the enzyme-folate complex. However, NADPH and NADP+ addition to both the enzyme-trimethoprim and enzyme-pyrimethamine complexes have significantly different effects on the circular dichroism spectra, suggesting that the inhibitors which are less homologous to the natural dihydrofolate substrate allow more conformational freedom in the enzyme-inhibitor-cofactor complex. In most cases the prior binding of the folate analog greatly increases the binding of the first molar equivalent of cofactor so that at concentrations of approx. 5-20 muM the binding appears stoichiometric. Pyrimethamine is an exception in that it apparently has no effect on the binding of NADPH to the enzyme.


Lipid bilayer induces contraction of the denatured state ensemble of a helical-bundle membrane protein.
Defining the denatured state ensemble (DSE) and disordered proteins is essential to understanding folding, chaperone action, degradation, and translocation. As compared with water-soluble proteins, the DSE of membrane proteins is much less characterized. Here, we measure the DSE of the helical membrane protein GlpG of Escherichia coli (E. coli) in native-like lipid bilayers. The DSE was obtained using our steric trapping method, which couples denaturation of doubly biotinylated GlpG to binding of two streptavidin molecules. The helices and loops are probed using limited proteolysis and mass spectrometry, while the dimensions are determined using our paramagnetic biotin derivative and double electron-electron resonance spectroscopy. These data, along with our Upside simulations, identify the DSE as being highly dynamic, involving the topology changes and unfolding of some of the transmembrane (TM) helices. The DSE is expanded relative to the native state but only to 15 to 75% of the fully expanded condition. The degree of expansion depends on the local protein packing and the lipid composition. E. coli's lipid bilayer promotes the association of TM helices in the DSE and, probably in general, facilitates interhelical interactions. This tendency may be the outcome of a general lipophobic effect of proteins within the cell membranes.


Outcome after abnormal exercise echocardiography for patients with good exercise capacity: prognostic importance of the extent and severity of exercise-related left ventricular dysfunction.
We sought to define the prognostic implications of the extent and severity of exercise echocardiographic abnormalities in patients with good exercise capacity. BACKGROUND; The exercise capacity of patients with known or suspected coronary artery disease (CAD) is of prognostic importance, as is the extent of exercise-related left ventricular (LV) hypoperfusion or dysfunction. We examined the outcomes of 1,874 patients with known or suspected CAD (mean age 64 +/- 10 years, 64% men) who had good exercise capacity (> or = 5 metabolic equivalents [METs] for women, > or = 7 METs for men) but abnormal exercise echocardiograms and analyzed the potential association between clinical, exercise and echocardiographic variables and subsequent cardiac events. Multivariate predictors of time to cardiac death or nonfatal myocardial infarction (MI) were diabetes mellitus (risk ratio [RR] 1.88; 95% confidence interval [CI] 1.2 to 3.0), history of MI (RR 2.44; 95% CI 1.6 to 3.6) and an increase or no change in LV end-systolic size in response to exercise (RR 1.61; 95% CI 1.1 to 2.5). Using echocardiographic variables that were of incremental prognostic value, we were able to stratify the cardiac risk of the study population; cardiac death or nonfatal MI rate per person-year of follow-up was 1.6% for patients who had a decrease in LV end-systolic size in response to exercise (n = 1,330) and 1.2% for patients who did not have any severely abnormal LV segments immediately after exercise (n = 868). In patients with good exercise capacity, echocardiographic descriptors of the extent and severity of exercise-related LV dysfunction were of independent and incremental prognostic value. Stratification of patients into low- and higher risk subgroups was possible using these exercise echocardiographic characteristics.


The potential of computers in patient education.
Typical computer programs for patient education are didactic and fail to tailor information to an individual's specific needs. New technology greatly enhances the potential of computers in patient education. Computer-assisted instruction programs can now elicit information from users before leading them through problem-solving exercises. New authoring systems enable health professionals to develop their own programs. The capacity to elicit and report back information about factors that influence patients' health behaviors give the newest computer programs one of the strengths of face-to-face patient counseling: the ability to tailor an educational message for an individual patient. These programs are not intended to replace but rather to enhance personal interaction between providers and patients. This article describes the advantages of using computers for individualizing patient education and assessing trends across groups of patients. Innovative programs and features to look for in programs and equipment selection are also described.


Extended totally extraperitoneal (eTEP) treatment for lateral primary and incisional hernias. New approach to old problems.
To describe the eTEP approach for treating lateral primary and incisional hernia and show its results in a prospective series of cases. A descriptive prospective study with patients treated surgically for lateral hernias using eTEP approach. Every patient was operated by the same surgeon from November 2018 to December 2021. Inclusion criteria were primary and incisional hernia, lateral and W1 and W2 sized using the EHS classification. Exclusion criteria were W3 hernia, loss of domain, need to remove previous mesh, dystrophic or ulcerative skin, history of previous complex surgery. Details of the surgical technique are described. 34 patients were operated. Median age was 65 years old and BMI, 29.9 (22.1-47.1). There were several locations being the most frequent L3 in 18 patients. The median length was 41 mm (10-129) and width, 44 mm (10-97). The median of defect-mesh ratio was 5.05 (0.9-447.64). TAR was practised in 21 patients (61.8%). Only one patient suffered a clinically relevant complication, being a hematoma (Dindo-Clavien II). 50% of patients were operated in ambulatory surgery. After a median follow-up of 13.5 months, only one recurrence has been reported (2.9%). eTEP to treat lateral hernias is feasible and reproducible showing good results in terms of hernia recurrence and complications. A further prospective randomized clinical trial is needed to support these results.


Interaction of L-leucyl-L-leucyl-L-leucine thin film with water and organic vapors: receptor properties and related morphology.
The ability of highly ordered tripeptide structures to keep or change their morphology in contact with organic vapors was studied. A thin film of tripeptide L-leucyl-L-leucyl-L-leucine (LLL) was prepared having microcrystals and nanocrystals on its surface, which are stable upon vacuum drying but become objects of selective morphology change after a contact with vapors of organic solvents. Fine separate LLL crystals and their agglomerates of submicron and larger dimensions were observed by atomic force microscopy and scanning electron microscopy. After saturation with guest vapors, these crystals can remain intact or change their morphology with the increase in size or complete destruction depending on the guest molecular structure. The crystals completely lose their shape after the binding of pyridine vapors. The other studied guests produce much smaller transformations or have no effect on crystal morphology despite being sorbed by solid LLL, which was shown using quartz crystal microbalance sensor. The observed size-exclusion effect for guest sorption by LLL was found to be broken by the same guests that can change the initial crystal shape. This helps to explain the morphology changes of LLL crystals after the guest sorption and release.


IL-2 and proteoglycans synergistically induce antigen-specific B-cell responses--a possible immune response in the hyperplastic myasthenia thymus.
To understand developmental mechanisms of effector B-cells in the hyperplastic MG thymus, we have evaluated immunological roles of IL-2 and the 100-kDa haemopoietic biglycan, because the number of their producers increases pathologically there. When these two factors were added to an immune system together, the number of antibody-producing cells was markedly increased in a synergistic fashion. Further, IL-2 and the conditioned medium of myoid cells induced immunoglobulin isotype switches, suggesting that new B-cell stimulatory microenvironments were generated in the hyperplastic thymus. In relation to this, we also discuss a new biological feature, an immunomodulator, of conventional biglycan and decorin.


Cold acclimation preserves hindgut reabsorption capacity at low temperature in a chill-susceptible insect, Locusta migratoria.
Cold acclimation increases cold tolerance of chill-susceptible insects and the acclimation response often involves improved organismal ion balance and osmoregulatory function at low temperature. However, the physiological mechanisms underlying plasticity of ion regulatory capacity are largely unresolved. Here we used Ussing chambers to explore the effects of cold exposure on hindgut KCl reabsorption in cold- (11 °C) and warm-acclimated (30 °C) Locusta migratoria. Cooling (from 30 to 10 °C) reduced active reabsorption across recta from warm-acclimated locusts, while recta from cold-acclimated locusts maintained reabsorption at 10 °C. The differences in transport capacity were not linked to major rearrangements of membrane phospholipid profiles. Yet, the stimulatory effect of two signal transduction pathways were altered by temperature and/or acclimation. cAMP-stimulation increased reabsorption in both acclimation groups, with a strong stimulatory effect at 30 °C and a moderate stimulatory effect at 10 °C. cGMP-stimulation also increased reabsorption in both acclimation groups at 30 °C, but their response to cGMP differed at 10 °C. Recta from warm-acclimated locusts, characterised by reduced reabsorption at 10 °C, recovered reabsorption capacity following cGMP-stimulation at 10 °C. In contrast, recta from cold-acclimated locusts, characterised by sustained reabsorption at 10 °C, were unaffected by cGMP-stimulation. Furthermore, cold-exposed recta from warm-acclimated locusts were insensitive to bafilomycin-α1, a V-type H+-ATPase inhibitor, whereas this blocker reduced reabsorption across cold-exposed recta from cold-acclimated animals. In conclusion, bafilomycin-sensitive and cGMP-dependent transport mechanism(s) are likely blocked during cold exposure in warm-acclimated animals while preserved in cold-acclimated animals. These may in part explain the large differences in rectal ion transport capacity between acclimation groups at low temperature.


Oscillation-Driven Memory Encoding, Maintenance, and Recall in an Entorhinal-Hippocampal Circuit Model.
During the execution of working memory tasks, task-relevant information is processed by local circuits across multiple brain regions. How this multiarea computation is conducted by the brain remains largely unknown. To explore such mechanisms in spatial working memory, we constructed a neural network model involving parvalbumin-positive, somatostatin-positive, and vasoactive intestinal polypeptide-positive interneurons in the hippocampal CA1 and the superficial and deep layers of medial entorhinal cortex (MEC). Our model is based on a hypothesis that cholinergic modulations differently regulate information flows across CA1 and MEC at memory encoding, maintenance, and recall during delayed nonmatching-to-place tasks. In the model, theta oscillation coordinates the proper timing of interactions between these regions. Furthermore, the model predicts that MEC is engaged in decoding as well as encoding spatial memory, which we confirmed by experimental data analysis. Thus, our model accounts for the neurobiological characteristics of the cross-area information routing underlying working memory tasks.


New records of Muscidae (Diptera) from Mediterranean countries.
New records are provided for Muscidae from four different Mediterranean countries, with new distribution records for species in ten different genera. Seven species are newly recorded for Croatia, four species for Montenegro and one species for Bosnia & Herzegovina. In this paper we give the first confirmation of an aquatic larval stage for Lispocephalabrachialis (Rondani, 1877), Lispocephalaspuria (Zetterstedt, 1838) and Lispocephalamikii (Strobl, 1893). A first record of the species Coenosialyneborgi Pont, 1972 since its original description is also provided.


Dexmedetomidine suppresses proinflammatory mediator production in human whole blood in vitro.
It has been demonstrated that proinflammatory mediators increase in patients with sepsis, trauma, and burns. These mediators are associated with the development of septic shock and organ dysfunction. Dexmedetomidine (DEX), a selective agonist of the α2-adrenergic receptors, is used in intensive care units for sedation. However, it still remains unclear whether DEX administration has any effects on the production of proinflammatory mediators. In this study, we investigated the effects of DEX on lipopolysaccharide (LPS)-induced production of tumor necrosis factor α, interleukin 6 (IL-6), IL-8, and high-mobility group box 1 protein in human whole blood. Human whole blood was cultured with LPS for up to 24 hours, and LPS-induced proinflammatory mediator production was measured. Next, we tested the effect of DEX on whole blood proinflammatory mediator production. Human whole blood was cultured with LPS and various concentrations of DEX for 12 hours. Then, we investigated the influence of yohimbine, an antagonist of the α2-adrenergic receptors, on the effects of DEX. The effect of DEX on necrosis factor κB (NFκB) activation was also investigated. DEX suppressed tumor necrosis factor α, IL-6, IL-8, and high-mobility group box 1 protein production in human whole blood. The suppressing effects of DEX on proinflammatory mediator production were reversed by yohimbine. The results suggested that the mechanism for the suppressive effects of DEX on proinflammatory mediator production is meditated via α2-adrenergic receptors. These effects of DEX also include an inhibitory effect on NFκB activation. We demonstrate the suppressing effect of DEX on inflammatory mediator production in human whole blood after LPS stimulation. The mechanism for the suppressive effect of DEX on proinflammatory mediator production may be through the α2-adrenergic receptors and NFκB inhibition.


Efficacy of adding nutritional supplements in unipolar depression: A systematic review and meta-analysis.
In this article, we aimed to assess the efficacy of adjunctive administration of nutritional supplements to antidepressants by means of a systematic review and meta-analysis. The supplements included were inositol, vitamin D, folic acid, vitamin B12, S-adenosyl-L-methionine (SAMe), omega-3 polyunsaturated fatty acids (n-3 PUFA) and zinc. A structured database search (MEDLINE, EBSCO, CENTRAL, Web of Science) was performed using terms for the respective substances in conjunction with terms for depression and the mode of treatment ("add-on" OR "adjunctive" OR "augmentation"). Meta-analyses, randomized controlled trials (RCTs) and non-randomized comparative studies that investigated the supplements as an add-on in the treatment of clinically diagnosed MDD were included. Agents had to be added to an existing antidepressant regime (augmentation) or started simultaneously with the antidepressant (acceleration). For n-3 PUFAs, folic acid and zinc, new meta-analyses were performed as part of this work. Our meta-analyses of 10 articles on n-3 PUFAs and four on zinc support their efficacy. For folic acid, our meta-analysis does not support efficacy. For n-3 PUFAs, sensitivity analysis showed no difference between acceleration and augmentation designs, but significant differences between individuals with or without comorbidities. For the remaining substances, only a few RCTs were available. The preliminary data on inositol was negative, while one RCT for vitamin D demonstrated positive results. For vitamin B12 one and for SAMe two RCTs and a few open trials are available reporting positive and mixed results. To summarize, for most of the substances, the available data is not yet sufficient or inconclusive.


Inventory, differentiation, and proportional diversity: a consistent terminology for quantifying species diversity.
Almost half a century after Whittaker (Ecol Monogr 30:279-338, 1960) proposed his influential diversity concept, it is time for a critical reappraisal. Although the terms alpha, beta and gamma diversity introduced by Whittaker have become general textbook knowledge, the concept suffers from several drawbacks. First, alpha and gamma diversity share the same characteristics and are differentiated only by the scale at which they are applied. However, as scale is relative--depending on the organism(s) or ecosystems investigated--this is not a meaningful ecological criterion. Alpha and gamma diversity can instead be grouped together under the term "inventory diversity." Out of the three levels proposed by Whittaker, beta diversity is the one which receives the most contradictory comments regarding its usefulness ("key concept" vs. "abstruse concept"). Obviously beta diversity means different things to different people. Apart from the large variety of methods used to investigate it, the main reason for this may be different underlying data characteristics. A literature review reveals that the multitude of measures used to assess beta diversity can be sorted into two conceptually different groups. The first group directly takes species distinction into account and compares the similarity of sites (similarity indices, slope of the distance decay relationship, length of the ordination axis, and sum of squares of a species matrix). The second group relates species richness (or other summary diversity measures) of two (or more) different scales to each other (additive and multiplicative partitioning). Due to that important distinction, we suggest that beta diversity should be split into two levels, "differentiation diversity" (first group) and "proportional diversity" (second group). Thus, we propose to use the terms "inventory diversity" for within-sample diversity, "differentiation diversity" for compositional similarity between samples, and "proportional diversity" for the comparison of inventory diversity across spatial and temporal scales.


Inhibition of miRNA-212/132 improves the reprogramming of fibroblasts into induced pluripotent stem cells by de-repressing important epigenetic remodelling factors.
MicroRNAs (miRNAs) repeatedly have been demonstrated to play important roles in the generation of induced pluripotent stem cells (iPSCs). To further elucidate the molecular mechanisms underlying transcription factor-mediated reprogramming we have established a model, which allows for the efficient screening of whole libraries of miRNAs modulating the generation of iPSCs from murine embryonic fibroblasts. Applying this model, we identified 14 miRNAs effectively inhibiting iPSC generation, including miR-132 and miR-212. Intriguingly, repression of these miRNAs during iPSC generation also resulted in significantly increased reprogramming efficacy. MiRNA target evaluation by qRT-PCR, Western blot, and luciferase assays revealed two crucial epigenetic regulators, the histone acetyl transferase p300 as well as the H3K4 demethylase Jarid1a (KDM5a) to be directly targeted by both miRNAs. Moreover, we demonstrated that siRNA-mediated knockdown of either p300 or Jarid1a recapitulated the miRNA effects and led to a significant decrease in reprogramming efficiency. Thus, conducting a full library miRNA screen we here describe a miRNA family, which markedly reduces generation of iPSC and upon inhibition in turn enhances reprogramming. These miRNAs, at least in part, exert their functions through repression of the epigenetic modulators p300 and Jarid1a, highlighting these two molecules as an endogenous epigenetic roadblock during iPSC generation.


Exceptionally old mice are highly resistant to lipoxidation-derived molecular damage.
Membrane unsaturation plays an important role in the aging process and the determination of inter-species animal longevity. Furthermore, the accumulation of oxidation-derived molecular damage to cellular components particularly in the nervous and immune systems over time leads to homeostasis loss, which highly influences age-related morbidity and mortality. In this context, it is of great interest to know and discern the degree of membrane unsaturation and the steady-state levels of oxidative damage in both physiological systems from long-lived subjects. In the present work, adult (28 ± 4 weeks), old (76 ± 4 weeks) and exceptionally old (128 ± 4 weeks) BALB/c female mice were used. Brain and spleen were analysed for membrane fatty acid composition and specific markers of protein oxidation, glycoxidation and lipoxidation damage, i.e. glutamic semialdehyde, aminoadipic semialdehyde, carboxyethyl-lysine, carboxymethyl-lysine and malondialdehyde-lysine, by gas chromatography-mass spectrometry. The results showed significantly lower peroxidizability index in brain and spleen from exceptionally old animals when compared to old specimens. The higher membrane resistance to lipid peroxidation and lower lipoxidation-derived molecular damage found in exceptionally old animals was associated with a significantly lower desaturase activity and peroxisomal β-oxidation. Protein oxidation markers in brain and spleen from adult and exceptionally old animals showed similar levels, which were higher in old mice. In addition, the higher levels of the glycoxidation-derived marker observed in exceptionally old animals, as well as in adult mice, could be considered as a good indicator of a better bioenergetic state of these animals when compared to the old group. In conclusion, low lipid oxidation susceptibility and maintenance of adult-like protein lipoxidative damage could be key mechanisms for longevity achievement.


Exploring the relationship between urban flood risk and resilience at a high-resolution grid cell scale.
The assessment of flood risk and resilience has become increasingly important in recent years for effective urban flood management. While flood resilience and risk are two distinct concepts with unique assessment metrics, there is lack of quantitative analysis and understanding of the relationship between them. This study aims to investigate this relationship at the grid cell level in urban areas. To assess flood resilience for high-resolution grid cells, this study proposes a performance-based flood resilience metric, which is calculated using the system performance curve based on flood duration and magnitude. Flood risk is calculated as the product of maximum flood depth and probability, considering multiple storm events. The case study of Waterloo in London, UK is analyzed using a two-dimensional cellular automata-based model CADDIES, which consists of 2.7 million grid cells (5 m × 5 m). The results indicate that over 2 % of grid cells have risk values exceeding 1. Furthermore, there is a 5 % difference in resilience values below 0.8 between the 200-year and 2000-year design rainfall events, specifically 4 % for the former and 9 % for the latter. Additionally, the results reveal a complex relationship between flood risk and resilience, though decreasing flood resilience generally leads to increasing flood risk. However, this relationship varies depending on the land cover type, with building, green land, and water body cells showing higher resilience for the same level of flood risk compared to other land uses such as roads and railways. Classifying urban areas into four categories, including high risk vs. low resilience, high risk vs. high resilience, low risk vs. low resilience, and low risk vs. high resilience, is crucial in identifying flood hotspots for intervention development. In conclusion, this study provides an in-depth understanding of the relationship between risk and resilience in urban flooding, which could help improve urban flood management. The proposed performance-based flood resilience metric and the findings from the case study of Waterloo in London could be valuable for decision-makers in developing effective flood management strategies in urban areas.


Enhanced effects of guggulsterone plus 1,25(OH)2D3 on 3T3-L1 adipocytes.
Guggulsterone (GS) and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] have been shown to influence adipogenesis in 3T3-L1 cells. We investigated the ability of GS and 1,25(OH)2D3, alone and in combination to inhibit adipogenesis and induce apoptosis in 3T3-L1 adipocytes. Maturing preadipocytes were treated with 1,25(OH)2D3 in combination with GS for 6 days during differentiation. GS and 1,25(OH)2D3 each inhibited lipid accumulation, but the combination potentiated the inhibition of lipid accumulation. Apoptosis was increased by 1,25(OH)2D3 while GS had no effect, but GS + 1,25(OH)2D3 increased apoptosis more than either compound alone. Furthermore, GS + 1,25(OH)2D3 caused a potentiated decrease in the expression of aP2 and farnesoid X receptor expression more than either compound alone. In addition, 1,25(OH)2D3 increased vitamin D receptor expression after 6 days, while GS had no effect. GS + 1,25(OH)2D3, however, caused a potentiated increase in the expression of VDR. These findings show that GS potentiates 1,25(OH)2D3's anti-adipogenic and pro-apoptotic effects in maturing 3T3-L1 preadipocytes.


Radioiodinated 1-(diethylaminopropyl)-4-phenylpiperazine: a potential brain imaging agent.
The preparation of radioiodinated 1-(diethylaminopropyl)-4-phenylpiperazine, an analog of HIPDM, and its tissue distribution in rats are described. The precursor undergoes facile electrophilic radioiodination with radionuclides of iodine at the no-carrier-added level to give isolated yields in the 69-85% range. Biodistribution studies indicate that the radiochemical is well extracted by the brain (1.68-1.79% ID) and activity is substantially retained for 4 h (greater than 67%). Brain-to-blood ratios during the 0.25-4.0 h period were 15-23:1. The brain uptake and retention as well as the high brain-to-blood ratios suggest the potential use of this agent for regional cerebral blood flow imaging.


Seminal prostasomes inhibit the angiogenesis activity of rat aortic rings.
Prostasomes are organelles secreted by prostatic epithelial cells, and are believed to have a role in fertility and prostatic disease. They are known to influence sperm motility and the acrosome reaction, and are thought to have a role in cell transformation, immunosuppression, proliferation, facilitation of local invasion, and angiogenesis. Previously, we have demonstrated the inhibitory effect of prostasomes derived from human semen on angiogenesis using HUVEC cells grown on matrigel. In this study, we use the rat aortic ring assay system, arguably a closer reflection of the in vivo situation. Quantification was by a spectrophotometric method, and underlying mechanisms assessed. Prostasomes demonstrated a clear inhibition of angiogenesis, and this effect persisted after heat treatment of prostasomes to denature protein. This fits with other known effects of prostasomes known to be due to the membrane lipid component, which is unusually high in sphingomyelin and cholesterol.


Degradation of anthracycline antitumor compounds catalysed by metal ions.
The influence of some metal ions on the degradation of anthracyclines was examined. One of the degradation products is the 7,8-dehydro-9,10-desacetyldoxorubicinone, D* ( yen), usually formed by hydrolysis at slightly basic pH. D* is a lipophilic compound with no cytostatic properties. Its formation could be responsible for the lack of antitumor activity of the parent compound. The coordination of metal ions to anthracycline derivatives is required to have degradation products. Cations such as Na(+), K(+), or Ca(2+) do not induce the D* formation however metals which can form stable complexes with doxorubicin afford D*. Iron(III) and copper(II) form appreciable amount of D* at slightly acidic pH. Terbium(III) forms D* but its complex is stable only at slightly basic pH. Palladium(II) which does not form D*. The influence of the coordination mode of metal ions to anthracycline on the D* formation is discussed.


Branhamella catarrhalis keratitis.
Branhamella catarrhalis, formerly known as Neisseria catarrhalis, has structural similarities to Neisseria gonorrhoeae, but is generally considered to be nonpathogenic. We studied the clinical and laboratory data of four previously reported cases and six additional cases of B. catarrhalis keratitis. All patients had a predisposing ocular or systemic condition, or both. There were various clinical characteristics, but in most cases the infiltrate occurred in the central or paracentral cornea. A prompt response to treatment with a cephalosporin and aminoglycoside antibiotic was noted in all cases. Two patients had corneal perforations, which probably resulted from a delay in treatment. Gram-negative diplococci from corneal scrapings may not necessarily represent N. gonorrhoeae.


[Screening, breeding and metabolic analysis of a succinic-acid-producing strain].
In order to obtain high yield mutant strains for the industrial bioconversion of succinic acid, we analyzed the metabolic networks of the strain Actinobacillus succinogenes S.JST in the course of screening and breeding. We previously identified the wild-type strain by API biochemical reactions and 16S r RNA sequence analysis. Following the discussion of the metabolic pathway, we calculated the flux by matrix and disturbed the node by intermediate. A succinic-acid-producing strain S.JST isolated from bovine rumen was identified as Actinobacillus succinogenes. Enzyme determination showed that the activities of phosphoenolpyruvate carboxykinase and malate dehydrogenase were very high. Metabolic flux from parent strain indicated that the flux of by-product ethanol was 1.51 mmol x g(-1) x h(-1) in the second place of those end products. After being mutated, the alcohol dehydrogenase activity of the mutant-strain S.JSTA decreased markedly, furthermore the flux of succinic acid increased by 34% and the flux of ethanol decreased by 93%. By analyzing the Adh gene, we found a mutated site. Bioinformatics showed that the corresponding amino acid sequence acted as the key active site binding with NADH. In succinic acid synthesis, directed breeding method was effective for improving the whole cell metabolism of Actinobacillus succinogenes, and succinic acid yield was increased.


Minocycline markedly reduces acute visceral nociception via inhibiting neuronal ERK phosphorylation.
Minocycline prevents the development of neuropathic and inflammatory pain by inhibiting microglial activation and postsynaptic currents. But, how minocycline obviates acute visceral pain is unclear. The present study investigated whether minocycline had an any antinociceptive effect on acetic acid-induced acute abdominal pain after intraperitoneal (i.p.) administration of saline or minocycline 1 hour before acetic acid injection (1.0%, 250 μl, i.p.). Minocycline (4, 10, or 40 mg/kg) significantly decreased acetic acid-induced nociception (0-60 minutes post-injection) and the enhancement in the number of c-Fos positive cells in the T5-L2 spinal cord induced by acetic acid injection. Also, the expression of spinal phosphorylated extracellular signal-regulated kinase (p-ERK) induced by acetic acid was reduced by minocycline pre-administration. Interestingly, intrathecal introduction of PD98059, an ERK upstream kinase inhibitor, markedly blocked the acetic acid-stimulated pain responses. These results demonstrate that minocycline effectively inhibits acetic acid-induced acute abdominal nociception via the inhibition of neuronal p-ERK expression in the spinal cord, and that minocycline may have therapeutic potential in suppressing acute abdominal pain.


Platelet CD36 links hyperlipidemia, oxidant stress and a prothrombotic phenotype.
Dyslipidemia is associated with a prothrombotic phenotype; however, the mechanisms responsible for enhanced platelet reactivity remain unclear. Proatherosclerotic lipid abnormalities are associated with both enhanced oxidant stress and the generation of biologically active oxidized lipids, including potential ligands for the scavenger receptor CD36, a major platelet glycoprotein. Using multiple mouse in vivo thrombosis models, we now demonstrate that genetic deletion of Cd36 protects mice from hyperlipidemia-associated enhanced platelet reactivity and the accompanying prothrombotic phenotype. Structurally defined oxidized choline glycerophospholipids that serve as high-affinity ligands for CD36 were at markedly increased levels in the plasma of hyperlipidemic mice and in the plasma of humans with low HDL levels, were able to bind platelets via CD36 and, at pathophysiological levels, promoted platelet activation via CD36. Thus, interactions of platelet CD36 with specific endogenous oxidized lipids play a crucial role in the well-known clinical associations between dyslipidemia, oxidant stress and a prothrombotic phenotype.


Conformational dynamics of a membrane protein chaperone enables spatially regulated substrate capture and release.
Membrane protein biogenesis poses enormous challenges to cellular protein homeostasis and requires effective molecular chaperones. Compared with chaperones that promote soluble protein folding, membrane protein chaperones require tight spatiotemporal coordination of their substrate binding and release cycles. Here we define the chaperone cycle for cpSRP43, which protects the largest family of membrane proteins, the light harvesting chlorophyll a/b-binding proteins (LHCPs), during their delivery. Biochemical and NMR analyses demonstrate that cpSRP43 samples three distinct conformations. The stromal factor cpSRP54 drives cpSRP43 to the active state, allowing it to tightly bind substrate in the aqueous compartment. Bidentate interactions with the Alb3 translocase drive cpSRP43 to a partially inactive state, triggering selective release of LHCP's transmembrane domains in a productive unloading complex at the membrane. Our work demonstrates how the intrinsic conformational dynamics of a chaperone enables spatially coordinated substrate capture and release, which may be general to other ATP-independent chaperone systems.


Oxytocin and cardioprotection in diabetes and obesity.
Oxytocin (OT) emerges as a drug for the treatment of diabetes and obesity. The entire OT system is synthesized in the rat and human heart. The direct myocardial infusion with OT into an ischemic or failing heart has the potential to elicit a variety of cardioprotective effects. OT treatment attenuates cardiomyocyte (CMs) death induced by ischemia-reperfusion by activating pro-survival pathways within injured CMs in vivo and in isolated cells. OT treatment reduces cardiac apoptosis, fibrosis, and hypertrophy. The OT/OT receptor (OTR) system is downregulated in the db/db mouse model of type 2 diabetes which develops genetic diabetic cardiomyopathy (DC) similar to human disease. We have shown that chronic OT treatment prevents the development of DC in the db/db mouse. In addition, OT stimulates glucose uptake in both cardiac stem cells and CMs, and increases cell resistance to diabetic conditions. OT may help replace lost CMs by stimulating the in situ differentiation of cardiac stem cells into functional mature CMs. Lastly, adult stem cells amenable for transplantation such as MSCs could be preconditioned with OT ex vivo and implanted into the injured heart to aid in tissue regeneration through direct differentiation, secretion of protective and cardiomyogenic factors and/or their fusion with injured CMs.


Minimally Invasive Decompression With Noninstrumented Facet Fusion Versus Minimally Invasive Transforaminal Lumbar Interbody Fusion for Stenosis Associated With Grade 1 Lumbar Degenerative Spondylolisthesis.
Retrospective matched cohort study. With a growing interest in minimally invasive spine surgery (MIS), the question of which technique is the most advantageous for patients with low-grade degenerative lumbar spondylolisthesis (DLS) still remains unclear. To compare patient-reported outcomes, perioperative morbidity, and rates of reoperation between MIS decompression with either unilateral noninstrumented facet fusion (MIS-F) or with transforaminal interbody fusion (MIS-T) for grade 1 DLS. Twenty patients who underwent MIS-T and 20 patients with MIS-F were matched based on age, sex, and preoperative ODI, VAS back, and VAS leg. All patients had DLS with at least 4 millimeters of translation on standing radiographs. Exclusion criteria included prior level surgery, multilevel instability, disk impinging on the exiting nerve root, spondylolisthesis from significant facet arthropathy, or foraminal compromise from disk collapse. ODI, VAS back, VAS leg, and patient satisfaction measured by the North American Spine Society questionnaire were tracked at 3, 6, 12, and 24 months postoperatively. Minimum clinically important differences and substantial clinical benefits were calculated. MIS-F and MIS-T resulted in decreased ODI at 3, 6, and 12 months following the index procedure. Sixty percent of MIS-F and 83% of MIS-T patients reached minimum clinically important difference at 1 year postoperatively; however, using the threshold of 30% ODI reduction from baseline, 67% of MIS-F and 83% MIS-T ( P = 0.25) achieved this goal. Forty-three percent of MIS-F and 59% of MIS-T patients met substantial clinical benefits. Satisfaction at 1 year, measured by a score of 1 or 2 on the North American Spine Society questionnaire, was 64% for MIS-F and 83% for MIS-T. MIS-F and MIS-T are effective treatment options for spinal stenosis associated with low-grade DLS. Both techniques result in comparable patient-reported outcomes and satisfaction up to 2 years and have similar long-term reoperation rates. More evidence is required to delineate optimal selection characteristics for MIS-F versus MIS-T.


The crucial value of serum ferritin in assessing high-risk factors and prognosis for patients with endometrial carcinoma.
Endometrial carcinoma is a common malignant tumor in female reproductive system. At present, there is no effective and economic prognostic index. This study aimed to investigate the effect of serum ferritin levels on the prognosis of endometrial carcinoma. Data of 367 patients who diagnosed with endometrial carcinoma at the First Affiliated Hospital of Chongqing Medical University between January 2012 and August 2018 was retrospectively analyzed. The prediction accuracy was evaluated by receiver operating characteristics curves and Youden's J statistics. Hosmer-lemeshow test was used to confirm the goodness of fit of the model. The prognostic value of serum ferritin on disease free survival (DFS) and overall survival (OS) of endometrial carcinoma was evaluated by univariate log-rank tests and multivariate cox regression models. Preoperative high serum ferritin was correlated with older age, high grade, specific histological subtypes and recurrence of endometrial carcinoma (P < 0.05). The DFS and OS of 198 patients with elevated serum ferritin levels were significantly lower than those with low serum ferritin levels (P = 0.001 and P = 0.002, respectively). In multivariate analysis, serum ferritin was an independent prognostic factor for DFS and OS in endometrial carcinoma (P = 0.012, P = 0.028). Through our research, we found that the high expression of serum ferritin level was not only related to low DFS and OS in patients with endometrial carcinoma, but also related to the high-risk factors of endometrial carcinoma recurrence. So serum ferritin levels may be used to predict the poor prognosis of patients with endometrial carcinoma.


A controlled clinical trial of artemether (qinghaosu derivative) versus quinine in complicated and severe falciparum malaria.
31 pairs of patients with complicated falciparum malaria (with anaemia, jaundice, raised blood urea, hyperpyrexia or more than 2% of erythrocytes parasitized) were treated with artemether or quinine. All patients in the artemether group survived but 2 of those treated with quinine died. Fever clearance time and parasite clearance time of patients treated with artemether were significantly shorter than in the quinine-treated group. One patient who failed to respond to quinine within 72 h was saved with artemether. Follow-up of the patients showed that 9 of 23 (39.1%) recrudesced on day 28 in the artemether group. In the quinine group the recrudescence rate was 9% (2 of 22). Hence artemether may be considered as one of the drugs of choice for severely ill patients; it may even be better than quinine.


Can China's carbon trading policy help achieve Carbon Neutrality? - A study of policy effects from the Five-sphere Integrated Plan perspective.
The carbon trading policy seeks to control carbon emissions by putting a price on carbon emissions and establishing a corresponding carbon market for trading. It is a significant move by China to address climate issues and achieve its Carbon Neutrality target. Therefore, assessing the policy effects of carbon trading is fundamental to its implementation nationwide. Based on the panel data of 30 provinces and cities in China from 2008 to 2018, this paper uses the Synthetic Control Method and Differences-in-Differences method to assess the effects of carbon trading policy on achieving Carbon Neutrality. By measuring the net carbon emissions, this research explores the level of Carbon Neutrality in each region. Based on the Five-sphere Integrated Plan (which covers the economy, politics, culture, social and ecological civilization), this research further verifies the impact paths of carbon trading policy on Carbon Neutrality. The results show that: First, carbon trading policy has a significant and sustainable effect on Carbon Neutrality. Second, from the perspective of the Five-sphere Integrated Plan, the carbon trading policy can help to reduce carbon sources and increase carbon sinks by adjusting the industrial structure, coordinating low-carbon policies, promoting cultural dissemination, increasing green space construction, and reducing energy intensity to achieve Carbon Neutrality. Third, cultural construction plays the most significant role in mediating carbon trading and Carbon Neutrality, followed by political construction.


A comparison of the relative efficacy of self-control therapy and a behavioral problem-solving therapy for depression in children.
Twenty-nine children 9 to 12 years old who were identified as moderately to severely depressed using the Children's Depression Inventory were randomly assigned to either a self-control, behavioral problem-solving, or waiting list condition. The self-control treatment focused on teaching children self-management skills. The behavioral problem-solving therapy consisted of education, self-monitoring of pleasant events, and group problem solving directed toward improving social behavior. Subjects were assessed pre- and posttreatment and at 8-week follow-up with multiple assessment procedures and from multiple perspectives. At posttreatment, subjects in both active treatments reported significant improvement on self-report and interview measures of depression while subjects in the waiting list condition reported minimal change. Results were maintained at follow-up. The general success of the experimental treatments was discussed and recommendations for further treatment components were provided.


Proteome composition in Plasmodium falciparum: higher usage of GC-rich nonsynonymous codons in highly expressed genes.
The parasite Plasmodium falciparum, responsible for the most deadly form of human malaria, is one of the extremely AT-rich genomes sequenced so far and known to possess many atypical characteristics. Using multivariate statistical approaches, the present study analyzes the amino acid usage pattern in 5038 annotated protein-coding sequences in P. falciparum clone 3D7. The amino acid composition of individual proteins, though dominated by the directional mutational pressure, exhibits wide variation across the proteome. The Asn content, expression level, mean molecular weight, hydropathy, and aromaticity are found to be the major sources of variation in amino acid usage. At all stages of development, frequencies of residues encoded by GC-rich codons such as Gly, Ala, Arg, and Pro increase significantly in the products of the highly expressed genes. Investigation of nucleotide substitution patterns in P. falciparum and other Plasmodium species reveals that the nonsynonymous sites of highly expressed genes are more conserved than those of the lowly expressed ones, though for synonymous sites, the reverse is true. The highly expressed genes are, therefore, expected to be closer to their putative ancestral state in amino acid composition, and a plausible reason for their sequences being GC-rich at nonsynonymous codon positions could be that their ancestral state was less AT-biased. Negative correlation of the expression level of proteins with respective molecular weights supports the notion that P. falciparum, in spite of its intracellular parasitic lifestyle, follows the principle of cost minimization.