Ultrastructure of the ovary and oogenesis in the flatworm Prosthiostomum siphunculus (Polycladida, Cotylea).
Based on light and electron microscopy observations, oogenesis in the cotylean polyclad Prosthiostomum siphunculus was investigated for the first time. The numerous ovarian follicles are dispersed essentially in the dorsal parenchyma. In the follicles, a ventral germinative zone with undifferentiated germs cells of different sizes and a dorsal growth zone with larger growing and abortive oocytes are present. The oogenesis could be subdivided into four stages: (1) Oogonia with a dark nucleus and a dark, ribosome-rich cytoplasm. (2) Early oocyte stage, represented by relatively small cells (10 μm in diameter), a cytoplasm showing some mitochondria and some endoplasmic reticula. (3) Previtellogenic stage, with a decrease of the nucleo-cytoplasmic ratio due to the remarkable increase in ooplasm volume. Immature eggshell globules are observed. (4) Vitellogenic stage, including early vitellogenic ovarian stage, in which a second type of globule (inclusion globule) is formed, and a late vitellogenic uterine stage, in which the inclusion globules are not present anymore. The mature eggshell globules form a peripheral layer under the cell membrane. Eggshell and inclusion globules were analyzed with electron energy loss spectroscopy, electron spectroscopic imaging, protease treatment, and with periodic acid thiocarbohydracide silver proteinate to detect polysaccharides. Chromatoid bodies are present in all four stages. For the first time in a flatworm, we provide evidence that accessory cells, forming a tunica around the ovarian follicles, are epithelial or epithelium-like and likely contribute nutrients for the growth of the oocytes.


A novel peritoneum derived vascular prosthesis formed on a latex catheter in an SDF-1 chemokine enriched environment: a pilot study.
Although saphenous vein grafts are widely used conduits for coronary artery bypass graft surgery, their clinical value remains limited due to high failure rates. The aim of the study was to evaluate feasibility, safety, and biocompatibility of peritoneal derived vascular grafts (PDVG) formed on a silicone-coated, latex, Foley catheter in a stromal cell-derived factor (SDF-1)- enriched environment. Foley catheters were implanted into the parietal wall of 8 sheep. After 21 days the peritoneal cavity was re-opened and the newly formed tissue fragments were harvested. The animals were randomly assigned into: (1) study group in which conduits were incubated in a solution containing SDF-1, (2) control group without SDF-1 incubation. Left carotid arteries were accessed and "end-to-side" anastomoses were performed. Biological materials for histological examination were taken at 4, 7, 10, and 14 days. The study proved safety, feasibility, and biocompatibility of PDVG formed on the basis of a silicone-coated, latex catheter in an SDF-1 chemokine-enriched environment. These biological grafts effectively integrated with the native high-pressure arterial environment in an ovine model and provided favorable vascular profile. The potential clinical value of this technology needs to be further elucidated in long-term preclinical and clinical studies.


Implant supported overdentures in Sjögren's disease patients: a multicentre prospective cohort study.
To prospectively investigate patient-reported outcomes and clinical performance of implant supported overdentures in edentulous Sjögren's disease (SjD) patients compared to subjects without SjD. 51 implants were placed in 12 patients with SjD and 50 implants in 12 non-SjD patients to support overdentures. Clinical performance, marginal bone-level changes, patient satisfaction and oral health related quality of life (OHRQoL) were assessed at 1 (T1), 6 (T6), 12 (T12) and 18 (T18) months after placement of the overdenture. Patient satisfaction, ability to chew and OHRQoL were assessed with validated questionnaires. Marginal bone-level changes were measured on standardised dental radiographs. Clinical parameters included implant and overdenture survival, plaque, bleeding and gingival indices, and probing depth. OHRQoL in patients with SjD improved significantly after placement of implant supported overdentures at all measuring moments compared to baseline (p<0.05). Nevertheless, ability to chew tough and hard food was significantly better for non-SjD patients at all timepoints after placement of an implant supported overdenture (p<0.05). Implant survival at T18 was 100% in the patients with SjD and 98% in the non-SS group. Mean marginal bone loss at T18 did not differ between patients with SjD and non-SS patients, 1.12±0.74 mm and 1.43±1.66 mm, respectively (p=0.58). Clinical performance was good with no differences between the groups for all outcome measures (p>0.05). Implant-supported overdentures have a positive effect on OHRQoL and dental implants can be successfully applied in edentulous patients with SjD with nearly similar outcomes as in non-SjD subjects.


Field extension inside guided-mode-resonance filters under a focused beam.
We present a theoretical study of the mid-infrared guided mode resonance spectral filters made of two subwavelength metallic gratings and a dielectric waveguide under a focused beam with a finite spot size. This Letter shows that, at the resonant wavelength, the lateral extension of the electromagnetic field in the waveguide is close to the width of the beam. We compare the performance of filters using gratings with a one-slit pattern and gratings with a two-slit pattern, and we show that the latter gratings (biatom gratings) provide a higher transmission and a better limitation of field extension, due to an improved angular acceptance. These results open new perspectives for pixel-sized infrared filters.


Endogenous tumor necrosis factor alpha (TNFalpha) requires TNF receptor type 2 to generate heat hyperalgesia in a mouse cancer model.
To provide a tool to investigate the mechanisms inducing and maintaining cancer-related pain and hyperalgesia, a soft tissue tumor/metastasis model was developed that is applicable in C57BL/6J wild-type and transgenic mice. We show that the experimental tumor-induced heat hyperalgesia and nociceptor sensitization were prevented by systemic treatment with the tumor necrosis factor alpha (TNFalpha) antagonist etanercept. In naive mice, exogenous TNFalpha evoked heat hyperalgesia in vivo and sensitized nociceptive nerve fibers to heat in vitro. TNFalpha enhanced the expression of the nociceptor-specific heat transducer ion channel transient receptor potential vanilloid 1 (TRPV1) and increased the amplitudes of capsaicin and heat-activated ionic currents via p38/MAP (mitogen-activated protein) kinase and PKC (protein kinase C). Deletion of the tumor necrosis factor receptor type 2 (TNFR2) gene attenuated heat hyperalgesia and prevented TRPV1 upregulation in tumor-bearing mice, whereas TNFR1 gene deletion played a minor role. We propose endogenous TNFalpha as a key player in cancer-related heat hyperalgesia and nociceptor sensitization that generates TRPV1 upregulation and sensitization via TNFR2.


Francisella tularensis molecular typing using differential insertion sequence amplification.
Tularemia is a potentially fatal disease that is caused by the highly infectious and zoonotic pathogen Francisella tularensis. Despite the monomorphic nature of sequenced F. tularensis genomes, there is a significant degree of plasticity in the organization of genetic elements. The observed variability in these genomes is due primarily to the transposition of direct repeats and insertion sequence (IS) elements. Since current methods used to genotype F. tularensis are time-consuming and require extensive laboratory resources, IS elements were investigated as a means to subtype this organism. The unique spatial location of specific IS elements provided the basis for the development of a differential IS amplification (DISA) assay to detect and distinguish the more virulent F. tularensis subsp. tularensis (subtypes A.I and A.II) and subsp. holarctica (type B) strains from F. tularensis subsp. novicida and other near neighbors, including Francisella philomiragia and Francisella-like endosymbionts found in ticks. Amplicon sizes and sequences derived from DISA showed heterogeneity within members of the subtype A.I and A.II isolates but not the type B strains. These differences were due to a 312-bp fragment derived from the IS element ISFtu1. Analysis of wild-type F. tularensis isolates by DISA correlated with pulsed-field gel electrophoresis genotyping utilizing two different restriction endonucleases and provided rapid results with minimal sample processing. The applicability of this molecular typing assay for environmental studies was demonstrated by the accurate identification and differentiation of tick-borne F. tularensis. The described approach to IS targeting and amplification provides new capability for epidemiological investigations and characterizations of tularemia source outbreaks.


Characterization and comparison of microsatellites derived from repeat-enriched libraries and expressed sequence tags.
The construction of high-density linkage maps for use in identifying loci underlying important traits requires the development of large numbers of polymorphic genetic markers spanning the entire genome at regularly spaced intervals. As part of our efforts to develop markers for rainbow trout (Oncorhynchus mykiss), we performed a comparison of allelic variation between microsatellite markers developed from expressed sequence tag (EST) data and anonymous markers identified from repeat-enriched libraries constructed from genomic DNA. A subset of 70 markers (37 from EST databases and 33 from repeat enriched libraries) was characterized with respect to polymorphism information content (PIC), number of alleles, repeat number, locus duplication within the genome and ability to amplify in other salmonid species. Higher PIC was detected in dinucleotide microsatellites derived from ESTs than anonymous markers (72.7% vs. 54.0%). In contrast, dinucleotide repeat numbers were higher for anonymous microsatellites than for EST derived microsatellites (27.4 vs.18.1). A higher rate of cross-species amplification was observed for EST microsatellites. Approximately half of each marker type was duplicated within the genome. Unlike single-copy markers, amplification of duplicated microsatellites in other salmonids was not correlated to phylogenetic distance. Genomic microsatellites proved more useful than EST derived microsatellites in discriminating among the salmonids. In total, 428 microsatellite markers were developed in this study for mapping and population genetic studies in rainbow trout.


His Belly, Her Seed: Gender and Medicine in Early Modern Demonic Possession.
This article reassesses the role of gender in early modern demonic possession from a medical perspective. It takes as its starting point the demoniac Richard Mainy, who in 1585 claimed to be suffering from hysteria. Best known for its influence on Shakespeare's King Lear, Mainy's gender-crossing diagnosis should be read in the context of the close historical relationship between hysteria and epilepsy. While medical historians have viewed hysteria as the key possession-related illness, epilepsy was equally important. Both were seen as convulsive illnesses caused by an excess of reproductive fluids. Emphasizing the similarities rather than the differences between male and female sexuality, this shared etiology underpinned medical approaches to demonic possession.


Dopaminergic-like neurons derived from oral mucosa stem cells by developmental cues improve symptoms in the hemi-parkinsonian rat model.
Achieving safe and readily accessible sources for cell replacement therapy in Parkinson's disease (PD) is still a challenging unresolved issue. Recently, a primitive neural crest stem cell population (hOMSC) was isolated from the adult human oral mucosa and characterized in vitro and in vivo. In this study we assessed hOMSC ability to differentiate into dopamine-secreting cells with a neuronal-dopaminergic phenotype in vitro in response to dopaminergic developmental cues and tested their therapeutic potential in the hemi-Parkinsonian rat model. We found that hOMSC express constitutively a repertoire of neuronal and dopaminergic markers and pivotal transcription factors. Soluble developmental factors induced a reproducible neuronal-like morphology in the majority of hOMSC, downregulated stem cells markers, upregulated the expression of the neuronal and dopaminergic markers that resulted in dopamine release capabilities. Transplantation of these dopaminergic-induced hOMSC into the striatum of hemi-Parkinsonian rats improved their behavioral deficits as determined by amphetamine-induced rotational behavior, motor asymmetry and motor coordination tests. Human TH expressing cells and increased levels of dopamine in the transplanted hemispheres were observed 10 weeks after transplantation. These results demonstrate for the first time that soluble factors involved in the development of DA neurons, induced a DA phenotype in hOMSC in vitro that significantly improved the motor function of hemiparkinsonian rats. Based on their neural-related origin, their niche accessibility by minimal-invasive procedures and their propensity for DA differentiation, hOMSC emerge as an attractive tool for autologous cell replacement therapy in PD.


[Complications after conduction of hemorrhoidectomy].
The results of examination of 724 patients after hemorrhoidectomy conduction were analyzed. In term from 6 month to 7 years in 172 patients the diseases of colon and rectum occurred. While the immunologic investigation conduction in them the secondary immune deficient state was noted, causing the purulent-inflammatory complications and other postoperative disorders origination.


Inactivation of DNA-dependent protein kinase leads to spindle disruption and mitotic catastrophe with attenuated checkpoint protein 2 Phosphorylation in response to DNA damage.
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is well known as a critical component involving the nonhomologous end joining pathway of DNA double-strand breaks repair. Here, we showed another important role of DNA-PKcs in stabilizing spindle formation and preventing mitotic catastrophe in response to DNA damage. Inactivation of DNA-PKcs by small interfering RNA or specific inhibitor NU7026 resulted in an increased outcome of polyploidy after 2-Gy or 4-Gy irradiation. Simultaneously, a high incidence of multinucleated cells and multipolar spindles was detected in DNA-PKcs-deficient cells. Time-lapse video microscopy revealed that depression of DNA-PKcs results in mitotic catastrophe associated with mitotic progression failure in response to DNA damage. Moreover, DNA-PKcs inhibition led to a prolonged G(2)-M arrest and increased the outcome of aberrant spindles and mitotic catastrophe in Ataxia-telangiectasia mutated kinase (ATM)-deficient AT5BIVA cells. We have also revealed the localizations of phosphorylated DNA-PKcs/T2609 at the centrosomes, kinetochores, and midbody during mitosis. We have found that the association of DNA-PKcs and checkpoint kinase 2 (Chk2) is driven by Ku70/80 heterodimer. Inactivation of DNA-PKcs strikingly attenuated the ionizing radiation-induced phosphorylation of Chk2/T68 in both ATM-efficient and ATM-deficient cells. Chk2/p-T68 was also shown to localize at the centrosomes and midbody. These results reveal an important role of DNA-PKcs on stabilizing spindle formation and preventing mitotic catastrophe in response to DNA damage and provide another prospect for understanding the mechanism coupling DNA repair and the regulation of mitotic progression.


A role for the helix-loop-helix protein Id2 in the control of oligodendrocyte development.
Compared to neurons, the intracellular mechanisms that control glial differentiation are still poorly understood. We show here that oligodendrocyte lineage cells express the helix-loop-helix proteins Mash1 and Id2. Although Mash1 has been found to regulate neuronal development, we found that in the absence of Mash1 oligodendrocyte differentiation occurs normally. In contrast, we found that overexpression of Id2 powerfully inhibits oligodendrocyte differentiation, that Id2 normally translocates out of the nucleus at the onset of differentiation, and that absence of Id2 induces premature oligodendrocyte differentiation in vitro. These findings demonstrate that Id2 is a component of the intracellular mechanism that times oligodendrocyte differentiation and point to the existence of an as yet unidentified MyoD-like bHLH protein necessary for oligodendrocyte differentiation.


Wnt and Src signals converge on YAP-TEAD to drive intestinal regeneration.
Wnt signalling induces a gradient of stem/progenitor cell proliferation along the crypt-villus axis of the intestine, which becomes expanded during intestinal regeneration or tumour formation. The YAP transcriptional co-activator is known to be required for intestinal regeneration, but its mode of regulation remains controversial. Here we show that the YAP-TEAD transcription factor is a key downstream effector of Wnt signalling in the intestine. Loss of YAP activity by Yap/Taz conditional knockout results in sensitivity of crypt stem cells to apoptosis and reduced cell proliferation during regeneration. Gain of YAP activity by Lats1/2 conditional knockout is sufficient to drive a crypt hyperproliferation response. In particular, Wnt signalling acts transcriptionally to induce YAP and TEAD1/2/4 expression. YAP normally localises to the nucleus only in crypt base stem cells, but becomes nuclear in most intestinal epithelial cells during intestinal regeneration after irradiation, or during organoid growth, in a Src family kinase-dependent manner. YAP-driven crypt expansion during regeneration involves an elongation and flattening of the Wnt signalling gradient. Thus, Wnt and Src-YAP signals cooperate to drive intestinal regeneration.


First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.
Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma. After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1 ; initially registered 19 September 2002.


Neurofibromatosis and a Portrait of 1 in 3000.
Neurofibromatosis, a genetic disorder that occurs in 1 in 3000 births, can cause tumors to grow anywhere on or in the body. The first author (RM), an artist-researcher and mother of a son living with neurofibromatosis, has painted and exhibited more than 200 portraits of people living with neurofibromatosis to raise awareness of and resources for this little-known disorder. Among many stories shared through RM's works is the story of Ashok, a Nepali man who has undergone 3 surgeries to remove facially disfiguring tumors that developed as a result of neurofibromatosis. This article analyzes portraits of Ashok and interviews that the senior author (RI) conducted with Ashok and RM during each phase of his surgical process to present a case study of their lived experience at the intersection of art and medicine that illustrates the power of portraiture as medicine.


Mutually exclusive exon splicing of the cardiac calcium channel alpha 1 subunit gene generates developmentally regulated isoforms in the rat heart.
Several clones were isolated from a rat genomic library in order to further characterize a region of variability within the third membrane-spanning region of the fourth motif (IVS3) of the L-type voltage-dependent calcium channel. We report here that this diversity arises from alternative splicing of a primary transcript containing a single pair of adjacent exons each encoding a unique sequence for the IVS3 region. Definitive proof of a mutually exclusive splicing mechanism was obtained by genomic mapping of flanking upstream and downstream exons and by extensive sequence analysis of the relevant exon/intron boundaries. S1 nuclease protection experiments revealed that both variant forms of the IVS3 were equally expressed in newborn and fetal rat heart, whereas only a single isoform predominated in adult rat heart. The results demonstrate the existence of an important developmentally regulated switch mediated by alternatively spliced exons in cardiac tissue at a time when major changes in excitation occur.


Role of dose-dense chemotherapy in high-risk early breast cancer.
Adjuvant chemotherapy for breast cancer significantly reduces the risk of recurrence and improves overall survival (OS). The purpose of the current article is to review available evidence on dose-dense chemotherapy, also focusing on special population, including premenopausal women and those with HER2-positive disease. A recent patient-level meta-analysis showed that the use of dose-dense chemotherapy is associated with significant reduction in disease recurrence, breast cancer mortality and improvement in OS. The benefit of dose-dense chemotherapy is irrespective from HER2 status, although women with HER2-positive disease enrolled in trials included in the meta-analysis did not receive the current standard of treatment with anti-HER2 agents. Among premenopausal women, dose-dense chemotherapy improved OS, and thus should be considered standard of care for them. In conclusion, high-risk early stage breast cancer patients should be treated with (neo)adjuvant dose-dense anthracycline-based chemotherapy followed by paclitaxel. In the era of trastuzumab, the benefit of dose-dense chemotherapy is still unclear for patients with HER2-positive breast cancer.


Cytokine Signature Associated with Disease Severity in Dengue.
Dengue is the most rapidly spreading viral disease transmitted by the bite of infected Aedes mosquitos. The pathogenesis of dengue is still unclear; although host immune responses and virus serotypes have been proposed to contribute to disease severity. In this study, we examined the circulating dengue virus (DENV) and measured plasma levels of inflammatory mediators. Ninety-eight patients during a dengue outbreak in eastern India in 2016 were included in the study. The presence of DENV was demonstrated by detecting NS1 antigen; IgM capture ELISA and serotypes were discriminated by type-specific RT-PCR and/or sequencing. Plasma samples were assayed for 41-plex cytokine/chemokines using multiplex Luminex assay. Eighty-five (87%) samples were positive by NS1/IgM capture ELISA/RT-PCR. All four serotypes of DENV were detected in this outbreak, with DENV-2 as the predominant type, seen in 55% of cases. Mixed infections were seen in 39% of subjects. Among the host inflammatory biomarkers, GM-CSF, IFN-γ, IL-10, IL-15, IL-8, MCP-1, IL-6, MIP-1β, and TNF-α levels were significantly increased in dengue with and without warning signs, in severe dengue patients in comparison to healthy controls. Four cytokines IFN-γ, GM-CSF, IL-10, and MIP-1β correlated significantly with disease severity and could serve as potential predictor for disease severity. Information on the host biomarkers and the dengue serotype may help guide in optimizing effective intervention strategies.


[Occupational accidents and female workers' reproductive health].
The article covers analysis and summary of data on occupational traumatism among female workers engaged into various economic branches of RF. The authors analysed distribution of victims according to occupational accident types, causes of traumatism, studied dependence on the victims' age and length of service, followed the relationships with possible reproductive disorders.


Liver enzymes and lipid levels in patients with lipodermatosclerosis and venous ulcers treated with a prototypic anabolic steroid (stanozolol): a prospective, randomized, double-blinded, placebo-controlled trial.
Anabolic steroids have been used to treat lower extremity ulcerations, including venous and cryofibrinogenemic ulcers and lipodermatosclerosis (LDS). Yet there have been no studies to determine the severity and reversibility of side effects of anabolic steroids on liver enzymes and lipid profiles in elderly patients. We therefore evaluated, in a prospective, randomized, double-blinded, placebo-controlled trial, the extent and reversibility of abnormal liver enzymes and lipid profiles in patients with LDS and venous leg ulcers treated with stanozolol at 2 mg twice daily for up to 6 months. Follow-up laboratory testing was done for 2 months after cessation of treatment. A total of 44 patients with LDS and venous ulcers were enrolled and treated with either leg compression alone (placebo) or leg compression plus oral stanozolol 2 mg twice daily (active). Baseline and follow-up laboratory testing of liver enzymes and lipid profiles were obtained. A total of 21 active and 23 placebo patients were treated and evaluated. We measured liver enzymes (aspartate aminotransferase [AST/SGOT], alanine aminotransferase [ALT/SGPT], γ-glutamyl transferase [GGT]) and lipid profile components (high-density lipoprotein [HDL], low-density lipoprotein [LDL], total cholesterol) before, during, and after the treatment period. We found that AST/SGOT and ALT/SGPT became significantly elevated in 29% (P = .0415 at 2 months) and 33% (P = .0182 at 1 month) of patients treated with stanozolol or placebo, respectively, with return to baseline in the posttreatment period. Unexpectedly, 91% of patients on stanozolol developed a significant (P < .0001) decrease in HDL levels, by as much as 37 U/L. All patients remained asymptomatic and levels returned to baseline after discontinuation of the drug. We conclude that low-dose stanozolol, 2 mg twice daily, produces asymptomatic and temporary elevation of liver transaminases and depression of the HDL level in a significant proportion of patients.


Can it be worse? On the sub-Saharan HIV/AIDS epidemic at the beginning of the new millennium.
According to the data in the relevant literature, it seems that at the millennium the worldwide HIV/AIDS epidemic shows no decline. In the most heavily affected area of tropical (sub-Saharan) Africa the situation is getting worse. There is a number of factors which are responsible for this situation. Considering the lack of necessary funds, it is evident that the most important task is a vigorous health education.


Cellular localization of ROS and NO in olive reproductive tissues during flower development.
Recent studies have shown that reactive oxygen species (ROS) and nitric oxide (NO) are involved in the signalling processes taking place during the interactions pollen-pistil in several plants. The olive tree (Olea europaea L.) is an important crop in Mediterranean countries. It is a dicotyledonous species, with a certain level of self-incompatibility, fertilisation preferentially allogamous, and with an incompatibility system of the gametophytic type not well determined yet. The purpose of the present study was to determine whether relevant ROS and NO are present in the stigmatic surface and other reproductive tissues in the olive over different key developmental stages of the reproductive process. This is a first approach to find out the putative function of these signalling molecules in the regulation of the interaction pollen-stigma. The presence of ROS and NO was analyzed in the olive floral organs throughout five developmental stages by using histochemical analysis at light microscopy, as well as different fluorochromes, ROS and NO scavengers and a NO donor by confocal laser scanning microscopy. The "green bud" stage and the period including the end of the "recently opened flower" and the "dehiscent anther" stages displayed higher concentrations of the mentioned chemical species. The stigmatic surface (particularly the papillae and the stigma exudate), the anther tissues and the pollen grains and pollen tubes were the tissues accumulating most ROS and NO. The mature pollen grains emitted NO through the apertural regions and the pollen tubes. In contrast, none of these species were detected in the style or the ovary. The results obtained clearly demonstrate that both ROS and NO are produced in the olive reproductive organs in a stage- and tissue- specific manner. The biological significance of the presence of these products may differ between early flowering stages (defence functions) and stages where there is an intense interaction between pollen and pistil which may determine the presence of a receptive phase in the stigma. The study confirms the enhanced production of NO by pollen grains and tubes during the receptive phase, and the decrease in the presence of ROS when NO is actively produced.


[Organochlorine pesticides and polychlorinated biphenyls in the Vistula river water].
The composition and loads of organochlorine pesticides (DDTs, HCBs, HCHs, CHLs) and polychlorinated biphenyls (PCBs) transported with the Vistula River waters to the Gulf of Gdansk in 1991-1992 has been determined. The method of organochlorine compounds measurement was capillary gas chromatography with ECD after adsorption of the analyte on Ambertlite XAD-2, resin and subsequent elution, clean-up and HPLC fraction of the extract. The concentrations of DDTs, HCBs, HCHs, CHLs and PCBs in the Vistula River water ranged between 120-840, 7.6-52, 1600-410,000, 8.1-57 and 120-300 pg/l, respectively. During 12 months period of the study the total load of DDTs, HCBz, HCHs, CHLs and PCBs transported with the Vistula River water to the Gulf of Gdańsk was assessed on 10.54, 0.73, 1377, 0.38 and 5.02 kg, respectively.


Levobupivacaine 0.25% compared with ropivacaine 0.25% by the caudal route in children.
Levobupivacaine is the most recently introduced local anaesthetic into clinical practice. In a randomized double-blinded study, the onset, intraoperative tolerance, postoperative analgesic effect, motor blockade and any adverse reactions produced by levobupivacaine were compared with ropivacaine. Sixty children, ASA I-II, 2-6 yr old, undergoing elective minor surgery, received a single caudal injection of 1 mL kg(-1) of either levobupivacaine 0.25% or ropivacaine 0.25%. Caudal blocks were performed after induction of inhalation general anaesthesia using sevoflurane; anaesthesia was maintained via a laryngeal mask airway using a mixture of sevoflurane, oxygen and air. Onset time, intraoperative tolerance, postoperative analgesic effect and motor blockade were comparable between the two groups. The mean onset of the block was 8.2 +/- 2.2 min for levobupivacaine and 8.5 +/- 3.0 min for ropivacaine (P = 0.66). Additional analgesics during operation were not required in any of the children. No significant difference was found for mean time to requirement of additional analgesia with rectal acetaminophen (paracetamol) (302 +/- 29 min for the levobupivacaine group and 230 +/- 38 min for the ropivacaine group (P = 0.32)). During the first 4 h after placement of caudal block, the pain assessment score (according to the Children Hospital Eastern Ontario Pain Scale) was comparable for the two groups. No motor block was observed in any group on awakening, nor during the observation period. We conclude that levobupivacaine 0.25% 1 mL kg(-1) provides caudal block of comparable onset and duration, as produced by the same volume and concentration of ropivacaine.


Importance of Driving and Potential Impact of Driving Cessation for Rural and Urban Older Adults.
Analyses compared older drivers from urban, suburban, and rural areas on perceived importance of continuing to drive and potential impact that driving cessation would have on what they want and need to do. The AAA LongROAD Study is a prospective study of driving behaviors, patterns, and outcomes of older adults. A cohort of 2,990 women and men 65-79 years of age was recruited during 2015-2017 from health systems or primary care practices near 5 study sites in different parts of the United States. Participants were classified as living in urban, surburban, or rural areas and were asked to rate the importance of driving and potential impact of driving cessation. Logistic regression models adjusted for sociodemographic and driving-related characteristics. The percentages of older drivers rating driving as "completely important" were 76.9%, 79.0%, and 83.8% for urban, suburban, and rural drivers, respectively (P = .009). The rural drivers were also most likely to indicate driving cessation would have a high impact on what they want or need to do (P < .001). After adjustment for sociodemographic and driving-related characteristics, there was a 2-fold difference for rural versus urban older drivers in odds that driving cessation would have a high impact on what they need to do (OR = 2.03; 95% CI: 1.60-2.58). Older drivers from rural areas were more likely to rate driving as highly important and the prospect of driving cessation as very impactful. Strategies to enhance both the ability to drive safely and the accessibility of alternative sources of transportation may be especially important for older rural adults.


Modulating TRADD to restore cellular homeostasis and inhibit apoptosis.
Cell death in human diseases is often a consequence of disrupted cellular homeostasis. If cell death is prevented without restoring cellular homeostasis, it may lead to a persistent dysfunctional and pathological state. Although mechanisms of cell death have been thoroughly investigated1-3, it remains unclear how homeostasis can be restored after inhibition of cell death. Here we identify TRADD4-6, an adaptor protein, as a direct regulator of both cellular homeostasis and apoptosis. TRADD modulates cellular homeostasis by inhibiting K63-linked ubiquitination of beclin 1 mediated by TRAF2, cIAP1 and cIAP2, thereby reducing autophagy. TRADD deficiency inhibits RIPK1-dependent extrinsic apoptosis and proteasomal stress-induced intrinsic apoptosis. We also show that the small molecules ICCB-19 and Apt-1 bind to a pocket on the N-terminal TRAF2-binding domain of TRADD (TRADD-N), which interacts with the C-terminal domain (TRADD-C) and TRAF2 to modulate the ubiquitination of RIPK1 and beclin 1. Inhibition of TRADD by ICCB-19 or Apt-1 blocks apoptosis and restores cellular homeostasis by activating autophagy in cells with accumulated mutant tau, α-synuclein, or huntingtin. Treatment with Apt-1 restored proteostasis and inhibited cell death in a mouse model of proteinopathy induced by mutant tau(P301S). We conclude that pharmacological targeting of TRADD may represent a promising strategy for inhibiting cell death and restoring homeostasis to treat human diseases.


[Creatine kinase and creatine kinase isoenzyme MB: determination of normal values and values for myocardial infarct, using the new, optimized method with N-acetyl cysteine as the activator (author's transl)].
Preliminary results are reported for the determination of creatine kinase and its isoenzyme MB in healthy individuals and in patients with acute, transmural myocardial infarct, using N-acetyl cysteine as the activator of the enzyme. In healthy individuals, the upper normal limit for creatine kinase activity was 54 U/l; the decision level for the presence of creatine kinase MB activity 9 U/l. The limiting values were only slightly different from those for the GSH-activated creatine kinase, and the results with the old and new methods showed a linear relationship with a slope of 1.0. The differences in the activation of creatine kinase MM by GSH and by N-acetyl cysteine are discussed; the activities obtained for creatine kinase and creatine kinase-MB by the GSH-activation method cannot simply be recalculated to give the appropriate values of the N-acetyl cysteine activation method.


Evaluating connectivity in the brooding brittle star Astrotoma agassizii across the drake passage in the Southern Ocean.
Studies examining population structure and genetic diversity of benthic marine invertebrates in the Southern Ocean have emerged in recent years. However, many taxonomic groups remain largely unstudied, echinoderms being one conspicuous example. The brittle star Astrotoma agassizii is distributed widely throughout Antarctica and southern South America. This species is a brooding echinoderm and therefore may have limited dispersal capacity. In order to determine the effect of hypothesized isolating barriers in the Southern Ocean, such as depth, geographic distance, and the polar front, 2 mitochondrial DNA markers were used to compare populations from the South American and Antarctic continental shelves. Astrotoma agassizii was shown to be genetically discontinuous across the polar front. In fact, populations previously assumed to be panmictic instead represent 3 separate lineages that lack morphological distinction. However, within lineages, genetic continuity was displayed across a large geographic range (>500 km). Therefore, despite lacking a pelagic larval stage, A. agassizii can disperse across substantial geographic distance within continental shelf regions. These results indicate that geographic distance alone may not be a barrier to dispersal, but rather the combined effects of distance, depth, and the polar front act to prevent gene flow between A. agassizii populations in the Southern Ocean.


Analysis of Published Papers by Keywords and Research Methods in the Korean Journal of Women Health Nursing (2007~2009).
This study s aim was to analyze literature using the identified key words of published literature within the Korean Journal of Womens Health Nursing from 2007~2009. The study explored the major subjects and research methodology used and evaluated the quality of this Journal articles. Survey design using a structured analysis format was used for consistent evaluation of research subjects, type of research, research methodology, data analysis, along with comparing intervention research, theoretical framework, ethical consideration, and the implications. The frequency of the use of each keyword was classified by 8 domains. Ninety eight papers were analyzed altogether. Most of the subjects in these papers were women with 86.7% being quantitative research. In these studies, 76.5% used convenience sampling; 70.6% used a survey design whereas 23.5% used experimental design. Health related concepts (n=159) was mentioned the most among the 8 domains. The key words frequently used were women, depression, knowledge, quality of life, attitude, elderly, anxiety and stress in descending order. It can be concluded that most papers in this Journal during this time period addressed recent women's health issues. Also it showed this Journal and its literature has reached the indexing for Medline.


Gender difference in skin reactivity to purified protein derivative among carriers of HTLV-I in Japan.
The incidence of malignancies due to oncogenic virus infections tends to be higher in men than in women. Gender-related differences in cell-mediated immunity, which plays a role in viral pathogenesis, may explain this observation. To explore this possibility in the context of HTLV-I infection, we examined skin reactivity to purified protein derivative (PPD) among 128 residents of an HTLV-I endemic area in Japan, who were born before 1921 and are assumed to have been exposed to M. tuberculosis bacilli. The odds ratio (OR) for reduced PPD reactivity (erythema <10 mm in diameter) was calculated by multiple logistic regression analysis. Men were significantly less likely than women to have reduced PPD reactivity among HTLV-I-negative individuals (26% versus 59%; p < .01); whereas this gender difference was not apparent among HTLV-I carriers (63% versus 62%; p = .87). HTLV-I positivity was strongly associated with reduced PPD reactivity in men, but not in women (odds ratio [OR], 7.3 versus 1.2; p = .05). Although this observation may be due, in part, to a longer average duration of HTLV-I infection in men compared with women, the finding also raises the possibility that men may be inherently more susceptible to loss of PPD reactivity by HTLV-I infection.


Efficacy of functional movement screening for predicting injuries in coast guard cadets.
Functional movement screening (FMS) examines the ability of individuals to perform highly specific movements with the aim of identifying individuals who have functional limitations or asymmetries. It is assumed that individuals who can more effectively accomplish the required movements have a lower injury risk. This study determined the ability of FMS to predict injuries in the United States Coast Guard (USCG) cadets. Seven hundred seventy male and 275 female USCG freshman cadets were administered the 7 FMS tests before the physically intense 8-week Summer Warfare Annual Basic (SWAB) training. Physical training-related injuries were recorded during SWAB training. Cumulative injury incidence was calculated at various FMS cutpoint scores. The ability of the FMS total score to predict injuries was examined by calculating sensitivity and specificity. Determination of the FMS cutpoint that maximized specificity and sensitivity was determined from the Youden's index (sensitivity + specificity - 1). For men, FMS scores ≤ 12 were associated with higher injury risk than scores >12; for women, FMS scores ≤ 15 were associated with higher injury risk than scores >15. The Youden's Index indicated that the optimal FMS cutpoint was ≤ 11 for men (22% sensitivity, 87% specificity) and ≤ 14 for women (60% sensitivity, 61% specificity). Functional movement screening demonstrated moderate prognostic accuracy for determining injury risk among female Coast Guard cadets but relatively low accuracy among male cadets. Attempting to predict injury risk based on the FMS test seems to have some limited promise based on the present and past investigations.


Consistent etiology of severe, frequent psychotic experiences and milder, less frequent manifestations: a twin study of specific psychotic experiences in adolescence.
The onset of psychosis is usually preceded by psychotic experiences (PE). Little is known about the etiology of PE and whether the degree of genetic and environmental influences varies across different levels of severity. A recognized challenge is to identify individuals at high risk of developing psychotic disorders prior to disease onset. To investigate the degree of genetic and environmental influences on specific PE, assessed dimensionally, in adolescents in the community and in those who have many, frequent experiences (defined using quantitative cutoffs). We also assessed the degree of overlap in etiological influences between specific PE. Structural equation model-fitting, including univariate and bivariate twin models, liability threshold models, DeFries-Fulker extremes analysis, and the Cherny method, was used to analyze a representative community sample of 5059 adolescent twin pairs (mean [SD] age, 16.31 [0.68] years) from England and Wales. Psychotic experiences assessed as quantitative traits (self-rated paranoia, hallucinations, cognitive disorganization, grandiosity, and anhedonia, as well as parent-rated negative symptoms). Genetic influences were apparent for all PE (15%-59%), with modest shared environment for hallucinations and negative symptoms (17%-24%) and significant nonshared environment (49%-64%) for the self-rated scales and 17% for parent-rated negative symptoms. Three empirical approaches converged to suggest that the etiology in extreme-scoring groups (most extreme scoring: 5%, 10%, and 15%) did not differ significantly from that of the whole distribution. There was no linear change in heritability across the distribution of PE, with the exception of a modest increase in heritability for increasing severity of parent-rated negative symptoms. Of the PE that showed covariation, this appeared to be due to shared genetic influences (bivariate heritabilities, 0.54-0.71). These findings are consistent with the concept of a psychosis continuum, suggesting that the same genetic and environmental factors influence both extreme, frequent PE and milder, less frequent manifestations in adolescents. Individual PE in adolescence, assessed quantitatively, have lower heritability estimates and higher estimates of nonshared environment than those for the liability to schizophrenia. Heritability varies by type of PE, being highest for paranoia and parent-rated negative symptoms and lowest for hallucinations.


Studies with tryptophan metabolites in vitro. Kynurenine metabolism in liver homogenates of normal and Schistosoma mansoni-infested mice.
The conversion of kynurenine into kynurenic acid and anthranilic acid in both normal and Schistosoma mansoni-infested mouse liver was investigated. It was found that in the S. mansoni-infested mouse liver there is probably a deficiency of pyridoxal phosphate that resulted in an inhibition of kynurenine transaminase and a low production of kynurenic acid. Deoxypyridoxine and its phosphorylated derivative inhibited kynurenine transaminase in the normal liver in a pattern qualitatively similar to that observed with infested liver. The lowered concentration of pyridoxal phosphate in the infested liver is discussed in view of the possibility of two combined mechanisms: (a) an antimetabolite being secreted by the infesting worms or present in its eggs that partially inhibited the phosphorylation of pyridoxal, and (b) concentration of pyridoxal phosphate by the worms, resulting in a lowered concentration of the cofactor in the host tissue.


The development of children born to young mothers with no, first- or second-generation HIV acquisition in the Eastern Cape province, South Africa: a cross-sectional study.
The intergenerational effects of HIV require long-term investigation. We compared developmental outcomes of different generations impacted by HIV-children of mothers not living with HIV, the 'second generation' (ie, with recently infected mothers) and the 'third generation' (ie, children of perinatally infected mothers). A cross-sectional community sample of N=1015 young mothers (12-25 years) and their first children (2-68 months, 48.2% female), from South Africa's Eastern Cape Province. 71.3% (n=724) of children were born to mothers not living with HIV; 2.7% (n=27; 1 living with HIV) were third-generation and 26.0% (n=264; 11 living with HIV) second-generation children. Child scores on the Mullen Scales of Early Learning (MSEL), the WHO Ten Questions Screen for Disability and maternal demographics were compared between groups using χ2 tests and univariate approach, analysis of variance analysis. Hierarchical linear regressions investigated predictive effects of familial HIV infection patterns on child MSEL composite scores, controlling for demographic and family environment variables. Second-generation children performed poorer on gross (M=47.0, SD=13.1) and fine motor functioning (M=41.4, SD=15.2) and the MSEL composite score (M=90.6, SD=23.0) than children with non-infected mothers (gross motor: M=50.4, SD=12.3; fine motor: M=44.4, SD=14.1; composite score: M=94.1, SD=20.7). The third generation performed at similar levels to non-exposed children (gross motor: M=52.4, SD=16.1; fine motor: M=44.3, SD=16.1, composite score: M=94.7, SD=22.2), though analyses were underpowered for definite conclusions. Hierarchical regression analyses suggest marginal predictive effects of being second-generation child compared with having a mother not living with HIV (B=-3.3, 95% CI=-6.8 to 0 .1) on MSEL total scores, and non-significant predictive effects of being a third-generation child (B=1.1, 5% CI=-7.5 to 9.7) when controlling for covariates. No group differences were found for disability rates (26.9% third generation, 27.7% second generation, 26.2% non-exposed; χ2=0.02, p=0.90). Recently infected mothers and their children may struggle due to the disruptiveness of new HIV diagnoses and incomplete access to care/support during pregnancy and early motherhood. Long-standing familial HIV infection may facilitate care pathways and coping, explaining similar cognitive development among not exposed and third-generation children. Targeted intervention and fast-tracking into services may improve maternal mental health and socioeconomic support.


United States experience of insulin degludec alone or in combination for type 1 and type 2 diabetes.
Insulin degludec has been the product of a sophisticated and systematic biochemical engineering program which began with the release of insulin detemir. The goal was to produce a long-lasting basal insulin with low individual variability. Certainly, this goal has been achieved. Degludec has a duration of action approaching twice that of glargine. Another advantage of degludec is in its lack of unpredictable copolymerization of added aspart. In several studies, degludec has shown lower rates of nocturnal hypoglycemia than glargine. Degludec can be administered flexibly with a very flat insulin concentration curve at any time of day. Initial US Food and Drug Administration concerns about a possible increase in cardiac events in degludec-treated patients have been allayed by the results of a study targeting individuals with high cardiac risk. Degludec is now marketed in the US competing with glargine. Despite the long duration of action of degludec, attempted administration three times weekly resulted in less effective lowering of glycated hemoglobin and an increased incidence of hypoglycemia compared to daily glargine. Conversely the coformulation of degludec and liraglutide has proven very successful in reducing glycated hemoglobin levels with less hypoglycemia and less weight gain than with degludec alone and with less gastrointestinal symptoms than with liraglutide alone. A large study comparing glargine insulin and degludec in patients with increased cardiac risk is now ongoing. This study may or may not prove superiority of one or the other insulin, but, with the coming of biosimilar glargine insulin, cost factors may be dominant in determining which basal insulin is to be used. Nonetheless, the coformulation with liraglutide will likely insure the future of degludec insulin in the treatment of type 2 diabetes.


[Activity and isoenzymatic makeup of the hexokinase of rapid and slow muscles in the rabbit normally and the experimental allergic polyneuritis].
An activity and isozyme spectrum of hexokinase were studied in rapid (gastrocnemius) and slow (soleus) muscles of rabbit in normal state and in experimental allergic polyneuritis, caused by administration of myelin from peripheric nerves mixed with Freund's stimulator. In normal organism the hexokinase activity was shown to be several times higher in soleus muscle than in gastrocnemius one. In these muscles the isozyme spectrum of the enzyme was markedly differentiated. In gastrocnemius muscle of rabbits with experimental allergic polyneuritis the hexokinase activity was distinctly increased due to increase in amount of the II type of the enzyme; in soleus muscle the decrease in the total activity of the enzyme depended upon the decrease in amount ofhexokinase II.


Long-Term Follow-up Study of MRI-Guided Bilateral Anterior Capsulotomy in Patients With Refractory Anorexia Nervosa.
Anorexia nervosa (AN) is one of the most challenging psychiatric disorders to treat. The poor clinical outcomes warrant novel treatments for AN, especially in severe and persistent cases. To explore the feasibility of magnetic resonance imaging-guided bilateral anterior capsulotomy in the treatment of refractory AN. Seventy-four patients diagnosed with refractory AN who underwent capsulotomy completed this 3-yr follow-up study. Outcomes included body mass index (BMI) and results from a series of psychiatric scales (for obsessive, depressive, and anxious symptoms) that were implemented at baseline (presurgery), and 1 mo, 1 yr, and 3 yr after surgery. Compared to presurgical levels, BMI increased significantly at 1-yr and 3-yr follow-ups. Compared to presurgery scores, psychiatric scale scores were significantly improved at 1-mo postsurgery, and continued to remain low at the 1-yr and 3-yr follow-ups. In addition, Mini-Mental State Examination (MMSE) scores were in the normal range during the long-term follow-up. The most common short-term side effects included urinary incontinence (n = 7), sleep disorders (n = 8), and fatigue (n = 6). Long-term complications included disinhibition (n = 6), memory loss (n = 3), and lethargy (n = 4). No patient in this study experienced death or disability. Capsulotomy enabled patients with refractory AN to normalize their weight, especially those in life-threatening conditions. While it appears to be an acceptable life-saving treatment, it is indicated only when fulfilling strict criteria given its complications and irreversibility.


[The battle for health during the social movement in Aratiba].
This article is a study about the process of fight and organization for health, developed in Aratiba country in RS/Brasil, on a period between 1985 and 1993. For this we tried to articulate theoretical discussion and empirical data, reflecting about the State as a conflictive space, about the dominant ideology and the counter-ideology mechanisms (reproduced by the social movement), the educational spaces originated in the interior of the social movement and the possibilities of citizenship construction resulting from social participation.


A Structure-Aware Framework of Unsupervised Cross-Modality Domain Adaptation via Frequency and Spatial Knowledge Distillation.
Unsupervised domain adaptation (UDA) aims to train a model on a labeled source domain and adapt it to an unlabeled target domain. In medical image segmentation field, most existing UDA methods rely on adversarial learning to address the domain gap between different image modalities. However, this process is complicated and inefficient. In this paper, we propose a simple yet effective UDA method based on both frequency and spatial domain transfer under a multi-teacher distillation framework. In the frequency domain, we introduce non-subsampled contourlet transform for identifying domain-invariant and domain-variant frequency components (DIFs and DVFs) and replace the DVFs of the source domain images with those of the target domain images while keeping the DIFs unchanged to narrow the domain gap. In the spatial domain, we propose a batch momentum update-based histogram matching strategy to minimize the domain-variant image style bias. Additionally, we further propose a dual contrastive learning module at both image and pixel levels to learn structure-related information. Our proposed method outperforms state-of-the-art methods on two cross-modality medical image segmentation datasets (cardiac and abdominal). Codes are avaliable at https://github.com/slliuEric/FSUDA.


Understanding physical activity in spinal cord injury rehabilitation: translating and communicating research through stories.
The purpose of this article is to develop an evidence-based resource for knowing and communicating the complexities involved for both males and females in implementing and sustaining a physically active lifestyle shortly after spinal cord injury (SCI). Synthesizing a set of qualitative and quantitative studies with over 500 spinal cord injured people, the article represents research utilizing the genre of ethnographic creative non-fiction. This genre of representation holds enormous potential for researchers in terms of disseminating their findings to diverse audiences beyond the academy, and having real impact. The ethnographic creative non-fictions show together for the first time the barriers, determinants, benefits, trajectories, emotions, fears, preferred methods and messengers for delivering important physical activity information to men and women with a SCI. The article contributes to knowledge by showing the embodied complexities involved when in rehabilitation for both males and females in implementing and sustaining a physically active lifestyle shortly after SCI. It also makes a contribution to practice by providing researchers, health care professionals and disability user-groups with a theory and evidence based resource to assist in informing, teaching and enabling people living with SCI to initiate and maintain a physically active lifestyle. Stories may be a highly effective tool to communicate with and to influence spinal cord injured people's activity. The findings of this research showed the many benefits and barriers to developing and sustaining a physically active lifestyle shortly after spinal cord injury. The preferred methods and messengers for delivering physical activity information as well as the activity types, intensities and durations of physical activity for men and women were also shown. Within rehabilitation, spinal cord injured people need to be offered accessible knowledge about how to implement and sustain a physically active lifestyle over the life course. Stories may serve as a unique and powerful means to achieve this.


Polarization-holographic gratings for analysis of light. 1. Analysis of completely polarized light.
We consider the possibility of a complete real-time analysis of the polarization state of light using two types of polarization-holographic grating that decompose the light analyzed into orthogonal circular and orthogonal linear bases. It is shown that it is possible to determine the ellipticity, the direction of rotation, and the azimuth of the polarization ellipse of light by the measurement of the intensity of the diffraction orders by the obtained formulas. The possibility of creating gratings that give an orthogonal linear basis on actual polarization-sensitive materials is shown. A comparison of the experimental results with the theory is given.


Sample bias from different recruitment strategies in a randomised controlled trial for alcohol dependence.
Participants may be recruited from diverse sources for randomised controlled trials (RCT) of treatments for alcohol dependence. A mixed recruitment strategy might facilitate recruitment and increase generalisability at the expense of introducing systematic selection bias. The current study aims to compare the effects of recruitment method on socio-demographics, baseline illness characteristics, treatment retention and treatment outcome measures. A secondary analysis from a previous 12 week RCT of naltrexone, acamprosate and placebo for alcohol dependence was conducted. Participants (n = 169) were obtained via four channels of recruitment including in-patient and outpatient referral, live media and print media solicitation. Baseline parameters, retention in treatment and treatment outcomes were compared in these groups. Relative to in-patient subjects, those recruited via live and print media had significantly lower scores on taking steps, less in-patient rehabilitation admissions and less previous abstinence before entering the trial. Subjects recruited via print media had significantly lower scores of alcohol dependence relative to all other modes recruitment. There were no differences between recruitment strategies on treatment retention or compliance. At outcome, no significant effect of recruitment method was detected. These results suggest that different recruitment methods may be sourcing subjects with different baseline characteristics of illness. Nonetheless, these differences did not significantly impact on treatment retention or outcome, suggesting that in this population it was appropriate to recruit subjects from mixed sources.


Hsp-70 is closely associated with the transferrin receptor in exosomes from maturing reticulocytes.
The presence of the heat shock protein (hsp-70) has been detected in exocytosed vesicles (which are named exosomes) from mammalian and avian immature red cells (i.e. reticulocytes) as well as from a differentiating avian erythroleukaemic cell line. The close, but non-covalent, association of hsp-70 with the transferrin receptor (TFR) in exosomes is demonstrated by: (1) the ability to cross-link hsp-70 to TFR; (2) the co-immunoprecipitation of hsp-70 and TFR with an antibody against TFR, and the co-immunoprecipitation of TFR and hsp-70 with antibody against hsp-70; and (3) the retention of TFR by hsp-70 bound to ATP-agarose and the simultaneous elution of both proteins by excess ATP. Semi-quantitative analysis of the relative efficiency of cross-linking of these proteins in exosomes versus plasma membranes shows that TFR in exosomes is preferentially bound to hsp-70. From an analysis of the relative amounts of hsp-70 and TFR regenerated from the cross-linked complex, the ratio of TFR monomer bound to hsp-70 is approximately 1.5 to 1. Given the presence of hsp-70 in exosomes from several species and its close association with TFR (the major protein lost during reticulocyte maturation) it is proposed that hsp-70 plays a role in exosome formation and/or release in immature red cells.


Dentists' use of caries risk assessment in children: findings from the Dental Practice-Based Research Network.
This study surveyed Dental Practice-Based Research Network (DPBRN) member dentists (from four regions in the U.S. and Scandinavia) who perform restorative dentistry in their practices. The survey asked a range of questions about caries risk assessment in patients aged 6 to 18. Among respondents, 73% of dentists reported performing caries risk assessment among these patients, while 14% assessed caries risk by using a special form. Regions in which most dentists were in a private practice model were the least likely to perform caries risk assessment, while regions where most dentists practiced in a large group practice model were the most likely to use a special form for caries risk assessment. Recent graduates from dental school were more likely to use a caries risk assessment compared to older graduates. Current oral hygiene, decreased salivary flow, and the presence of active caries were rated as the most important caries factors. Some differences by region were also evident for the risk factor ratings. These results suggest that not all community dentists assess caries risk. The results of this study also indicate considerable variability in dentists' views concerning the importance of specific caries risk factors in treatment planning and weak evidence that caries risk assessment is driving clinical practice when preventive treatment recommendations are being considered.


Charge variants in IgG1: Isolation, characterization, in vitro binding properties and pharmacokinetics in rats.
Antibody charge variants have gained considerable attention in the biotechnology industry due to their potential influence on stability and biological activity. Subtle differences in the relative proportions of charge variants are often observed during routine biomanufacture or process changes and pose a challenge to demonstrating product comparability. To gain further insights into the impact on biological activity and pharmacokinetics (PK) of monoclonal antibody (mAb) charge heterogeneity, we isolated the major charge forms of a recombinant humanized IgG1 and compared their in vitro properties and in vivo PK. The mAb starting material had a pI range of 8.7-9.1 and was composed of about 20% acidic variants, 12% basic variants, and 68% main peak. Cation exchange displacement chromatography was used to isolate the acidic, basic, and main peak fractions for animal studies. Detailed analyses were performed on the isolated fractions to identify specific chemical modification contributing to the charge differences, and were also characterized for purity and in vitro potency prior to being administered either subcutaneously (SC) or intravenously (IV) in rats. All isolated materials had similar potency and rat FcRn binding relative to the starting material. Following IV or SC administration (10 mg/kg) in rats, no difference in serum PK was observed, indicating that physiochemical modifications and pI differences among charge variants were not sufficient to result in PK changes. Thus, these results provided meaningful information for the comparative evaluation of charge-related heterogeneity of mAbs, and suggested that charge variants of IgGs do not affect the in vitro potency, FcRn binding affinity, or the PK properties in rats.


SOX2 Regulates P63 and Stem/Progenitor Cell State in the Corneal Epithelium.
Mutations in key transcription factors SOX2 and P63 were linked with developmental defects and postnatal abnormalities such as corneal opacification, neovascularization, and blindness. The latter phenotypes suggest that SOX2 and P63 may be involved in corneal epithelial regeneration. Although P63 has been shown to be a key regulator of limbal stem cells, the expression pattern and function of SOX2 in the adult cornea remained unclear. Here, we show that SOX2 regulates P63 to control corneal epithelial stem/progenitor cell function. SOX2 and P63 were co-expressed in the stem/progenitor cell compartments of the murine cornea in vivo and in undifferentiated human limbal epithelial stem/progenitor cells in vitro. In line, a new consensus site that allows SOX2-mediated regulation of P63 enhancer was identified while repression of SOX2 reduced P63 expression, suggesting that SOX2 is upstream to P63. Importantly, knockdown of SOX2 significantly attenuated cell proliferation, long-term colony-forming potential of stem/progenitor cells, and induced robust cell differentiation. However, this effect was reverted by forced expression of P63, suggesting that SOX2 acts, at least in part, through P63. Finally, miR-450b was identified as a direct repressor of SOX2 that was required for SOX2/P63 downregulation and cell differentiation. Altogether, we propose that SOX2/P63 pathway is an essential regulator of corneal stem/progenitor cells while mutations in SOX2 or P63 may disrupt epithelial regeneration, leading to loss of corneal transparency and blindness. Stem Cells 2019;37:417-429.


Different actions of salt and pyrophosphate on protein extraction from myofibrils reveal the mechanism controlling myosin dissociation.
Myosin is the major functional protein in muscle foods for water retention, protein binding/gelation and fat holding/emulsification. To maximize its functionality, myosin needs to be released from thick filaments. Understanding of the mechanism controlling myosin extraction will help improve quality traits of meat products. The data obtained show that actomyosin binding is the rate-limiting constraint for myosin release in rigor condition. Magnesium pyrophosphate (MgPPi) increased myosin extraction by weakening actomyosin interaction and maximized myosin extraction at 0.4 mol L(-1) NaCl, which was not attained at 1.0 mol L(-1) NaCl in the absence of PPi. Interaction between myosin rod domains is another critical constraint for myosin extraction, which is, rather than PPi, salt dependent. Further, our data suggest that MyBP-C (myosin binding protein C) and M-line might not be of significance in the process of NaCl-induced myosin extraction, though further study was needed. Our study provides new insight into the mechanism that controls myosin extraction from intact sarcomere, which could be applied to maximize myosin function and to improve meat quality in practice.


Update on Novel Hormonal and Nonhormonal Male Contraceptive Development.
The advent of new methods of male contraception would increase contraceptive options for men and women and advance male contraceptive agency. Pharmaceutical R&D for male contraception has been dormant since the 1990s. The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) has supported a contraceptive development program since 1969 and supports most ongoing hormonal male contraceptive development. Nonhormonal methods are in earlier stages of development. Several hormonal male contraceptive agents have entered clinical trials. Novel single agent products being evaluated include dimethandrolone undecanoate, 11β-methyl-nortestosterone dodecylcarbonate, and 7α-methyl-19-nortestosterone. A contraceptive efficacy trial of Nestorone®/testosterone gel is underway. Potential nonhormonal methods are at preclinical stages of development. Many nonhormonal male contraceptive targets that affect sperm production, sperm function, or sperm transport have been identified. NICHD supports development of reversible male contraceptive agents. Other organizations such as the World Health Organization, the Population Council, and the Male Contraception Initiative are pursuing male contraceptive development, but industry involvement remains limited.


Oral health education and prevention strategies among remote Aboriginal communities: a qualitative study.
The delivery of effective oral health promotion strategies is essential to improving oral health outcomes among remote Aboriginal communities. This study aimed to explore the perceptions and attitudes of Aboriginal Australians living in remote Kimberley communities towards oral health education and disease prevention. Semi-structured interviews and yarning circles were carried out following purposive sampling of Aboriginal adults living in the East Kimberley region of Western Australia. A total of 80 community members participated in the yarning process. School-based oral health promotion and community-driven restrictions on the sale of sugary food and drink were seen as positive strategies in improving oral health. Lifestyle changes brought about by modernity, internet availability and fixed community stores were perceived to create new challenges and shift the priorities for those living in remote communities. Community-based yarning may better inform future oral health strategies in the Kimberley. A neoliberal approach of shifting responsibility onto the individual ignores the complex social inequities faced by Aboriginal people living in remote communities where macro-level determinants such as remoteness, food security and education significantly influence decisions around diet and oral health.


Enzymatic deposition of gold nanoparticles at vertically aligned carbon nanotubes for electrochemical stripping analysis and ultrasensitive immunosensing of carcinoembryonic antigen.
Herein we combine the sandwich immunoreaction at a vertically aligned single-walled carbon nanotube (SWCNT)-based immunosensor and the enzymatically catalytic deposition of gold nanoparticles (Au NPs) by a gold nanoprobe to develop a novel electrochemical immunosensing method. The vertically arranged nanostructure was prepared through the covalent linking of terminally carboxylated SWCNTs at an aryldiazonium-modified electrode. It not only provides an excellent platform for the high density immobilization of antibodies to obtain the immunosensor but also serves as useful molecular wires to accelerate electron transfer during the electrochemical immunosensing process. Meanwhile, the enzymatic reaction of the nanoprobe prepared by surface functionalization of the nanocarrier of Au NPs by high-content glucoamylases can catalyze the deposition of a large number of Au NPs at the immunosensor. The electrochemical stripping analysis of these nanoparticles enabled the convenient signal transduction of the method. Due to the sensitive gold stripping analysis at the vertically aligned SWCNTs and the multi-enzyme signal amplification of the nanoprobe, the electrochemical signal response was greatly enhanced. Thus, the method can be used for the ultrasensitive detection of the tumor biomarker of carcinoembryonic antigen in a wide linear range of 5 orders of magnitude with a low detection limit of 0.48 pg mL-1. Considering its obvious performance superiorities, this immunosensing method exhibits an extensive prospect for practical applications.


Custos controls β-catenin to regulate head development during vertebrate embryogenesis.
Precise control of the canonical Wnt pathway is crucial in embryogenesis and all stages of life, and dysregulation of this pathway is implicated in many human diseases including cancers and birth defect disorders. A key aspect of canonical Wnt signaling is the cytoplasmic to nuclear translocation of β-catenin, a process that remains incompletely understood. Here we report the identification of a previously undescribed component of the canonical Wnt signaling pathway termed Custos, originally isolated as a Dishevelled-interacting protein. Custos contains casein kinase phosphorylation sites and nuclear localization sequences. In Xenopus, custos mRNA is expressed maternally and then widely throughout embryogenesis. Depletion or overexpression of Custos produced defective anterior head structures by inhibiting the formation of the Spemann-Mangold organizer. In addition, Custos expression blocked secondary axis induction by positive signaling components of the canonical Wnt pathway and inhibited β-catenin/TCF-dependent transcription. Custos binds to β-catenin in a Wnt responsive manner without affecting its stability, but rather modulates the cytoplasmic to nuclear translocation of β-catenin. This effect on nuclear import appears to be the mechanism by which Custos inhibits canonical Wnt signaling. The function of Custos is conserved as loss-of-function and gain-of-function studies in zebrafish also demonstrate a role for Custos in anterior head development. Our studies suggest a role for Custos in fine-tuning canonical Wnt signal transduction during embryogenesis, adding an additional layer of regulatory control in the Wnt-β-catenin signal transduction cascade.


Intense flight and endotoxin injection elicit similar effects on leukocyte distributions but dissimilar effects on plasma-based immunological indices in pigeons.
Most birds rely on flight for survival. Yet as an energetically taxing and physiologically integrative process, flight has many repercussions. Studying pigeons (Columba livia) and employing physiological and immunological indices that are relevant to ecologists working with wild birds, we determined what, if any, acute immune-like responses result from bouts of intense, non-migratory flight. We compared the effects of flight with the effects of a simulated bacterial infection. We also investigated indices in terms of their post-flight changes within individuals and their relationship with flight speed among individuals. Compared to un-flown controls, flown birds exhibited significant elevations in numbers of heterophils relative to numbers of lymphocytes and significant reductions in numbers of eosinophils and monocytes. Furthermore, within-individual changes in concentrations of an acute phase protein were greater in flown birds than in controls. However, none of the flight-affected indices showed any evidence of being related to flight speed. While some of the effects of flight were comparable to the effects of the simulated bacterial infection, other effects were observed only after one of these two physiological challenges. Our study suggests that flight by pigeons yields immune-like responses, and these responses have the potential to complicate the conclusions drawn by ecologists regarding immune function in free-living birds. Still, a better understanding of the repercussions of flight can help clarify the ties between the physiology of exercise and the disease ecology of migration and will ultimately assist in the broader goal of accounting for immunological variation within and among species.


Expression of RET finger protein predicts chemoresistance in epithelial ovarian cancer.
Resistance to platinum- and taxane-based chemotherapy is a major cause of treatment failure in ovarian cancer. Thus, it is necessary to develop a predictive marker and molecular target for overcoming drug resistance in ovarian cancer treatment. In a previous report, using an in vitro model, we found that the RET finger protein (RFP) (also known as tripartite motif-containing protein 27, TRIM27) confers cancer cell resistance to anticancer drugs. However, the significance of RFP expression in cancer patients remains elusive. In this study, we showed that RFP was expressed in 62% of ovarian cancer patients and its positivity significantly correlated with drug resistance. Consistent with clinical data, depletion of RFP by RNA interference (RNAi) in ovarian cancer cell lines, SKOV3 and HEY, significantly increased carboplatin- or paclitaxel-induced apoptosis and resulted in reduced anticancer drug resistance. In a nude mouse tumor xenograft model, inoculated RFP-knockdown ovarian cancer cells exhibited lower carboplatin resistance than control cells. These findings suggest that RFP could be a predictive marker for chemoresistance in ovarian cancer patients and also a candidate for a molecular-targeted agent.


[Comparative study of intestinal anastomosis with manual suture and biofragmentable ring in dogs under corticosteroid administration].
This study analyzed intestinal anastomoses by manual suture and by compression with biofragmentable ring under delay of cicatrization administering parenteral corticoids. Twenty dogs were divided into two groups: control and test, the latter submitted to intramuscular administration of hydrocortisone hemisuccinate, 25 to 33 mg/kg/day, on the 30th preoperative and 7th postoperative days. During surgery, each animal underwent two colon sections with anastomosis by manual suture in a single extramucous plane and compression with biofragmentable ring. The animals were sacrificed 7 days after the procedure to evaluate the anastomoses. In the postoperative period, one death occurred in the test group and two in the control group, caused by nonblocked fistula in the anastomoses by ring compression. Statistically, there was a similar incidence of adherences, fistulas, afferent dilatation and obstruction using comparison methods. On microscopy, deficiency in mucous regeneration of the anastomoses by compression was observed. Computerized histological analysis evidenced in the anastomoses by compression, a greater inflammatory reaction, greater edema of the submucous membrane and enlarged scars. It was concluded that, with the biofragmentable ring, in colonic anastomosis under delay of cicatrization induced by corticoids, similar results to manual suture regarding to postoperative complications incidence were obtained; ring, however, determined worse mucous regeneration and greater cicatricial inflammatory reaction.


Early prognosis of noise-induced hearing loss.
Occupationally acquired noise-induced hearing loss (NIHL) is the most prevalent occupational disease in Austria and among the most common in many other countries. Because of the wide variation in hearing loss after equivalent exposures it has long been assumed that some individuals are more vulnerable to occupational NIHL than others. Earlier attempts to define predictors of NIHL before starting occupational noise exposure have largely failed. We present results of a prospective study evaluating the potential of temporary threshold shift (TTS) after a test exposure to predict NIHL. Between 1982 and 1989, overall 311 apprentices were included into a prospective study during their initial health screening visit. At this occasion, a standardised noise exposure was applied (20 min, 200-500 Hz, 100 dBA) and the TTS at 4 kHz was determined during at least 10 min after exposure. Hearing loss was monitored at follow-up visits every 3-5 years. Follow-up was 13 years on average. Permanent threshold shift was predicted by duration of noise exposure, frequency of wearing noise protectors and especially by the initial TTS at 4 kHz. Using 14 dB TTS as a cut-off had 82% sensitivity and 53% specificity to predict 20 dB or higher levels of NIHL. The TTS model can be successfully applied as a method to detect individuals at greater risk of occupational NIHL. It is recommended to routinely include such a procedure into initial workers' examinations for suitability to work under occupational noise conditions and for counselling on the use of hearing protectors.


Immunization coverage and its determinants among children born in 2008-2009 by questionnaire survey in Zhejiang, China.
The study aimed to assess the determinants of immunization coverage in children born in 2008-2009, living in Zhejiang Province. The World Health Organization's cluster sampling technique was applied. Immunization coverage of 5 vaccines was assessed: BCG vaccine, diphtheria and tetanus toxoids and pertussis vaccine, poliomyelitis vaccine, hepatitis B vaccine, and measles-containing vaccine. Determinants for age-appropriate immunization coverage rates were explored using logistic regression models. Immunization coverage of 5 vaccines were all greater than 90%, but the age-appropriate immunization coverage rates for 3 months and for first dose of measles-containing vaccine was 41.3% and 64.5%, respectively. Siblings in household, mother's education level, household registration, socioeconomic level of resident areas, satisfaction with clinical immunization service, and convenient access to local immunization clinic were associated with age-appropriate coverage rates. Age-appropriate immunization coverage rates should be given more attention and should be considered as a benchmark to strive for in the future intervention.


Tomato SOBIR1/EVR Homologs Are Involved in Elicitin Perception and Plant Defense Against the Oomycete Pathogen Phytophthora parasitica.
During host-pathogen interactions, pattern recognition receptors form complexes with proteins, such as receptor-like kinases, to elicit pathogen-associated molecular pattern-triggered immunity (PTI), an evolutionarily conserved plant defense program. However, little is known about the components of the receptor complex, as are the molecular events leading to PTI induced by the oomycete Phytophthora pathogen. Here, we demonstrate that tomato (Solanum lycopersicum) SlSOBIR1 and SlSOBIR1-like genes are involved in defense responses to Phytophthora parasitica. Silencing of SlSOBIR1 and SlSOBIR1-like enhanced susceptibility to P. parasitica in tomato. Callose deposition, reactive oxygen species production, and PTI marker gene expression were compromised in SlSOBIR1- and SlSOBIR1-like-silenced plants. Interestingly, P. parasitica infection and elicitin (ParA1) treatment induced the relocalization of SlSOBIR1 from the plasma membrane to endosomal compartments and silencing of NbSOBIR1 compromised ParA1-mediated cell death on Nicotiana benthamiana. Moreover, the SlSOBIR1 kinase domain is indispensable for ParA1 to trigger SlSOBIR1 internalization and plant cell death. Taken together, these results support the idea of participation of solanaceous SOBIR1/EVR homologs in the perception of elicitins and indicate their important roles in plant basal defense against oomycete pathogens.


Evaluation of chronic immune system stimulation models in growing pigs.
Two experiments (EXPs) were conducted to evaluate models of immune system stimulation (ISS) that can be used in nutrient metabolism studies in growing pigs. In EXP I, the pig's immune response to three non-pathogenic immunogens was evaluated, whereas in EXP II the pig's more general response to one of the immunogens was contrasted with observations on non-ISS pigs. In EXP I, nine growing barrows were fitted with a jugular catheter, and after recovery assigned to one of three treatments. Three immunogens were tested during a 10-day ISS period: (i) repeated injection of increasing amounts of Escherichia coli lipopolysaccharide (LPS); (ii) repeated subcutaneous injection of turpentine (TURP); and (iii) feeding grains naturally contaminated with mycotoxins (MYCO). In EXP II, 36 growing barrows were injected repeatedly with either saline (n = 12) or increasing amounts of LPS (n = 24) for 7 days (initial dose 60 μg/kg body weight). Treating pigs with TURP and LPS reduced feed intake (P < 0.02), whereas feed intake was not reduced in pigs on MYCO. Average daily gain (ADG; kg/day) of pigs on LPS (0.50) was higher than that of pigs on TURP (0.19), but lower than that of pigs on MYCO (0.61; P < 0.01). Body temperature was elevated in pigs on LPS and TURP, by 0.8°C and 0.7°C, respectively, relative to pre-ISS challenge values (39.3°C; P < 0.02), but remained unchanged in pigs on MYCO. Plasma concentrations of interleukin-1β were increased in pigs treated with LPS and TURP (56% and 55%, respectively, relative to 22.3 pg/ml for pre-ISS; P < 0.01), but not in MYCO-treated pigs. Plasma cortisol concentrations remained unchanged for pigs on MYCO and TURP, but were reduced in LPS-treated pigs (30% relative to 29.8 ng/ml for pre-ISS; P < 0.05). Red blood cell glutathione concentrations were lower in TURP-treated pigs (13% relative to 1.38 μM for pre-ISS; P < 0.05), but were unaffected in pigs on LPS and MYCO. In EXP I, TURP caused severe responses including skin ulceration and substantial reductions in feed intake and ADG, whereas MYCO did not induce effective ISS. In EXP II, ISS increased relative organ weights, eye temperature, white blood cell count and plasma acute-phase proteins (P < 0.05), confirming that repeated injection with increasing amounts of LPS induced chronic and relatively mild ISS. Repeated injection with increasing amounts of LPS is a suitable model for studying nutrient metabolism and evaluating the efficacy of nutritional intervention during chronic ISS in growing pigs.


[Strategy of the surgical treatment of postoperative complications in patients with obstructive ileus of the colon of tumorous etiology].
Under analysis were postoperative intraperitoneal complications and results of relaparotomies in 33 patients (13 women and 20 men) aged from 33 to 76 years with obturative ileus caused by stenosing cancer of different portions of the colon. High frequency of peritonitis in the general picture of postoperative complications was due to incompetent sutures of the colonic anastomoses applied during emergency and urgent operations in patients with sub- and decompensated forms of intestinal obstruction. The best variant of completion of radical operations in emergency surgery in this category of patients is the formation of a single- or double-trunk colostomy without a primary reestablishment of the continuity of the intestinal tube especially when stenosing cancer is localized in the left part of the colon.


Temporal Variation in Introgressed Segments' Length Statistics Computed from a Limited Number of Ancient Genomes Sheds Light on Past Admixture Pulses.
Hybridization is recognized as an important evolutionary force, but identifying and timing admixture events between divergent lineages remain a major aim of evolutionary biology. While this has traditionally been done using inferential tools on contemporary genomes, the latest advances in paleogenomics have provided a growing wealth of temporally distributed genomic data. Here, we used individual-based simulations to generate chromosome-level genomic data for a 2-population system and described temporal neutral introgression patterns under a single- and 2-pulse admixture model. We computed 6 summary statistics aiming to inform the timing and number of admixture pulses between interbreeding entities: lengths of introgressed sequences and their variance within genomes, as well as genome-wide introgression proportions and related measures. The first 2 statistics could confidently be used to infer interlineage hybridization history, peaking at the beginning and shortly after an admixture pulse. Temporal variation in introgression proportions and related statistics provided more limited insights, particularly when considering their application to ancient genomes still scant in number. Lastly, we computed these statistics on Homo sapiens paleogenomes and successfully inferred the hybridization pulse from Neanderthal that occurred approximately 40 to 60 kya. The scarce number of genomes dating from this period prevented more precise inferences, but the accumulation of paleogenomic data opens promising perspectives as our approach only requires a limited number of ancient genomes.


Arbekacin: another novel agent for treating infections due to methicillin-resistant Staphylococcus aureus and multidrug-resistant Gram-negative pathogens.
Arbekacin sulfate (ABK), an aminoglycoside antibiotic, was discovered in 1972 and was derived from dibekacin to stabilize many common aminoglycoside modifying enzymes. ABK shows broad antimicrobial activities against not only Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) but also Gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. ABK has been approved as an injectable formulation in Japan since 1990, under the trade name Habekacin, for the treatment of patients with pneumonia and sepsis caused by MRSA. The drug has been used in more than 250,000 patients, and its clinical benefit and safety have been proven over two decades. ABK currently shows promise for the application for the treatment of multidrug-resistant Gram-negative bacterial infections such as multidrug-resistant strains of P. aeruginosa and Acinetobacter baumannii because of its synergistic effect in combination with beta-lactams.


Polyphenols from Blossoms of Citrus aurantium L. var. amara Engl. Show Significant Anti-Complement and Anti-Inflammatory Effects.
Citrus aurantium L. var. amara Engl. (CAVA) was traditionally used as a digestant or expectorant in China. Crude polyphenols (CAVAP-W) extracted from blossoms of CAVA were mainly composed of eriocitrin/neoeriocitrin, eriocitrin/neoeriocitrin, rhoifolin, hesperidin, naringin, rutin, veronicastroside, neohesperidin, and hesperetin by LC-MS analysis. CAVAP-W showed significant anticomplement and anti-inflammatory effects. Due to the close relationship between anticomplement and anti-inflammatory activity, the anti-inflammatory effect was further investigated and the results showed that CAVAP-W significantly suppressed production of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and mRNA expression of inducible nitric oxide synthase (iNOS), IL-6, TNF-α, IL-1β, and cyclooxygenase-2 (COX-2) in lipopolysaccharides-stimulated RAW264.7 cells. Furthermore, CAVAP-W inhibited mitogen-activated protein kinase (MAPK) phosphorylation and NF-κB activation through suppressing nuclear translocation of nuclear factor-kappa B (NF-κB) P65, degradation and phosphorylation of IκBα, phosphorylation of IκKα/ß, c-Jun N-terminal kinase (JNK), and P38, and activation of COX-2, thereby exerting the anti-inflammatory effects.


Identification of surface proteins in Enterococcus faecalis V583.
Surface proteins are a key to a deeper understanding of the behaviour of Gram-positive bacteria interacting with the human gastro-intestinal tract. Such proteins contribute to cell wall synthesis and maintenance and are important for interactions between the bacterial cell and the human host. Since they are exposed and may play roles in pathogenicity, surface proteins are interesting targets for drug design. Using methods based on proteolytic "shaving" of bacterial cells and subsequent mass spectrometry-based protein identification, we have identified surface-located proteins in Enterococcus faecalis V583. In total 69 unique proteins were identified, few of which have been identified and characterized previously. 33 of these proteins are predicted to be cytoplasmic, whereas the other 36 are predicted to have surface locations (31) or to be secreted (5). Lipid-anchored proteins were the most dominant among the identified surface proteins. The seemingly most abundant surface proteins included a membrane protein with a potentially shedded extracellular sulfatase domain that could act on the sulfate groups in mucin and a lipid-anchored fumarate reductase that could contribute to generation of reactive oxygen species. The present proteome analysis gives an experimental impression of the protein landscape on the cell surface of the pathogenic bacterium E. faecalis. The 36 identified secreted (5) and surface (31) proteins included several proteins involved in cell wall synthesis, pheromone-regulated processes, and transport of solutes, as well as proteins with unknown function. These proteins stand out as interesting targets for further investigation of the interaction between E. faecalis and its environment.


Barriers to Medication Decision Making in Women with Lupus Nephritis: A Formative Study using Nominal Group Technique.
To assess the perspectives of women with lupus nephritis on barriers to medication decision making. We used the nominal group technique (NGT), a structured process to elicit ideas from participants, for a formative assessment. Eight NGT meetings were conducted in English and moderated by an expert NGT researcher at 2 medical centers. Participants responded to the question: "What sorts of things make it hard for people to decide to take the medicines that doctors prescribe for treating their lupus kidney disease?" Patients nominated, discussed, and prioritized barriers to decisional processes involving medications for treating lupus nephritis. Fifty-one women with lupus nephritis with a mean age of 40.6 ± 13.3 years and disease duration of 11.8 ± 8.3 years participated in 8 NGT meetings: 26 African Americans (4 panels), 13 Hispanics (2 panels), and 12 whites (2 panels). Of the participants, 36.5% had obtained at least a college degree and 55.8% needed some help in reading health materials. Of the 248 responses generated (range 19-37 responses/panel), 100 responses (40%) were perceived by patients as having relatively greater importance than other barriers in their own decision-making processes. The most salient perceived barriers, as indicated by percent-weighted votes assigned, were known/anticipated side effects (15.6%), medication expense/ability to afford medications (8.2%), and the fear that the medication could cause other diseases (7.8%). Women with lupus nephritis identified specific barriers to decisions related to medications. Information relevant to known/anticipated medication side effects and medication cost will form the basis of a patient guide for women with systemic lupus erythematosus, currently under development.


Genome Regions Associated with Functional Performance of Soybean Stem Fibers in Polypropylene Thermoplastic Composites.
Plant fibers can be used to produce composite materials for automobile parts, thus reducing plastic used in their manufacture, overall vehicle weight and fuel consumption when they replace mineral fillers and glass fibers. Soybean stem residues are, potentially, significant sources of inexpensive, renewable and biodegradable natural fibers, but are not curretly used for biocomposite production due to the functional properties of their fibers in composites being unknown. The current study was initiated to investigate the effects of plant genotype on the performance characteristics of soybean stem fibers when incorporated into a polypropylene (PP) matrix using a selective phenotyping approach. Fibers from 50 lines of a recombinant inbred line population (169 RILs) grown in different environments were incorporated into PP at 20% (wt/wt) by extrusion. Test samples were injection molded and characterized for their mechanical properties. The performance of stem fibers in the composites was significantly affected by genotype and environment. Fibers from different genotypes had significantly different chemical compositions, thus composites prepared with these fibers displayed different physical properties. This study demonstrates that thermoplastic composites with soybean stem-derived fibers have mechanical properties that are equivalent or better than wheat straw fiber composites currently being used for manufacturing interior automotive parts. The addition of soybean stem residues improved flexural, tensile and impact properties of the composites. Furthermore, by linkage and in silico mapping we identified genomic regions to which quantitative trait loci (QTL) for compositional and functional properties of soybean stem fibers in thermoplastic composites, as well as genes for cell wall synthesis, were co-localized. These results may lead to the development of high value uses for soybean stem residue.


Radical alpha-C-H hydroxyalkylation of ethers and acetal.
[reaction: see text] Epsilonthers and an acetal were found to undergo direct intermolecular addition to aldehydes under the Et(3)B/air conditions. This study presents a very unique and simple means for the radical alpha-C-H hydroxyalkylation of oxygen-containing compounds.