Theragnosis-based combined cancer therapy using doxorubicin-conjugated microRNA-221 molecular beacon.
Recently, microRNA (miRNA or miR) has emerged as a new cancer biomarker because of its high expression level in various cancer types and its role in the control of tumor suppressor genes. In cancer studies, molecular imaging and treatment based on target cancer markers have been combined to facilitate simultaneous cancer diagnosis and therapy. In this study, for combined therapy with diagnosis of cancer, we developed a doxorubicin-conjugated miR-221 molecular beacon (miR-221 DOXO MB) in a single platform composed of three different nucleotides: miR-221 binding sequence, black hole quencher 1 (BHQ1), and doxorubicin binding site. Imaging of endogenous miR-221 was achieved by specific hybridization between miR-221 and the miR-221 binding site in miR-221 DOXO MB. The presence of miR-221 triggered detachment of the quencher oligo and subsequent activation of a fluorescent signal of miR-221 DOXO MB. Simultaneous cancer therapy in C6 astrocytoma cells and nude mice was achieved by inhibition of miRNA-221 function that downregulates tumor suppressor genes. The detection of miR-221 expression and inhibition of miR-221 function by miR-221 DOXO MB provide the feasibility as a cancer theragnostic probe. Furthermore, a cytotoxic effect was induced by unloading of doxorubicin intercalated into miR-221 DOXO MB inside cells. Loss of miR-221 function and cytotoxicity induced by the miR-221 DOXO MB provides combined therapeutic efficacy against cancers. This method could be used as a new theragnostic probe with enhanced therapy to detect and inhibit many cancer-related miRNAs.


Sirtuin 3-dependent mitochondrial redox homeostasis protects against AGEs-induced intervertebral disc degeneration.
Intervertebral disc (IVD) degeneration contributes largely to pathoanatomical and degenerative changes of spinal structure that increase the risk of low back pain. Apoptosis in nucleus pulposus (NP) can aggravate IVD degeneration, and increasing studies have shown that interventions targeting NP cell apoptosis can ameliorate IVD degeneration, exhibiting their potential for use as therapeutic strategies. Recent data have shown that advanced glycation end products (AGEs) accumulate in NP tissues in parallel with the progression of IVD degeneration and form a microenvironment of oxidative stress. This study examined whether AGEs accumulation aggravates NP cell apoptosis and IVD degeneration, and explored the mechanisms underlying these effects. We observed that the viability and proliferation of human NP cells were significantly suppressed by AGEs treatment, mainly due to apoptosis. Furthermore, activation of the mitochondrial apoptosis pathway was detected after AGEs treatment. In addition, the molecular data showed that AGEs could significantly aggravate the generation of mitochondrial reactive oxygen species and prolonged activation of the mitochondrial permeability transition pore, as well as the increased level of Bax protein and decreased level of Bcl-2 protein in mitochondria. These effects could be reduced by antioxidant (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride (MitoTEMPO) and Visomitin (SKQ1). Importantly, we identified that impairment of Sirtuin3 (SIRT3) function and the mitochondrial antioxidant network were vital mechanisms in AGEs-induced oxidative stress and secondary human NP cell apoptosis. Finally, based on findings that nicotinamide mononucleotide (NMN) could restore SIRT3 function and rescue human NP cell apoptosis through adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor-γ coactivator 1α (AMPK-PGC-1α) pathway in vitro, we confirmed its protective effect on AGEs-induced IVD degeneration in vivo. In conclusion, our data demonstrate that SIRT3 protects against AGEs-induced human NP cell apoptosis and IVD degeneration. Targeting SIRT3 to improve mitochondrial redox homeostasis may represent a potential therapeutic strategy for attenuating AGEs-associated IVD degeneration.


Estimating the social value of mechanical thrombectomy randomized trials on an established stroke network.
Given the relative strength of prior mechanical thrombectomy (MT) data in face of the perceived poor natural history of emergent large vessel occlusion strokes, randomization to medical therapy during the recent clinical MT trials raised ethical challenges at individual and institutional levels despite overall clinical equipoise. In a thrombectomy stroke registry, we compared treatment rates preceding and following the SWIFT-PRIME and DAWN trials. Based on effect sizes of treatment in both trials, we estimated missed opportunities due to randomization to medical therapy and estimated the societal benefit resulting from additional patients who benefited as a result of these studies. The average monthly thrombectomy rate in the SWIFT-PRIME time window increased from 14.1±4 patients-per-month (ppm) to 23.8±6 ppm (p<0·001). Twelve subjects were enrolled in SWIFT-PRIME and we estimated a missed opportunity of benefiting 2.3 of six subjects randomized to medical therapy. This was offset by providing treatment to an additional 9.7 ppm, resulting in an additional functional benefit to 3.7 ppm. Similarly, the thrombectomy rate in the DAWN window increased from 8.6±4 ppm pre-DAWN to 11.9±3.6 ppm post-DAWN (p<0.01). 38 subjects were enrolled in the DAWN trial with a missed opportunity to benefit eight of 16 subjects randomized to medical therapy. This was offset by the ability to offer MT to an additional 3.3 ppm, bringing definite benefit to an additional 1.65 ppm. Completion of recent trials resulted in observable increases in rates of thrombectomy, translating to functional benefits that rapidly offset any missed opportunities due to randomization to medical therapy arms.


Evaluation of aortopulmonary window using virtual dissection of multidetector computed tomography angiography data sets.
The present study sought to evaluate the morphology and associated cardiovascular anomalies in patients with aortopulmonary window on virtual dissection of multidetector computed tomography (CT) angiography data sets. We conducted a retrospective search of our departmental database from January 2014 to September 2021 to identify patients with aortopulmonary window and relevant information was extracted from the electronic case records and from routine examination as well as virtual dissection of CT data sets. An aortopulmonary window was observed in 26 patients (20 males; 6 females). Based on location of the defect, a distal aortopulmonary window was the most common subtype, seen in 13/26 (50%) patients followed by a proximal, complete and intermediate subtypes seen in 7/26 (27%), 5/26 (19%) and 1/26 (4%) patients respectively. Associated ventricular septal defect was observed in 9/26 (34.6%) patients while an interrupted aortic arch was present in 5/26 (19.2%) patients. Tetralogy of Fallot was seen in 5/26 (19.2%) patients. Anomalous origin of right pulmonary artery from ascending aorta and crossed pulmonary arteries were seen in 2/26 (7.6%) patients each. An isolated aortopulmonary window without any simple/complex congenital anomaly was seen in 10/26 (38.5%) patients. Aortopulmonary window is associated with a wide gamut of cardiovascular lesions, with ventricular septal defect being the commonest associated anomaly followed by tetralogy of Fallot and interrupted aortic arch respectively. Virtual dissection of multidetector CT angiography allows detailed anatomical evaluation of aortopulmonary window, allowing a clear visualization of the defect and associated cardiovascular anomalies.


Eukaryotic elongation factor Tu is present in mRNA-protein complexes.
By two-dimensional gel electrophoresis, partial peptide mapping, and antibody binding we have shown that eukaryotic elongation factor Tu is in close contact with mRNA in rabbit reticulocytes. It can be crosslinked to mRNA by irradiating both polysomes and 40-80 S mRNA-protein complexes with short-wave UV light. To our knowledge this is the first case in which a known translation factor has been shown to be associated with mRNA in native ribonucleoproteins.


Electroanalytical performance of a terbium(III)-selective sensor based on a neutral ionophore in environmental and medicinal samples.
A new highly selective terbium(III) electrode was prepared with a polymeric film doped using S-2-benzothiazolyl-2-amino-alpha-(methoxyimino)-4-thiazolethiol acetate as an electroactive material, benzyl acetate (BA) as a plasticizer, and potassium tetrakis(4-chlorophenyl) borate (KTpClPB) as an anionic site in the percentage ratio 3.17:1.58:63.4:31.7 (ionophore-KTpClPB-BA-PVC, w/w). The electrode exhibited a linear response with a near Nernstian slope of 19.5 mV/decade within the concentration range 1.5 x 10(-7)-1.0 x 10(-2) M terbium ions, with a working pH range from 2.0 to 8.0, and a fast response time of 10 s and presented satisfactory reproducibility. The limit of detection was 9.3 x 10(-8) M. The results show that this electrode can be used in ethanol media up to 30% (v/v) concentration without interference. It can be used for 3 months without any considerable divergence in the potentials. Selectivity coefficients for terbium(III) with respect to many cations were investigated. The electrode is highly selective for terbium(III) ions over a large number of monovalent, bivalent, and trivalent cations. This shows the valuable property of the proposed electrode. The stability constant of the ionophore towards Tb(3+) ions was determined with the sandwich membrane method. It was successfully used as an indicator electrode in potentiometric determination of terbium(III) ions with EDTA and in direct determination in tap water and binary mixtures with quantitative results. The utility of the proposed electrode was also determined in the presence of ionic and nonionic surfactants and in the presence of fluoride ions in four pharmaceutical (mouthwash) preparations. [figure: see text]


Methionine sulfoxide reductase A protects dopaminergic cells from Parkinson's disease-related insults.
Parkinson's disease (PD) is a neurologic disorder characterized by dopaminergic cell death in the substantia nigra. PD pathogenesis involves mitochondrial dysfunction, proteasome impairment, and alpha-synuclein aggregation, insults that may be especially toxic to oxidatively stressed cells including dopaminergic neurons. The enzyme methionine sulfoxide reductase A (MsrA) plays a critical role in the antioxidant response by repairing methionine-oxidized proteins and by participating in cycles of methionine oxidation and reduction that have the net effect of consuming reactive oxygen species. Here, we show that MsrA suppresses dopaminergic cell death and protein aggregation induced by the complex I inhibitor rotenone or mutant alpha-synuclein, but not by the proteasome inhibitor MG132. By comparing the effects of MsrA and the small-molecule antioxidants N-acetylcysteine and vitamin E, we provide evidence that MsrA protects against PD-related stresses primarily via methionine sulfoxide repair rather than by scavenging reactive oxygen species. We also demonstrate that MsrA efficiently reduces oxidized methionine residues in recombinant alpha-synuclein. These findings suggest that enhancing MsrA function may be a reasonable therapeutic strategy in PD.


Hematoporphyrin-mediated fluorescence reflectance imaging: application to early tumor detection in vivo in small animals.
The in vivo early detection of subcutaneous human tumors implanted in small animals was studied by laser-induced fluorescence reflectance imaging (FRI), with a hematoporphyrin (HP) compound as an exogenous optical contrast agent. Tumor detection was shown to be possible just 3 days after the inoculation of tumor cells, when tumors were neither visible nor palpable. However, this detection capability is limited to a temporal window of approximately 100 h from HP administration and to a low optical contrast of the tumor (<2).


Determination of adenosine 3',5'-cyclic monophosphate levels in tissues of the free living nematode, Panagrellus redivivus.
1. Tissue levels of adenosine 3', 5'-cyclic monophosphate (c-AMP) were determined by a protein binding assay in mixed populations of the free living nematode Panagrellus redivivus. 2. The values were 2.6 pmoles/mg dry weight (range 1.3-3.4 pmoles). 3. The identity of the c-AMP assayed was confirmed by both anion exchange and TLC as well as enzymatic degradation.


Customizing palatal contours of a denture to improve speech intelligibility.
Accurate approximation of palatal contours of a maxillary complete denture to a patient's tongue can improve speech intelligibility, if other factors such as tooth position, occlusal plane, and occlusal vertical dimension are satisfactory. Customizing palatal contours of a maxillary complete denture can be accomplished by using tissue-conditioning material, which provides sufficient working time for a patient to pronounce a series of sibilant sounds while recording dynamic impression of the tongue. This article describes a technique for customizing palatal contours of a maxillary complete denture with autopolymerizing acrylic resin to improve speech intelligibility.


Growth-regulated formation of heteromeric complexes of the centromere and promoter factor, Cbf1p, in yeast.
Transcriptional regulation of the yeast cytochrome c1 gene (CYT1) in response to oxygen and carbon source is mediated by Haplp and the Hap2 complex. Furthermore, the centromere-binding factor 1 (Cbflp) associates with the CYT1 upstream region (UAS(CYT1)), but its direct activation potential is insignificant. The possible role of Cbflp as a modulator of transcriptional adaptation to changes in nutritional conditions was examined. In electrophoretic mobility shift assays (EMSA) using yeast nuclear extracts, Cbflp was found to exist as homo- and heterodimers of processed subforms of 54 and 37 kDa. An additional 18-kDa version was the only species found in anaerobic cells grown under an atmosphere of purified nitrogen, but not when CO2 was used to establish anaerobiosis. All three dimers of the 37 and 54 kDa versions of Cbflp that occurred in oxidatively growing cells gave rise to hetero-oligomeric complexes containing other as yet unidentified protein(s). Complex formation was not observed with extracts from cultures grown on high levels of glucose and was dependent on pre-assembly in the absence of target DNA. Pre-treatment with alkaline phosphatase enhanced formation of these higher-order complexes. The C-terminal 18-kDa segment of Cbflp, which can undergo dimerization and bind DNA, does not induce supershifts after preincubation and is not influenced by dephosphorylation. We propose that the N-terminal domain is subject to carbon source- or growth-dependent phosphorylation/dephosphorylation events that result in differential recruitment of additional factors to promoters of genes that encode proteins required for non-fermentative growth.


Gpc3 expression correlates with the phenotype of the Simpson-Golabi-Behmel syndrome.
Interest in glypican-3 (GPC3), a member of the glypican-related integral membrane heparan sulfate proteoglycans (GRIPS) family, has increased with the finding that it is mutated in the Simpson-Golabi-Behmel overgrowth syndrome (Pilia et al. [1996] Nat. Genet. 12:241-247). The working model suggested that the membrane-bound protein acts locally to limit tissue and organ growth and that it may function by interacting with insulin-like growth factor 2 (IGF2) to limit its local effective level. Here we have tested two predictions of the model. In situ hybridization with the mouse gene cDNA was used to study the expression pattern during embryonic and fetal development. In agreement with predictions, the gene is expressed in precisely the organs that overgrow in its absence; and the patterns of expression of Gpc3 and those reported for Igf2 are strictly correlated.


MicroRNA-1 and microRNA-206 suppress LXRα-induced lipogenesis in hepatocytes.
Liver X receptor α (LXRα) plays a critical role in the transcriptional control of lipid metabolism. LXR activation induces the expression of lipogenic genes, which promote hepatic steatosis and steatohepatitis. However, the regulation of LXR is not fully understood. MicroRNAs (miRs) are regarded as important negative regulators of gene expression. In this study, we found that miR-1/miR-206 repressed LXRα-induced accumulation of lipid droplets in hepatocytes. In addition, bioinformatic analysis predicted a same putative target-site for miR-1/miR-206 located within the 3'-untranslated region (3'-UTR) of LXRα mRNA. The reporter assay revealed that miR-1/miR-206 directly targeted the 3'-UTR of LXRα mRNA. Furthermore, miR-1/miR-206 repressed LXRα expression at both mRNA and protein levels, accompanied with the inhibition of expression of LXRα target genes, such as sterol-regulatory element binding protein 1c, fatty acid synthase, carbohydrate responsive element-binding protein and acetyl-CoA carboxylase 1, which are important effectors of LXRα implicated in lipogenesis. Moreover, ectopic expression of LXRα without the 3'-UTR dramatically attenuated the miR-1/miR-206-induced decrease of lipogenic genes and lipid droplet accumulation. Taken together, we for the first time demonstrated that miR-1/miR-206 attenuated LXRα-induced lipogenesis by targeting the 3'-UTR of LXRα mRNA, suggesting that miR-1/miR-206-LXRα pathway may be a novel target for the treatment of lipogenesis-associated diseases.


Whole-exome sequencing identifies rare genetic variants associated with human plasma metabolites.
Metabolite levels measured in the human population are endophenotypes for biological processes. We combined sequencing data for 3,924 (whole-exome sequencing, WES, discovery) and 2,805 (whole-genome sequencing, WGS, replication) donors from a prospective cohort of blood donors in England. We used multiple approaches to select and aggregate rare genetic variants (minor allele frequency [MAF] < 0.1%) in protein-coding regions and tested their associations with 995 metabolites measured in plasma by using ultra-high-performance liquid chromatography-tandem mass spectrometry. We identified 40 novel associations implicating rare coding variants (27 genes and 38 metabolites), of which 28 (15 genes and 28 metabolites) were replicated. We developed algorithms to prioritize putative driver variants at each locus and used mediation and Mendelian randomization analyses to test directionality at associations of metabolite and protein levels at the ACY1 locus. Overall, 66% of reported associations implicate gene targets of approved drugs or bioactive drug-like compounds, contributing to drug targets' validating efforts.


The use of the cuffed oropharyngeal airway in paediatric patients.
The cuffed oropharyngeal airway (COPA) is a device which has already been demonstrated to be suitable for anaesthetized adult patients undergoing either spontaneous or mechanical ventilation. There are few reports on the use of the COPA in children. In this study, the authors assessed the COPA in paediatric patients undergoing minor surgery. The same anaesthesiologist inserted the COPA in 40 consecutive paediatric patients, ASA I and II, aged 1.8-15.3 years. (7.4 +/- 3.9), after induction of anaesthesia with N2O/O2/sevoflurane. COPA size was chosen by measuring the distal tip of the device at the angle of the jaw with the COPA perpendicular to the patient's bed. The proper positioning of the COPA was assessed by observing thoracoabdominal movements, regular capnograph trace, the reservoir bag movements and SpO2 > 94% with a fraction of inspired oxygen of 0.5. Anaesthesia was maintained with 1 MAC halothane, sevoflurane, or isoflurane in N2O/O2 (50%) and the patients were spontaneously breathing. The stability of the COPA following changes in head, neck and body position was tested. We recorded the duration time for COPA insertion, the side-effects of placement of the COPA and during the intraoperative period, the number of attempts, the type of manipulation in order to provide an effective airway and postoperative symptoms, such as the presence of blood on the device, sore throat, neckache, jaw pain and PONV. Successful COPA insertion at the first attempt was 90% and at the second attempt in the remaining 10%. The most frequent airway manipulations were head tilt in 27.5% (obtained by a pillow under shoulders) and chin lift in 5%. No complications both at COPA placement nor during the intraoperative period were observed. On the basis of weight and age, the COPA size was no. 8 in 50%, no. 9 in 30%, no. 10 in 12.5%, and no. 11 in 7.5%. The COPA demonstrated stability after changes in head, neck and body position. Postoperative complications were the presence of blood stains in one case and PONV in six cases (15%). The COPA is an extratracheal airway device suitable in paediatric patients undergoing general anaesthesia with spontaneous ventilation for minor surgery and other painful procedures. This study shows that for paediatric patients: (i) complications seem to be rare; (ii) the COPA allows hands free anaesthesia; (iii) specific indication for the COPA could be obese patients with a small mouth; and (iv) COPA sizing can be easily established by the weight or age of the patients.


Hydroxyurea-sensitive thymidine incorporation in rat liver and kidney following administration of dimethylnitrosamine.
In rats treated with dimethylnitrosamine (DMN), the sensitivity of [3H] thymidine incorporation to inhibition by hydroxyurea was determined in the liver and kidney. A 70% inhibition was produced in control animals with doses of hydroxyurea from 50 to 250 mg/kg body wt. Twelve hours after administration of DMN, hepatic thymidine incorporation was unaffected by 50 mg/kg hydroxyurea, progressive reduction in incorporation occurred as the dose of inhibitor was increased. A similar result was obtained in kidney only by dietary conditioning of rats to ensure a high renal metabolism of the DMN. In contrast, at 72 h after DMN treatment thymidine incorporation in both liver and kidney was rapidly inhibited by administration of 50 mg/kg hydroxyurea. The data, assessed together with various parameters of DMN-induced repair and replicative DNA synthesis, suggest the use of hydroxyurea as a means to study DNA repair in intact animals.


Autonomy-supportive decision-making in maternity care during prenatal consultations: a qualitative interaction analysis.
The aim of this study was to identify mechanisms of autonomy-supportive consultation (ASC) that maternity care professionals use during decision-making in prenatal consultations. This study was a descriptive, qualitative analysis of professional-patient interactions in maternity care, using concepts and analytic procedures of conversation analysis. The prenatal consultations took place in hospitals and midwifery practices in the Netherlands. This study was part of a larger project. For the current study, we selected prenatal consultations concerning three topics in which patients make their own choices. The first author invited the patient who was waiting in the waiting room. Participants were not selected a priori. The main outcome measures were mechanisms of ASC. We selected 20 consultations which were conducted by 20 different professionals. We found eight mechanisms in the professional-patient interaction which were categorised into three overarching themes. The first theme, 'Lightheartedness', comprises the interactional mechanisms 'minimising language' and 'humour'. The theme 'Orientation to agreement' describes how professionals and patients seem to be oriented towards demonstrating agreement and mutual understanding. The last theme, 'Offering information and options', describes the professional formally giving factual information almost completely without verbal interaction between the professional and the patient. The results of this study show that the model of ASC can be enriched by adding minimising language and humour to the mechanisms that can be used to fulfil the psychological need 'relatedness'. Second, our results show that professionals use only few mechanisms to meet the patients' psychological needs 'competence' and 'autonomy'. They mainly use information giving to meet patients' need competence. To meet patients' need for autonomy, the professionals keep all options open. This suggests that professionals could pay more attention to other mechanisms to meet patients' needs for 'competence' and 'autonomy'.


RNA-Seq Analysis Reveals Expression Regulatory Divergence of W-Linked Genes between Two Contrasting Chicken Breeds.
The regulation of gene expression is a complex process involving organism function and phenotypic diversity, and is caused by cis- and trans- regulation. While prior studies identified the regulatory pattern of the autosome rewiring in hybrids, the role of gene regulation in W sex chromosomes is not clear due to their degradation and sex-limit expression. Here, we developed reciprocal crosses of two chicken breeds, White Leghorn and Cornish Game, which exhibited broad differences in gender-related traits, and assessed the expression of the genes on the W chromosome to disentangle the contribution of cis- and trans-factors to expression divergence. We found that female-specific selection does not have a significant effect on W chromosome gene-expression patterns. For different tissues, there were most parental divergence expression genes in muscle, and also more heterosis compared with two other tissues. Notably, a broader pattern of trans regulation in the W chromosome was observed, which is consistent with autosomes. Taken together, this work describes the regulatory divergence of W-linked genes between two contrasting breeds and indicates sex chromosomes have a unique regulation and expression mechanism.


Effects of exposure to an extremely low frequency electromagnetic field on hippocampal long-term potentiation in rat.
Modern lifestyle exposes nearly all humans to electromagnetic fields, particularly to extremely low frequency electromagnetic fields (ELF-EMFs). Prolonged exposure to ELF-EMFs induces persistent changes in neuronal activity. However, the modulation of synaptic efficiency by ELF-EMFs in vivo is still unclear. In the present study, we investigated whether ELF-EMFs can change induction of long-term potentiation (LTP) and paired-pulse ratio (PPR) in the rat hippocampal area. Twenty-nine adult male Wistar rats were divided into 3 groups (ELF-EMF exposed, sham and control groups). The ELF-EMF group was exposed to a magnetic field for 90 consecutive days (2h/day). ELF-EMFs were produced by a circular coil (50Hz, 100 micro Tesla). The sham-exposed controls were placed in an identical chamber with no electromagnetic field. After this period, rats were deeply anesthetized with urethane (2.0mg/kg) and then a bipolar stimulating and recording electrode was implanted into the perforant pathway (PP) and dentate gyrus (DG), respectively. LTP in hippocampal area was induced by high-frequency stimulation (HFS). Prolonged exposure to ELF-EMFs increased LTP induction. There was a significant difference in the slope of EPSP and amplitude of PS between the ELF-EMF group and other groups. In conclusion, our data suggest that exposure to ELF-EMFs produces a marked change in the synaptic plasticity generated in synapses of the PP-DG. No significant difference in PPR of ELF-EMF group before and after HFS suggests a postsynaptic expression site of LTP.


The Effect of Use of Individualized Pain Plans in Sickle Cell Patients Presenting to the Emergency Department.
Sickle cell disease (SCD) is an inherited hematologic disorder that affects approximately 100,000 US individuals and results in greater than 200,000 emergency department (ED) visits annually in the United States, with pain being the most common complaint. The objective of this retrospective study is to determine the effect of implementing individualized pain plans in the treatment of patients with SCD in the ED on time to first opioid, length of stay, and disposition. At The Ohio State University Wexner Medical Center, a multidisciplinary group including hematologists and ED physicians was formed and enacted a protocol for using individualized pain plans, with the goal of decreasing time to treatment for patients with SCD who presented to the ED with chief complaint of pain. In this retrospective study, data from the year before through the year of implementation were gathered. Generalized linear models were fit to compare time to first opioid, length of stay, and disposition before and after protocol implementation. Data showed a 48% decrease in time to first opioid and a 22% decrease in length of ED stay after protocol implementation. No significant change was found in disposition or length of inpatient admission before and after protocol initiation. The use of individualized pain plans in the treatment of patients with SCD in the ED is a useful method of not only ensuring rapid and adequate treatment but also decreasing use of health care resources.


Epidemiological features of acute medial meniscus posterior root tears.
Untreated or overlooked medial meniscus posterior root tears (MMPRTs) induce sequential knee joint degradation. We evaluated epidemiological features of acute MMPRT for its early detection and accurate diagnosis. Among 330 MMPRT patients from 2018 to 2020, those who underwent arthroscopic pullout repairs were enrolled. Patients who underwent non-operative treatment or knee arthroplasty, those with a cruciate ligament-deficient knee or advanced osteoarthritis of the knee, and those with insufficient data were excluded. Finally, we retrospectively evaluated data from 234 MMPRTs (female: 79.9%, complete tears: 92.7%, mean age: 65 years). Welch's t-test and Chi-squared test were used for pairwise comparisons. Spearman's rank correlation analysis was performed between age at surgery and body mass index (BMI). Multivariable logistic regression analysis with stepwise backward elimination was applied to the values as risk factors for painful popping events. In both sexes, there were significant differences in height, weight, and BMI. In all patients, there was a significant negative correlation between BMI and age (ρ = - 0.36, p < 0.001). The BMI cutoff value of 27.7 kg/m2 had a 79.2% sensitivity and a 76.9% specificity for detecting MMPRT patients aged < 50 years. A painful popping event was confirmed in 187 knees (79.9%), and the frequency was significantly reduced in partial tears as compared to complete tears (odds ratio: 0.080, p < 0.001). Higher BMI was associated with a significantly younger age of MMPRT onset. Partial MMPRTs had a low frequency of painful popping events (43.8%).


The heuristics of biologic theory: the case of self-nonself discrimination.
Mel Cohn has responded to our critique of the minimal model of self-nonself discrimination proposed by Langman and him. In this response to Mel Cohn, we summarize the essential differences between our points of view and highlight one criterion (of many) for preferring one theory to another in the complex field of biology: a preferred theory, rather than solving a problem, is heuristic. A good theory is one that activates a scientist to perform experiments that are novel and productive.


Development of the cholinergic system in the brain and retina of the zebrafish.
We have analyzed the distribution pattern of choline acetyltransferase (ChAT) in the zebrafish brain and retina during ontogeny. ChAT-immunoreactive (ChAT-ir) neurons are observed in the prosencephalon from 60 h postfertilization (hpf) onwards, exclusively in the preoptic area (basal plate of p6) derived from the secondary prosencephalon. In the mesencephalon, ChAT-ir cells are observed in both the optic tectum and the tegmentum. Stained cells in the tegmentum are observed from 60 hpf onwards, while in the optic tectum they appear after hatching. In the rhombencephalon, ChAT-ir cells are first observed in the isthmic region (rh1) and in the medulla oblongata (rh5-rh7) at the end of embryonic life. The rhombencephalic cholinergic cell groups develop in a gradual caudorostral sequence. Motoneurons of the spinal cord are ChAT-ir from 48 hpf onwards. The retina displays ChAT-ir neuropil in both the inner and outer plexiform layers from embryonic life, whereas stained amacrine cells are only observed after hatching. The staining in the outer plexiform layer gradually decreases during juvenile development. The optic nerve axons show a transient expression of ChAT at the end of embryonic development. The early presence of ChAT immunolabeling suggests an important neuromodulator role for acetylcholine in the first developmental stages.


The validity and reliability of Turkish version of the self-efficacy scale in nursing care of children with epilepsy.
This study was conducted to the Turkish validity and reliability study of the 'Scale of Self-efficacy in Nursing Care of Children with Epilepsy' (SSENCCE). The construct validity of the scale was evaluated with explanatory factor analysis (EFA) and confirmatory factor analysis. The reliability of the scales used in the research was examined with composite reliability and Cronbach's alpha coefficients. A total of 144 nurses participated in the study. The variance explained in the 12-item scale was 53.6%, and the eigenvalue was found as 6.442. The commonality values of the scale items ranged from 0.304 to 0.712, and the factor loads ranged from 0.552 to 0.844. Cronbach's α of the SSENCCE was calculated as 0.907. The Turkish version of the ESSENCE is a valid, reliable, and appropriate tool for assessing the self-efficacy of nurses providing care for children with epilepsy. Considering that there is no scale that is used to evaluate the self-efficacy of nurses who provide care for children with epilepsy in Turkey, it is thought that this study will guide future research on the subject and the improvement of the clinical experience of nurses.


Conformational restriction of peptidyl immunogens with covalent replacements for the hydrogen bond.
A new strategy for designing synthetic vaccines is presented. In this approach synthetic peptides are conformationally restricted by replacing putative hydrogen bonds with covalent mimics. The chemistry for substituting a hydrazone-ethane link (N-N = CH-CH2-CH2) for an (i + 4)----i hydrogen bond in a pentapeptide with alpha-helical potential is reported. Chemically shaping peptides to mimic the three-dimensional surfaces of proteins may enhance their immunogenicity. To test this strategy, a potential synthetic vaccine for malaria, Cys-(Asn-Pro-Asn-Ala)3-NH2, was conformationally restricted by replacing putative hydrogen bonds between asparagine side chains with a covalent replacement, an ethylene bridge, to give first generation chemically shaped immunogens. Antibodies to one of the shaped malarial peptides show a strong reaction with living Plasmodium falciparum sporozoites, a form of malaria which infects hundreds of millions of people yearly.


Expression of Ki-67 as proliferation biomarker in imprint smears of endometrial carcinoma.
The aims of this study were to determine the expression of Ki-67 in type I and type II endometrial adenocarcinomas as well as normal endometrium in imprint smears and to correlate the results with clinicopathologic parameters of primary untreated endometrial cancer patients. During a 29-month period, 255 patients were evaluated with entometrial imprint cytology. Endometrial samples freshly resected from women who underwent total abdominal hysterectomy were studied. One hundred twenty-six patients had endometrial carcinoma and 129 cases were diagnosed as normal endometrium. The expression of Ki-67 was assessed by immunocytochemistry. Positive staining was correlated with increased stage, grade and lymph node metastases. High expression was more frequent in type II than type I endometrial adenocarcinoma and high-grade endometrial carcinoma had higher proportions of Ki-67 positive immunostaining compared with low-grade carcinoma. Proliferative endometrium showed high Ki-67 expression level, even higher than those of grade 1 and type I. On the other hand, secretory endometrium Ki-67 positive cells were markedly diminished and even disappeared. Completely negative staining was found to be related to atrophic endometrium. Immunocytochemical findings from Ki-67 stain, in addition to cytomorphologic features, appeared to be useful for the diagnosis of endometrial carcinoma in endometrial cytology with imprint smears. High Ki-67 expression correlates with morphologic features of aggressiveness and the expression pattern of Ki-67 correspond to the expected cyclic/atrophic pattern in normal endometrium.


A Systematic Review of Pharmacovigilance Systems in Developing Countries Using the WHO Pharmacovigilance Indicators.
In the context of the growth of pharmacovigilance (PV) among developing countries, this systematic review aims to synthesise current research evaluating developing countries' PV systems' performance. EMBASE, MEDLINE, CINAHL Plus and Web of Science were searched for peer-reviewed studies published in English between 2012 and 2021. Reference lists of included studies were screened. Included studies were quality assessed using Hawker et al.'s nine-item checklist; data were extracted using the WHO PV indicators checklist. Scores were assigned to each group of indicators and used to compare countries' PV performance. Twenty-one unique studies from 51 countries were included. Of a total possible quality score of 36, most studies were rated medium (n = 7 studies) or high (n = 14 studies). Studies obtained an average score of 17.2 out of a possible 63 of the WHO PV indicators. PV system performance in all 51 countries was low (14.86/63; range: 0-26). Higher average scores were obtained in the 'Core' (9.27/27) compared to 'Complementary' (5.59/36) indicators. Overall performance for 'Process' and 'Outcome' indicators was lower than that of 'Structural'. This first systematic review of studies evaluating PV performance in developing countries provides an in-depth understanding of factors affecting PV system performance.


The mithramycin gene cluster of Streptomyces argillaceus contains a positive regulatory gene and two repeated DNA sequences that are located at both ends of the cluster.
Sequencing of a 4.3-kb DNA region from the chromosome of Streptomyces argillaceus, a mithramycin producer, revealed the presence of two open reading frames (ORFs). The first one (orfA) codes for a protein that resembles several transport proteins. The second one (mtmR) codes for a protein similar to positive regulators involved in antibiotic biosynthesis (DnrI, SnoA, ActII-orf4, CcaR, and RedD) belonging to the Streptomyces antibiotic regulatory protein (SARP) family. Both ORFs are separated by a 1.9-kb, apparently noncoding region. Replacement of the mtmR region by an antibiotic resistance cassette completely abolished mithramycin biosynthesis. Expression of mtmR in a high-copy-number vector in S. argillaceus caused a 16-fold increase in mithramycin production. The mtmR gene restored actinorhodin production in Streptomyces coelicolor JF1 mutant, in which the actinorhodin-specific activator ActII-orf4 is inactive, and also stimulated actinorhodin production by Streptomyces lividans TK21. A 241-bp region located 1.9 kb upstream of mtmR was found to be repeated approximately 50 kb downstream of mtmR at the other end of the mithramycin gene cluster. A model to explain a possible route for the acquisition of the mithramycin gene cluster by S. argillaceus is proposed.


[Identification of extracellular polysaccharide-associated genes in Xanthomonas oryzae pv. oryzicola].
Previously, seventeen extracellular polysaccharide-associated mutants of Xanthomonas oryzae pv. oryzicola (Xoc) were acquired from our randomly Tn5-inserted mutant library. To know the Tn5-inserted genes of these mutants and their contribution to EPS production and virulence in rice, in this study, we first identified and characterized the Tn5-targeted genes in these mutants and then inoculated them in susceptible rice for virulence assessment. Tn5 transposon was inserted in genes of the gum, xan and wxoc clusters in the majority of EPS-reduced mutants. Of the EPS-reduced mutants, three were due to the Tn5 insertion in Xoryp_4217, Xoryp 2488 and Xoryp_0918 genes, respectively. In six EPS-increased mutants, three were in mutagenesis in fimO, pilY and xopQ genes, respectively, resulting in higher EPS production than the wild-type strain RS105. Other three were because of the mutation in Xoryp2392, Xoryp_4221 and Xoryp_3511 genes. Interestingly, XocORF-3511 only exists in X. oryzae but not in other Xanthomomas species. Virulence assays in rice showed that the less EPS production by the mutant, the weaker the virulence in rice. However, those mutants in higher EPS production did not increase virulence significantly in rice compared to that by the wild-type strain. Our findings will help further understand the metabolic pathways for EPS synthesis in Xoc and the specific roles of EPS-associated genes in Xoc-rice interactions.


Prevention of heart failure.
In light of the increasing prevalence, morbidity, and mortality of heart failure, preventative strategies are urgently needed. Risk factors include coronary artery disease, renal insufficiency, diabetes, and smoking. Essential strategies for prevention of heart failure are modification of risk factors for its development, and detection and treatment of asymptomatic left ventricular dysfunction (ALVD). In patients with ALVD, angiotensin-converting enzyme (ACE) inhibitor and beta-blocker therapy can prevent progression to symptomatic heart failure. Additional recently identified preventative strategies include ACE inhibitor therapy for all coronary artery disease and diabetic patients, clopidogrel therapy in acute coronary syndromes, and avoidance of calcium channel blockers and alpha-blockers as first-line antihypertensive therapy.


Delaire's cheilorhinoplasty: unilateral cleft aesthetic outcome scored according to the EUROCLEFT guidelines.
The aim of our study is to evaluate, in accordance with EUROCLEFT guidelines, the aesthetics of nasolabial area in a sample of complete unilateral cleft of lip and palate patients (UCLP), after surgical correction with Delaire' technique. Twenty-two UCLP patients (16 males and 6 females, 9 right and 13 left side clefts) were enrolled in this retrospective study. Patients were operated at 7 (mean value) months of age by a single surgeon. Frontal and sub-mental photos for each baby were recorded at 8.5 (mean value) years of age, and evaluated twice, by three independent maxillofacial surgeons. A five-point scale (EUROCLEFT guidelines) was used. Nonparametric analysis (Kruskal-Wallis test) was applied to detect differences in medians obtained in studied groups. Kruskal-Wallis test showed no statistical significant differences among evaluations of three surgeons and between the first and the second evaluation of the same surgeon. The global appearance of the upper lip and nose was scored with a mean value of 2 (i.e. good). The sample was then divided into two subgroups, according with patient' age; the aesthetics and the symmetry of the nose resulted better in elder patients (i.e. subgroup A, mean period of observation=10.2 years), whereas upper lip achieved better results in younger patients (i.e. subgroup B, mean period of observation=4.9 years). EUROCLEFT guidelines are a useful method to evaluate--aesthetically and over time--cleft lip and palate patients, treated with a single surgical procedure. We hypothesize that Delaire technique could progressively improve aesthetics and symmetry of the nose, throughout the growth of the patient.


Preoperative quality of life and surgical outcomes in gynecologic oncology patients: a new predictor of operative risk?
Quality of life (QoL) for women with gynecologic malignancies is predictive of chemotherapy related toxicity and overall survival but has not been studied in relation to surgical outcomes and hospital readmissions. Our goal was to evaluate the association between baseline, pre-operative QoL measures and 30-day post-operative morbidity and health resource utilization by gynecologic oncology patients. We analyzed prospectively collected survey data from an institution-wide cohort study. Patients were enrolled from 8/2012 to 6/2013 and medical record data was abstracted (demographics, comorbid conditions, and operative outcomes). Responses from several validated health-related QoL instruments were collected. Bivariate tests and multivariable linear and logistic regression models were used to evaluate factors associated with QoL scores. Of 182 women with suspected gynecologic malignancies, 152 (84%) were surveyed pre-operatively and 148 (81%) underwent surgery. Uterine (94; 63.5%), ovarian (26; 17.5%), cervical (15; 10%), vulvar/vaginal (8; 5.4%), and other (5; 3.4%) cancers were represented. There were 37 (25%) cases of postoperative morbidity (PM), 18 (12%) unplanned ER visits, 9(6%) unplanned clinic visits, and 17 (11.5%) hospital readmissions (HR) within 30days of surgery. On adjusted analysis, lower functional well-being scores resulted in increased odds of PM (OR 1.07, 95%CI 1.01-.1.21) and HR (OR 1.11, 95%CI 1.03-1.19). A subjective global assessment score was also strongly associated with HR (OR 1.89, 95%CI 1.14, 3.16). Lower pre-operative QoL scores are significantly associated with post-operative morbidity and hospital readmission in gynecologic cancer patients. This relationship may be a novel indicator of operative risk.


The new life of a centenarian: signalling functions of NAD(P).
Since the beginning of the last century, seminal discoveries have identified pyridine nucleotides as the major redox carriers in all organisms. Recent research has unravelled an unexpectedly wide array of signalling pathways that involve nicotinamide adenine dinucleotide (NAD) and its phosphorylated form, NADP. NAD serves as substrate for protein modification including protein deacetylation, and mono- and poly-ADP-ribosylation. Both NAD and NADP represent precursors of intracellular calcium-mobilizing molecules. It is now beyond doubt that NAD(P)-mediated signal transduction does not merely regulate metabolic pathways, but might hold a key position in the control of fundamental cellular processes. The comprehensive molecular characterization of NAD biosynthetic pathways over the past few years has further extended the understanding of the multiple roles of pyridine nucleotides in cell biology.


Localized Optical Coherence Tomography Precursors of Macular Atrophy and Fibrotic Scar in the Comparison of Age-Related Macular Degeneration Treatments Trials.
To identify precursors of macular atrophy (MA) and of fibrotic scar (FS) in eyes treated with anti-vascular endothelial growth factor through pixel-mapping analysis of baseline optical coherence tomography (OCT). Design: Cross-sectional analysis. Multicenter clinical trial. 68 eyes from the Comparison of Age-Related Macular Degeneration Treatments Trials. Treatment with anti-vascular endothelial growth factor agents. The percentage of MA or FS pixels with each OCT feature at baseline, and the odds ratio for baseline pixels with an OCT feature to develop MA or FS. Retinal pigment epithelium atrophy and photoreceptor loss on OCT were highly predictive of MA at that location at years 2 and 5 (P < .0001), but accounted for only 22.5% of the ensuing atrophy at year 2 and less at year 5. Among pixels of MA at year 2, 78% were preceded by thick drusen, 54% by subretinal macular neovascularization (MNV), and 22.5% by no detectable OCT features. MNV, subretinal hyperreflective material, pigment epithelial detachment, intraretinal fluid, and sub-retinal pigment epithelium fluid were predictive of FS at that location (P values <.05). More than 75% of the pixels of FS at years 2 and 5 were preceded by pixels of baseline MNV. Most pixels of FS were preceded by components of neovascularization. Although one-quarter of MA was accounted for by pre-existing evidence of atrophy on OCT alone, the development of MA in areas of thick drusen, areas with and without subretinal MNV lesion, and areas without detectable OCT precursors argues that the development of MA is multifactorial and may follow, in part, a non-neovascular pathway.


Efficacy of two different methods of cold air analgesia for pain relief in PDT of actinic keratoses of the head region - a randomized controlled comparison study.
Photodynamic therapy (PDT) is an effective method for treating actinic keratosis (AK) with pain during illumination representing the major side effect. The efficacy of two different cooling methods for pain relief in PDT of AK in the head region was compared. Randomized, assessor-blinded, half side comparison study in 20 patients with symmetrically distributed AK on the head. Conventional PDT was performed on both halves of the scalp or face by applying 20% aminolevulinic acid cream (ALA) and subsequent illumination with incoherent red light. During illumination one side was cooled with a cold air blower (CAB) and the other with a standard fan (FAN) in a randomized fashion. Pain and skin temperature were recorded during and after PDT. The phototoxic skin reaction was evaluated up to seven days after PDT. The clearance rate of AK was assessed at 3 and 6 months after PDT. Mean pain (VASmean), maximum pain intensity (VASmax) and the mean skin temperature during PDT were significantly lower with CAB as compared to FAN (VASmean: 2.7 ± 1.4 vs. 3.7 ± 2.1, p = 0.003; VASmax: 3.8 ± 2.0 vs. 4.8 ± 2.5, p = 0.002; 26.8 ± 2.0 °C vs. 32.1 ± 1.7 °C; p=<0.001). The severity of the phototoxic skin reaction and the clearance rate of AK did not differ between the two cooling methods. Cooling with CAB during PDT has a greater analgesic effect than cooling with FAN. Patients with a lower skin temperature during illumination tended to experience less pain, however, this effect did not reach the level of statistical significance.


Immunotherapy in a spontaneously developed murine mammary carcinoma with syngeneic monoclonal antibody.
A new spontaneously arisen murine breast tumor, designated JC, has been established in immunocompetent BALB/c mice. Upon reestablishment of tumor in vitro and in vivo, the epithelial murine tumor cells retained their original papillary adenocarcinoma morphology. Various immunotherapy protocols have been performed in previously implanted and progressively growing JC tumor in syngeneic hosts with a murine monoclonal antibody (McAb), F36/22 (IgG3). Affinity of McAb binding to JC tumor cells was determined to be 6.1 x 10(7) L/M. Quantitatively 1.2 x 10(5) molecules of McAb bound to a JC tumor cell. Immunotherapeutic effectiveness in vivo on a tumor mass after its establishment is a major feature of this experimental tumor model. When four sequential administration of McAb, i.p., at a dose of 400 micrograms 4 days apart were used, McAb-treated animals showed statistically significant tumor regression and longer survival than those of control animals treated with an irrelevant McAb of the same isotype. Two temporal phases of tumoricidal activity were observed as measured by tumor volume reduction. The first phase of tumoricidal response (tumor regression) was detected within days upon the first administration of McAb. A distinct second phase followed within 3-5 weeks after the last McAb administration, which resulted in tumor necrosis even in large tumors. Histological examinations revealed heavy infiltration of inflammatory cells at the beginning of the second phase. Similar tumor regression was also obtained from animals treated with a single dose (400 micrograms) of McAb followed by injections of McAb with complete and incomplete adjuvant, respectively. These results demonstrate that this syngeneic murine mammary tumor can serve as a potential preclinical model for investigation of parameters and mechanisms associated with McAb immunotherapy.


Antagonistic toxicity of arsenate and cadmium in a freshwater amphipod (Gammarus pulex).
Because toxicants rarely occur alone in the environment, a major challenge in risk assessment is to address the combined effects of chemicals on aquatic organisms. This work is aimed at investigating the joint toxicity action of binary mixtures of cadmium and arsenate on Gammarus pulex. Individuals were exposed during 240 h to four single arsenate or cadmium concentrations and binary mixtures of these metals according to a complete factorial plane. Observed mortality in binary mixtures was compared to observed mortality in single arsenate or cadmium exposures. In addition, interactive effects (antagonistic, additive or synergistic) were evaluated using a predictive model for the theoretically expected interactive effect of chemicals. For all the tested concentration combinations, we observed an antagonist 'between-metals' interaction on G. pulex mortality. This antagonistic effect was more marked for the lowest than for the highest (i.e. 1502.0 μg(AsV) L(-1) and 28.5 μg(Cd) L(-1)) tested concentrations of individual metals in binary mixtures. Metal concentrations in body tissues were evaluated and were significantly lower in binary mixtures than in single metal exposures at similar concentration, especially for combinations corresponding to the highest concentrations of both metals (1502.0 μg(AsV) L(-1) and 28.5 μg(Cd) L(-1)). Results were discussed in terms of (1) mechanisms of uptake and bioconcentration and (2) relationships between metal concentration in gammarid body and observed toxicity.


Optimized Nanostructured Lipid Carriers Integrated into in situ Nasal Gel for Enhancing Brain Delivery of Flibanserin [Retraction].
[This retracts the article DOI: 10.2147/IJN.S258791.].


[Non tuberculous mycobacterial infections].
Non tuberculous mycobacterial (NTM) infections, also called atypical mycobacterial infections, are caused by environmental mycobacteria and usually occur in cases of general or local immunosupression. These infections usually concern the lungs, the lymphatic system, the skin or the bones tissues. They are sometimes disseminated. In spite of new efficient antibiotics, including macrolides, therapeutic failures are common and favoured by long treatments with their potential adverse effects and drug interactions. The prevalence of atypical mycobacterial infections is increasing and is also observed in internal medicine and geriatric wards. Their clinical expression can be varied. Nowadays, these infections are more and more frequent in non-infected HIV patients, whether immunosupressed or not. Concerning other localisations of atypical mycobacterial infections, iatrogenic causes seem to be increasing and cases of nosocomial transmissions have also been described. When a NTM is found in a sample, its role in the cause of an infection must be assessed with criterias distinguishing infection from colonisation. For those who are not locally or generally immunosupressed, it is important to search for an immunological deficiency. Indeed, patients having congenital deficiencies occurring in the interferon and interleukine pathways can develop repeated NTM infections. Therefore, for pulmonary infections in treatment failure and for disseminated infections, an adjuvant treatment by interferon gamma could be proposed. New molecules have recently been tested and can be used in some atypical mycobacterial infections.


Origin of the left common carotid artery from ascending aorta in association with tetralogy of Fallot and hypoplastic right cervical aortic arch.
We present a case of a 6-year-old girl with tetralogy of Fallot (TOF) and hypoplastic aortic arch with anomalous origin of left common carotid artery from the ascending aorta. The case highlights the importance of screening for abnormalities of aortic arch and arch vessels in TOF patients for accurate presurgical planning and to predict the postoperative outcomes.


Detection of SYT-SSX fusion transcripts in synovial sarcoma by reverse transcription-polymerase chain reaction using archival paraffin-embedded tissues.
The reciprocal translocation t(X;18)(p11;q11) is known to be highly characteristic of synovial sarcoma, and its consequence, an SYT-SSX fusion gene, is expected to be a diagnostic molecular marker. In this study, we conducted a reverse transcription-polymerase chain reaction-based assay to detect the SYT-SSX fusion gene transcripts using archival formalin-fixed, paraffin-embedded tumor specimens from a series of 32 synovial sarcoma cases including 6 tumors found in unusual anatomical sites. The SYT-SSX fusion transcripts could be detected in 30 of 32 paraffin-embedded specimens (94%). A subsequent sequence analysis using the polymerase chain reaction products confirmed that the detected messages were derived from either the SYT-SSX1 (22 cases) or SYT-SSX2 (8 cases) fusion gene. Of 23 SYT-SSX-positive monophasic tumors, 16 tumors had an SYT-SSX1 fusion transcript. Fusion transcripts were detectable in all the 7 biphasic tumors analysed, one of which had an SYT-SSX2 fusion transcript. All of the six tumors at unusual locations (lung; 3, metastasis to the abdominal cavity from a tumor of retroperitoneal origin; 1, sacral region; 1, iliopsoas muscle; 1) contained detectable messages. Our results indicate that this molecular assay can be applied to archival formalin-fixed, paraffin-embedded tumor tissues as a feasible and reliable molecular technique for the diagnosis of synovial sarcoma.


Fabrication of a bioconjugated dual-functional SERS probe for facile compound screening and detection.
Surface-enhanced Raman spectroscopy (SERS) is an ultrasensitive technique for both detection and structural characterizations. To further exploit these advantages, we designed and fabricated a dual-functional SERS probe for specific capture and fast detection of small molecule ligands binding to target protein from a mixture of compounds such as extracts of natural products. As a proof of concept, we synthesized SiO2@Ag nanoclusters that are coated with 6-chlorohexanoic acid for covalent immobilization of serotonin transporter (5-HTT) fused with a Halo-tag through enzyme-substrate recognition. As such, we fabricated a bioconjugated SERS probe, and the synthesis, coating, protein immobilization, and affinity-based ligand binding have been characterized and verified by transmission electron microscope (TEM), X-ray photoelectron spectroscopy (XPS), and elemental mapping. By applying this probe to analyze Gardenia jasminoides extract, we have successfully identified crocin I as a compound binding to 5-HTT, which was further proved by using mass spectrometry (MS) and nuclear magnetic resonance (NMR). Taken together, we have developed a novel SERS probe by integrating the inherent strength of SERS in molecular analysis with an extended functionality of affinity-guided molecular capture, which has demonstrated the potential in drug screening of challenging systems.


Structure and action of heteronemertine polypeptide toxins: disulfide bonds of Cerebratulus lacteus toxin B-IV.
The positions of the disulfide bonds in Cerebratulus lacteus toxin B-IV were investigated by hydrolysis of the unreduced protein with a variety of proteases. The resulting peptides were purified by gel filtration, ion exchange chromatography, and preparative paper electrophoresis and chromatography. Determination of the amino acid compositions of the cystine-containing peptides purified demonstrated the existence of disulfide bonds linking half-cystine residues 12 and 24, 21 and 51, and 35 and 38. The fourth bond, involving half-cystines 10 and 47, was assigned by difference.


Favourable spontaneous eruption of severely displaced maxillary canines with associated follicular disturbance.
Cases of severely displaced unerupted maxillary canines are presented, related to disturbance of the follicle. Removal of the deciduous predecessor produced favourable eruption of the permanent canine and should be considered as a treatment option in similar cases.


Regulation of PD-1/PD-L1 Pathway in Cancer by Noncoding RNAs.
Immune checkpoint blockade has demonstrated significant anti-tumor immunity in an array of cancer types, yet the underlying regulatory mechanism of it is still obscure, and many problems remain to be solved. As an inhibitory costimulatory signal of T-cells, the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway can paralyze T-cells at the tumor site, enabling the immune escape of tumor cells. Although many antibodies targeting PD-1/PD-L1 have been developed to block their interaction for the treatment of cancer, the reduced response rate and resistance to the therapies call for further comprehension of this pathway in the tumor microenvironment. MicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are two main types of noncoding RNAs that play critical parts in the regulation of immune response in tumorigenesis, including the PD-1/PD-L1 pathway. Here we summarize the most recent studies on the control of this pathway by noncoding RNAs in cancer and hopefully will offer new insights into immune checkpoint blockade therapies.


Risk of emergent bradycardia associated with the use of carvedilol and metoprolol in routine clinical practice.
Large randomized trials have reported mixed results regarding the risk of bradycardia between metoprolol and carvedilol. We compared the incidence of emergent bradycardia (measured by an emergency department visit or hospitalization due to bradycardia) for patients initiating metoprolol and carvedilol. Adult beneficiaries of Medi-Cal, the State of California Medicaid program, without a diagnosis of bradycardia who initiated metoprolol or carvedilol between May 1, 2004, and November 1, 2009, were included. Cox proportional hazard regression analysis was performed to model the time to first occurrence of emergent bradycardia after initiation of the study drugs as a dependent variable and the study drug (metoprolol vs carvedilol) as the primary predictor with adjustments for total daily metoprolol-equivalent dose, formulations, and use of nonstudy drugs as time-varying covariates, as well as demographics and comorbidities. Among 38,186 subjects, 77.7% initiated metoprolol and 22.3% initiated carvedilol. The incidence of emergent bradycardia was low and comparable between the drugs (18.1 per 1000 person-years using metoprolol vs 17.7 per 100 person-years using carvedilol; unadjusted hazard ratio, 1.07; 95% confidence interval, 0.76-1.49). However, carvedilol users had substantially different population characteristics compared with metoprolol users. After adjustments for demographics, comorbidities, metoprolol-equivalent dose, formulations, and use of nonstudy drugs, initiation of metoprolol was associated with an increased risk of emergent bradycardia compared with that of carvedilol (adjusted hazard ratio, 1.64; 95% confidence interval, 1.14-2.36). Initiation of metoprolol is associated with an increased risk of emergent bradycardia compared with carvedilol, although the overall incidence of emergent bradycardia is low in routine clinical practice.


Temporal reliability of personality in psychiatric patients.
The Personality Assessment Schedule, an interview schedule specifically designed for assessing personality disorder, was administered twice to 28 psychiatric patients, with a mean interval of 2.9 years between each assessment. The first assessment was made by a psychiatrist and the second by a medical student who had no prior knowledge of the patients. The reliability of the 2 assessments was measured using 4 different techniques. Although the reliability of individual personality traits was inconsistent over time, the categorical diagnosis of personality disorder was good (Kw = 0.64), giving some support to the validity of the schedule. Reasons for discordance in the assessments were examined and appeared to be due mainly to confusion between clinical symptoms and personality traits, retrospective errors in recording past personality in chronic patients, and special difficulties in determining the primary abnormality in severe personality disorder.


Add-on therapy with dapagliflozin under full closed loop control improves time in range in adolescents and young adults with type 1 diabetes: The DAPADream study.
To investigate the effect of the sodium-glucose co-transporter-2 inhibitor dapagliflozin on glucose levels overnight and during the following day after two unannounced meals under full closed loop (FCL) conditions. For this single-centre, double-blind, randomized, placebo-controlled, cross-over trial, non-obese persons with type 1 diabetes (T1D) were studied twice (10 mg dapagliflozin bid vs. placebo) for 24 hours with two unannounced mixed meal tests 6 hours apart under FCL conditions. Primary outcome was sensor glucose time in range (TIR; 3.9-10 mmol/L). For safety evaluation, ß-hydroxybutyrate (BHB), glucagon, insulin and gastric inhibitory polypeptide were measured. Fifteen adolescents (aged 15.4 ± 1.6 years, diabetes duration 10.0 ± 3.4 years, HbA1c 8.4% ± 0.9% [67.7 ± 10.1 mmol/mol]) and 15 young adults (aged 18.7 ± 0.8 years; diabetes duration 12.5 ± 3.6 years; HbA1c 8.3% ± 0.9% [68.5 ± 11.2 mmol/mol]) completed the trial. TIR was significantly higher in the intervention group compared with placebo (68% ± 6% vs. 50% ± 13%; P < .001); nocturnal glucose was significantly lower with dapagliflozin (6.2 ± 0.7 vs. 7.3 ± 1.7 mmol/L; P = .003) without an increase in time at less than 3.9 mmol/L (3.3% ± 6.0% vs 3.1% ± 5.2%; P = .75). Urinary glucose excretion was increased 3-fold using dapagliflozin (149 ± 42 vs. 49 ± 23 g/24 hours) with a total insulin reduction of 22% (39.7 ± 12.7 vs. 30.6 ± 10.4 U; P = .004). No abnormal elevated BHB values were observed. In adolescents and adults with T1D, dapagliflozin significantly increased TIR on average by 259 minutes/day while reducing glycaemic variability during FCL control without any signs of hypoglycaemia or ketosis.


Induction of malformations by X-ray exposure of various stages of the oogenesis of mice.
We studied the effects of ionizing radiation (X-rays, 0-3 Gy, dose rate 1 Gy/min) on various stages of oogenesis of a mouse strain (HLG/Zte) that had been shown previously to respond with an increased number of malformations after radiation exposure of preimplantation stages. Like the results obtained with preimplantation stages, we observed a statistically significant increase in the number of malformed fetuses (exclusively gastroschises) on day 19 of gestation, when oocytes within 1-4 weeks before ovulation were exposed to 2 or 3 Gy. Less mature oocytes were killed by radiation doses of 0.5 Gy and higher. In addition to the increased frequency of malformations, we found a dose-dependent increase of lethal effects (affecting either oocytes or specific gestational stages) and of runts ('dwarfs').


Protozoan parasite-specific carbohydrate structures.
The carbohydrate moieties displayed by pathogenic protozoan parasites exhibit many unusual structural features and their expression is often developmentally regulated. These unique structures suggest a specific relationship between such carbohydrates and parasite pathogenicity. Studies of infected humans indicate that immune responses to protozoan parasites are elicited by glycan determinants on cell-surface or secreted molecules. Infections by protozoa are a major worldwide health problem, and no vaccines or efficacious treatments exist to date. Recent progress has been made in elucidating the structure and function of carbohydrates displayed by major protozoan parasites that infect man. These structures can be used as prototypes for the chemical or combined chemo-enzymatic synthesis of new compounds for diagnosis and vaccine development, or as inhibitors specifically designed to target parasite glycan biosynthesis.


Random monoallelic expression: making a choice.
Monoallelic gene expression exposes an organism to the risks associated with the unmasking of recessive mutations. A recent study by Gimelbrant and colleagues, supported by results from two methodologically different studies, demonstrated that random monoallelic expression is surprisingly widespread among autosomal genes. This raises important questions about why, when and how cells choose and tolerate monoallelism and whether functional hemizygosity might provide an unappreciated advantage.


[Uteroglobin].
Uteroglobin has been studied under two aspects: 1) as a model of specific interaction between a protein and a steroid hormone: crystals were obtained and analyzed by X-ray diffraction; 2) as a marker of progesterone action in the endometrium: messenger RNA was translated, purified and transcribed into complementary DNA.


Impact of comorbidity on colorectal cancer screening cost-effectiveness study in diabetic populations.
Although comorbidity has been shown to affect the benefits and risks of colorectal cancer (CRC) screening, it has not been accounted for in prior cost-effectiveness analyses of CRC screening. To evaluate the impact of diagnosis of diabetes mellitus, a highly prevalent comorbidity in U.S. adults aged 50 and older, on health and economic outcomes of CRC screening. Cost-effectiveness analysis using an integrated modeling framework. Derived from basic and epidemiologic studies, clinical trials, cancer registries, and a colonoscopy database. U.S. 50-year-old population. Lifetime. Costs are based on Medicare reimbursement rates. Colonoscopy screening at ten-year intervals, beginning at age 50, and discontinued after age 50, 60, 70, 80 or death. Health outcomes and cost effectiveness. Diabetes diagnosis significantly affects cost-effectiveness of CRC screening. For the same CRC screening strategy, a person without diabetes at age 50 gained on average 0.07-0.13 life years more than a person diagnosed with diabetes at age 50 or younger. For a population of 1,000 patients diagnosed with diabetes at baseline, increasing stop age from 70 years to 80 years increased quality-adjusted life years (QALYs) gained by 0.3, with an incremental cost-effectiveness ratio of $206,671/QALY. The corresponding figures for 1,000 patients without diabetes are 2.3 QALYs and $46,957/QALY. Cost-effectiveness results are sensitive to cost of colonoscopy and adherence to colonoscopy screening. Results depend on accuracy of model assumptions. Benefits of CRC screening differ substantially for patients with and without diabetes. Screening for CRC in patients diagnosed with diabetes at age 50 or younger is not cost-effective beyond age 70. Screening recommendations should be individualized based on the presence of comorbidities.


Conversion of open tibial IIIb to IIIa fractures using intentional temporary deformation and the Taylor Spatial Frame.
The closure of small-to-moderate-sized soft tissue defects in open tibial fractures can be successfully achieved with acute bony shortening. In some instances, it may be possible to close soft tissue envelope defects by preserving length and intentionally creating a deformity of the limb. As the soft tissue is now able to close, this manoeuvre converts an open IIIb to IIIa fracture. This obviates the need for soft tissue reconstructive procedures such as flaps and grafts, which have the potential to cause donor-site morbidity and may fail. In this article, the authors demonstrate the technique for treating anterior medial soft tissue defects by deforming the bone at the fracture site, permitting temporary malalignment and closure of the wound. After healing of the envelope, the malalignment is gradually corrected with the use of the Taylor Spatial Frame. We present two such cases and discuss the technical indications and challenges of managing such cases.


Lymphocyte subpopulations in Chinese women with Turner syndrome.
Turner syndrome (TS) is associated with deficiency of cellular and humoral immunity. However, the characteristics of lymphocyte subpopulations in Chinese women with TS have not been reported. In this study, the percentage of lymphocyte subpopulations and the mRNA expression of some transcription factors were determined in patients with TS. The effect of the hormone substitution on lymphocyte subpopulations was also analyzed. Thirteen Chinese TS women and eight age and sex-matched healthy volunteers were studied. The percentage and mean fluorescence intensity (MFI) of lymphocyte subpopulations including CD3+CD4+, CD3+CD8+, CD19-CD138+, CD4+CD25+FoxP3+ and CD4+CD8-IL17A+ cells were determined by flow cytometry. The mRNA expression of some transcription factors were detected by RT-PCR. Compared to control, the percentage of CD3+CD4+ cells was significantly reduced (p < 0.05), while the percentage of CD19-CD138+, CD4+CD25+FoxP3+ and CD4+CD8-IL17A+ cells was significantly increased in TS patients. No difference was observed in the percentage of CD3+CD8+, CD19+ B cells between TS patients and healthy volunteers, with the similar changes in the mean fluorescence intensity of these cells. The mRNA expression of some transcription factors slightly enhanced in TS patients. Estrogen therapy did not affect the percentage of lymphocyte subpopulations. These findings suggested that Turner syndrome might be associated with changes of lymphocyte subpopulations.


Prognostic features and treatment of endocervical adenocarcinoma of the cervix.
Adenocarcinoma of the cervix represents an increasing percentage of cervical cancers as well as a controversial clinical problem. One hundred seventy-two cases of adenocarcinoma were treated at The University of Michigan Medical Center from 1970 to 1984, representing 16.8% of cervical cancers. Of this group 84 patients were diagnosed with endocervical columnar cell type and form the study population for this report. Survival was influenced by stage, grade, and nodal metastases. Age did not influence survival. Survival in stage I disease was not influenced by treatment modality. Radical surgery or radiation therapy provided equal survival and ovarian conservation did not adversely influence survival. Radical surgery can be considered a primary means of therapy in young women and offers the same advantages over radiation therapy as those offered for squamous cell disease.


Comparisons between ankle distraction arthroplasty and supramalleolar osteotomy for treatment of post-traumatic varus ankle osteoarthritis.
Ankle distraction arthroplasty and supramalleolar osteotomy were both options for post-traumatic varus ankle arthritis (VAA), but their comparative effectiveness was scarcely reported. This study aimed to compare the outcomes of two operative methods for treatment of Takakura-Tanaka stage 3 post-traumatic VAA. This was a retrospective study, comprising 73 consecutive patients who presented with Takakura-Tanaka stage 3 post-traumatic VAA treated by either ankle distraction arthroplasty (n = 32) or supramalleolar osteotomy (n = 41) from January 2016 to December 2019. All patients had a minimum 24-month follow-up assessments. The outcome measures were visual analog scale (VAS), the American Orthopedic Foot & Ankle Society (AOFAS) ankle-hindfoot scores, complications, patient-rated overall satisfaction and ankle function. At an average of 32 months (range, 24-52 months) follow-up, significant improvement was observed for VAS, AOFAS, range of motion (ROM) and most radiographic parameters (except for TAS and TLS for ankle distraction arthroplasty group) compared to preoperative baselines (p < 0.05) for both groups. However, both groups did not differ significantly in terms of VAS or AOFAS, excellent and good rate (78.1% versus 85.4%, p = 0.422), overall rate of postoperative complications (28.1% vs. 17.1%, p = 0.257), or various radiographic parameters (e.g. tibial anterior surface angle, talar tilt angle and tibial lateral surface angle) (all p > 0.05). The ankle distraction arthroplasty group had a better postoperative ankle motion than did the supramalleolar osteotomy group, in terms of plantarflexion (37.8 ± 4.2 vs. 30.4 ± 3.6, p = 0.006), dorsiflexion (36.5 ± 6.4 vs. 28.3 ± 5.5, p = 0.004), varus (32.1 ± 4.5 vs. 27.1 ± 3.1, p = 0.017) and valgus (28.4 ± 3.7 vs. 25.2 ± 2.8, p = 0.046). Both operative treatments are effective for Takakura-Tanaka stage 3 post-traumatic VAA. In practice, individualized treatment option tailored to the ankle condition and patients' specific need should be considered. III, retrospective comparative series.


Disorders of early language development in Dravet syndrome.
The aim of this study was to investigate language disorders prospectively in patients with Dravet syndrome (DS) during the first years of life in order to identify their features and possibly the underlying mechanisms of the disease. At the Child Neurology Unit of Catholic University in Rome (Italy), thirteen patients with typical findings of DS were enrolled in the study. Full clinical observations, including neurological examination and long-term EEG monitoring, were prospectively and serially performed until a mean of 6years of age (range: 4years to 7years and 8months). The epileptic history was also collected in each case. In particular, developmental, cognitive, and detailed language assessments were performed with different tests according to the age of the patient. In addition to cognitive decline, characteristic language impairment was also found with a relative preservation of receptive abilities (comprehension) and a strong impairment of productive skills. This defect in sensorimotor verbal processing integration is discussed to highlight the possible mechanisms underlying cognitive decline.


Survey of extreme heat public health preparedness plans and response activities in the most populous jurisdictions in the United States.
Increasingly frequent and intense extreme heat events (EHEs) are indicative of climate change impacts, and urban areas' social and built environments increase their risk for health consequences. Heat action plans (HAPs) are a strategy to bolster municipal EHE preparedness. The objective of this research is to characterize municipal interventions to EHEs and compare U.S. jurisdictions with and without formal heat action plans. An online survey was sent to 99 U.S. jurisdictions with populations > 200,000 between September 2021 and January 2022. Summary statistics were calculated to describe the proportion of total jurisdictions, as well as jurisdictions with and without HAPs and in different geographies that reported engagement in extreme heat preparedness and response activities. Thirty-eight (38.4%) jurisdictions responded to the survey. Of those respondents, twenty-three (60.5%) reported the development of a HAP, of which 22 (95.7%) reported plans for opening cooling centers. All respondents reported conducting heat-related risk communications; however, communication approaches focused on passive, technology-dependent mechanisms. While 75.7% of jurisdictions reported having developed a definition for an EHE, less than two-thirds of responding jurisdictions reported any of the following activities: conducting heat-related surveillance (61.1%), implementing provisions for power outages (53.1%), increasing access to fans or air conditioners (48.4%), developing heat vulnerability maps (43.2%), or evaluating activities (34.2%). There were only two statistically significant (p ≥ .05) differences in the prevalence of heat-related activities between jurisdictions with and without a written HAP, possibly attributable to a relatively small sample size: surveillance and having a definition of extreme heat. Jurisdictions can strengthen their extreme heat preparedness by expanding their consideration of at-risk populations to include communities of color, conducting formal evaluations of their responses, and by bridging the gap between the populations determined to be most at-risk and the channels of communication designed to reach them.


Rhabdomyolysis and acute renal failure associated with pyloric stenosis.
Rhabdomyolysis and acute tubular necrosis (ATN) are described in a patient with pyloric stenosis in whom severe hypokalemia developed due to repetitive vomiting. Furthermore, the importance of hypokalemia in the development of acute renal failure is emphasized.


Anxious behavior and fenfluramine-induced prolactin secretion in young rhesus macaques with different alleles of the serotonin reuptake transporter polymorphism (5HTTLPR).
Anxiety is a normal aspect of human personality, which can manifest in a variety of disorders and other negative traits. The primary treatment for anxiety is the class of drugs known as the selective serotonin reuptake inhibitors (SSRIs), which bind to the serotonin reuptake transporter. The upstream region of the gene that codes for this transporter contains a polymorphism that is an insertion/deletion event that in turn, produces long (l) and short (s) alleles in the population. This particular polymorphism in the serotonin transporter, the 5HTTLPR (serotonin transporter linked polymorphic region), is thought to be involved in the genesis of anxious traits and disorders. Most studies with human subjects have examined adult behavior, which may derive from diverse experiential and environmental backgrounds, as well as genetic differences. To better isolate the effect of genetics, we genotyped 128 infant and juvenile monkeys for the 5HTTLPR and tested for behavioral response in four testing paradigms designed to elicit fearful-anxious behaviors: a free play, remote-controlled car, human intruder, and novel fruit test. The s/s monkeys were found to be behaviorally inhibited in the free play test, engaged in more fear behaviors in the remote-controlled car test, and threatened more in the stare portion of the human intruder test, even though a small number of monkeys were assessed. There was no difference between genotypes of either sex in the prolactin response to fenfluramine. These data indicate greater anxiety in the s/s monkeys for distinct facets of anxious behavior, which are independent of a global neurohormonal challenge test. These neurobehavioral data support recent neuroimaging findings in humans indicating the importance of the 5HTTLPR for amygdala-dependent anxious behavior.


Medial temporal lobe activity associated with the successful retrieval of destination memory.
Destination memory is the process of remembering to whom we tell particular things. Although recent behavioral studies have clarified the cognitive nature of destination memory, the neural mechanisms underlying destination memory retrieval remain unclear. We used functional magnetic resonance imaging (fMRI) to determine whether the medial temporal lobe (MTL), a structure that has been implicated in recollection-based memory, is activated during the successful retrieval of destination information. During a study phase before fMRI scanning, the subjects told a series of facts to either a woman or a man. During fMRI scanning, the subjects were asked to judge whether each fact presented was old or new, and if they judged it as old, to indicate, including a confidence rating (high or low), whether the subjects had told that fact to either a man or a woman. We found that successful destination retrieval, when compared to failed destination retrieval, was associated with increased activity in the parahippocampal gyrus. We also found that the confidence level (high vs. low) for destination memory retrieval was associated with increased activity in another (posterior) region of the parahippocampal gyrus. The present study suggests that the successful retrieval of destination information depends highly on MTL-mediated recollection processes.


Flavone inhibits migration through DLC1/RhoA pathway by decreasing ROS generation in breast cancer cells.
Tumor suppressor protein deleted in liver cancer 1 (DLC1) is a RhoGTPase-activating protein (RhoGAP) and inhibits cancer cell migration by inactivating downstream target protein RhoA. A few studies have reported the regulations of reactive oxygen species (ROS) on RhoGAP. In this study, we investigated flavone (the core structure of flavonoids)-induced regulation on ROS generation and DLC1/RhoA pathway in MCF-7 and MDA-MB-231 breast cancer cells and explored whether flavone-induced upregulation of DLC1 is mediated by ROS. Our results showed that flavone decreased ROS production and inhibited cell migration through DLC1/RhoA pathway. To further investigate the role of ROS in flavone-induced regulation on DLC1/RhoA pathway, hydrogen peroxide was added to restore the ROS levels. Flavone-induced upregulation of DLC1 expression, downregulation of RhoA activity, and inhibition of cell migration were all restrained by hydrogen peroxide. We also found that flavone increased DLC1 stability by inhibiting DLC1 protein degradation in breast cancer cells. In summary, our study demonstrated that flavone inhibited cell migration through DLC1/RhoA pathway by decreasing ROS generation and suppressed DLC1 degradation in MCF-7 and MDA-MB-231 breast cancer cells.


Malignization of an arachnoid cyst.
A case of evolvement of fibrosarcoma from a supratentorial arachnoid cyst (verified in surgery five years before) is presented, with brief comments on the embryonic origin of the tissues involved.


Mianserin and trazodone for cardiac patients with depression.
In a placebo controlled double-blind cross-over study, the cardiovascular and antidepressant effects of three weeks' treatment with mianserin (30-80 mg daily) and trazodone (150-400 mg daily) were studied in depressed patients who had co-existant cardiac disease. In 14 of the 16 patients, no haemodynamic deterioration occurred with either drug. Two patients withdrew from the study. One with coronary artery disease, whose concomitant medication included a calcium-antagonist and a beta-adrenoceptor blocker and who developed severe postural hypotension after his first dose of trazodone while the other had an increased frequency of transient cerebral ischaemic attacks with both mianserin and trazodone, but not with placebo. Mianserin and trazodone are comparable for both antidepressant efficacy and paucity of cardiovascular effects. Although unwanted effects were generally mild, the incidence of dizziness was greater in those patients receiving trazodone. Caution is advised, however, when prescribing either drug to patients with transient cerebral ischaemic attacks or those with coronary artery disease receiving medication.


How retroviruses select their genomes.
As retroviruses assemble in infected cells, two copies of their full-length, unspliced RNA genomes are selected for packaging from a cellular milieu that contains a substantial excess of non-viral and spliced viral RNAs. Understanding the molecular details of genome packaging is important for the development of new antiviral strategies and to enhance the efficacy of retroviral vectors used in human gene therapy. Recent studies of viral RNA structure in vitro and in vivo and high-resolution studies of RNA fragments and protein-RNA complexes are helping to unravel the mechanism of genome packaging and providing the first glimpses of the initial stages of retrovirus assembly.


Acoustic-phonetic context considerations for speech recognition testing of hearing-impaired listeners.
To test for differences in the identification of consonants in carrier sentences versus in VCVs extracted from the sentences, as a function of listeners' hearing-loss categories: moderate, severe, profound. To examine whether pauses inserted in the sentences will facilitate identification of the consonants. Voiced stops and fricatives were identified by 11 listeners with moderate hearing losses and by 7 listeners with severe losses (between subjects design) for the conditions of consonants in sentences and in VCVs extracted from the sentences (repeated measures). Nine of these listeners also identified the consonants in the sentences with pauses. Six normal-hearing listeners were tested for the consonants in the extracted VCVs and the sentences. Voiceless stops and fricatives were identified by 4 listeners with profound losses, 18 with severe losses, and 8 with moderate losses (between subjects) for the conditions of extracted VCVs and the sentences (repeated measures). All listeners were selected on the basis of their hearing levels. The listeners with moderate to severe hearing loss identified the voiced stops and fricatives more poorly when the syllables were in the carrier sentences than when extracted. Insertion of the pauses in the sentence did not improve performance significantly. The normal hearing listeners showed no differences in consonant identification between the two conditions, perhaps due to "ceiling effects". The voiceless stops and fricatives were also identified more poorly when in the extracted VCVs than in the carrier sentences by other listeners with moderate to profound hearing loss. Listeners with moderate or greater hearing loss can show poorer identification of consonants that are embedded midway in carrier sentences than when the acoustically identical consonants are in VCVs extracted from the sentences. The performance reduction for the consonants in sentences is not relieved from insertion of brief artificial pauses in the sentences. Further research is needed determine whether hearing-impaired listeners' identification of consonants in target words of clinical word recognition tests is facilitated when the words are extracted from carrier phrases.


LncRNA and mRNA expression profiles in brown adipose tissue of obesity-prone and obesity-resistant mice.
Obesity-prone or obesity-resistant phenotypes can exist in individuals who consume the same diet type. Brown adipose tissue functions to dissipate energy in response to cold exposure or overfeeding. Long noncoding RNAs play important roles in a wide range of biological processes. However, systematic examination of lncRNAs in phenotypically divergent mice has not yet been reported. Here, the lncRNA expression profiles in BAT of HFD-induced C57BL/6J mice were investigated by high-throughput RNA sequencing. Genes that play roles in thermogenesis and related pathways were identified. We found lncRNA (Gm44502) may play a thermogenic role in obesity resistance by interacting with six mRNAs. Our results also indicated that seven differentially expressed lncRNAs (4930528G23Rik, Gm39490, Gm5627, Gm15551, Gm16083, Gm36860, Gm42002) may play roles in reducing heat production in obesity susceptibility by interacting with seven differentially expressed mRNAs. The screened lncRNAs may participate in the pathogenesis of weight regulation and provide insight into obesity therapy.


Functional and Behavioral Responses of the Natural Enemy Anthocoris nemoralis to Cacopsylla pyri, at Different Temperatures.
Anthocoris nemoralis is the dominant predator of pear sucker (Cacopsylla pyri) in the UK. Anthocoris nemoralis migrates into orchards in spring or is introduced as a biocontrol agent, reaching peak population levels in July-August, contributing to effective control of summer pear sucker populations. However, due to temperature dependent development and metabolism there are concerns that C. pyri populations or feeding rates may increase due to changing climatic conditions. Thus, how A. nemoralis responds to temperature, impacts its ability as a biocontrol agent. Functional response assays, monitoring attack rate and handling time of A. nemoralis and behavioral assays, using Ethovision tracking software occurred, to assess the impact of temperature on predation. Experiments were conducted at current and future July-August mean temperatures, predicted using RCP4.5 and RCP8.5 (medium and high, representative concentration pathway) emissions scenarios, using 2018 UK Climate Projections (UKCP18). All treatments demonstrated a Type II functional response, with female anthocorids demonstrating shorter handling times and higher attack rates than males. Males showed longer prey handling times at 18 °C compared to 23 °C and more time was spent active at lower temperatures for both sexes. Females did not show significant differences in attack rate or handling time in response to temperature. Overall prey consumption was also not significantly affected by temperature for either sex. This study suggests that anthocorids are likely to remain effective natural enemies under future predicted temperatures, due to non-significant differences in prey consumption. The online version contains supplementary material available at 10.1007/s10905-023-09836-5.


History of successful ballot initiatives--California.
In this report, the author examines the factors that led to a tobacco tax ballot initiative in California, the coalition-building process, the strong arguments for tax increases, and important decisions regarding the distribution of revenues.


Is feline foamy virus really apathogenic?
Feline foamy virus (FFV) is a retrovirus commonly found in cats. It is generally thought to be apathogenic, making it a suitable candidate as a gene therapy vector. However, there have been reports of association of FFV with chronic progressive arthritis and a cofactor effect with feline immunodeficiency virus. This study investigated experimental FFV infection and whether this was associated with signs of disease. Eight young specific pathogen free cats were inoculated intramuscularly with FFV. The cats were examined twice weekly and blood and pharyngeal samples were taken. Haematology, biochemistry and FFV quantitative polymerase chain reaction (qPCR) were performed. Tissue samples were also collected throughout the six month period. FFV was initially detected by qPCR in the blood within the first two weeks of infection and viraemia persisted throughout the study. Two peaks of viraemia were observed, at day 20 (80-170FFU/ml blood) and day 155 (332-415FFU/ml blood). FFV was also consistently detected in oropharyngeal samples after day 36. Anti-FFV IgG was detected in all cats by ELISA; antibody levels had an early peak around day 35 and then increased again following the second rise in circulating viral load. All cats remained clinically normal, except for one cat with an unrelated gingivitis. None of the cats developed pyrexia. The biochemical profile and blood cell counts remained within normal limits except for one cat with a persistent eosinophilia. Initial fluctuations in white cell counts settled within three weeks and did not deviate outside of the normal ranges. All tissue samples contained FFV DNA; lymphoreticular tissues, salivary gland and lung had the highest viral loads. Although there were no gross pathological lesions on post mortem examination, histologically a mild glomerulonephritis and a moderate interstitial pneumonia were observed in all cats. We conclude that during the six month period of infection, although cats appeared clinically normal, histopathological changes were observed in the lungs and kidneys. Further investigation of the significance of these changes is warranted before FFV is developed as a vector for gene delivery.


HKI-272 contributes to gemcitabine-mediated anti-proliferative and anti-metastatic effects through EGFR suppression in gallbladder cancer.
Gallbladder cancer (GBC) is a rare malignancy of the biliary system and characterized by early metastasis and poor prognosis. To date, no efficient treatment is available for GBC patients. Based on the data from cBioPortal, TIMER, and GDSC, we performed an unbiased screening with 25 candidate compounds that predominantly target ErbB family and identified HKI-272, a highly selective EGFR/ErbB2 inhibitor, displayed decreased IC50 values in three GBC cell lines. HKI-272 not only promoted gemcitabine-mediated anti-proliferative and pro-apoptotic effects and induced cell cycle arrest in GBC, but also enhanced gemcitabine-induced suppressive effects of GBC cell migration and invasion by inhibiting pathways downstream of EGFR. Furthermore, HKI-272, together with gemcitabine, effectively suppressed tumor growth and metastases in mouse models. Immunostaining and HE staining data from both primary tumor and lung metastasis indicated that the anti-proliferative and anti-metastatic effects were mediated through EGFR suppression. Moreover, the expression of EGFR, measured by both immunostaining and HE staining, was correlated with a poor prognosis in GBC. In addition, EGFR in tumor tissues are independent indicators for overall survival in GBC patients. Taken together, our findings suggest that HKI-272 could be a potential therapeutic agent and EGFR might serve as a potential biomarker for patients with GBC.


Extrapulmonary effects of maintenance corticosteroid therapy with alternate-day prednisone and inhaled beclomethasone in children with chronic asthma.
Extrapulmonary effects of alternate-day prednisone and inhaled beclomethasone dipropionate therapy were examined in 24 and 32 children with asthma, respectively. Early morning serum cortisol values were significantly lower among patients receiving alternate-day prednisone than among patients receiving inhaled beclomethasone dipropionate and control subjects at 24 hours but not at 48 hours after an alternate-day prednisone dose. Urinary-free cortisol output during the second 24 hours of the alternate-day prednisone regimen were similar to values among patients receiving inhaled beclomethasone and were significantly lower than among control subjects for both groups. Mean heights among patients before being placed on maintenance corticosteroids were at the thirty-fifth percentile and were similar for both regimens. This was significantly lower than initial measurements for control subjects who, on average, were near the fiftieth percentile for both children with asthma not requiring maintenance corticosteroids and normal healthy Iowa children. Mean heights for both corticosteroid-treated groups remained at the thirty-fifth percentile after more than a 2-year average duration of follow-up. Heights of children with chronic asthma not requiring maintenance corticosteroids were initially significantly higher (fifty-first percentile) than the patients who subsequently required maintenance corticosteroids and increased significantly to the sixty-first percentile during a mean 2.7-year follow-up. Heights of healthy Iowa children remained near the fiftieth percentile during a mean 7-year follow-up. Disproportionate weight gain, although it was not consistently present, was significantly more likely with the alternate-day prednisone. Other extrapulmonary effects of the corticosteroid regimens appeared not to be of clinical importance during the time period of the study.