Tailor-Made Autophagy Cascade Amplification Polymeric Nanoparticles for Enhanced Tumor Immunotherapy.
Chemotherapeutics can induce immunogenic cell death (ICD) by triggering autophagy and mediate antitumor immunotherapy. However, using chemotherapeutics alone can only cause mild cell-protective autophagy and be incapable of inducing sufficient ICD efficacy. The participation of autophagy inducer is competent to enhance autophagy, so the level of ICD is promoted and the effect of antitumor immunotherapy is highly increased. Herein, tailor-made autophagy cascade amplification polymeric nanoparticles STF@AHPPE are constructed to enhance tumor immunotherapy. Arginine (Arg), polyethyleneglycol-polycaprolactone, and epirubicin (EPI) are grafted onto hyaluronic acid (HA) via disulfide bond to form the AHPPE nanoparticles and autophagy inducer STF-62247 (STF) is loaded. When STF@AHPPE nanoparticles target to tumor tissues and efficiently enter into tumor cells with the help of HA and Arg, the high glutathione concentration leads to the cleavage of disulfide bond and the release of EPI and STF. Finally, STF@AHPPE induces violent cytotoxic autophagy and strong ICD efficacy. As compared to AHPPE nanoparticles, STF@AHPPE nanoparticles kill the most tumor cells and show the more obvious ICD efficacy and immune activation ability. This work provides a novel strategy for combining tumor chemo-immunotherapy with autophagy induction.


Myc-induced proliferation and transformation require Akt-mediated phosphorylation of FoxO proteins.
Myc synergizes with Ras and PI3-kinase in cell transformation, yet the molecular basis for this behavior is poorly understood. We now show that Myc recruits TFIIH, P-TEFb and Mediator to the cyclin D2 and other target promoters, while the PI3-kinase pathway controls formation of the pre-initiation complex and loading of RNA polymerase II. The PI3-kinase pathway involves Akt-mediated phosphorylation of FoxO transcription factors. In a nonphosphorylated state, FoxO factors inhibit induction of multiple Myc target genes, Myc-induced cell proliferation and transformation by Myc and Ras. Abrogation of FoxO function enables Myc to activate target genes in the absence of PI3-kinase activity and to induce foci formation in primary cells in the absence of oncogenic Ras. We suggest that the cooperativity between Myc and Ras is at least in part due to the fact that Myc and FoxO proteins control distinct steps in the activation of an overlapping set of critical target genes.


Development of gene delivery systems for the epsilon-poly-L-lysine producer, Streptomyces albulus.
Streptomyces albulus IFO14147 produces epsilon-poly-L-lysine (epsilon-PL), an amino acid homopolymer antibiotic that is used as a food preservative in many countries, including Japan, South Korea, and the United States. To construct an overproducer of the industrially important epsilon-PL and to develop a deeper understanding of its biosynthetic mechanism, we developed systems for DNA delivery into the S. albulus strain based on both polyethylene glycol-mediated protoplast transformation and intergeneric conjugation from Escherichia coli. The successes of these transformations in particular were accomplished by employing the new cryptic-plasmid-based shuttle vectors constructed in this study. The genetic systems developed here should facilitate a molecular genetic approach to S. albulus.


Expression of RNAs Coding for Metal Transporters in Blood of Patients with Huntington's Disease.
Recent studies have demonstrated elevated levels of iron (Fe) in brains of patients with Huntington's disease (HD). Striatal cells carrying mutated Huntingtin presented increased sensitivity to cadmium (Cd) toxicity, decreased sensitivity to manganese (Mn) toxicity and deficits in Mn uptake. The hypothesis arose that the observed alterations result from the altered expression and/or activity of proteins engaged in the transport of these metals, that is: transferrin (TF), transferrin receptor (TFR), divalent metal transporter 1 (DMT1) and ZIP8 protein. Here we examined the expression levels of genes encoding these proteins in blood of HD patients and control subjects. A decreasing tendency in the level of TF transcript and increasing tendency of SLC11A2 mRNA encoding DMT1 was observed in the blood of HD patients compared to the control subjects, but neither attained statistical significance. No changes were found in the levels of TFRC coding for TFR and SLC39A8 coding for ZIP8 between HD patients and controls. The results indicate that HD-associated changes in metal homeostasis occur are not related to mechanisms other than the expression level of the here analyzed metal transporters.


Effect of Human Peripheral Blood Mononuclear Cells on Mouse Endometrial Cell Proliferation: A Potential Therapeutics for Endometrial Regeneration.
The persistently thin endometrium is a major cause of repeated implantation failure; however, there is no definite treatment for it yet. This study aimed to confirm the potential of human peripheral blood mononuclear cells (hPBMCs) as a therapeutic agent for endometrial regeneration. An experimental study was carried out. To assess the in vitro effect of hPBMC, the human primary endometrial epithelial cell lines SNU-685 and SNU-1077 were co-cultured with or without 1 × 105 hPBMCs for 24 h. To evaluate the in vivo effect, either 1 × 105 hPBMCs in PBS or PBS alone were injected into the left uterine horn of nonobese diabetic-severe combined immune-deficient mice, and the right untreated uterine horn was used as control. Co-culture with hPBMCs stimulated significant proliferation in both SNU-685 and SNU-1077 cell lines (p = 0.002 and 0.044, respectively). Moreover, treatment with hPBMCs significantly increased the thickness in all parts of the endometrium compared with that in the untreated control uterine horn (proximal: 1.69 ± 0.19 vs. 1.00 ± 0.10, p = 0.009; middle: 1.51 ± 0.14 vs. 1.00 ± 0.12, p = 0.010; distal: 1.72 ± 0.22 vs. 1.00 ± 0.12, p = 0.003, respectively). Compared with the PBS injection group, the hPBMC injection group had significantly thickened endometrium in the middle (p = 0.036) and distal segments (p = 0.002) of the uterine horn. Immunohistochemical analysis revealed the presence of exogenously injected hPBMCs in the uterus of recipient mice. hPBMC-recipient mice had cyclic uterus with normal histology in the endometrium. hPBMCs were not applied directly to a mouse model with thin endometrium, so further study is needed. The beneficial effect of hPBMCs on endometrium may suggest their clinical feasibility for the safe treatment of infertile patients with persistently thin endometrium.


Effect of SHR0302 on the pharmacokinetics of CYP3A4, CYP2C8, CYP2C9 and CYP2C19 probe substrates in healthy volunteers: A cocktail analysis.
This study evaluated the effects of SHR0302 on the pharmacokinetics of cytochrome P450 (CYP) probe substrates. We performed a single-centre, open-label, three-period drug-drug interaction (DDI) study in 24 healthy subjects (NCT05392127). Subjects received a single oral dose of 5 mg warfarin (CYP2C9), 20 mg omeprazole (CYP2C19) and 15 mg midazolam (CYP3A4) on Days 1, 8 and 22, and received 0.5 mg repaglinide (CYP2C8) on Days 7, 14 and 28. Multiple oral doses of 8 mg SHR0302 were administered once daily from Day 8 to Day 28. The exposure of S-warfarin and repaglinide were comparable before and after SHR0302 administration. AUC of midazolam was not affected by SHR0302, whereas the administration of SHR0302 slightly decreased the Cmax of midazolam by 7.6% (single dose) and 15.7% (once daily for 14 days). The AUC0-t , AUC0-inf , and Cmax of omeprazole were slightly decreased after a single dose of SHR0302 by 19.2%, 21.8% and 23.5%, respectively. In the presence of SHR0302 for 14 days, the AUC0-t , AUC0-inf , and Cmax of omeprazole were marginally reduced by 3.0%, 16.4% and 8.3%, respectively. According to the induction mechanism of the CYP enzyme, for the investigation of the induction effect, the results of multiple administrations of the perpetrator were more reliable than those of the single dose. The results demonstrated that co-administration of SHR0302 8 mg once daily is unlikely to have a clinically meaningful effect on the exposure of drugs metabolized by CYP3A4, CYP2C8, CYP2C9 and CYP2C19 in healthy subjects.


IWP2 impairs the development of porcine somatic cell nuclear transfer embryos via Wnt signaling pathway inactivation.
Wnt signaling is critical in embryonic development and post-embryonic tissue homeostasis. The aim of the present study was to evaluate the expression levels of canonical Wnt signaling genes in porcine somatic cell nuclear transfer (SCNT) embryos. Quantitative polymerase chain reaction analysis was performed in porcine SCNT embryos, and the results indicated that the temporal expression patterns of canonical signaling genes were similar between in vivo and SCNT embryos from the 2-cell to the blastocyst stage. In addition, aberrant expression in a small number of Wnt signaling genes in SCNT embryos was identified. IWP2, an inhibitor of Wnt processing, was applied to the culture of SCNT embryos. The Wnt signaling pathway in the SCNT blastocysts may be inactivated via IWP2 treatment, reflecting the low expression levels of c-Myc and peroxisome proliferator-activated receptor δ. Furthermore, blastocyst hatching was damaged by IWP2 treatment. These findings indicate that the canonical Wnt signaling pathway is important for SCNT embryo development.


Factors influencing the level of patients using the internet to gather information before anaesthesia: a single-centre survey of 815 patients in Switzerland : The internet for patient information before anaesthesia.
Aim of this study was to identify factors associated with patients using the internet to find information about their upcoming surgery in general, and more specifically about anaesthesia. With Ethics committee approval, 1000 consecutive patients seen before elective surgery in the anaesthesia preoperative clinic of a Swiss Level 2 hospital were asked to complete a questionnaire. Primary outcome were patients using the internet to gather any medical information related to their upcoming hospital stay, secondary outcome patients using the internet to gather information regarding the upcoming anaesthesia. Multiple regression was performed to identify independent factors associated with internet use. Eighty-two percent of the patients (n = 815) participated. 97% of those were ASA physical status 1 or 2; 83% (n = 676) had experience with previous anaesthetics, 86% (n = 700) reported to use the internet in general. Overall, about one-third of the participants used the internet to learn more about their medical condition, 26% regarding their upcoming surgical procedure. Only 7% (n = 55) obtained information about the anaesthetic. In multivariate analyses, factors associated with internet use were generally doing so, and planned moderate compared to minor surgery; not using the internet was associated with previous anaesthetic experience. Of those who did not use the Internet to learn about their anaesthetic, 34% indicated that they would have visited a trusted website. Only few patients used the internet to obtain information about their upcoming procedure and the anaesthetic part played an even smaller role. However, many patients would have appreciated guidance to find trustworthy internet sites. German Clinical Trials Register ( DRKS00005434 ; date of registration: 27th December 2013); date of enrolment of first patient: 1st August 2013; study retrospectively registered.


Predictive factors for perioperative blood transfusions in partial nephrectomy for renal masses.
Allogeneic perioperative blood transfusions (PBT) have been associated with higher rates of postoperative complications and tumour recurrence in a number of malignancies. This study evaluates the risk factors for PBT in patients undergoing partial nephrectomy (PN), in order to identify patients who could benefit from alternatives to allogenic blood. Data on 822 patients who underwent elective PN between 1988 and 2013 were analysed. Patient demographics and clinicopathologic variables were collected retrospectively. PBT was defined as transfusion of allogeneic red blood cells during PN (in the operating-room) or postoperative hospitalization. Of the 822 patients, 122 (14.8%) received PBT. Of these, 45.9% were transfused intraoperatively and 47.5% in the postoperative period. Only 14.3% of the patients who were transfused intraoperatively required additional postoperative transfusions. On multivariable analysis, age ≥65 (P < 0.01), lower preoperative haemoglobin levels (P < 0.001), larger renal masses (P < 0.001), central lesions (P < 0.01) and cumulative surgical experience (P < 0.001) were found to be associated with higher rate of PBT. Age, low preoperative haemoglobin level, lesion size, surgeons' experience and central renal lesions are independent pre-operative risk factors for PBT in patients undergoing PN. Evaluation of these risk factors prior to surgery may be helpful in constituting guidelines for a more responsible use of allogeneic blood and its alternatives.


Bevacizumab in Advanced Cervical Cancer: Issues and Challenges for Low- and Middle-Income Countries.
Bevacizumab became the first molecular antibody to show survival benefit in advanced cervical cancer. In the GOG-0240 (Paclitaxel and Cisplatin or Topotecan With or Without Bevacizumab in Treating Patients With Stage IVB, Recurrent, or Persistent Cervical Cancer) trial, it improved overall survival by a significant 3.7 months over platinum doublet chemotherapy alone. However, this discovery is not likely to improve the status of global cervical cancer because more than 85% of patients with cervical cancer live in low- and middle-income countries and cannot afford bevacizumab. This commentary looks at the options by which this drug can be made more affordable and cost-effective for patients in low- and middle-income countries. We also discuss other important questions related to its affordability and cost issues such as the optimal number of cycles and personalizing the treatment. Finally, we emphasize that although the unaffordability of bevacizumab in cervical cancer seems to be a very important issue, the best cost-effective strategy against cervical cancer is prevention with screening and vaccination.


Mitochondrial permeability transition in apoptosis and necrosis.
Apoptosis has classically been viewed as a process not involving mitochondria, whereas the implication of mitochondrial dysfunction in necrosis has been recognized for several decades. Recently, it has become clear that apoptosis implies a disruption of mitochondrial membrane intregrity that is decisive for the cell death process. Cytofluorometric methods assessing the mitochondrial membrane function and structure can be employed to demonstrate that, at least in most models of apoptosis, mitochondrial changes precede caspase and nuclease activation. Moreover, pharmacological and genetic experiments suggest that the loss of mitochondrial membrane integrity is a critical event of the apoptotic process, beyond or at the point of no return of programmed cell death. Inhibitors of the mitochondrial megachannel (= permeability transition pore) can prevent both the mitochondrial and the post-mitochondrial manifestations of apoptosis.


Importance of isothermal titration calorimetry for the detection of the direct binding of metal ions to mismatched base pairs in duplex DNA.
Metal ion-nucleic acid interactions contribute substantially to the structure and biological activity of nucleic acids and have a wide range of potential applications in nanotechnology. In this study, we examined the interactions between metal ions and mismatched base pairs in duplex DNA to reveal the underlying molecular mechanism. UV melting analyses showed that the melting temperature (Tm) of a 21-base pair duplex DNA with each of the C-A, C-C and C-T mismatched base pairs increased upon the addition of Ag+. However, isothermal titration calorimetry (ITC) demonstrated that Ag+ only bound to the C-C mismatched base pair of the duplex DNA to form C-Ag-C bonds, without binding to the C-A and C-T mismatches. These results showed that Tm increased even when metal ions did not bind to the mismatched base pairs of the duplex DNA. Although the increase in Tm upon the addition of the metal ions is often used to detect metal ion binding to mismatched base pairs of duplex DNA, these results indicated that UV melting analyses are unable to detect the direct binding of metal ions to the mismatched base pairs. Because ITC analyses directly detect the heat derived from metal ion binding to mismatched base pairs of duplex DNA, we concluded that this may be an effective detection approach.


High-intensity interval training is not superior to other forms of endurance training during cardiac rehabilitation.
High-intensity interval training has recently emerged as superior to continuous endurance training in cardiac rehabilitation upon other training regimes. Individually tailored continuous endurance training and pyramid training could induce comparable effects on peak work capacity as high intensity interval training. A prospective, randomized study. Effects of the following isocaloric cycle ergometer protocols on peak work capacity have been assessed in patients with coronary artery disease (n = 60) during 6 weeks of outpatient cardiac rehabilitation, i.e. 18 supervised sessions of exercise training: (1) continuous endurance training (n = 20): 33 min at 65-85% peak heart rate; (2) high intensity interval training (n = 20): 4 × 4 min intervals at 85-95% peak heart rate, each followed by 3 min of active recovery at 60-70% peak heart rate; (3) pyramid training (n = 20): 3 × 8 min of stepwise load increase and subsequent decrease from 65-95-65% peak heart rate, supplemented by 2 min recovery at 60-70% peak heart rate between pyramids. All protocols were preceded by 5 min of warm-up and followed by 5 min cool-down at 60-70% peak heart rate. Attendance during exercise sessions was 99.2%. There were significant increases in peak work capacity of comparable magnitude in all three training groups (begin vs. end: continuous endurance training: 136.0 ± 49.6 W vs. 163.4 ± 60.8 W (21.1 ± 8.5%); high-intensity interval training: 141.0 ± 60.4 W vs. 171.1 ± 69.8 W (22.8 ± 6.6%); pyramid training: 128.7 ± 50.6 W vs. 158.5 ± 57.9 W (24.8 ± 10.8%); within groups all p < 0.001; between groups, p = not significant). Endurance training protocols assessed in this study all led to significant increases in peak work capacity of comparable magnitude. Our findings suggest that these protocols can be used interchangeably, which will lead to further individualization of exercise prescription and may therefore result in improved adherence to lifelong behavioural changes.


G-protein-coupled receptors for neurotransmitter amino acids: C-terminal tails, crowded signalosomes.
G-protein-coupled receptors (GPCRs) represent a superfamily of highly diverse integral membrane proteins that transduce external signals to different subcellular compartments, including nuclei, via trimeric G-proteins. By differential activation of diffusible G(alpha) and membrane-bound G(beta)gamma subunits, GPCRs might act on both cytoplasmic/intracellular and plasma-membrane-bound effector systems. The coupling efficiency and the plasma membrane localization of GPCRs are regulated by a variety of interacting proteins. In this review, we discuss recently disclosed protein interactions found with the cytoplasmic C-terminal tail regions of two types of presynaptic neurotransmitter receptors, the group III metabotropic glutamate receptors and the gamma-aminobutyric acid type-B receptors (GABA(B)Rs). Calmodulin binding to mGluR7 and other group III mGluRs may provide a Ca(2+)-dependent switch for unidirectional (G(alpha)) versus bidirectional (G(alpha) and G(beta)gamma) signalling to downstream effector proteins. In addition, clustering of mGluR7 by PICK1 (protein interacting with C-kinase 1), a polyspecific PDZ (PSD-95/Dlg1/ZO-1) domain containing synaptic organizer protein, sheds light on how higher-order receptor complexes with regulatory enzymes (or 'signalosomes') could be formed. The interaction of GABA(B)Rs with the adaptor protein 14-3-3 and the transcription factor ATF4 (activating transcription factor 4) suggests novel regulatory pathways for G-protein signalling, cytoskeletal reorganization and nuclear gene expression: processes that may all contribute to synaptic plasticity.


Neuropathological Staging of Brain Pathology in Sporadic Parkinson's disease: Separating the Wheat from the Chaff.
A relatively small number of especially susceptible nerve cell types within multiple neurotransmitter systems of the human central, peripheral, and enteric nervous systems (CNS, PNS, ENS) become involved in the degenerative process underlying sporadic Parkinson's disease (sPD). The six-stage model we proposed for brain pathology related to sPD (Neurobiol Aging 2003) was a retrospective study of incidental and clinically diagnosed cases performed on unconventionally thick tissue sections (100 μm) from a large number of brain regions.The staging model emphasized what we perceived to be a sequential development of increasing degrees of Lewy pathology in anatomically interconnected regions together with the loss of aminergic projection neurons in, but not limited to, the locus coeruleus and substantia nigra. The same weight was assigned to axonal and somatodendritic Lewy pathology, and the olfactory bulb was included for the first time in a sPD staging system. After years of research, it now appears that the earliest lesions could develop at nonnigral (dopamine agonist nonresponsive) sites, where the surrounding environment is potentially hostile: the olfactory bulb and, possibly, the ENS. The current lack of knowledge regarding the development of Lewy pathology within the peripheral autonomic nervous system, however, means that alternative extra-CNS sites of origin cannot be disregarded as possible candidates. The PD staging system not only caused controversy but contributed a framework for (1) assessing pathology in the spinal cord, ENS, and PNS in relationship to that evolving in the brain, (2) defining prodromal disease and cohorts of at-risk individuals, (3) developing potential prognostic biomarkers for very early disease, (4) testing novel hypotheses and experimental models of α-synuclein propagation and disease progression, and (5) finding causally-oriented therapies that intervene before the substantia nigra becomes involved. The identification of new disease mechanisms at the molecular and cellular levels indicates that physical contacts (transsynaptic) and transneuronal transmission between vulnerable nerve cells are somehow crucial to the pathogenesis of sPD.


Supplementation of sperm media with zinc, D-aspartate and co-enzyme Q10 protects bull sperm against exogenous oxidative stress and improves their ability to support embryo development.
High levels of reactive oxygen species in the semen of infertile patients or spontaneously generated during in vitro sperm handling may impair sperm quality, fertilization and embryo developmental competence. We recently reported that zinc, d-aspartate and co-enzyme Q10, contained in the dietary supplement Genadis® (Merck Serono), have protective effects on human and bull sperm motility, lipid peroxidation and DNA fragmentation in vitro; furthermore, in bovine, treated spermatozoa had an improved ability to support embryo development. However, only a few studies have investigated the protective role of antioxidants during in vitro sperm handling in the presence of an exogenous oxidative stress. Herein, to simulate such conditions in an animal model, we induced exogenous oxidative stress on spermatozoa through the xanthine-xanthine oxidase system and investigated its effects on sperm function and subsequent embryo developmental competence in the presence of zinc, d-Asp and CoQ10 protection. The main results showed that exogenous oxidative stress decreased sperm motility, increased sperm DNA fragmentation, and reduced fertilization and blastocyst rates and quality. Pre-treatment with zinc, d-aspartate and co-enzyme Q10 before exogenous oxidative stress was able to prevent these effects. Supplementation of sperm culture media with zinc, d-aspartate and co-enzyme Q10 could protect sperm from oxidative stress damage during in vitro handling in assisted reproductive technologies.


Effect of intermittent fasting on circadian rhythms in mice depends on feeding time.
Calorie restriction (CR) resets circadian rhythms and extends life span. Intermittent fasting (IF) also extends life span, but its affect on circadian rhythms has not been studied. To study the effect of IF alongside CR, we imposed IF in FVB/N mice or IF combined with CR using the transgenic FVB/N alphaMUPA mice that, when fed ad libitum, exhibit spontaneously reduced eating and extended life span. Our results show that when food was introduced during the light period, body temperature peak was not disrupted. In contrast, IF caused almost arrhythmicity in clock gene expression in the liver and advanced mPer2 and mClock expression. However, IF restored the amplitudes of clock gene expression under disruptive light condition regardless whether the animals were calorically restricted or not. Unlike daytime feeding, nighttime feeding yielded rhythms similar to those generated during ad libitum feeding. Taken together, our results show that IF can affect circadian rhythms differently depending on the timing of food availability, and suggest that this regimen induces a metabolic state that affects the suprachiasmatic nuclei (SCN) clock.


Halofuginone attenuates osteoarthritis by inhibition of TGF-β activity and H-type vessel formation in subchondral bone.
Examine whether osteoarthritis (OA) progression can be delayed by halofuginone in anterior cruciate ligament transection (ACLT) rodent models. 3-month-old male C57BL/6J (wild type; WT) mice and Lewis rats were randomised to sham-operated, ACLT-operated, treated with vehicle, or ACLT-operated, treated with halofuginone. Articular cartilage degeneration was graded using the Osteoarthritis Research Society International (OARSI)-modified Mankin criteria. Immunostaining, flow cytometry, RT-PCR and western blot analyses were conducted to detect relative protein and RNA expression. Bone micro CT (μCT) and CT-based microangiography were quantitated to detect alterations of microarchitecture and vasculature in tibial subchondral bone. Halofuginone attenuated articular cartilage degeneration and subchondral bone deterioration, resulting in substantially lower OARSI scores. Specifically, we found that proteoglycan loss and calcification of articular cartilage were significantly decreased in halofuginone-treated ACLT rodents compared with vehicle-treated ACLT controls. Halofuginone reduced collagen X (Col X), matrix metalloproteinase-13 and A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS 5) and increased lubricin, collagen II and aggrecan. In parallel, halofuginone-attenuated uncoupled subchondral bone remodelling as defined by reduced subchondral bone tissue volume, lower trabecular pattern factor (Tb.pf) and increased thickness of subchondral bone plate compared with vehicle-treated ACLT controls. We found that halofuginone exerted protective effects in part by suppressing Th17-induced osteoclastic bone resorption, inhibiting Smad2/3-dependent TGF-β signalling to restore coupled bone remodelling and attenuating excessive angiogenesis in subchondral bone. Halofuginone attenuates OA progression by inhibition of subchondral bone TGF-β activity and aberrant angiogenesis as a potential preventive therapy for OA.


Fertility preservation for patients with gynecologic malignancies: The Korean Society for Fertility Preservation clinical guidelines.
Fertility preservation plays a central role in cancer care since an increasingly large number of cancer patients are surviving as a result of improvements in diagnostic and therapeutic strategies. Physicians who take part in the initial diagnosis and management of gynecologic cancer should understand the importance of fertility preservation. Since indications for fertility preservation are limited to early-stage gynecologic cancer, a surgeon must carefully consider each indication. Before performing fertility-sparing surgery, health professionals should compare its oncologic and pregnancy outcomes with those of other standard treatments. Individualized treatment strategies should be delivered depending on the patient's situation, and physicians should provide timely information and appropriate counseling.


Pharmacokinetics of prazosin administered as gastro-intestinal-therapeutic-systems to 24 healthy volunteers.
Pharmacokinetics of prazosin was investigated after single dose administrations of four different formulations, according to a randomized trial, to 24 young healthy volunteers: immediate release tablets (3 x 1 mg) used as reference (Treatment A), two new Gastro-Intestinal-Therapeutic-Systems (GITS) containing 2.5 mg (Treatment B) and 5 mg (Treatment C) of prazosin, and a traditional sustained release formulation (4 mg, treatment D). Relative bioavailability of prazosin administered as GITS was only 49.4 +/- 19.5% (B) and 45.5 +/- 18.7 (C) versus 73.8 +/- 13.9% (D) (area under the curve normalized at 3 mg dosing); but absorption was sustained and plasma concentrations were maintained at a virtually constant level for a time period close to 24 h. As a result, mean residence time (MRT) of prazosin was considerably increased after GITS administration: 21.6 +/- 1.0 h (B), 22.5 +/- 1.6 h (C) instead of 5.9 +/- 0.2 h for the reference formulation (A) and 10.8 +/- 0.8 h for the traditional sustained release formulation (D). Although extrapolation to multiple dosing situations is difficult, this study demonstrates the potential suitability of prazosin GITS for once daily administrations.


Nutritional evaluation and ruminal fermentation patterns of kochia compared with alfalfa and orchardgrass hays and ephedra and cheatgrass compared with orchardgrass hay as alternative arid-land forages for beef cattle in two dual-flow continuous culture system experiments.
The objective was to evaluate the ruminal fermentation patterns of forage kochia (FK) compared with alfalfa hay (AH) and orchardgrass hay (OH) (Exp. 1), and ephedra (EPH) and immature cheatgrass (CG) compared with OH (Exp. 2), using a dual-flow continuous culture system. Two in vitro experiments were conducted, and in each experiment, treatments were randomly assigned to six dual-flow fermenters (1,223 ± 21 mL) in a replicated 3 × 3 Latin square design, with three consecutive periods of 10 d each, consisting of 7 d for diet adaptation and 3 d for sample collection. Each fermenter was fed a total of 72 g/d (DM basis) and treatments were as follows: Exp. 1: 1) 100% OH, 2) 100% AH, and 3) 100% dried FK. Exp. 2: 1) 100% OH, 2) 100% dried CG, and 3) 100% dried EPH. On day 8, 9, and 10, samples of solid and liquid effluent from each fermenter were taken for digestibility analysis, and subsamples were collected for NH3-N, VFA, and bacterial N determinations. Data were analyzed using the MIXED procedure of SAS. In Exp. 1, treatments did not affect DM, OM, and NDF digestibilities, total VFA and molar proportions of acetate, propionate, butyrate, and branched-chain VFA. True CP digestibility, ruminal NH3-N concentration, and total N, NH3-N, NAN, and dietary N flows (g/d) were greater (P < 0.05) for FK compared with the other forages. However, treatments did not affect bacterial efficiency. In Exp. 2, DM, OM, and CP digestibilities were greater (P = 0.01) for EPH, and NDF digestibility was greater (P < 0.05) for EPH and CG compared with OH. Ephedra had the highest (P < 0.05) pH and acetate:propionate ratio and the lowest (P < 0.05) total VFA concentration. Total VFA, ruminal NH3-N concentration, and NH3-N flow (g/d) were highest (P < 0.05) for CG. Total N flow and bacterial efficiency were highest (P < 0.05) for OH and CG, while the flows (g/d) of NAN, bacterial N, and dietary N were greater (P < 0.05) for OH compared with the other forages. Results indicate that when compared with AH and OH (Exp. 1), FK has similar ruminal fermentation patterns and may be an adequate alternative for beef cattle producers. Furthermore, when compared with OH (Exp. 2), immature CG may also be an adequate forage alternative. This is especially important for areas in which conventional forages may not grow well such as the U.S. arid-land. However, EPH should not be used as the sole forage due to its poor ruminal fermentation as evidenced by the lowest total VFA concentration and propionate molar proportion.


Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study.
The Epilepsy Genetics (EPIGEN) Consortium was established to undertake genetic mapping analyses with augmented statistical power to detect variants that influence the development and treatment of common forms of epilepsy. We examined common variations across 279 prime candidate genes in 2717 case and 1118 control samples collected at four independent research centres (in the UK, Ireland, Finland, and Australia). Single nucleotide polymorphism (SNP) and combined set-association analyses were used to examine the contribution of genetic variation in the candidate genes to various forms of epilepsy. We did not identify clear, indisputable common genetic risk factors that contribute to selected epilepsy subphenotypes across multiple populations. Nor did we identify risk factors for the general all-epilepsy phenotype. However, set-association analysis on the most significant p values, assessed under permutation, suggested the contribution of numerous SNPs to disease predisposition in an apparent population-specific manner. Variations in the genes KCNAB1, GABRR2, KCNMB4, SYN2, and ALDH5A1 were most notable. The underlying genetic component to sporadic epilepsy is clearly complex. Results suggest that many SNPs contribute to disease predisposition in an apparently population-specific manner. However, subtle differences in phenotyping across cohorts, combined with a poor understanding of how the underlying genetic component to epilepsy aligns with current phenotypic classifications, might also account for apparent population-specific genetic risk factors. Variations across five genes warrant further study in independent cohorts to clarify the tentative association.


A split-and-merge deep learning approach for phenotype prediction.
Phenotype prediction with genome-wide markers is a critical but difficult problem in biomedical research due to many issues such as nonlinearity of the underlying genetic mapping and high-dimensionality of marker data. When using the deep learning method in the small-n-large-p data, some serious issues occur such as over-fitting, over-parameterization, and biased prediction. In this study, we propose a split-and-merge deep learning method, named SM-DL method, to learn a neural network on the dimension reduce data by using the split-and-merge technique. Numerically, the proposed method has significant performance in phenotype prediction for a simulated example. A real example is used to demonstrate how the proposed method can be applied in practice.


Reduction of teat skin mastitis pathogen loads: differences between strains, dips, and contact times.
The purpose of these experiments was to (1) assess differences in mastitis pathogen strain sensitivities to teat disinfectants (teat dips), and (2) determine the optimum time for premilking teat dips to remain in contact with teat skin to reduce pathogen loads on teat skin. Two experiments were conducted using the excised teat model. In experiment 1, the differences in mastitis pathogen strain sensitivities to 4 commercially available dips (dip A: 1% H2O2; dip B: 1% chlorine dioxide; dip C: 1% iodophor; and dip D: 0.5% iodophor) were evaluated. Four strains of 11 common mastitis pathogens (Staphylococcus aureus, Streptococcus agalactiae, Mycoplasma bovis, Streptococcus dysgalactiae, Streptococcus uberis, Escherichia coli, Staphylococcus chromogenes, Staphylococcus epidermidis, Staphylococcus hyicus, Staphylococcus xylosus, and Staphylococcus haemolyticus) were tested. In experiment 2, the percentage log reduction of mastitis pathogens (Escherichia coli, Streptococcus uberis, Streptococcus dysgalactiae, Klebsiella species, Staphylococcus chromogenes, Staphylococcus haemolyticus, Staphylococcus xylosus, and Staphylococcus epidermidis) on teat skin with 3 commercially available teat dips: dip A; dip D; and dip E: 0.25% iodophor, using dip contact times of 15, 30, and 45 s, was evaluated. Experiment 1 results indicated significant differences in strain sensitivities to dips within pathogen species: Staphylococcus aureus, Staphylococcus chromogenes, and Streptococcus uberis. Species differences were also found where Mycoplasma bovis (97.9% log reduction) was the most sensitive to tested teat dips and Staphylococcus haemolyticus (71.4% log reduction) the most resistant. Experiment 2 results indicated that contact times of 30 and 45 s were equally effective in reducing recovered bacteria for dips D and E and were also significantly more effective than a 15-s contact time. No differences were seen in recovered bacteria between tested contact times after treatment with dip A. It can be concluded that different mastitis pathogen species and strains within species may possess different sensitivities to teat dips, which may have implications in selection of teat dips on dairies. Furthermore, a 30-s premilking dip contact time for iodophors and 15 s for H2O2 dips may be optimal in reducing pathogen load in the shortest amount of time. A reduction in premilking teat dip contact time may improve milking parlor efficiency.


Multi-Site Statistical Mapping of Along-Tract Microstructural Abnormalities in Bipolar Disorder with Diffusion MRI Tractometry.
Investigating alterations in brain circuitry associated with bipolar disorder (BD) may offer a valuable approach to discover brain biomarkers for genetic and interventional studies of the disorder and related mental illnesses. Some diffusion MRI studies report evidence of microstructural abnormalities in white matter regions of interest, but we lack a fine-scale spatial mapping of brain microstructural differences along tracts in BD. We also lack large-scale studies that integrate tractometry data from multiple sites, as larger datasets can greatly enhance power to detect subtle effects and assess whether effects replicate across larger international datasets. In this multisite diffusion MRI study, we used BUndle ANalytics (BUAN, Chandio 2020), a recently developed analytic approach for tractography, to extract, map, and visualize profiles of microstructural abnormalities on 3D models of fiber tracts in 148 participants with BD and 259 healthy controls from 6 independent scan sites. Modeling site differences as random effects, we investigated along-tract white matter (WM) microstructural differences between diagnostic groups. QQ plots showed that group differences were gradually enhanced as more sites were added. Using the BUAN pipeline, BD was associated with lower mean fractional anisotropy (FA) in fronto-limbic, interhemispheric, and posterior pathways; higher FA was also noted in posterior bundles, relative to controls. By integrating tractography and anatomical information, BUAN effectively captures unique effects along white matter (WM) tracts, providing valuable insights into anatomical variations that may assist in the classification of diseases.


Immunomodulatory effects of azithromycin on the establishment of lipopolysaccharide tolerance in mice.
Recent reports suggest that azithromycin can shift macrophage polarization towards the alternatively activated M2 phenotype. In order to investigate its immunomodulatory activity in vivo, the influence of azithromycin on survival and cytokine production was assessed in the LPS tolerance model which is characterized by an M2 skewed response. For induction of tolerance, mice received an intraplantar injection of 30 μg LPS, 24 h prior to intravenous challenge with 350 μg LPS. Azithromycin (100 mg/kg) was administered orally, 2 h before LPS application. Influence of treatment on survival and cytokine concentration in serum was monitored. Azithromycin alone, instead of LPS, could not induce an LPS tolerant state. However, when administered before LPS priming it significantly increased survival, which was enhanced by concomitant azithromycin before LPS challenge. Azithromycin had no effect on survival when administered only prior to the LPS challenge. Tolerance induction by LPS priming was associated, upon LPS challenge, with decreased serum concentrations of pro-inflammatory cytokines, TNFα, IL-12p40 and CCL5, and increased serum concentrations of the anti-inflammatory cytokines, IL-10 and IL-1ra. Azithromycin treatment, prior to LPS priming, further reduced serum TNFα and CCL5, yielding the greatest inhibition when the macrolide was also given prior to LPS challenge. Serum concentrations of the anti-inflammatory cytokines, IL-10 and IL-1ra, were unchanged following azithromycin treatment. In summary, we have confirmed the immunomodulatory activity of azithromycin, as reflected in its ability to augment tolerance induction to LPS, promoting increased survival and reduced pro-inflammatory cytokine production, without affecting overt inflammation to LPS or anti-inflammatory cytokine production.


[Partial left lateral subcutaneous sphincterotomy for anal fissure: role and results].
This is a retrospective analysis of the results obtained with surgical treatment consisting in left lateral partial subcutaneous sphincterotomy for anal fissure. Fifty patients observed from January 2002 to June 2005 in our Coloproctology outpatients' department were recruited. Five patients (10%) did not undergo an operation and all 5 presented an acute anal fissure. Their treatment was conservative consisting in fibre ingestion, use of stool softeners, ointments, anti-inflammatory agents after opening the bowel, and a corticosteroid ointment. Forty-five patients (90%) were operated on. Twelve of these (26%) were operated on for an acute anal fissure after early failure of conservative therapy and demanded immediate surgical therapy; 14 (31%) of those operated on for acute anal fissure underwent a surgical procedure after at least a month of conservative treatment. The remaining 19 patients (42%) presented chronic anal fissures, with symptoms lasting more than 1 month and with sentinel haemorrhage, a hypertrophied anal papilla, and hardening of the edge of the fissures. Forty of the patients operated on (88%) presented a posterior anal fissure, 3 patients (6.5%) an anterior anal fissure and 2 patients (4.5%) synchronous anterior and posterior anal fissures. The surgical procedure carried out on all patients undergoing operation was a partial left lateral subcutaneous internal sphincterotomy using the closed technique according to Notoras under general anaesthesia. Follow-up was carried out 15 days and 2, 3 and 6 months postoperatively. The results were considered very good in 89% of the cases, while 5 patients (11%) complained of pain after opening the bowels, albeit of acceptable intensity and such as not to require another operation or significant pharmacological treatment. No complications were observed. The conclusion after the analysis of our experience is in agreement with the 8th recommendation, class I, recommendation grade A of the "The Standards Practice Task Force of the American Society of Colon and Rectal Surgeons" stating that "surgery may be appropriately offered without a trial of pharmacologic treatment after failure of conservative therapy" and that "in our experience can be proposed in those cases of acute anal fissure". In our experience, the 89% success rate and substantial patient satisfaction make this procedure more appropriate than medical treatment and alternative surgical treatments.


Pain from a Bullet Lingers on: An Uncommon Case of Lead Toxicity.
Lead toxicity from a retained bullet as a cause for abdominal pain is rarely considered. Given its unpredictable latent period and nonspecific clinical symptoms, such cases are difficult to diagnose but may be fatal if unrecognized. We present the case of a 48-year-old man who presented with complaints of abdominal pain, weight loss and constipation. His past history was significant for a gunshot wound to the left hip about 20 years before. Radiographic studies confirmed the same with the presence of numerous intra-articular bullet fragments and a calcified hemarthrosis surrounding the left femoral head. Blood lead levels were elevated following which the patient was started on chelation therapy with succimer which resulted in symptomatic improvement. The aim of this paper is to highlight the importance of considering lead toxicity from a retained bullet as a cause of abdominal pain and to review the relevant literature.


The genetic determinants of renal impairment following cardiac surgery.
Cardiac surgery is frequently performed, and acute renal dysfunction is a common adverse event following this procedure. Cardiac surgery-related renal injury independently predicts longer hospital stays and greater rates of morbidity and mortality. Although much work has been completed toward better understanding of this phenomenon, the state of knowledge concerning surgery-related renal injury remains limited. Currently, there is no effective paradigm to identify patients who are at risk for this condition; the specific mechanisms of renal injury during surgery are incompletely understood; and few therapies exist to prevent or treat this phenomenon. To better understand this common clinical problem, recent research has focused on the importance of genetic variability within the physiological and patho-physiological systems that underlie renal dysfunction following cardiac surgery. Emphasizing the importance of using genetics to elucidate molecular mechanisms of this disease, this article reviews the current literature on genetic polymorphisms and post cardiac surgery-related renal dysfunction.


Effects of feed deprivation and electrical, gas, and captive needle stunning on early postmortem muscle metabolism and subsequent meat quality.
The general method for stunning poultry before slaughter is by immersion of a chicken's head into an electrified waterbath. This method results in carcass and meat quality deficiencies. The major problems are hemorrhages and a delay in onset of rigor mortis, which increases the risk of cold shortening with early deboning. In two experiments, this study examines the early postmortem metabolism in the breast muscle and its effect on ultimate meat quality. The first experiment describes the effects of 5 h feed deprivation on the availability of glycogen from the liver and the breast muscle, of waterbath and head-only electrical stunning on pH and metabolite levels up to 6 h in unprocessed muscle, and the consequences on meat quality. The second experiment compares the same measurements after waterbath and head-only electrical stunning, CO2/O2/N2 and Ar/CO2 gases, and captive needle stunning. Metabolic degradation halted after 6 h without processing or after 4 h under conventional conditions after waterbath and CO2/O2/N2 stunning. With other stunning methods, this occurrence is at a faster rate, largely depending on muscle activity. Muscle glycogen does not need to be exhausted for energy generation to cease. If glycogen is a limiting factor, as found with head-only stunning, pH drops too rapidly and affects water-holding capacity and color. Hemorrhage scores were higher with electrical stunning than with other stunning methods. Gas stunning affected color and, to a lesser extent, water-holding capacity. Captive needle stunning scored between gas and electrical stunning on most measurements.


Burkholderia gladioli strain KJ-34 exhibits broad-spectrum antifungal activity.
Plant pathogens are one of the major constraints on worldwide food production. The antibiotic properties of microbes identified as effective in managing plant pathogens are well documented. Here, we used antagonism experiments and untargeted metabolomics to isolate the potentially antifungal molecules produced by KJ-34. KJ-34 is a potential biocontrol bacterium isolated from the rhizosphere soil of rice and can fight multiple fungal pathogens (i.e. Ustilaginoidea virens, Alternaria solani, Fusarium oxysporum, Phytophthora capsica, Corynespora cassiicola). The favoured fermentation conditions are determined and the fermentation broth treatment can significantly inhibit the infection of Magnaporthe oryzae and Botryis cinerea. The fermentation broth suppression ratio is 75% and 82%, respectively. Fermentation broth treatment disrupted the spore germination and led to malformation of hyphae. Additionally, we found that the molecular weight of antifungal products were less than 1000 Da through semipermeable membranes on solid medium assay. To search the potentially antifungal molecules that produce by KJ-34, we used comparative and bioinformatics analyses of fermentation broth before and after optimization by mass spectrometry. Untargeted metabolomics analyses are presumed to have a library of antifungal agents including benzoylstaurosporine, morellin and scopolamine. These results suggest that KJ-34 produced various biological control agents to suppress multiple phytopathogenic fungi and showed a strong potential in the ecological technologies of prevention and protection.


Blastocyst formation is a good indicator for attainment of assisted reproduction.
Blastocyst formation is a late stage of embryogenesis before implantation. The examination for the percentage of blastocyst formation (PBF) can predict the viability/pregnancy of the assisted reproduction trials. The PBF significantly correlates with age and pregnancy. The PBF is significantly lower in the intracytoplasmic sperm injection (ICSI) treatment than the conventional IVF treatment. The zygotes from immature oocytes give less blastocyst formation than the zygotes from mature oocytes. One pronucleus "zygotes" have significantly less chance to blastocyst than the normal 2 pronuclei zygotes. A mathematical model is proposed, verified, and predicts the hatching/hatched is the rate limiting step for the outcome of pregnancy.


Paenibacillus terrae NK3-4 regulates the transcription of growth-related and stress resistance-related genes in rice.
Paenibacillus terrae NK3-4 is a plant growth-promoting rhizobacterium. In this study, the effects of NK3-4 on rice growth and gene transcription were determined. The results indicated that a seed soaking treatment and a pre-germination seed treatment using NK3-4 promoted rice growth, especially spraying rice seedlings with NK3-4 increased the root number and root length by 34.2% and 34.1%, respectively. Moreover, NK3-4 induced the differential transcription of genes annotated with gene ontology (GO) terms; the number of up-regulated genes was 4.38-times higher than the number of down-regulated genes. The NK3-4 treatment induced the differential transcription of genes in 1794 GO functional groups, with 1531 functional groups containing up-regulated genes. Specific growth-related genes up-regulated by NK3-4 are involved in biological processes, including responses to auxin, hormone biosynthesis, cellular component biogenesis, root system development, and other functions. Furthermore, stress resistance-related genes were up-regulated, some of which encode WRKYs, NPK1-related protein kinase, NPR1-like 4, CaM-like proteins, MYBs, ERFs, TIFYs, NACs, EL5s, PR1s, PR2, PR8, PODs, and PAD4. Considered together, these findings imply that NK3-4 may promote plant growth and enhance stress resistance by regulating gene expression, making it a potentially useful microbe for regulating rice growth and stress resistance.


BUTTERFLIES AND PLANTS: A PHYLOGENETIC STUDY.
A database on host plant records from 437 ingroup taxa has been used to test a number of hypotheses on the interaction between butterflies and their host plants using phylogenetic methods (simple character optimization, concentrated changes test, and independent contrasts test). The butterfly phylogeny was assembled from various sources and host plant clades were identified according to Chase et al.'s rbcL-based phylogeny. The ancestral host plant appears to be associated within a highly derived rosid clade, including the family Fabaceae. As fossil data suggest that this clade is older than the butterflies, they must have colonized already diversified plants. Previous studies also suggest that the patterns of association in most insect-plant interactions are more shaped by host shifts, through colonization and specialization, than by cospeciation. Consequently, we have focused explicitly on the mechanisms behind host shifts. Our results confirm, in the light of new phylogenetic evidence, the pattern reported by Ehrlich and Raven that related butterflies feed on related plants. We show that host shifts have generally been more common between closely related plants than between more distantly related plants. This finding, together with the possibility of a higher tendency of recolonizing ancestral hosts, helps to explain the apparent large-scale conservation in the patterns of association between insects and their host plants, patterns which at the same time are more flexible on a more detailed level. Plant growth form was an even more conservative aspect of the interaction between butterflies and their host plants than plant phylogeny. However, this is largely explained by a higher probability of colonizations and host shifts while feeding on trees than on other growth forms.


Progression and distribution of plantar pressure in Type 2 diabetic patients.
The aim of this prospective 4-yr study was to analyse changes in mean plantar pressure (PP) over time and local shifts of maximal PP in Type 2 diabetic patients. One-hundred fifty-five Type 2 diabetic patients (age 58.9 +/- 7.5 yr, diabetes duration 11.0 +/- 7.6 yr, baseline HbA1c 9.6 +/- 1.6%) were examined with regard to foot abnormalities, neuropathy and measurement of PP during walking (pedobarography). They were assigned to two subgroups, namely normal PP (n=94) and elevated PP (n=57). Patients with an abnormal mean PP did not significantly differ from subjects with a normal PP with regard to sex, age, duration of diabetes and HbA1c. With the exception of the hallux, the mean PP was significantly increased in both groups at all other plantar sites. Maximum PP was located below the metatarsal heads (MTH) 2-5 and significantly increased from baseline (median, lower/upper quartile: 475, 355/715 kPa) to the end of the study (540, 435/749; p<0.0001). On the other hand, PP was normalized in 17 subjects (29.8%) who had an elevated PP at baseline. Furthermore, we observed a local shift in maximal PP towards the MTH 2-5 region. The percentage of patients who had their highest PP under MTH 2-5 was increased from 54.0% at baseline to 61.1% at the end of the study. In general, we registered an elevation of PP over time and a centralization towards sites which are generally prone to ulceration.


Synthesis and Luminescence Properties of Two-Electron Bimetallic Cu-Ag and Cu-Au Nanoclusters via Copper Hydride Precursors.
The synthesis, structural characteristics, and photophysical properties of luminescent Cu-rich bimetallic superatomic clusters [Au@Cu12(S2CNnPr2)6(C≡CPh)4]+ (1a+), [Au@Cu12{S2P(OR)2}6(C≡CPh)4]+ (2+), (2a+ = iPr; 2b+ = nPr), [Au@Cu12{S2P(C2H4Ph)2}6(C≡CPh)4]+ (2c+), and [Ag@Cu12{S2P(OnPr)2}6(C≡CPh)4]+ (3+) were studied. Compositionally uniform clusters 1+-3+ were isolated from the reaction of dithiolato-stabilized, polyhydrido copper clusters with phenylacetylene in the presence of heterometal salts. By using X-ray diffraction, the structures of 1a+, 2a+, 2b+, and 3+ were able to be determined. ESI-mass spectrometry and elemental analysis confirmed their compositions and purity. The structural characteristics of these clusters are similar with respect to displaying gold (or silver)-centered Cu12 cuboctahedra surrounded by six dithiocarbamate/dithiophosph(in)ate and four alkynyl ligands. The doping of Au and Ag atoms into the polyhydrido copper nanoclusters significantly enhances their PL quantum yields from Ag@Cu12 (0.58%) to Au@Cu12 (55%) at ambient temperature in solution. In addition, the electrochemical properties of the new alloys were investigated by cyclic voltammetry.


The role of the right cerebral hemisphere in processing novel metaphoric expressions taken from poetry: a divided visual field study.
Previous research suggests that the right hemisphere (RH) may contribute uniquely to the processing of metaphoric language. However, most studies have focused on familiar metaphoric expressions. The present study used the divided visual field paradigm to examine the role of the right cerebral hemisphere in processing novel metaphoric expressions taken from poetry. In two experiments, participants were presented with four types of word pairs, literal, conventional metaphoric and novel metaphoric expressions and unrelated word pairs, and asked to perform a semantic judgment task. Two different SOAs: 400 and 1100 ms were used. The results of both experiments showed that responses to LVF/RH presented target words were more accurate and faster than responses to RVF/LH target words for novel metaphoric expressions, but not for other types of word pairs. These results support previous research indicating that during word recognition, the RH activates a broader range of related meanings than the LH, including novel, nonsalient meanings. The findings thus suggest that the RH may be critically involved in at least one important component of novel metaphor comprehension, i.e., the integration of the individual meanings of two seemingly unrelated concepts into a meaningful metaphoric expression.


The influence of contextual variables on judgments about patients and their pain.
Professional judgments about persistent pain are influenced by contextual variables, which are features relating to the patient, the assessor, or the broader situation. Such judgments directly inform assessment and treatment and therefore represent an important area of research. While current formulations of persistent pain adopt a biopsychosocial framework, contextual variables relating to psychosocial information have not been well examined in the literature. We employed a within-subjects experimental vignette paradigm to investigate the influence of four contextual variables, 2 (medical evidence: present vs absent) × 2 (pain behavior: present vs absent) × 2 (referral to a psychologist: yes vs no) × 2 (responsibility: onset controllable vs onset uncontrollable), on perceptions of pain. Judgments about patients with chronic low back pain were made across several dimensions. One hundred sixteen medical and nursing students. Main findings revealed that identifiable pain pathology led to increased ratings of pain intensity and emotional distress, and decreased perceived likelihood of malingering. Pain behavior and referral to a psychologist were also found to increase ratings of pain intensity and emotional distress. Encouragingly, psychological referral was not found to increase the perceived likelihood of malingering. Responsibility for the initial injury was found to influence judgments, but this occurred in interaction with medical evidence as well as pain behavior. These findings suggest that contextual variables have an important influence on medical and nursing students' perceptions of patients and their pain. Theoretical and practical implications for provider training and community education are discussed.


The drug treatment of atrial fibrillation.
1. Atrial fibrillation is an inefficient cardiac rhythm associated with impaired exercise tolerance, exertional dyspnoea, palpitation and a substantial risk of thromboembolism. 2. The first decision in management is to consider cardioversion which can be achieved in suitable cases electrically, or pharmacologically with a class Ic antiarrhythmic drug like flecainide or propafenone. 3. Prophylaxis in paroxysmal atrial fibrillation is best achieved with a class Ic drug or a class III drug such as sotalol or amiodarone. 4. Control of ventricular rate in chronic atrial fibrillation can be achieved by pharmacological manipulation of the atrioventricular node by digoxin alone, or in combination with the calcium channel blockers verapamil or diltiazem, or beta-adrenoceptor blockers with intrinsic sympathomimetic activity like pindolol or xamoterol. 5. In view of the considerable risk of thromboembolism in patients with chronic atrial fibrillation anticoagulation or at least treatment with aspirin should be considered.


Autoimmune thyroiditis in infants with Down's syndrome.
Children with Down's syndrome are at high risk of thyroid dysfunction, including autoimmune thyroiditis. We describe two infants with Down's syndrome in whom chronic autoimmune thyroiditis was diagnosed at ages 5 months and 8 months. We suggest that follow-up of thyroid function and thyroid autoantibodies should be started from infancy in Down's syndrome to prevent further deterioration of mental development and growth.


Shear-Activated Nanoparticle Aggregates Combined With Temporary Endovascular Bypass to Treat Large Vessel Occlusion.
The goal of this study is to combine temporary endovascular bypass (TEB) with a novel shear-activated nanotherapeutic (SA-NT) that releases recombinant tissue-type plasminogen activator (r-tPA) when exposed to high levels of hemodynamic stress and to determine if this approach can be used to concentrate r-tPA at occlusion sites based on high shear stresses created by stent placement. A rabbit model of carotid vessel occlusion was used to test the hypothesis that SA-NT treatment coupled with TEB provides high recanalization rates while reducing vascular injury. We evaluated angiographic recanalization with TEB alone, intra-arterial delivery of soluble r-tPA alone, or TEB combined with 2 doses of intra-arterial infusion of either the SA-NT or soluble r-tPA. Vascular injury was compared against stent-retriever thrombectomy. Shear-targeted delivery of r-tPA using the SA-NT resulted in the highest rate of complete recanalization when compared with controls (P=0.0011). SA-NT (20 mg) had a higher likelihood of obtaining complete recanalization as compared with TEB alone (odds ratio 65.019, 95% confidence interval 1.77, >1000; P=0.0231), intra-arterial r-tPA alone (odds ratio 65.019, 95% confidence interval 1.77, >1000; P=0.0231), or TEB with soluble r-tPA (2 mg; odds ratio 18.78, 95% confidence interval 1.28, 275.05; P=0.0322). Histological analysis showed circumferential loss of endothelium restricted to the area where the TEB was deployed; however, there was significantly less vascular injury using a TEB as compared with stent-retriever procedure (odds ratio 12.97, 95% confidence interval 8.01, 21.02; P<0.0001). A novel intra-arterial, nanoparticle-based thrombolytic therapy combined with TEB achieves high rates of complete recanalization. Moreover, this approach reduces vascular trauma as compared with stent-retriever thrombectomy.


Fourier-based Synthetic-aperture Imaging for Arbitrary Transmissions by Cross-correlation of Transmitted and Received Wave-fields.
Investigations into Fourier beamforming for medical ultrasound imaging have largely been limited to plane-wave and single-element transmissions. The main aim of this work is to generalize Fourier beamforming to enable synthetic aperture imaging with arbitrary transmit sequences. When applied to focused transmit beams, the proposed approach yields a full-waveform-based alternative to virtual-source synthetic aperture, which has implications for both coherence imaging and sound speed estimation. When compared to virtual-source synthetic aperture and retrospective encoding for conventional ultrasound sequences (REFoCUS), the proposed imaging technique shows an 8.6 and 3.8 dB improvement in contrast over virtual source synthetic aperture and REFoCUS, respectively, and a 55% improvement in point target resolution over virtual source synthetic aperture. The proposed image reconstruction technique also demonstrates general imaging improvements in vivo, while avoiding limitations seen in prior techniques.


Witnessing images of extreme violence: a psychological study of journalists in the newsroom.
User Generated Content - photos and videos submitted to newsrooms by the public - has become a prominent source of information for news organisations. Journalists working with uncensored material can frequently witness disturbing images for prolonged periods. How this might affect their psychological health is not known and it is the focus of this study. Descriptive, exploratory. The newsrooms of three international news organisations. One hundred and sixteen journalists working with User Generated Content material. Psychometric data included the re-experiencing, avoidance and autonomic arousal indices of posttraumatic stress disorder (Impact of Event Scale-revised), depression (Beck Depression Inventory-II; BDI-II), a measure of psychological distress (GHQ-28), the latter comprising four subscales measuring somatisation, anxiety, social dysfunction and depression, and mean weekly alcohol consumption divided according to gender. Regression analyses revealed that frequent (i.e. daily) exposure to violent images independently predicted higher scores on all indices of the Impact of Event Scale-revised, the BDI-II and the somatic and anxiety subscales of the GHQ-28. Exposure per shift only predicted scores on the intrusion subscale of the Impact of Event Scale-revised. The present study, the first of its kind, suggests that frequency rather than duration of exposure to images of graphic violence is more emotionally distressing to journalists working with User Generated Content material. Given that good journalism depends on healthy journalists, news organisations will need to look anew at what can be done to offset the risks inherent in viewing User Generated Content material. Our findings, in need of replication, suggest that reducing the frequency of exposure may be one way to go.


Microbial growth on agar surfaces studied by incident light differential interference contrast microscopy.
Microbial surface growth on routine opaque agar media was examined by various incident light microscopical techniques. Only differential interference contrast regularly gave good resolution and contrast. The arrangement of units approaching the size of individual bacteria may be judged by low power dry objectives.


An approach to furolabdanes and their photooxidation derivatives from R-(+)-sclareolide.
A synthetic route to furolabdanes from commercially available R-(+)-sclareolide is reported, with the specific aim of preparing (12R and 12S,15xi)-12,15-dihydroxylabda-7,13-dien-16,15-olides (3 and 5) and (12R and 12S,16xi)-12,16-dihydroxylabda-7,13-dien-15,16-olides (4 and 6). The key points of our approach are the use of Weinreb's amide 11 to join the furan ring to the terpenic unit. Photooxidation of the furan moiety of compounds 15 and 16, and of their acetates 19 and 20, has been used to built the hydroxybutenolide fragment. In this way the four possible isomers at the butenolide moiety, compounds 3-6, and their C-12 acetyl derivatives 21-24 have been obtained. On the basis of comparison of the spectral data ((1)H NMR) of the synthetic peracetates 25-28 (derived from 21-24) with the reported data for the peracetate 2 (derived from the natural product 1), the relative configuration at carbon C-12 of the natural product has been corrected. Furthermore, the absolute configuration of the natural product 1, considered to belong to the enantio-series, has to be changed to the normal-series on the basis of the optical rotation obtained for the synthetic derivative.


A new genus and a new species of Schizomyiina (Diptera: Cecidomyiidae: Asphondyliini) inducing petiole galls on Macaranga bancana (Miq.) in Borneo, Malaysia.
We describe a gall midge Macarangamyia itiokai Elsayed Tokuda gen. n., sp. n. belonging to the subtribe Schizomyiina (Diptera: Cecidomyiidae: Asphondyliini) inducing petiole galls on Macaranga bancana (Miq.) in Lambir Hills National Park, Borneo, Malaysia. The new genus is distinguishable from all known genera of Schizomyiina by the unique dorsally-placed aedeagus slit, the short, membranous, protrusible ovipositor, with scattered strong setae ventrally and dorsally, and the presence of spiracles on all larval thoracic segments. It is compared and separated from its closely related Oriental genera of Schizomyiina.


Isolated tubercular liver abscess in children treated with percutaneous isoniazid infusion.
Isolated Tubercular liver abscess is mainly reported in adult patients. We report two cases of isolated tubercular liver abscess in paediatric patients. Diagnosis was made by clinical and ultrasound guided aspiration of pus showing acid fast bacilli in one case. In second case, biopsy of the abscess wall was confirmatory. In both cases percutaneous drainage of pus and transcatheter infusion of Isoniazid was given. After two weeks of infusion no acid fast bacilli was detected and cavity size decreased. Direct infusion of anti-tubercular drugs is more efficient than systemic therapy alone. This is first of its kind in treating isolated tubercular abscess in paediatric patients. So, percutaneous infusion of anti-tubercular agents can be considered in the treatment of tubercular liver abscess.


[Circadian rhythm of blood pressure in patients with chronic hypertension and pregnancy].
Ambulatory blood pressure monitoring during 24 hours shows a blood pressure variability. The prevalence of chronic hypertension in pregnant women is 1-5%, so it is important to know the changes in blood pressure and cardiovascular risk and prevent complications to the mother and fetus. To know the circadian rhythm of the blood pressure in the chronic hypertensive pregnant patients, through the ambulatory blood pressure monitoring. A cross-sectional and descriptive study included chronic hypertensive pregnant patients, with > 20 weeks of gestation. Assessment of factors related to gynaecologic characteristics, according to the inclusion criteria underwent a washout period of two weeks and they were monitored with a Spacelabs 90207 monitor blood pressure. Quantitative variables by Student t test, one-way ANOVA and Pearson correlation were analysed. 16 chronic hypertensive pregnant patients were included, whose ambulatory blood pressure monitoring for the systolic blood pressure in 24 hours averaged 117.12 ± 5.85 mmHg; 24 hours diastolic blood pressure 71.31 ± 5.89 mmHg; daytime systolic blood pressure 120.18 ± 5.75 mmHg, nocturnal systolic blood pressure 110.31 ± 8.41 mmHg; daytime diastolic blood pressure 75.43 ± 7.32 mmHg, nocturnal diastolic blood pressure 64.25 ± 8.27 mmHg. Significant differences between daytime and night time were found. 56% of chronic hypertensive pregnant patients had no nocturnal reduction in systolic blood pressure and 43.75% had no nocturnal changes on diastolic blood pressure. The fact that 50% of patients were non-dippers force us to use long-action antihypertensive therapy and obtain control of the blood pressure for 24 hours.


A journey from the endothelium to the tumor tissue: distinct behavior between PEO-PCL micelles and polymersomes nanocarriers.
Polymeric nanocarriers must overcome several biological barriers to reach the vicinity of solid tumors and deliver their encapsulated drug. This study assessed the in vitro and in vivo passage through the blood vessel wall to tumors of two well-characterized polymeric nanocarriers: poly(ethyleneglycol-b-ε-caprolactone) micelles and polymersomes charged with a fluorescent membrane dye (DiO: 3,3'-dioctadecyloxacarbo-cyanine perchlorate). The internalization and translocation from endothelial (human primary endothelial cells HUVEC) to cancer cells (human tumor cell line HCT-116) was studied in conventional 2D monolayers, 3D tumor spheroids, or in an endothelium model based on transwell assay. Micelles induced a faster DiO internalization compared to polymersomes but the latter crossed the endothelial monolayer more easily. Both translocation rates were enhanced by the addition of a pro-inflammatory factor or in the presence of tumor cells. These results were confirmed by early in vivo experiments. Overall, this study pointed out the room for the improvement of polymeric nanocarriers design to avoid drug losses when crossing the blood vessel walls.


Can Biochar Covers Reduce Emissions from Manure Lagoons While Capturing Nutrients?
The unique physical and chemical properties of biochars make them promising materials for odor, gas, and nutrient sorption. Floating covers made from organic materials (biocovers) are one option for reducing odor and gas emissions from livestock manure lagoons. This study evaluated the potential of floating biochar covers to reduce odor and gas emissions while simultaneously sorbing nutrients from liquid dairy manure. This new approach has the potential to mitigate multiple environmental problems. Two biochars were tested: one made via gasification of Douglas fir chips at 650°C (FC650), and the other made from a mixture of Douglas fir [ (Mirb.) Franco] bark and center wood pyrolyzed at 600°C (HF600). The HF600 biocover reduced mean headspace ammonia concentration by 72 to 80%. No significant reduction was found with the FC650 biocover. Nutrient uptake ranged from 0.21 to 4.88 mg N g biochar and 0.64 to 2.70 mg P g biochar for the HF600 and FC650 biochars, respectively. Potassium ranged from a loss of 4.52 to a gain of 2.65 mg g biochar for the FC650 and HF600 biochars, respectively. The biochars also sorbed Ca, Mg, Na, Fe, Al, and Si. In a separate sensory evaluation, judges assessed odor offensiveness and odor threshold of five biocover treatments including four biochars applied over dairy manure. Reductions in mean odor offensiveness and mean odor threshold were observed in three treatments compared with the control. These results show that biochar covers hold promise as an effective practice for reducing odor and gas emissions while sorbing nutrients from liquid dairy manure.


Management of chronic osteomyelitis in a developing country using ceftriaxone-PMMA beads: an initial study.
Chronic osteomyelitis is a debilitating disease that is fairly common in developing countries. Various operative techniques have been adopted in the management of this disease but there have been few reports of their use in Africa. In this report, we present our experience of the use of a modified two-staged Belfast operation in patients with chronic osteomyelitis in Ibadan, Nigeria. An important modification of the procedure was the substitution of gentamicin beads (Septopal) with ceftriaxone-polymethylmethacrylate (PMMA) beads at the saucerised segment of bone at the first stage. Thirty-four patients with chronic osteomyelitis had the two-stage Belfast operation in 35 long bones; of these, 32 patients had ceftriaxone-PMMA antibiotic beads inserted at the saucerised segment of bone at the first stage, while the other two patients had gentamicin beads inserted. One of the two patients who had gentamicin beads had a residual collection of pus at second stage surgery but, following a repeat debridement, the cavity was rid of infection. There was recurrence of infection in three patients (8.6%) who had a suction drain inserted at the first stage and in six patients (17.1%) who had no suction drain at the first stage. The locally produced ceftriaxone-PMMA beads were found to be as efficient as the commercially available gentamicin beads in eluting antibiotics locally, thereby eliminating the residual infection in the bone cavities after the first stage. Another important outcome was a fourfold saving in cost in choosing to use ceftriaxone-PMMA beads rather than gentamicin beads.


Pressure overload induced in newborn rats: effects on left ventricular growth, morphology, and function.
Gradual pressure overload was induced by abdominal aortic constriction in male rats on postnatal d 6 (AC6) or 2 (AC2). At the age of 8 wk, the systemic blood pressure was measured, and the contractile performance of the left ventricle (LV) was assessed after acute ligation of the ascending aorta in open chest anesthetized animals. The LV free wall was used for the determination of collagen concentration and morphometric analysis of cardiac myocytes and capillaries. Aortic constriction resulted in LV hypertrophy, which was more pronounced in AC2 (by 71%) as compared with AC6 (by 34%) groups and correlated closely with the degree of pressure overload (r = 0.88 and 0.80, respectively). The right ventricular weight was increased by 13% in the AC2 group only. Contractile performance of the LV of aortic constricted rats was significantly higher before as well as after the acute load, but the average functional reserve was unchanged in both experimental groups. Although the maximum value of the rate of pressure development increased linearly with the degree of ventricular hypertrophy in the AC6 group (r = 0.82), a negative correlation was observed in the AC2 animals (r = -0.61). The density of myocytes was decreased, and the calculated average myocyte cross-sectional area was increased in aortic constricted rats, but the coronary capillary density and myocardial concentration of collagen remained constant. Thus, in spite of the larger cardiac growth response in the younger age group, the capillary proliferation and collagen formation were proportional to the ventricular hypertrophy. Therefore, the degrees of overload and hypertrophy do not seem to be limiting factors. Pressure overload induced in newborn rats can be a useful model for the study of mechanisms that control either the growth and differentiation of myocardium soon after birth, as well as the transition from compensated to decompensated hypertrophy at later stages.


Approach-avoidance responses and categorical perception of ambiguous facial expressions.
Emotion perception of facial expressions involves two processes: quick approach-avoidance responses and subsequent sorting into emotional categories (i.e., happiness, anger), considering the context. Sorting of morphed ambiguous facial expressions is known to occur categorically, but the occurrence of approach-avoidance responses for morphed facial expressions is yet to be investigated. The present study used morphed angry and fearful facial expressions and measured approach-avoidance responses among Japanese university students (Experiment 1, n = 29). Similar experiments with linguistic load (Experiment 2, n = 28) and visual load (Experiment 3, n = 29) were conducted. The results indicated categorical perception in the sorting of facial expressions but no approach-avoidance response for morphed expressions. Furthermore, linguistic load affected the categorisation of facial expressions, but neither linguistic load nor visual load affected the approach-avoidance response. These results support the idea that the non-linguistic approach-avoidance response and the linguistic categorisation of facial expressions are two different processes. The nature of the emotional perception process is also discussed.


Potential application of neogalactosylalbumin in positron emission tomography evaluation of liver function.
To investigate the evaluation of neogalactosylalbumin (NGA) for liver function assessment based on positron emission tomography technology. Female Kunming mice were assigned randomly to two groups: fibrosis group and normal control group. A murine hepatic fibrosis model was generated by intraperitoneal injection of 10% carbon tetrachloride (CCl4) at 0.4 mL every 48 h for 42 d. 18F-labeled NGA ([18F]FNGA) was synthesized and administered at a dosage of 3.7 MBq/mouse to both fibrosis mice and normal control mice. Distribution of [18F]FNGA amongst organs was examined, and dynamic scanning was performed. Parameters were set up to compare the uptake of tracers by fibrotic liver and healthy liver. Serologic tests for liver function were also performed. The liver function of the fibrosis model mice was significantly impaired by the use of CCl4. In the fibrosis model mice, hepatic fibrosis was verified by naked eye assessment and pathological analysis. [18F]FNGA was found to predominantly accumulate in liver and kidneys in both control group (n = 21) and fibrosis group (n = 23). The liver uptake ability (LUA), peak time (Tp), and uptake rate (LUR) of [18F]FNGA between healthy liver (n = 8) and fibrosis liver (n = 10) were significantly different (P < 0.05, < 0.01, and < 0.05, respectively). LUA was significantly correlated with total serum protein level (TP) (P < 0.05). Tp was significantly correlated with both TP and glucose (Glu) concentration (P < 0.05 both), and LUR was significantly correlated with both total bile acid and Glu concentration (P < 0.01 and < 0.05, respectively). [18F]FNGA mainly accumulated in liver and remained for sufficient time. Functionally-impaired liver showed a significant different uptake pattern of [18F]FNGA compared to the controls.


A web-based tool for in silico biomarker discovery based on tissue-specific protein profiles in normal and cancer tissues.
Here we report the development of a publicly available Web-based analysis tool for exploring proteins expressed in a tissue- or cancer-specific manner. The search queries are based on the human tissue profiles in normal and cancer cells in the Human Protein Atlas portal and rely on the individual annotation performed by pathologists of images representing immunohistochemically stained tissue sections. Approximately 1.8 million images representing more than 3000 antibodies directed toward human proteins were used in the study. The search tool allows for the systematic exploration of the protein atlas to discover potential protein biomarkers. Such biomarkers include tissue-specific markers, cell type-specific markers, tumor type-specific markers, markers of malignancy, and prognostic or predictive markers of cancers. Here we show examples of database queries to generate sets of candidate biomarker proteins for several of these different categories. Expression profiles of candidate proteins can then subsequently be validated by examination of the underlying high resolution images. The present study shows examples of search strategies revealing several potential protein biomarkers, including proteins specifically expressed in normal cells and in cancer cells from specified tumor types. The lists of candidate proteins can be used as a starting point for further validation in larger patient cohorts using both immunological approaches and technologies utilizing more classical proteomics tools.


[Utilization of the new synthetic dissolving sutures caproag in obstetrics and gynecology].
The paper deals with the experience with synthetic resolving Caproag suture threads which have antibacterial properties for suturing the uterine section during Caesarean and other gynecological operations. There is evidence for its high efficacy in optimal tissue regeneration. Caproag was used in the most life-threatening infectious and septic complications. With this, a reduction has been achieved in the incidence of postoperative pyo-inflammatory diseases, which makes Caproag compare favourably with the conventional suture threads catgut and vicryl.


Using high spectral and spatial resolution bold MRI to choose the optimal oxygenating treatment for individual cancer patients.
We evaluate whether high spectral and spatial resolution (HiSS) BOLD MRI can correctly rank the effects of three tumor-oxygenating treatments on radiosensitivity in BA1112 rhabdomyosarcomas (n = 5). Significant decreases in spectral linewidth predict that treatment with carbogen gas combined with a perfluorocarbon emulsion will increase radiosensitivity more than either treatment alone, which agrees with the known effects of these treatments on hypoxic fraction. High-resolution maps show that tumor response to each treatment is spatially heterogeneous, and that there is a paradoxical response to the treatments in 7-12% of tumor pixels. Because HiSS MRI emphasizes changes in necrotic and/or hemorrhagic regions, it is more sensitive to oxygenation changes compared to conventional MRI. These results demonstrate that HiSS MRI is a practical, noninvasive method that could be used to choose the treatment that maximizes the size and extent of increases in tumor oxygenation for individual patients.


Circulating Inflammatory miRNAs Associated with Parkinson's Disease Pathophysiology.
Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, being largely characterized by motor features. MicroRNAs (miRNAs) are small non-coding RNAs, whose deregulation has been associated with neurodegeneration in PD. In this study, miRNAs targeting cell death and/or inflammation pathways were selected and their expression compared in the serum of PD patients and healthy controls. We used two independent cohorts (discovery and validation) of 20 idiopathic PD patients (iPD) and 20 healthy controls each. We also analyzed an additional group of 45 patients with a mutation in the leucine-rich repeat kinase 2 (LRRK2) gene (LRRK2-PD). miRNA expression was determined using Taqman qRT-PCR and their performance to discriminate between groups was assessed by receiver operating characteristic (ROC) curve analysis. We found miR-146a, miR-335-3p, and miR-335-5p downregulated in iPD and LRRK2-PD patients versus controls in both cohorts. In addition, miR-155 was upregulated in LRRK2-PD compared to iPD patients showing an appropriate value of area under the ROC curve (AUC 0.80) to discriminate between the two groups. In conclusion, our study identified a panel of inflammatory related miRNAs differentially expressed between PD patients and healthy controls that highlight key pathophysiological processes and may contribute to improve disease diagnosis.


[Cefaclor therapy followed by serum sickness-like symptoms].
Cefaclor is an oral cefalosporin for a wide range of gram-positive and gram-negative infection. A retrospective study of cefaclor toxicoderma cases at the Department of Dermatology of Heim Pál Children's Hospital found 11 cases. After the administration of the drug, serum sickness like syndromes were observed. The characteristic symptoms were: erythema multiforme like urticaria, polyarticular swelling and oedema of joints and fever. Laboratory findings were: arised activity of the liver enzymes. After the acute symptoms urticaria factitia appeared.


Transgenic plants expressing ω-ACTX-Hv1a and snowdrop lectin (GNA) fusion protein show enhanced resistance to aphids.
Recombinant fusion proteins containing arthropod toxins have been developed as a new class of biopesticides. The recombinant fusion protein Hv1a/GNA, containing the spider venom toxin ω-ACTX-Hv1a linked to snowdrop lectin (GNA) was shown to reduce survival of the peach-potato aphid Myzus persicae when delivered in artificial diet, with survival <10% after 8 days exposure to fusion protein at 1 mg/ml. Although the fusion protein was rapidly degraded by proteases in the insect, Hv1a/GNA oral toxicity to M. persicae was significantly greater than GNA alone. A construct encoding the fusion protein, including the GNA leader sequence, under control of the constitutive CaMV 35S promoter was transformed into Arabidopsis; the resulting plants contained intact fusion protein in leaf tissues at an estimated level of 25.6 ± 4.1 ng/mg FW. Transgenic Arabidopsis expressing Hv1a/GNA induced up to 40% mortality of M. persicae after 7 days exposure in detached leaf bioassays, demonstrating that transgenic plants can deliver fusion proteins to aphids. Grain aphids (Sitobion avenae) were more susceptible than M. persicae to the Hv1a/GNA fusion protein in artificial diet bioassays (LC50 = 0.73 mg/ml after 2 days against LC50 = 1.81 mg/ml for M. persicae), as they were not able to hydrolyze the fusion protein as readily as M. persicae. Expression of this fusion protein in suitable host plants for the grain aphid is likely to confer higher levels of resistance than that shown with the M. persicae/Arabidopsis model system.


Towards an ontogenetic understanding of inflorescence diversity.
Conceptual and terminological conflicts in inflorescence morphology indicate a lack of understanding of the phenotypic diversity of inflorescences. In this study, an ontogeny-based inflorescence concept is presented considering different meristem types and developmental pathways. By going back to the ontogenetic origin, diversity is reduced to a limited number of types and terms. Species from 105 genera in 52 angiosperm families are investigated to identify their specific reproductive meristems and developmental pathways. Based on these studies, long-term experience with inflorescences and literature research, a conceptual framework for the understanding of inflorescences is presented. Ontogeny reveals that reproductive systems traditionally called inflorescences fall into three groups, i.e. 'flowering shoot systems' (FSS), 'inflorescences' sensu stricto and 'floral units' (FUs). Our concept is, first, based on the identification of reproductive meristem position and developmental potential. The FSS, defined as a seasonal growth unit, is used as a reference framework. As the FSS is a leafy shoot system bearing reproductive units, foliage and flowering sequence play an important role. Second, the identification of two different flower-producing meristems is essential. While 'inflorescence meristems' (IMs) share acropetal primordia production with vegetative meristems, 'floral unit meristems' (FUMs) resemble flower meristems in being indeterminate. IMs produce the basic inflorescence types, i.e. compound and simple racemes, panicles and botryoids. FUMs give rise to dense, often flower-like units (e.g. heads). They occur solitarily at the FSS or occupy flower positions in inflorescences, rendering the latter thyrses in the case of cymose branching. The ontogenetic concept differs from all existing inflorescence concepts in being based on meristems and developmental processes. It includes clear terms and allows homology statements. Transitional forms are an explicit part of the concept, illustrating the ontogenetic potential for character transformation in evolution.


Too Loud for Comfort: A Simulated Evaluation of Cast Saw Noise.
Orthopaedic cast saws are an integral component to a pediatric orthopaedic practice but can also be associated with patient anxiety and noise exposure for patient. Although previous studies have deemed the noise generation from orthopaedic cast saws to be within safe occupational exposure levels, no study to date has compared the noise generation from a cast saw used in various exam room settings. A simulated fiberglass cast model was used. Noise generation was assessed using calibrated sound level meters with measurements performed at 18 inches, 36 inches, and 6 ft measured from the cast saw. Measurements were performed in 1 of 2 clinical settings: (1) an open bay setting and (2) an enclosed exam room. In the enclosed exam room, the 6-foot measurement was performed behind the closed exam door. An orthopaedic cast saw with built-in vacuum was used to continuously cut the fiberglass model for 1 minute with measurements of peak and mean sound generation, recorded in decibels (dB), a logarithmic scale. Three measurements were recorded at each distance. Between group comparisons were performed with statistical significance set at P=0.05. Baseline sound levels were similar between cohorts with progressive decreases in mean sound with increasing distance from the saw. Mean sound levels were significantly higher in the enclosed room setting at 18 inches (92.8 dB, 95% confidence interval (CI): 91.72-93.88 vs. 90.6 dB, 95% CI: 89.91-91.29; P=0.043] and 36 inches (90.3 dB, 95% CI: 89.9-90.7 vs. 86.0 dB, 95% CI: 85.18-86.82; P=0.017). At 6-ft distance, however, the enclosed room demonstrated a 13.8-fold sound reduction compared with the open bay (72.0 dB, 95% CI: 71.59-72.4 vs. 83.4 dB, 83.14-83.72; P<0.001). By closing the exam door, a 13-fold reduction in noise exposure can be achieved for adjacent patients and personnel. Consideration should be given for using orthopaedic cast saws in an enclosed exam room to prevent unnecessary noise exposure with hearing protection of cast saw operators and treated patients. Orthopaedic cast removal.


[Criteria for the optimal use of interleukin-6 receptor blockers in patients with COVID-19].
To determine the criteria for the optimal use of IL-6 receptor blockers in patients with COVID-19 community-acquired pneumonia based on predictors of adverse outcomes. The single-center, non-randomized prospective study included 190 patients with community-acquired pneumonia caused by coronavirus 2 between the beginning of March and the end of May 2020. Of these, 89 patients received tocilizumab and 101 patients received sarilumab. The study inclusion criterion for the patient was indications for initiating therapy with one of the inhibitors of IL-6 receptors (anti-IL-6R) according to the Interim guidelines (versions 4 and 5). The exclusion criterion was the need to re-prescribe genetically engineered biological therapy (GEBT). The severity of the patient's condition was assessed according to the early warning score (NEWS2), the volume of lung tissue lesions was assessed according to computed tomography (CT). Laboratory monitoring included counting the absolute (abs) number of lymphocytes, serum levels of C-reactive protein (CRP), interleukin 6 (IL-6), D-dimer, lactate dehydrogenase, fibrinogen. Statistical data processing was conducted by nonparametric methods using the IBM SPSS Statistics V-22 software. The phenotype of a patient with a negative outcome prognosis was described: a male patient over 50 years of age with aggravated premorbid background (with cardiovascular diseases, obesity and/or chronic renal disease), lung lesion CT 34, saturation less than 93% upon inhalation of atmospheric air, persisting for 2448 hours after GEBT. According to the blood test, lymphopenia was below 1000 U/L and CRP levels were above 50 mg/L. The laboratory parameters and clinical picture of the patient progressively worsened after 911 days of illness, regardless of the use of Anti-IL-6R. The features of patients monitoring when administering IL-6 receptor blockers have been determined. IL-6 receptor blockers should be administered to patients hospitalized with severe COVID-19 before the development of hyperinflammatory reactions. The optimal "therapeutic window" is 78 days of illness.


An interdisciplinary framework examining culture and adaptation in migrant children and adolescents.
With increasing rates of globalization, understanding the cultural factors that promote positive adaptation in migrant children and adolescents is vital. In prior research, acculturation and enculturation frameworks often rely on unidimensional or bidimensional conceptions of culture to study the effects of migration on child and adolescent development. However, the contemporary strategies that migrant children and adolescents utilize to navigate multicultural contexts remain undertheorized. Therefore, we advance an interdisciplinary framework that describes the factors and processes that affect migrant child and adolescent development across four contexts: global, macrosystem, microsystem, and the individual level. Additionally, conceptualizations of cultural adaptation are broadened in our framework by examining the intersections of community cultural wealth, cultural preservation, and cultural restoration. We highlight the importance of prioritizing the culture and experiential knowledge of migrant children and adolescents in the development of policy, research, and practice, to support their positive adaptation in a globalized society.


'Recover quicker, train harder, and increase flexibility': massage therapy for elite paracyclists, a mixed-methods study.
Massage therapy (MT) enhances recovery by reducing pain and fatigue in able-bodied endurance athletes. In athletes with disabilities, no studies have examined similar MT outcomes, yet participation in sport has increased by >1000 athletes from 1996 to 2016 Olympic games. We examined the effect of MT on pain, sleep, stress, function and performance goals on the bike, as well as quality of life off the bike, in elite paracycling athletes. This is a quasi-experimental, convergent, parallel, mixed-methods design study of one team, with nine paracycling participants, in years 2015 and 2016. One-hour MT sessions were scheduled one time per week for 4 weeks, and then every other week for the duration of the time the athlete was on the team and/or in the study. Closed and open-ended survey questions investigating athlete goals, stress, sleep, pain and muscle tightness were gathered pre and post each MT session, and every 6 months for health-related quality of life. Quantitative analysis timepoints include baseline, 4-6 months of intervention and final visit. Additional qualitative data were derived from therapists' treatment notes, exit surveys, and follow-up emails from the athletes and therapists. Significant improvement was found for sleep and muscle tightness; quantitative results were reinforced by athlete comments indicating MT assisted in their recovery while in training. There were no improvements in dimensions measuring quality of life; qualitative comments from athletes suggest reasons for lack of improvement. This real-world study provides new information to support MT for recovery in elite paracyclists.