Undernutrition as an underlying cause of child deaths associated with diarrhea, pneumonia, malaria, and measles.
Previous analyses derived the relative risk (RR) of dying as a result of low weight-for-age and calculated the proportion of child deaths worldwide attributable to underweight. The objectives were to examine whether the risk of dying because of underweight varies by cause of death and to estimate the fraction of deaths by cause attributable to underweight. Data were obtained from investigators of 10 cohort studies with both weight-for-age category (<-3 SDs, -3 to <-2 SDs, -2 to <-1 SD, and >-1 SD) and cause of death information. All 10 studies contributed information on weight-for-age and risk of diarrhea, pneumonia, and all-cause mortality; however, only 6 studies contributed information on deaths because of measles, and only 3 studies contributed information on deaths because of malaria or fever. With use of weighted random effects models, we related the log mortality rate by cause and anthropometric status in each study to derive cause-specific RRs of dying because of undernutrition. Prevalences of each weight-for-age category were obtained from analyses of 310 national nutrition surveys. With use of the RR and prevalence information, we then calculated the fraction of deaths by cause attributable to undernutrition. The RR of mortality because of low weight-for-age was elevated for each cause of death and for all-cause mortality. Overall, 52.5% of all deaths in young children were attributable to undernutrition, varying from 44.8% for deaths because of measles to 60.7% for deaths because of diarrhea. A significant proportion of deaths in young children worldwide is attributable to low weight-for-age, and efforts to reduce malnutrition should be a policy priority.


The effects of exposure of articular cartilage to air. A histochemical and ultrastructural investigation.
The effects of exposure of articular cartilage to air and the potential for reversibility of the histological and ultrastructural changes that were produced by this exposure were investigated in the knee joint of the rabbit. After a medial parapatellar arthrotomy and lateral dislocation of the patella, the surface of the articular cartilage was exposed to air for one, two, and three hours in forty-five rabbits. Reversibility of the changes was assessed in fifteen rabbits after exposure of the cartilage to air for three hours, closure of the joint, and six weeks of recovery. Histochemical and ultrastructural changes were evaluated, with use of the contralateral non-exposed knee joint as a control. Depletion of glycosaminoglycans in the matrix of articular cartilage, as indicated by a loss of surface staining with toluidine blue, occurred after one hour of exposure to air. Ultrastructural changes occurred in chondrocytes throughout the full thickness of articular cartilage after one hour of exposure. Increases in the time of exposure to air resulted in more pronounced ultrastructural abnormalities in chondrocytes throughout the entire thickness of the articular cartilage, but there was no apparent irreversible cellular injury. Six weeks after arthrotomy, the chondrocytes had fully recovered from the changes that had been noted immediately after exposure to air, and they were devoid of degenerative changes. The cells showed ultrastructural evidence of increased metabolic activity in the nucleus and cytoplasm. In addition, the chondrocytes had partially restored the depleted glycosaminoglycans.


Mediators between self-criticism and depression: Fear of compassion, self-compassion, and importance to others.
This study was an investigation of the relationships between internalized self-criticism and depression and between comparative self-criticism and depression as these relationships are mediated by the fear of self-compassion, fear of compassion from others, self-compassion, and the perception that one is important to others. To examine these relationships, data were gathered via online survey methods from 206 university students at a large public Midwestern university in the United States. The Self-Criticism/Compassion Mediation Model, in which internalized and comparative self-criticism were both modeled to predict depression, was built and tested via structural equation modeling (SEM). In the presence of 4 competing models, this model effectively modeled relationships among the study variables. In the Self-Criticism/Compassion Mediation Model, the fear of self-compassion, and the perception that one is important to others serially mediated the relationship between comparative self-criticism and depression. Additionally, self-compassion partially mediated both the relationship between internalized self-criticism and depression, and the relationship between comparative self-criticism and depression. Implications include the use of the model as a guide to developing evidence-based practice for highly self-critical, depressed clients.


Towards time-resolved serial crystallography in a microfluidic device.
Serial methods for crystallography have the potential to enable dynamic structural studies of protein targets that have been resistant to single-crystal strategies. The use of serial data-collection strategies can circumvent challenges associated with radiation damage and repeated reaction initiation. This work utilizes a microfluidic crystallization platform for the serial time-resolved Laue diffraction analysis of macroscopic crystals of photoactive yellow protein (PYP). Reaction initiation was achieved via pulsed laser illumination, and the resultant electron-density difference maps clearly depict the expected pR(1)/pR(E46Q) and pR(2)/pR(CW) states at 10 µs and the pB1 intermediate at 1 ms. The strategies presented here have tremendous potential for extension to chemical triggering methods for reaction initiation and for extension to dynamic, multivariable analyses.


Knowledge transfer in the field of parental mental illness: objectives, effective strategies, indicators of success, and sustainability.
Mental health problems are often transmitted from one generation to the next. However, transferring knowledge about interventions that reduce intergenerational transmission of disease to the field of parental mental illness has been very difficult. One of the most critical issues in mental health services research is the gap between what is generally known about effective treatment and what is provided to consumers in routine care. In this article we discuss several aspects of knowledge transfer in the field of parental mental illness. Effective strategies and implementation prerequisites are explored, and we also discuss indicators of success and sustainability. Altogether, this article presents a rationale for the importance of preventive strategies for children of mentally ill parents. Furthermore, the discussion shows how complex it is to change clinical practice.


Clinical evaluation of the effects of a single oral dose of gabapentin on fear-based aggressive behaviors in cats during veterinary examinations.
To investigate the effects of a single oral dose of gabapentin on fear-based aggressive behaviors (FABs) in cats during veterinary examinations. 55 healthy pet cats (26 with and 29 without a history of FAB during veterinary visits [FAB and untreated control groups, respectively]). A standardized 9-step clinical examination protocol (with patient compliance scored from 0 to 9 according to the highest completed step) was tested on untreated control group cats. The protocol was then used in a double-blind, randomized, placebo-controlled, crossover-design trial in which FAB-group cats received owner-administered gabapentin (100 or 200 mg/cat) or placebo capsules 2 hours before the first of 2 veterinary visits and received the alternate treatment before the second visit ≥ 1 day later. Ease of administration (scored from 1 [very difficult] to 4 [very easy]) and adverse effects were recorded. Compliance scores were compared between treatments for the FAB group and between FAB and untreated control groups. Changes in scores between treatments for the FAB group were used to investigate associations between selected variables and the outcome of interest. FAB group compliance scores after gabapentin administration (median, 9; range, 0 to 9) were significantly higher than scores after placebo administration (median 0.5; range, 0 to 7) and did not differ from scores for the untreated control group. Owner scores indicated capsule administration was easy. Adverse effects (most commonly drowsiness, myorelaxation, and ataxia) resolved ≤ 10 hours after detection. Results suggested oral administration of gabapentin to cats 2 hours before a veterinary visit can reduce FAB during physical examination, enabling more complete evaluation.


Histopathologic features of splenic small B-cell lymphomas. A study of 42 cases with a definitive diagnosis by the World Health Organization classification.
We studied 42 cases of splenic small B-cell lymphoma (SBL) (21 women, 21 men; aged 32-82 years; median, 65 years) with a definitive diagnosis by the World Health Organization classification: chronic lymphocytic leukemia (CLL), 8; mantle cell lymphoma (MCL), 9; follicular lymphoma (FL), 12; marginal zone lymphoma, 13 (splenic [SMZL], 12; extranodal [EMZL], 1). Splenectomy was performed for diagnosis or therapy; splenic weights were 0.2 to 3.8 kg (median, 1.4 kg). In general, splenic SBLs showed white pulp (WP) expansion; morphologic features of the nodules recapitulated the corresponding lymph node histopathologic features. "Marginal zones" were observed commonly in SMZL and FL, may be present in MCL involving the spleen, and may be seen in hilar lymph nodes (HLNs) in SBLs other than SMZL. FL may simulate SMZL and can be distinguished by the presence of neoplastic follicles and HLN morphologic features. Extracellular hyaline deposits (EH) are common in FL and SMZL. MCL typically shows WP expansion by a monotonous small lymphocytic infiltrate, without diffuse red pulp (RP) infiltration or EH; leukemic MCL may show RP infiltration. Splenic morphologic features in CLL vary in WP or RP dominance; marginal zones usually are not observed in CLL.


Interexaminer agreement on the American Board of Emergency Medicine oral certification examination.
One of the principal criticisms of performance assessments, particularly those using an oral format to evaluate physician performance, is the lack of interrater reliability. The objective of this study was to assess interexaminer agreement in the scoring of candidates taking the American Board of Emergency Medicine (ABEM) oral certification examination. Examiner-observer pairs independently scored individual candidates on each of the 6 simulated cases selected for the October 1999 examination. Simple proportionate agreement for "acceptable" and "unacceptable" scores on critical actions and performance ratings were used to measure interexaminer (examiner-observer) agreement. Further analyses were performed to assess interexaminer agreement at the level of the raw scores of all performance ratings. The candidate's actual score was determined entirely by the examiner administering the case. The study examiner was present only to observe and independently score the candidate. Examiners were blinded to each other's scoring. All examiner-observer, examiner-candidate, and observer-candidate pairings were uniquely randomized and occurred only once during the examination. Of 564 candidates, 186 were randomly selected for scoring by examiner-observer pairs drawn from a pool of 107 trained oral examiners. Interexaminer agreement for 47 critical actions was 97% (95% confidence interval [CI] 96% to 98%), and interexaminer agreement for 68 performance ratings was 95% (95% CI 94% to 96%). Further analyses of raw scores of performance ratings indicated that 94% (95% CI 93% to 95%) of 2,648 pairs of ratings differed by 1 point or less. High interexaminer agreement on the scoring of the ABEM oral certification examination supports the reliability of this final step in the certification process. On the basis of these findings, ABEM has incorporated this methodology into the administration of each oral examination as an ongoing quality control measure.


Long-Term Adaptation Among Adolescent and Young Adult Children to Familial Cancer Risk.
It is important to examine adolescent and young adult (AYA) children's long-term psychosocial and behavioral adaptation to disclosure of maternal BRCA-positive carrier status (BRCA+) to inform approaches for familial cancer risk communication, education, and counseling. Mothers underwent BRCA genetic testing 1 to 5 years earlier. Group differences in AYAs' self-reported outcomes were analyzed by maternal health and carrier status, and child age and sex. A total of N = 272 AYAs were enrolled: 76.1% of their mothers were breast or ovarian cancer survivors and 17.3% were BRCA+. AYAs' cancer risk behavior (tobacco and alcohol use, physical activity) and psychologic distress levels did not vary by maternal status. In bivariate analyses, AYAs of cancer-surviving mothers believed themselves to be at greater risk for, and were more knowledgeable about, cancer than AYAs of mothers without cancer. AYAs of BRCA+ mothers were more concerned about cancer, held stronger beliefs about genetic risk, and placed a higher value on learning about genetics. In adjusted models, maternal cancer history (not BRCA+) remained associated with AYAs' greater perceptions of cancer risk (P = .002), and knowledge about cancer (P = .03) and its causes (P = .002). Disclosing maternal BRCA+ status did not influence children's lifestyle behavior or adversely affect quality of life long term. AYAs of BRCA+ mothers were more aware of and interested in genetic risk information. Such families may benefit from support to promote open communication about genetic testing choices.


Septin 9 isoforms promote tumorigenesis in mammary epithelial cells by increasing migration and ECM degradation through metalloproteinase secretion at focal adhesions.
The cytoskeletal interacting protein Septin 9 (SEPT9), a member of the septin gene family, has been proposed to have oncogenic functions. It is a known hot spot of retroviral tagging insertion and a fusion partner of both de novo and therapy-induced mixed lineage leukemia (MLL). Of all septins, SEPT9 holds the strongest link to cancer, especially breast cancer. Murine models of breast cancer frequently exhibit SEPT9 amplification in the form of double minute chromosomes, and about 20% of human breast cancer display genomic amplification and protein over expression at the SEPT9 locus. Yet, a clear mechanism by which SEPT9 elicits tumor-promoting functions is lacking. To obtain unbiased insights on molecular signatures of SEPT9 upregulation in breast tumors, we overexpressed several of its isoforms in breast cancer cell lines. Global transcriptomic profiling supports a role of SEPT9 in invasion. Functional studies reveal that SEPT9 upregulation is sufficient to increase degradation of the extracellular matrix, while SEPT9 downregulation inhibits this process. The degradation pattern is peripheral and associated with focal adhesions (FAs), where it is coupled with increased expression of matrix metalloproteinases (MMPs). SEPT9 overexpression induces MMP upregulation in human tumors and in culture models and promotes MMP3 secretion to the media at FAs. Downregulation of SEPT9 or chemical inhibition of septin filament assembly impairs recruitment of MMP3 to FAs. Our results indicate that SEPT9 promotes upregulation and both trafficking and secretion of MMPs near FAs, thus enhancing migration and invasion of breast cancer cells.


The cuticle modulates ultraviolet reflectance of avian eggshells.
Avian eggshells are variedly coloured, yet only two pigments, biliverdin and protoporphyrin IX, are known to contribute to the dramatic diversity of their colours. By contrast, the contributions of structural or other chemical components of the eggshell are poorly understood. For example, unpigmented eggshells, which appear white to the human eye, vary in their ultraviolet (UV) reflectance, which may be detectable by birds. We investigated the proximate mechanisms for the variation in UV-reflectance of unpigmented bird eggshells using spectrophotometry, electron microscopy, chemical analyses, and experimental manipulations. We specifically tested how UV-reflectance is affected by the eggshell cuticle, the outermost layer of most avian eggshells. The chemical dissolution of the outer eggshell layers, including the cuticle, increased UV-reflectance for only eggshells that contained a cuticle. Our findings demonstrate that the outer eggshell layers, including the cuticle, absorb UV-light, probably because they contain higher levels of organic components and other chemicals, such as calcium phosphates, compared to the predominantly calcite-based eggshell matrix. These data highlight the need to examine factors other than the known pigments in studies of avian eggshell colour.


Prevention of urinary tract infections with vaccinium products.
Cranberries exert a dose-dependent inhibition of the adherence of E. coli fimbriae to uroepithelial cells. This was demonstrated in vitro but also ex vivo in vitro with urine from cranberry consumers. The active principle has not been identified in detail but type-A proanthocyanidins (PAC) play an important role in the mechanism of action. Since the three species, American cranberry (Vaccinium macrocarpon), European cranberry (Vaccinium oxycoccus) and/or lingonberry (Vaccinium vitis-idaea), have different patterns of type-A PACs, results from one species cannot be transferred to the others. It seems likely that most of the studies with monopreparations from V. macrocarpon were underdosed. Whereas photometric PAC quantification may overestimate the true content on co-active compounds, reversed phase high-performance liquid chromatograpy may underestimate them. Recent studies with PAC doses in the upper range (DMAC method) or declared type-A PAC content in the daily dose reveal a dose-dependent trend of clinical effectiveness, however, with a possible ceiling effect. In order to clarify this, future three-arm studies should investigate Vaccinium preparations with higher type-A PAC doses than previously used. We analysed two popular European vitis-idaea products, a mother juice and a proprietary extract. Both preparations may be appropriate to confirm the Vaccinium urinary tract infection-preventive effect beyond doubt.


Connectivity-driven bi-thermoelectricity in heteroatom-substituted molecular junctions.
To improve the thermoelectric performance of molecular junctions formed by polyaromatic hydrocarbon (PAH) cores, we present a new strategy for enhancing their Seebeck coefficient by utilizing connectivities with destructive quantum interference combined with heteroatom substitution. Starting from the parent PAH, with a vanishing mid-gap Seebeck coefficient, we demonstrate that the corresponding daughter molecule obtained after heteroatom substitution possesses a non-zero, mid-gap Seebeck coefficient. For the first time, we demonstrate a "bi-thermoelectric" property, where for a given heteroatom and parent PAH, the sign of the mid-gap Seebeck coefficient depends on connectivity and therefore the daughter can exhibit both positive and negative Seebeck coefficients. This bi-thermoelectric property is important for the design of tandem thermoelectric devices, where materials with both positive and negative Seebeck coefficients are utilized to boost the thermovoltage. Simple parameter-free rules for predicting the Seebeck coefficient of such molecules are presented, which form a powerful tool for designing efficient molecular thermoelectric devices.


Use of vinyl polysiloxane impression material to protect and identify the nasolacrimal sac in endonasal dacryocystorhinostomy.
To determine the role of vinyl polysiloxane impression material (trade name Reprosil) in endonasal dacryocystorhinostomy. Case series of 15 consecutive endonasal dacryocystorhinostomies in which vinyl polysiloxane material was used to mark and protect the nasolacrimal sac. Vinyl polysiloxane is mixed from two tubes, then immediately injected in the sac through a preplaced 21-gauge cannula. It is important to be sure the cannula is in the sac to avoid false injection and extravasation. We have found it best to inject a small amount, usually 0.2 to 0.3 mL. A patent osteum was successfully created in 13 of the 15 cases (87%). Complications included two cases of retained vinyl polysiloxane that necessitated removal through an external excision. Endonasal dacryocystorhinostomy has several advantages compared with the external approach. There is no external scar and the bruising and swelling are substantially reduced, allowing patients to return to work more quickly. In addition, the adjacent nasal anatomy is directly visualized, allowing for simultaneous treatment of any relevant nasal pathology and precise manipulation of the nasal tissues.


Biofunctionalized protein resistant oligo(ethylene glycol)-derived polymer brushes as selective immobilization and sensing platforms.
Poly(oligo(ethylene glycol) methacrylate) (POEGMA) brushes are extremely protein resistant polymer coatings that can reduce nonspecific adsorption of proteins from complex mixtures such as blood, sera and plasma. These coatings can be prepared via atom transfer radical polymerization with excellent control of their thickness and grafting density. We studied their direct functionalization with streptavidin and developed an assay for determining which coupling conditions afford the highest streptavidin loading efficiency. Disuccinimidyl carbonate was found to be the most efficient activating agent for covalent capture of the receptor. Using infrared and X-ray photoelectron spectroscopy, fluorescence microscopy, surface plasmon resonance, and ellipsometry, we examined how structural parameters such as the length of the oligo(ethylene glycol) side chain affect streptavidin functionalization, but also immobilization of biotinylated antibodies, subsequent selective secondary recognition and nonspecific binding of proteins. We found evidence that large macromolecules cannot infiltrate dense polymer brushes and that bulky antibody recognition occurs in the upper part of these coatings.


Tweaking the magnetism of MoS2 nanoribbon with hydrogen and carbon passivation.
Using density functional theory (DFT), we report the modulated electronic and magnetic properties of MoS2 nanoribbon by passivating the ribbon edges with H and C separately. For the modeled symmetric MoS2 nanoribbon with a zig-zag type edge, one side is terminated at Mo and the other side is terminated at S. For the zig-zag type, we have studied two ribbons of width ~3 Å and 6 Å respectively. Both of these pristine zig-zag type nanoribbons are found to be metallic and also ferromagnetic. However, the increase in the ribbon width results in a decrease in the net magnetic moment of the nanoribbon. Thereafter, we study the modulated electronic and magnetic properties of the nanoribbon of ~3 Å width by saturating the ribbon edges with H and C. In one case, by passivating the zig-zag type ribbon with H at the S terminated edge, we find a net increase in magnetic moment of the ribbon when compared with the pristine one. Furthermore, when the ribbon is passivated with H at both of the edges, the net magnetic moment shows a decreasing trend. In another case, the zig-zag nanoribbon is passivated with C in a similar fashion to H and we find with one edge passivation the net magnetic moment of the ribbon decreases, whereas with both edges C passivated the ribbon magnetism increases significantly. However, the nanoribbon modeled with the armchair type of edge and terminated with Mo at both sides is found to be non-magnetic and semiconducting. Passivating the armchair type nanoribbon with H and C, we find the band gap shows an increasing trend when going from one side to both sides passivation. In all cases, the armchair type nanoribbons show non-magnetic behavior.


Mechanisms of magnetic orientation in birds.
Behavior and electrophysiological studies have demonstrated a sensitivity to characteristics of the Geomagnetic field that can be used for navigation, both for direction finding (compass) and position finding (map). The avian magnetic compass receptor appears to be a light-dependent, wavelength-sensitive system that functions as a polarity compass (i.e., it distinguishes poleward from equatorward rather than north from south) and is relatively insensitive to changes in magnetic field intensity. The receptor is within the retina and is based on one or more photopigments, perhaps cryptochromes. A second receptor system appears to be based on magnetite and might serve to transduce location information independent of the compass system. This receptor is associated with the ophthalmic branch of the trigeminal nerve and is sensitive to very small (<50 nanotesla) changes in the intensity of the magnetic field. In neither case has a neuron that responded to changes in the magnetic field been traced to a structure that can be identified to be a receptor. Almost nothing is known about how magnetic information is processed within the brain or how it is combined with other sensory information and used for navigation. These remain areas of future research.


Role of epidermal growth factor receptor in breast cancer.
Decades of research in molecular oncology have brought about promising new therapies which are designed to target specific molecules which promote tumor growth and survival. The epidermal growth factor receptor (EGFR) is one of the first identified important targets of these novel antitumor agents. Approximately half of cases of triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC) overexpress EGFR. Thus, EGFR inhibitors for treatment of breast cancer have been evaluated in several studies. However, results so far have been disappointing. One of the reasons for these unexpected results is the lack of biomarkers for predicting which patients are most likely to respond to EGFR inhibitors. Recent studies have shown that EGFR and its downstream pathway regulate epithelial-mesenchymal transition, migration, and tumor invasion and that high EGFR expression is an independent predictor of poor prognosis in IBC. Further, recent studies have shown that targeting EGFR enhances the chemosensitivity of TNBC cells by rewiring apoptotic signaling networks in TNBC. These studies indicate that EGFR-targeted therapy might have a promising role in TNBC and IBC. Further studies of the role of EGFR in TNBC and IBC are needed to better understand the best way to use EGFR-targeted therapy-e.g., as a chemosensitizer or to prevent metastases-to treat these aggressive diseases.


Chemosensitizing effect of vitamin C in combination with 5-fluorouracil in vitro.
The antiproliferative effect and apoptosis-inducing action of 5-fluorouracil (5-FU) in combination with vitamin C were tested in vitro against the chemosensitive mouse lymphoma, the chemoresistant HEp-2 and a human lung fibroblast cell line. Vitamin C itself had no antiproliferative effect on the fibroblasts, but increased the anticancer effect of 5-FU dose-dependently. In the case of the chemoresistant cell line, only a high concentration of vitamin C increased the cytotoxicity of 5-FU. A combination of 5-FU and vitamin C exerted a significantly enhanced apoptotic effect on the mouse lymphoma cell line, whereas for the HEp-2 cell line this effect was less marked and was achieved only at a high concentration of vitamin C. These findings suggest that the administration of a high dose of vitamin C in combination with 5-FU chemotherapy enhances the chemoresponsiveness of cancer cells and serves as a potential sensitizer, especially in chemo-resistant cell lines. One of the mechanisms by which vitamin C potentiates cytostatics could be apoptosis induction.


Risk and the pregnant body.
Reasoning well about risk is most challenging when a woman is pregnant, for patient and doctor alike. During pregnancy, we tend to note the risks of medical interventions without adequately noting those of failing to intervene, yet when it's time to give birth, interventions are seldom questioned, even when they don't work. Meanwhile, outside the clinic, advice given to pregnant women on how to stay healthy in everyday life can seem capricious and overly cautious. This kind of reasoning reflects fear, not evidence.


In vitro synthesis of minus-strand RNA by an isolated cereal yellow dwarf virus RNA-dependent RNA polymerase requires VPg and a stem-loop structure at the 3' end of the virus RNA.
Cereal yellow dwarf virus (CYDV) RNA has a 5'-terminal genome-linked protein (VPg). We have expressed the VPg region of the CYDV genome in bacteria and used the purified protein (bVPg) to raise an antiserum which was able to detect free VPg in extracts of CYDV-infected oat plants. A template-dependent RNA-dependent RNA polymerase (RdRp) has been produced from a CYDV membrane-bound RNA polymerase by treatment with BAL 31 nuclease. The RdRp was template specific, being able to utilize templates from CYDV plus- and minus-strand RNAs but not those of three unrelated viruses, Red clover necrotic mosaic virus, Cucumber mosaic virus, and Tobacco mosaic virus. RNA synthesis catalyzed by the RdRp required a 3'-terminal GU sequence and the presence of bVPg. Additionally, synthesis of minus-strand RNA on a plus-strand RNA template required the presence of a putative stem-loop structure near the 3' terminus of CYDV RNA. The base-paired stem, a single-nucleotide (A) bulge in the stem, and the sequence of a tetraloop were all required for the template activity. Evidence was produced showing that minus-strand synthesis in vitro was initiated by priming by bVPg at the 3' end of the template. The data are consistent with a model in which the RdRp binds to the stem-loop structure which positions the active site to recognize the 3'-terminal GU sequence for initiation of RNA synthesis by the addition of an A residue to VPg.


Assessing the impact of Melendez-Diaz on the investigation and prosecution of biological weapons incidents.
In June 2009, the U.S. Supreme Court asserted in Melendez-Diaz v Massachusetts that the admission of a laboratory analyst's certificate to validate forensic evidence against a defendant violated the defendant's Sixth Amendment Confrontation Clause rights. The Court stated that if a prosecution wished to use forensic science evidence against a defendant, the plaintiff must ensure that an actual lab analyst could testify live before the court as to the nature of the laboratory certificate being presented against the defendant, in order to uphold a defendant's constitutional right to confront the adverse witnesses against him or her. The opinion itself, as well as dicta in both the majority and the dissenting opinions, has potential implications for the success of any future prosecutions of alleged biological weapons use involving microbial forensics. Not only does the Melendez-Diaz opinion create an added burden on laboratory investigators, but the case called into question the reliability of the use of forensic science in the courtroom. Analysts and policymakers should be aware of this ruling and any potential impact the Court may have on the ability to successfully prosecute a biological weapons use event.


Transgenerational attenuation of opioid self-administration as a consequence of adolescent morphine exposure.
The United States is in the midst of an opiate epidemic, with abuse of prescription and illegal opioids increasing steadily over the past decade. While it is clear that there is a genetic component to opioid addiction, there is a significant portion of heritability that cannot be explained by genetics alone. The current study was designed to test the hypothesis that maternal exposure to opioids prior to pregnancy alters abuse liability in subsequent generations. Female adolescent Sprague Dawley rats were administered morphine at increasing doses (5-25 mg/kg, s.c.) or saline for 10 days (P30-39). During adulthood, animals were bred with drug-naïve colony males. Male and female adult offspring (F1 animals) were tested for morphine self-administration acquisition, progressive ratio, extinction, and reinstatement at three doses of morphine (0.25, 0.75, 1.25 mg/kg/infusion). Grandoffspring (F2 animals, from the maternal line) were also examined. Additionally, gene expression changes within the nucleus accumbens were examined with RNA deep sequencing (PacBio) and qPCR. There were dose- and sex-dependent effects on all phases of the self-administration paradigm that indicate decreased morphine reinforcement and attenuated relapse-like behavior. Additionally, genes related to synaptic plasticity, as well as myelin basic protein (MBP), were dysregulated. Some, but not all, effects persisted into the subsequent (F2) generation. The results demonstrate that even limited opioid exposure during adolescence can have lasting effects across multiple generations, which has implications for mechanisms of the transmission of drug abuse liability in humans.


Disease painting or painting disease: how does illness and hospitalisation affect children's artistry?
There are numerous speculations about famous artists and how their perception was affected by their medical conditions. In this study, we examined how illness and hospitalisation affect children's art. A total of 157 paintings by 122 hospitalised children were interpreted by three reputed artists. Works of ill children were compared with those of a control group from an international art exhibition. We also comment on how diseases influenced the technique of famous artists to further examine the possible impact of illness on the artistry of hospitalised children. Developmental delay in painting was evident in the study group. Use of ready-made schemas was a common practice (55%). 56% of the work from patients older than eight years failed in perspective and site perception. The theme in 89% of the drawings had no human figures. Projection of self sufferings, prominent elementary lines, and reflection of distorted perception could be clearly recognised in various study materials; anxiety about assigned surgery was exhibited by scribbling. There exists a close relationship between medicine and humanities. The interpretation of fine art from a medical perspective may help to increase our appreciation of the suffering of an individual. It is obvious that diseases change the artistic style and inner perspective. The question is how do healthcare specialists view this?


The effect of paraquat on the incorporation of radiolabelled proline into acid-extractable lung proteins and collagens.
In this comparative study we describe the influence of paraquat on the rate of L-2,3-3H-proline incorporation into the acid-extractable proteins and into newly synthesized protropocollagen molecules from the lungs of rats and rabbits. Exposure to paraquat took two forms: (a) addition of paraquat in vitro to lung tissue taken from rats and rabbits, and (b) intraperitoneal injection of paraquat prior to death. Paraquat (0,5 - 1,0 mM) added in vitro significantly slowed the rates of 3H-proline incorporation into the acid-extractable proteins and into newly synthesized protropocollagen in both rat and rabbit lung tissue. Paraquat administered intraperitoneally (27 mg/kg) to rabbits did not markedly influence the rate of 3H-proline incorporation into acid-extractable proteins and collagen assessed in vitro 24, 48 and 96 hours after injection. Paraquat injected intraperitoneally into rats induced no significant difference in synthesis rates of acid-soluble proteins up to 48 hours after injection. During the same period, the collagen synthesis rate of rat lung tissue was reduced. At 96 hours an increase was found when the rate of synthesis was expressed as cpm/mg DNA and as cpm/microgram hydroxyproline.


Bioinspired drug delivery systems.
The way Nature designs, processes and assembles molecular building blocks to fabricate high performance materials with a minimum of resources is a suitable model for the design of drug delivery systems (DDS) with advanced functionalities. Bioinspired preparation methods that involve the use of superhydrophobic surfaces, layer-by-layer assembly or protein-driven growth are being successfully implemented to create a wide range of polymeric and hybrid structures. Mimicking the surface, shape, texture and movement of cells and microorganisms help to overcome phagocytosis and attain efficient targeting of the drug carriers, while transposition of the feed-back regulation mechanisms and the functions of membrane channels and physiological receptors may notably enhance the spatiotemporal control of drug release. These aspects are addressed in the present review.


Ocean acidification and its potential effects on marine ecosystems.
Ocean acidification is rapidly changing the carbonate system of the world oceans. Past mass extinction events have been linked to ocean acidification, and the current rate of change in seawater chemistry is unprecedented. Evidence suggests that these changes will have significant consequences for marine taxa, particularly those that build skeletons, shells, and tests of biogenic calcium carbonate. Potential changes in species distributions and abundances could propagate through multiple trophic levels of marine food webs, though research into the long-term ecosystem impacts of ocean acidification is in its infancy. This review attempts to provide a general synthesis of known and/or hypothesized biological and ecosystem responses to increasing ocean acidification. Marine taxa covered in this review include tropical reef-building corals, cold-water corals, crustose coralline algae, Halimeda, benthic mollusks, echinoderms, coccolithophores, foraminifera, pteropods, seagrasses, jellyfishes, and fishes. The risk of irreversible ecosystem changes due to ocean acidification should enlighten the ongoing CO(2) emissions debate and make it clear that the human dependence on fossil fuels must end quickly. Political will and significant large-scale investment in clean-energy technologies are essential if we are to avoid the most damaging effects of human-induced climate change, including ocean acidification.


Striatal neuroinflammation promotes Parkinsonism in rats.
Sporadic Parkinson's disease (PD) is a progressive neurodegenerative disorder with unknown cause, but it has been suggested that neuroinflammation may play a role in pathogenesis of the disease. Neuroinflammatory component in process of PD neurodegeneration was proposed by postmortem, epidemiological and animal model studies. However, it remains unclear how neuroinflammatory factors contribute to dopaminergic neuronal death in PD. In this study, we analyzed the relationship among inducible nitric oxide synthase (iNOS)-derived NO, mitochondrial dysfunction and dopaminergic neurodegeneration to examine the possibility that microglial neuroinflammation may induce dopaminergic neuronal loss in the substantia nigra. Unilateral injection of lipopolysaccharide (LPS) into the striatum of rat was followed by immunocytochemical, histological, neurochemical and biochemical analyses. In addition, behavioral assessments including cylinder test and amphetamine-induced rotational behavior test were employed to validate ipsilateral damage to the dopamine nigrostriatal pathway. LPS injection caused progressive degeneration of the dopamine nigrostriatal system, which was accompanied by motor impairments including asymmetric usage of forelimbs and amphetamine-induced turning behavior in animals. Interestingly, some of the remaining nigral dopaminergic neurons had intracytoplasmic accumulation of alpha-synuclein and ubiquitin. Furthermore, defect in the mitochondrial respiratory chain, and extensive S-nitrosylation/nitration of mitochondrial complex I were detected prior to the dopaminergic neuronal loss. The mitochondrial injury was prevented by treatment with L-N(6)-(l-iminoethyl)-lysine, an iNOS inhibitor, suggesting that iNOS-derived NO is associated with the mitochondrial impairment. These results implicate neuroinflammation-induced S-nitrosylation/nitration of mitochondrial complex I in mitochondrial malfunction and subsequent degeneration of the nigral dopamine neurons.


Identification of AQP5 in lipid rafts and its translocation to apical membranes by activation of M3 mAChRs in interlobular ducts of rat parotid gland.
Aquaporin-5 (AQP5), an apical plasma membrane (APM) water channel in salivary glands, lacrimal glands, and airway epithelium, has an important role in fluid secretion. M(3) muscarinic acetylcholine receptor (mAChR)-induced changes in AQP5 localization in rat parotid glands were investigated with immunofluorescence or immunoelectron microscopy, detergent solubility, and gradient density floatation assays. Confocal microscopy revealed AQP5 localization in intracellular vesicles of interlobular duct cells in rat parotid glands and AQP5 trafficking to the APM 10 min after injection of the mAChR agonist cevimeline. Conversely, 60 min after injection, there was a diffuse pattern of AQP5 staining in the cell cytoplasm. The calcium ionophore A-23187 mimicked the effects of cevimeline. Immunoelectron microscopic studies confirmed that cevimeline induced AQP5 trafficking from intracellular structures to APMs in the interlobular duct cells of rat parotid glands. Lipid raft markers flotillin-2 and GM1 colocalized with AQP5 and moved with AQP5 in response to cevimeline. Under control conditions, the majority of AQP5 localized in the Triton X-100-insoluble fraction and floated to the light-density fraction on discontinuous density gradients. After 10-min incubation of parotid tissue slices with cevimeline or A-23187, AQP5 levels decreased in the Triton X-100-insoluble fraction and increased in the Triton X-100-soluble fraction. Thus AQP5 localizes in the intracellular lipid rafts, and M(3) mAChR activation induces AQP5 trafficking to the APM with lipid rafts via intracellular Ca(2+) signaling and induces AQP5 dissociation from lipid rafts to nonrafts on the APM in the interlobular duct cells of rat parotid glands.


Joint RElaxation-Diffusion Imaging Moments to Probe Neurite Microstructure.
Joint relaxation-diffusion measurements can provide new insight about the tissue microstructural properties. Most recent methods have focused on inverting the Laplace transform to recover the joint distribution of relaxation-diffusion. However, as is well-known, this problem is notoriously ill-posed and numerically unstable. In this work, we address this issue by directly computing the joint moments of transverse relaxation rate and diffusivity, which can be robustly estimated. To zoom into different parts of the joint distribution, we further enhance our method by applying multiplicative filters to the joint probability density function of relaxation and diffusion and compute the corresponding moments. We propose an approach to use these moments to compute several novel scalar indices to characterize specific properties of the underlying tissue microstructure. Furthermore, for the first time, we propose an algorithm to estimate diffusion signals that are independent of echo time based on the moments of the marginal probability density function of diffusion. We demonstrate its utility in extracting tissue information not contaminated with multiple intra-voxel relaxation rates. We compare the performance of four types of filters that zoom into tissue components with different relaxation and diffusion properties and demonstrate it on an in-vivo human dataset. Experimental results show that these filters are able to characterize heterogeneous tissue microstructure. Moreover, the filtered diffusion signals are also able to distinguish fiber bundles with similar orientations but different relaxation rates. The proposed method thus allows to characterize the neural microstructure information in a robust and unique manner not possible using existing techniques.


Reciprocal relations between positive alcohol expectancies and peer use on adolescent drinking: An accelerated autoregressive cross-lagged model using the NCANDA sample.
Positive alcohol expectancies (PAE) and associating with drinking peers are reliable predictors of adolescent alcohol use. Knowledge of when and for whom these risk factors are most influential could enhance intervention effectiveness. Reciprocal relations between PAE and adolescent and peer alcohol use were examined between the ages of 13 and 18 in a sample (N = 566; 50% female) from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA), as well as sex differences in these associations. Associating with drinking peers prospectively predicted more frequent alcohol use for both sexes, although peer socialization was evident earlier for girls compared with boys. Higher PAE influenced later drinking in mid-adolescence, from age 14 to 16, for boys only. PAE influenced peer group selection for both sexes, although the influence was evident earlier in boys than girls. The relative impact of environmental risk factors for problematic alcohol use may vary over time and across developmental periods. These results suggest that prevention and treatment efforts for adolescent drinking can be improved by targeting age-appropriate risk factors. Early adolescent interventions may be best served by minimizing involvement with drinking peers and correcting normative beliefs of peer use. Among adolescent girls, early interventions focused on reducing peer influence may be most effective. Prevention and treatment programs aimed at addressing PAE would likely prove more effective for boys in mid- to late adolescence. (PsycINFO Database Record


Crystal structure of species D adenovirus fiber knobs and their sialic acid binding sites.
Adenovirus serotype 37 (Ad37) belongs to species D and can cause epidemic keratoconjunctivitis, whereas the closely related Ad19p does not. Primary cell attachment by adenoviruses is mediated through receptor binding of the knob domain of the fiber protein. The knobs of Ad37 and Ad19p differ at only two positions, Lys240Glu and Asn340Asp. We report the high-resolution crystal structures of the Ad37 and Ad19p knobs, both native and in complex with sialic acid, which has been proposed as a receptor for Ad37. Overall, the Ad37 and Ad19p knobs are very similar to previously reported knob structures, especially to that of Ad5, which binds the coxsackievirus-adenovirus receptor (CAR). Ad37 and Ad19p knobs are structurally identical with the exception of the changed side chains and are structurally most similar to CAR-binding knobs (e.g., that of Ad5) rather than non-CAR-binding knobs (e.g., that of Ad3). The two mutations in Ad19p result in a partial loss of the exceptionally high positive surface charge of the Ad37 knob but do not affect sialic acid binding. This site is located on the top of the trimer and binds both alpha(2,3) and alpha(2,6)-linked sialyl-lactose, although only the sialic acid residue makes direct contact. Amino acid alignment suggests that the sialic acid binding site is conserved in several species D serotypes. Our results show that the altered viral tropism and cell binding of Ad19p relative to those of Ad37 are not explained by a different binding ability toward sialyl-lactose.


Growth retardation and altered autonomic control in mice lacking brain serotonin.
Serotonin synthesis in mammals is initiated by 2 distinct tryptophan hydroxylases (TPH), TPH1 and TPH2. By genetically ablating TPH2, we created mice (Tph2(-/-)) that lack serotonin in the central nervous system. Surprisingly, these mice can be born and survive until adulthood. However, depletion of serotonin signaling in the brain leads to growth retardation and 50% lethality in the first 4 weeks of postnatal life. Telemetric monitoring revealed more extended daytime sleep, suppressed respiration, altered body temperature control, and decreased blood pressure (BP) and heart rate (HR) during nighttime in Tph2(-/-) mice. Moreover, Tph2(-/-) females, despite being fertile and producing milk, exhibit impaired maternal care leading to poor survival of their pups. These data confirm that the majority of central serotonin is generated by TPH2. TPH2-derived serotonin is involved in the regulation of behavior and autonomic pathways but is not essential for adult life.


[Evaluation of the functional component underlying the frequent attendance to a hospital emergency service and its economic consequences].
To analyse the psychosocial characteristics of frequent emergency department (ER) users with a relevant non-organic component and estimate the generated costs. Retrospective-descriptive study (Jan 1996-Jun 1997) about overusers (OU) defined as > = 3 visits/6 months during at least two 6 months periods, coming to our hospital's emergency department. Reviewing their medical records and making a psychiatric interview we identified Non-organic OU (NOU). Subsequently we estimated the cost generated by discharge visits during the first six months of 1997. Sixty six out of 220 OU were identified as NOU. The mean consultation rate was 11.3 +/- 9.4. Clinician-psychiatrist agreement on non-organicity was 72.7%. The most frequent diagnoses were: personality disorders (37.5%) and depression-anxiety (35%). Psychiatric OU were significantly younger (51.7 vs 62.5 years) and attended more often (17.6 vs. 9.9 times). In six months only one of 240 ER consultation cause admission. The mean cost of each discharge episode was 8682.9 +/- 6633.8 pta (25.06% due to variable costs). The cost per minute of emergency room stay was 19.26 ptas. Overall NOU attention cost during the six month period studied was 1,903,775 ptas (0.36% of overall ER costs). Compared with the rest of users, NOU entail a higher burden for the ER. Mentally-ill patients are younger and consult more frequently than the rest of OU. Only 25% of the cost per consultation is due to treatments, tests or diets.


Expression of TGFß1 and its receptors is associated with biological features of ovarian cancer and sensitivity to paclitaxel/carboplatin.
It has been suggested that expression of TGFß1 and its receptors [TGFß receptor type I (TßRI) and TGFß receptor type II (TßRII)] may play a key role in the proliferation and progression of epithelial ovarian cancer. We investigated the biological significance of TGFß1 and its receptors, as well as their association with the tumor response to paclitaxel (PTX) and carboplatin (CBDCA). We studied 24 patients with ovarian cancer, primary peritoneal cancer, or fallopian tube cancer who had undergone surgery and chemotherapy with PTX and CBDCA. Tissues from the primary tumor were examined and the expression of TGFß1, TßRI, and TßRII mRNA was assessed by the RNase protection assay. It was found that TGFß1 mRNA expression was significantly lower in the tumors of patients who had optimal surgery than in the tumors of patients with suboptimal surgery. TGFß1 mRNA expression was also significantly lower in tumors with high sensitivity to PTX and CBDCA than in those with low sensitivity. TßRI mRNA expression was not associated with any clinicopathological factors. Expression of TßRII mRNA was significantly higher in clear cell adenocarcinoma and mucinous adenocarcinoma, while it was lower in serous adenocarcinoma and endometrioid adenocarcinoma. Moreover, it tended to be higher in early-stage tumors compared with advanced tumors. Among TGFß1, TßRI, and TßRII, expression of TGFß1 mRNA was most strongly associated with progression-free survival. When the prognosis of the patients with advanced cancer was compared on the basis of TGFß1 mRNA expression, those whose tumors showed low expression tended to have a better prognosis than those whose tumors showed high expression. It is suggested that TGFß1 mRNA expression is an indicator of tumor sensitivity to standard therapy with PTX and CBDCA, that it can identify biologically aggressive and highly malignant tumors and that it can predict the prognosis of patients with ovarian cancer.


Metabolomics of Chronic Kidney Disease Progression: A Case-Control Analysis in the Chronic Renal Insufficiency Cohort Study.
Whereas several longitudinal metabolomics studies have been conducted in individuals with normal estimated glomerular filtration rate (eGFR) at baseline, disease progression among individuals with established chronic kidney disease (CKD) has not been rigorously examined. We performed a nested case-control study of rapid CKD progression in the Chronic Renal Insufficiency Cohort Study, profiling baseline plasma from 200 individuals each with eGFR slope <-3 ml/min/1.73 m2/year (cases) or between -1 and +1 ml/min/1.73 m2/year (controls), matched on baseline eGFR and proteinuria. To directly assess how the kidney modulates circulating metabolites, we profiled plasma from the aorta and renal vein of 25 hospital-based individuals. At baseline, cases and controls had a mean eGFR of 41.7 ± 13.3 and 45.0 ± 14.5 ml/min/1.73 m2, respectively. Ten plasma metabolites were nominally associated with CKD progression in logistic regression models adjusted for age, sex, race/ethnicity, hypertension, systolic and diastolic blood pressure, diabetes, eGFR and proteinuria; no metabolite achieved the Bonferroni-adjusted significance threshold (p < 0.0003). In a cross-sectional analysis, all 6 of the metabolites that were higher in cases than controls were significantly associated with eGFR at baseline. By contrast, threonine, methionine and arginine were lower in cases than in controls and had no association with baseline eGFR. Furthermore, in the hospital-based cohort that underwent renal arteriovenous sampling, these 3 metabolites were net released from the kidney. Combining these metabolites into a panel of markers further strengthened their association with CKD progression. Our results motivate interest in arginine, methionine and threonine as potential indicators of renal metabolic function and markers of renal prognosis.


Continued Decay of HIV Proviral DNA Upon Vaccination With HIV-1 Tat of Subjects on Long-Term ART: An 8-Year Follow-Up Study.
Introduction: Tat, a key HIV virulence protein, has been targeted for the development of a therapeutic vaccine aimed at cART intensification. Results from phase II clinical trials in Italy (ISS T-002) and South Africa (ISS T-003) indicated that Tat vaccination promotes increases of CD4+ T-cells and return to immune homeostasis while reducing the virus reservoir in chronically cART-treated patients. Here we present data of 92 vaccinees (59% of total vaccinees) enrolled in the ISS T-002 8-year extended follow-up study (ISS T-002 EF-UP, ClinicalTrials.gov NCT02118168). Results: Anti-Tat antibodies (Abs) induced upon vaccination persisted for the entire follow-up in 34/92 (37%) vaccinees, particularly when all 3 Ab classes (A/G/M) were present (66% of vaccinees), as most frequently observed with Tat 30 μg regimens. CD4+ T cells increased above study-entry levels reaching a stable plateau at year 5 post-vaccination, with the highest increase (165 cells/μL) in the Tat 30 μg, 3 × regimen. CD4+ T-cell increase occurred even in subjects with CD4+ nadir ≤ 250 cells/uL and in poor immunological responders and was associated with a concomitant increase of the CD4+/CD8+ T-cell ratio, a prognostic marker of morbidity/mortality inversely related to HIV reservoir size. Proviral DNA load decreased over time, with a half-life of 2 years and an estimated 90% reduction at year 8 in the Tat 30 μg, 3 × group. In multivariate analysis the kinetic and amplitude of both CD4+ T-cell increase and proviral DNA reduction were fastest and highest in subjects with all 3 anti-Tat Ab classes and in the 30 μg, 3 × group, irrespective of drug regimens (NNRTI/NRTI vs. PI). HIV proviral DNA changes from baseline were inversely related to CD4+/CD8+ T-cell ratio and CD4+ T-cell changes, and directly related to the changes of CD8+ T cells. Further, HIV DNA decay kinetics were inversely related to the frequency and levels of intermittent viremia. Finally, Tat vaccination was similarly effective irrespective of the individual immunological status or HIV reservoir size at study entry. Conclusions: Tat immunization induces progressive immune restoration and reduction of virus reservoirs above levels reached with long-term cART, and may represent an optimal vaccine candidate for cART intensification toward HIV reservoirs depletion, functional cure, and eradication strategies.


Platelet serotonin transporter function predicts default-mode network activity.
The serotonin transporter (5-HTT) is abundantly expressed in humans by the serotonin transporter gene SLC6A4 and removes serotonin (5-HT) from extracellular space. A blood-brain relationship between platelet and synaptosomal 5-HT reuptake has been suggested, but it is unknown today, if platelet 5-HT uptake can predict neural activation of human brain networks that are known to be under serotonergic influence. A functional magnetic resonance study was performed in 48 healthy subjects and maximal 5-HT uptake velocity (Vmax) was assessed in blood platelets. We used a mixed-effects multilevel analysis technique (MEMA) to test for linear relationships between whole-brain, blood-oxygen-level dependent (BOLD) activity and platelet Vmax. The present study demonstrates that increases in platelet Vmax significantly predict default-mode network (DMN) suppression in healthy subjects independent of genetic variation within SLC6A4. Furthermore, functional connectivity analyses indicate that platelet Vmax is related to global DMN activation and not intrinsic DMN connectivity. This study provides evidence that platelet Vmax predicts global DMN activation changes in healthy subjects. Given previous reports on platelet-synaptosomal Vmax coupling, results further suggest an important role of neuronal 5-HT reuptake in DMN regulation.


Therapeutic effect of topical administration of red onion extract in a murine model of allergic rhinitis.
The aim of this study was to evaluate the effect of topical administration of onion (Allium cepa) extract on nasal cavity for treatment of allergic rhinitis (AR). BALB/c mice were sensitized by intraperitoneal injection of ovalbumin (OVA) and challenged with intranasal instillation of OVA with or without onion extracts for five times a week on 3 consecutive weeks. Allergic symptom score according to frequencies of sneezing, serum total and OVA specific immunoglobulin E (IgE) level, cytokine levels of nasal mucosa and eosinophilic infiltration were analyzed. Allergic symptom score, serum total and OVA specific IgE, cytokine levels of nasal mucosa (interleukin (IL)-4, IL-5, IL-10, IL-13, IFN-γ, TNF-α and COX-2) and eosinophilic infiltration were higher in allergic mouse group than negative control group. Topical application of onion extracts significantly reduced allergic symptoms and OVA specific IgE levels. Cytokine levels of IL-4, IL-5, IL-10, IL-13 and IFN-γ were significantly decreased in groups treated with onion extract. In addition, eosinophil infiltration of nasal turbinate mucosa was also significantly decreased after treatment with onion extract. Topical administration of onion extract significantly reduces allergic rhinitis symptom and allergic inflammatory reaction in a murine allergic model. It can be assumed that the topical application of onion extract regulates allergic symptoms by suppressing the type-1 helper (Th1) and type-2 helper (Th2) responses and reducing the allergic inflammatory reaction.


Rapid visualization of macromolecular orientation by discrete frequency mid-infrared spectroscopic imaging.
Infrared (IR) spectroscopic imaging has been used to measure the composition and orientation of polymeric systems for decades. IR microscopy can provide detailed views of microscopic regions, allowing the observation of both morphology and molecular properties of a sample, but involves a trade-off between the spatial extent and details of molecular content. Here we describe an approximately two orders of magnitude faster approach to measure the spherulitic structure and molecular orientation in large semi-crystalline polymer samples compared to extant Fourier transform infrared (FT-IR) spectroscopic imaging. This discrete frequency approach utilizes individual narrowband emission lines of a quantum cascade laser (QCL) source to spectrally image large areas rapidly. The inherent polarization of the laser beam is employed to measure orientation, enabling calculation of Hermans in-plane orientation function along with molecular chain angles distribution.


Glutamine potentiates gentamicin to kill lab-evolved gentamicin-resistant and clinically isolated multidrug-resistant Escherichia coli.
Gentamicin is a conventional antibiotic in clinic. However, with the wide use of antibiotics, gentamicin-resistant Escherichia coli (E. coli) is an ever-increasing problem that causes infection in both humans and animals. Thus, it is especially important to restore gentamicin-mediated killing efficacy. E. coli K12 BW25113 cells were passaged in medium with and without gentamicin and obtain gentamicin-resistant (K12-R GEN ) and control (K12-S) strains, respectively. Then, the metabonomics of the two strains were analyzed by GC-MS approach. K12-R GEN metabolome was characterized as more decreased metabolites than increased metabolites. Meantime, in the most enriched metabolic pathways, almost all of the metabolites were depressed. Alanine, aspartate and glutamate metabolism and glutamine within the metabolic pathway were identified as the most key metabolic pathways and the most crucial biomarkers, respectively. Exogenous glutamine potentiated gentamicin-mediated killing efficacy in glutamine and gentamicin dose-and time-dependent manners in K12-R GEN . Further experiments showed that glutamine-enabled killing by gentamicin was effective to clinically isolated multidrug-resistant E. coli. These results suggest that glutamine provides an ideal metabolic environment to restore gentamicin-mediated killing, which not only indicates that glutamine is a broad-spectrum antibiotic synergist, but also expands the range of metabolites that contribute to the bactericidal efficiency of aminoglycosides.


Binaural hearing in children using Gaussian enveloped and transposed tones.
Children who use bilateral cochlear implants (BiCIs) show significantly poorer sound localization skills than their normal hearing (NH) peers. This difference has been attributed, in part, to the fact that cochlear implants (CIs) do not faithfully transmit interaural time differences (ITDs) and interaural level differences (ILDs), which are known to be important cues for sound localization. Interestingly, little is known about binaural sensitivity in NH children, in particular, with stimuli that constrain acoustic cues in a manner representative of CI processing. In order to better understand and evaluate binaural hearing in children with BiCIs, the authors first undertook a study on binaural sensitivity in NH children ages 8-10, and in adults. Experiments evaluated sound discrimination and lateralization using ITD and ILD cues, for stimuli with robust envelope cues, but poor representation of temporal fine structure. Stimuli were spondaic words, Gaussian-enveloped tone pulse trains (100 pulse-per-second), and transposed tones. Results showed that discrimination thresholds in children were adult-like (15-389 μs for ITDs and 0.5-6.0 dB for ILDs). However, lateralization based on the same binaural cues showed higher variability than seen in adults. Results are discussed in the context of factors that may be responsible for poor representation of binaural cues in bilaterally implanted children.


Normal Levels of Sox9 Expression in the Developing Mouse Testis Depend on the TES/TESCO Enhancer, but This Does Not Act Alone.
During mouse sex determination, transient expression of the Y-linked gene Sry up-regulates its direct target gene Sox9, via a 3.2 kb testis specific enhancer of Sox9 (TES), which includes a core 1.4 kb element, TESCO. SOX9 activity leads to differentiation of Sertoli cells, rather than granulosa cells from the bipotential supporting cell precursor lineage. Here, we present functional analysis of TES/TESCO, using CRISPR/Cas9 genome editing in mice. Deletion of TESCO or TES reduced Sox9 expression levels in XY fetal gonads to 60 or 45% respectively relative to wild type gonads, and reduced expression of the SOX9 target Amh. Although human patients heterozygous for null mutations in SOX9, which are assumed to have 50% of normal expression, often show XY female sex reversal, mice deleted for one copy of Sox9 do not. Consistent with this, we did not observe sex reversal in either TESCO-/- or TES-/- XY embryos or adult mice. However, embryos carrying both a conditional Sox9 null allele and the TES deletion developed ovotestes. Quantitative analysis of these revealed levels of 23% expression of Sox9 compared to wild type, and a significant increase in the expression of the granulosa cell marker Foxl2. This indicates that the threshold in mice where sex reversal begins to be seen is about half that of the ~50% levels predicted in humans. Our results demonstrate that TES/TESCO is a crucial enhancer regulating Sox9 expression in the gonad, but point to the existence of additional enhancers that act redundantly.


The genome of the Western clawed frog Xenopus tropicalis.
The western clawed frog Xenopus tropicalis is an important model for vertebrate development that combines experimental advantages of the African clawed frog Xenopus laevis with more tractable genetics. Here we present a draft genome sequence assembly of X. tropicalis. This genome encodes more than 20,000 protein-coding genes, including orthologs of at least 1700 human disease genes. Over 1 million expressed sequence tags validated the annotation. More than one-third of the genome consists of transposable elements, with unusually prevalent DNA transposons. Like that of other tetrapods, the genome of X. tropicalis contains gene deserts enriched for conserved noncoding elements. The genome exhibits substantial shared synteny with human and chicken over major parts of large chromosomes, broken by lineage-specific chromosome fusions and fissions, mainly in the mammalian lineage.


Relationships between triathlon performance and pacing strategy during the run in an international competition.
The purpose of the present study was to examine relationships between athlete's pacing strategies and running performance during an international triathlon competition. Running split times for each of the 107 finishers of the 2009 European Triathlon Championships (42 females and 65 males) were determined with the use of a digital synchronized video analysis system. Five cameras were placed at various positions of the running circuit (4 laps of 2.42 km). Running speed and an index of running speed variability (IRSVrace) were subsequently calculated over each section or running split. Mean running speed over the first 1272 m of lap 1 was 0.76 km·h-1 (+4.4%) and 1.00 km·h-1 (+5.6%) faster than the mean running speed over the same section during the three last laps, for females and males, respectively (P < .001). A significant inverse correlation was observed between RSrace and IRSVrace for all triathletes (females r = -0.41, P = .009; males r = -0.65, P = .002; and whole population -0.76, P = .001). Females demonstrated higher IRSVrace compared with men (6.1 ± 0.5 km·h-1 and 4.0 ± 1.4 km·h-1, for females and males, respectively, P = .001) due to greater decrease in running speed over uphill sections. Pacing during the run appears to play a key role in high-level triathlon performance. Elite triathletes should reduce their initial running speed during international competitions, even if high levels of motivation and direct opponents lead them to adopt an aggressive strategy.


The Chronic Pain Grade questionnaire: validation and reliability in postal research.
The Chronic Pain Grade questionnaire has been proposed as an interview-administered, multi-dimensional measure of chronic pain severity in selected populations with chronic pain in the United States of America. It has not previously been tested in the United Kingdom, in self-completion form or in an unselected general population. We undertook a postal survey to assess its reliability, validity and acceptability in these circumstances, using a general practice population in Scotland, with a practice population of 11202 patients. A random sample of 400 patients aged over 18 was drawn, stratified for age, gender and receipt or non-receipt of regular prescriptions for pain-relieving medication. The dimensions and sub-scales of the Chronic Pain Grade were compared with the SF-36 general health questionnaire and questions relating to duration of any pain and attempts to seek treatment for this. The methodological approach proposed by Streiner and Norman (1989) was used to assess validity and reliability. A response rate of 76% was achieved. Cronbach's alpha was > 0.9 and item-total correlations were all high, indicating good internal consistency and reliability. Validity was confirmed by psychometric testing, including confirmatory factor analysis. Good correlations with comparable dimensions of the SF-36 general health questionnaire confirmed convergent validity. Construct validity was confirmed by testing scores against duration of pain and treatment sought for pain. We concluded that the Chronic Pain Grade questionnaire is a useful, reliable and valid measure of severity of chronic pain. It translates well into UK English and is acceptable in general population postal research.


Cannabidiol increases survival and promotes rescue of cognitive function in a murine model of cerebral malaria.
Cerebral malaria (CM) is a severe complication resulting from Plasmodium falciparum infection that might cause permanent neurological deficits. Cannabidiol (CBD) is a nonpsychotomimetic compound of Cannabis sativa with neuroprotective properties. In the present work, we evaluated the effects of CBD in a murine model of CM. Female mice were infected with Plasmodium berghei ANKA (PbA) and treated with CBD (30mg/kg/day - 3 or 7days i.p.) or vehicle. On 5th day-post-infection (dpi), at the peak of the disease), animals were treated with single or repeated doses of Artesunate, an antimalarial drug. All groups were tested for memory impairment (Novel Object Recognition or Morris Water Maze) and anxiety-like behaviors (Open field or elevated plus maze test) in different stages of the disease (at the peak or after the complete clearance of the disease). Th1/Th2 cytokines and neurotrophins (brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF)) were measured in the prefrontal cortex and hippocampus of experimental groups. PbA-infected mice displayed memory deficits and exhibited increase in anxiety-like behaviors on the 5dpi or after the clearance of the parasitemia, effects prevented by CBD treatment. On 5dpi, TNF-α and IL-6 increased in the hippocampus, while only IL-6 increased in the prefrontal cortex. CBD treatment resulted in an increase in BDNF expression in the hippocampus and decreased levels of proinflammatory cytokines in the hippocampus (TNF-α) and prefrontal cortex (IL-6). Our results indicate that CBD exhibits neuroprotective effects in CM model and might be useful as an adjunctive therapy to prevent neurological symptoms following this disease.


Using drugs in un/safe spaces: Impact of perceived illegality on an underground supervised injecting facility in the United States.
Supervised injection facilities (SIFs) are spaces where people can consume pre-obtained drugs in hygienic circumstances with trained staff in attendance to provide emergency response in the event of an overdose or other medical emergency, and to provide counselling and referral to other social and health services. Over 100 facilities with formal legal sanction exist in ten countries, and extensive research has shown they reduce overdose deaths, increase drug treatment uptake, and reduce social nuisance. No facility with formal legal sanction currently exists in the United States, however one community-based organization has successfully operated an 'underground' facility since September 2014. Twenty three qualitative interviews were conducted with people who used the underground facility, staff, and volunteers to examine the impact of the facility on peoples' lives, including the impact of lack of formal legal sanction on service provision. Participants reported that having a safe space to inject drugs had led to less injections in public spaces, greater ability to practice hygienic injecting practices, and greater protection from fatal overdose. Constructive aspects of being 'underground' included the ability to shape rules and procedures around user need rather than to meet political concerns, and the rapid deployment of the project, based on immediate need. Limitations associated with being underground included restrictions in the size and diversity of the population served by the site, and reduced ability to closely link the service to drug treatment and other health and social services. Unsanctioned supervised injection facilities can provide a rapid and user-driven response to urgent public health needs. This work draws attention to the need to ensure such services remain focused on user-defined need rather than external political concerns in jurisdictions where supervised injection facilities acquire local legal sanction.


The provision of healthy food in a school tuck shop: does it influence primary-school students' perceptions, attitudes and behaviours towards healthy eating?
To investigate students' tuck shop buying behaviour, choices of lunchbox items and healthy eating perceptions and attitudes at a school with a nutritionally regulated tuck shop and a school with a conventional tuck shop. Mixed-methods research comprising a cross-sectional survey and focus groups. Bloemfontein, South Africa. Randomly selected grade 2 to 7 students from a school with a nutritionally regulated tuck shop (school A; n 116) and a school with a conventional tuck shop (school B; n 141) completed a self-administered questionnaire about perceptions, attitudes, buying behaviours and lunchbox content. Six students per grade (n 72) in each school took part in focus group discussions to further explore concepts pertaining to healthy eating. In school A, older students had a negative attitude towards their 'healthy' tuck shop, while younger students were more positive. School B students were positive towards their conventional tuck shop. In both schools students wanted their tuck shop to allow them to choose from healthy and unhealthy items. School A students mostly bought slushies, iced lollies and baked samoosas, while school B students mostly bought sweets and crisps. The lunchboxes of school A students contained significantly (P<0·05) more healthy items but also significantly more unhealthy items. A single intervention such as having a nutritionally regulated tuck shop at a primary school cannot advance the healthy school food environment in its totality. A multi-pronged approach is recommended and awareness must be created among all role players, including parents who are responsible for preparing lunchboxes.


Sellimonas intestinalis gen. nov., sp. nov., isolated from human faeces.
A Gram-stain-positive and obligately anaerobic bacterial strain, BR72T, forming ivory yellow colonies was isolated from a faecal sample of a healthy Korean woman. 16S rRNA gene sequence analysis indicated that strain BR72T belongs to Clostridium cluster XIVa and represents a distinct phyletic line within the family Lachnospiraceae. The most closely related strains were Clostridium nexile DSM 1787T (94.1 % 16S rRNA gene sequence similarity), Coprococcus comes ATCC 27758T (93.5 %), Ruminococcus torques ATCC 27756T (93.5 %), Ruminococcus lactaris ATCC 29176T (93.5 %), Clostridium aerotolerans DSM 5434T (93.1 %) and Eubacterium fissicatena DSM 3598T (92.9 %). The DNA G+C content of strain BR72T based on its genome sequence was 45.3 mol%. The major cellular fatty acids were C16 : 0, C14 : 0, and iso-C17 : 1 I and/or anteiso-C17 : 1 B. Acetic acid was produced from glucose fermentation. Other physiological and biochemical comparisons allowed the phenotypic differentiation of strain BR72T from the members of the family Lachnospiraceae. Based on the phylogenetic and phenotypic findings, this strain is considered to represent a novel species of a new genus belonging to the family Lachnospiraceae and the name Sellimonas intestinalis gen. nov., sp. nov. is proposed. The type strain of Sellimonas intestinalis is BR72T ( = KCTC 15479T = JCM 30749T).


A Privacy Preserving Scheme for Nearest Neighbor Query.
In recent years, location privacy concerns that arise when using the nearest neighbor query services have gained increasing attention, as such services have become pervasive in mobile social networks devices and the IoT environments. State-of-the-art privacy preservation schemes focus on the obfuscation of the location information, which has suffered from various privacy attacks and the tradeoff of the quality of service. By noticing the fact that the user's location could be replaced by their surrounding wireless sensor infrastructures in proximity, in this paper, we propose a wireless sensor access point-based scheme for the nearest neighbor query, without using the location of the user. Then, a noise-addition-based method that preserves user's location privacy was proposed. To further strengthen the adaptability of the approach to real-world environments, several performance-enhancing methods are introduced, including an R-tree-based Noise-Data Retrieval Algorithm (RNR), and a nearest neighbor query method based on our research. Both performance and security evaluations are conducted to validate our approach. The results show the effectiveness and the practicality of our work.


The Fas-FADD death domain complex structure reveals the basis of DISC assembly and disease mutations.
The death-inducing signaling complex (DISC) formed by the death receptor Fas, the adaptor protein FADD and caspase-8 mediates the extrinsic apoptotic program. Mutations in Fas that disrupt the DISC cause autoimmune lymphoproliferative syndrome (ALPS). Here we show that the Fas-FADD death domain (DD) complex forms an asymmetric oligomeric structure composed of 5-7 Fas DD and 5 FADD DD, whose interfaces harbor ALPS-associated mutations. Structure-based mutations disrupt the Fas-FADD interaction in vitro and in living cells; the severity of a mutation correlates with the number of occurrences of a particular interaction in the structure. The highly oligomeric structure explains the requirement for hexameric or membrane-bound FasL in Fas signaling. It also predicts strong dominant negative effects from Fas mutations, which are confirmed by signaling assays. The structure optimally positions the FADD death effector domain (DED) to interact with the caspase-8 DED for caspase recruitment and higher-order aggregation.


Tobacco promotion restriction policies on social media.
Tobacco promotion is prolific on social media, with each platform setting their own restrictions on tobacco promotion and sales. We evaluated the policies related to tobacco product promotion and sales on 11 sites that are popular with youth in May 2021: Discord, Facebook, Instagram, Pinterest, Reddit, Snapchat, TikTok, Tumblr, Twitch, Twitter and YouTube. Nine of the 11 sites prohibited paid advertising for tobacco products. However, only three of them clearly prohibited sponsored content (ie, social influencers) that promotes tobacco. Six platforms restricted content that sells tobacco products and three tried to prohibit underage access to content that promotes or sells tobacco products. Although most platform policies prohibited paid tobacco advertising, few addressed more novel strategies, such as sponsored/influencer content and few had age-gating to prevent youth access. There is a pressing need to regulate tobacco promotion on social media platforms.


Neuromelanin related ultra-high field signal intensity of the locus coeruleus differs between Parkinson's disease and controls.
Neuromelanin related signal changes in catecholaminergic nuclei are considered as a promising MRI biomarker in Parkinson's disease (PD). Until now, most studies have investigated the substantia nigra (SN), while signal changes might be more prominent in the locus coeruleus (LC). Ultra-high field MRI improves the visualisation of these small brainstem regions and might support the development of imaging biomarkers in PD. To compare signal intensity of the SN and LC on Magnetization Transfer MRI between PD patients and healthy controls (HC) and to explore its association with cognitive performance in PD. This study was conducted using data from the TRACK-PD study, a longitudinal 7T MRI study. A total of 78 early-stage PD patients and 36 HC were included. A mask for the SN and LC was automatically segmented and manually corrected. Neuromelanin related signal intensity of the SN and LC was compared between PD and HC. PD participants showed a lower contrast-to-noise ratio (CNR) in the right SN (p = 0.029) and left LC (p = 0.027). After adding age as a confounder, the CNR of the right SN did not significantly differ anymore between PD and HC (p = 0.055). Additionally, a significant positive correlation was found between the SN CNR and memory function. This study confirms that neuromelanin related signal intensity of the LC differs between early-stage PD patients and HC. No significant difference was found in the SN. This supports the theory of bottom-up disease progression in PD. Furthermore, loss of SN integrity might influence working memory or learning capabilities in PD patients.


Differentiation of cancer cells in two-dimensional and three-dimensional breast cancer models by Raman spectroscopy.
We demonstrate the first application of Raman spectroscopy in diagnosing nonmalignant, premalignant, malignant, and metastatic stages of breast cancer in a three-dimensional (3-D) cell culture model that closely mimics an in vivo environment. Comprehensive study comparing classification in two-dimensional (2-D) and 3-D cell models was performed using statistical methods composed of principal component analysis for exploratory analysis and outlier removal, partial least squares discriminant analysis, and elastic net regularized regression for classification. Our results show that Raman spectroscopy with an appropriate classification tool has excellent resolution to discriminate the four stages of breast cancer progression, with a near 100% accuracy for both 2-D and 3-D cell models. The diversity in chemical groups related to nucleic acids, proteins, and lipids, among other chemicals, were identified by appropriate peaks in the Raman spectra that correspond to the correct classification of the different stages of tumorigenesis model comprising of MCF10A, MCF10AneoT, MCF10CA1h, and MCF10CA1a cell lines. An explicit relationship between wavenumber and the stages of cancer progression was identified by the elastic net variable selection.


A sigma(54)-dependent PTS permease of the mannose family is responsible for sensitivity of Listeria monocytogenes to mesentericin Y105.
Sensitivity of Listeria monocytogenes to the bacteriocin mesentericin Y105 was previously shown to be dependent on the sigma(54) subunit of the RNA polymerase. This points towards expression of particular sigma(54)-dependent genes. The present study describes first, ManR, a new sigma(54)-associated activator, and second, Ell(t)(Man), a new sigma(54)-dependent PTS permease of the mannose family, both involved in sensitivity to mesentericin Y105, since interruption of their corresponding genes led to resistance of L. monocytogenes EGDe. Ell(t)(Man) is likely composed of three subunits encoded by the mpt operon (mptA, mptC and mptD genes). Interruption of either the proximal (mptA) or distal (mptD) gene led to resistance, supporting results obtained in Enterococcus faecalis. Accordingly, such PTS permeases of the mannose family should be involved in sensitivity of different target strains to mesentericin Y105. In L. monocytogenes, expression of the mpt operon is shown to be controlled by sigma(54) and ManR and to be induced by both glucose and mannose. The latter result indicates that these sugars are transported by the Ell(t)(Man) permease. Moreover, these sugars correlatively induce sensitivity of L. monocytogenes to mesentericin Y105, strongly favouring the primary role of Ell(t)(Man). MptD, a membrane subunit of Ell(t)(Man), presents an additional domain compared to most IID(Man) subunits described in data banks. An in-frame deletion of this domain in mptD led to resistance of L. monocytogenes, showing its connection with sensitivity and suggesting that it could be directly involved in the recognition of the target cell by mesentericin Y105. Taken together, the results of this work demonstrate that Ell(t)(Man) is prominent in sensitivity to mesentericin Y105 and could be a receptor for subclass IIa bacteriocins.


Srs2 and Sgs1-Top3 suppress crossovers during double-strand break repair in yeast.
Very few gene conversions in mitotic cells are associated with crossovers, suggesting that these events are regulated. This may be important for the maintenance of genetic stability. We have analyzed the relationship between homologous recombination and crossing-over in haploid budding yeast and identified factors involved in the regulation of crossover outcomes. Gene conversions unaccompanied by a crossover appear 30 min before conversions accompanied by exchange, indicating that there are two different repair mechanisms in mitotic cells. Crossovers are rare (5%), but deleting the BLM/WRN homolog, SGS1, or the SRS2 helicase increases crossovers 2- to 3-fold. Overexpressing SRS2 nearly eliminates crossovers, whereas overexpression of RAD51 in srs2Delta cells almost completely eliminates the noncrossover recombination pathway. We suggest Sgs1 and its associated topoisomerase Top3 remove double Holliday junction intermediates from a crossover-producing repair pathway, thereby reducing crossovers. Srs2 promotes the noncrossover synthesis-dependent strand-annealing (SDSA) pathway, apparently by regulating Rad51 binding during strand exchange.


Prevalence of overweight and obesity among U.S. military veterans.
Overweight and obesity are increasingly contributing to disease burden among military populations. The purpose of this study was to calculate and examine the prevalence of overweight and obesity among the veteran population. Data were obtained from the 2004 Behavioral Risk Factor Surveillance System. Overweight (body mass index > or = 25 kg/m2) prevalence in veterans was 73.3% (SE, 0.4%) for males and 53.6% (SE 1.7%) for females. Obesity (body mass index > or = 30 kg/m2) prevalence in veterans was 25.3% (SE, 0.4%) for males and 21.2% (SE, 1.4%) for females. After adjusting for sociodemographics and health status, veterans were no more likely to be overweight (odds ratio, 1.05; 95% confidence interval, 0.99-1.11) or obese (odds ratio 0.99; confidence interval, 0.93-1.05) than nonveterans. Despite previous participation in a culture and environment that selects for and enforces body weight standards, veterans have a high prevalence of overweight and obesity that is similar to general population estimates.


Palliative care service use by older people: Time trends from a mortality follow-back study between 2005 and 2014.
The need for increased use and timely initiation of palliative care for all people, not just those who die with cancer, has been advocated worldwide over the past decade. To investigate whether there has been a time trend in the use of palliative care services and the timing of their initiation for older people. Mortality follow-back survey among general practitioners in a nationally representative Sentinel Network in 2005-2010, 2013 and 2014 in Belgium. Of all their patients who died non-suddenly aged 65+ years, general practitioners reported sociodemographic and clinical data, use of any of the palliative care services available in Belgium and when the first of these services was initiated. General practitioners identified 5344 deaths. Overall, palliative care service use increased from 39% in 2005 to 63% in 2014 ( p < 0.001). The use of a reference person for palliative care in a care home increased from 12% to 26% ( p < 0.001) and of a palliative homecare team from 14% to 17.5% ( p < 0.01), but hospital-based palliative care services did not increase. Controlling for sociodemographic characteristics, no differences were obtained over time in the proportion of cancer/non-cancer patients for whom they provided care. The timing of initiation of palliative care services remained unchanged at a median of 15 days before death. Palliative care service use has increased mostly in care homes, possibly as a result of policy changes, while hospital-based palliative care services lag behind. Contrary to recommendations, access for non-cancer patients may remain difficult and palliative care is often initiated late in the disease trajectory.


Role of fosaprepitant, a neurokinin Type 1 receptor antagonist, in morphine-induced antinociception in rats.
Opioids such as morphine form the cornerstone in the treatment of moderate to severe pain. However, opioids also produce serious side effects such as tolerance. Fosaprepitant is a substance P (SP) receptor antagonist, which is used for treating chemotherapy-induced nausea and vomiting. SP is an important neuropeptide mediating transmission of pain at the spinal level. Thus, it was hypothesized that combining morphine with fosaprepitant would increase the antinociceptive effect of morphine. The objectives were to evaluate the effect of fosaprepitant on morphine-induced antinociception in rats and to investigate its mechanism of action. Sprague-Dawley rats were injected with morphine (10 mg/kg twice daily) and/or fosaprepitant (30 mg/kg once daily) for 7 days. Pain threshold was assessed by the hot plate test. Expression of SP and calcitonin gene-related peptide (CGRP) in the spinal cords of these rats was evaluated by immunohistochemistry. Morphine administration resulted in an antinociceptive effect compared to the control group (day 1 and to a lesser extent on day 4). The decreased antinociception despite continued morphine treatment indicated development of tolerance. Co-administration of fosaprepitant attenuated tolerance to morphine (days 1 and 3) and increased the antinociceptive effect compared to control group (days 1-4). Expression of SP was increased in the morphine + fosaprepitant group. The results show that fosaprepitant attenuates the development of tolerance to morphine and thereby, increases the antinociceptive effect. This is likely linked to decreased release of SP from presynaptic terminals.


The bio-interface between functionalized Au NR@GO nanoplatforms with protein corona and their impact on delivery and release system.
Interaction of nanoplatforms with biomolecules in biological fluids alters nanoplatforms approach to target tissue and deliver their cargo. Here in, three nanoplatforms were utilized as a carrier to detect the effects of subsequent biomolecules on gene delivery using NIR thermal therapy. Nanoplatforms included; graphene oxide coated gold nanorods (NR@GO), PEGylated NR@GO (NR@GO-PEG) and poly L arginine functionalized NR@GO-PEG (NR@GO-PEG-PLArg). Results indicated that incubation of nanoplatforms in different concentrations of human plasma induced the evolution of layer of proteins (corona) with different thickness on the surface of nanoplatforms. Protein corona decreased the surface charge and optical properties of nanoplatforms. Corona subunits of ITIH, HAS and APOs protein family were extracted from NR@GO-PEG-PLArg surface that play a major role in cellular internalization of nanoplatforms. Moreover, NR@GO-PEG-PLArg remarkably targeted the cancer cells due to uncovered long linear chains of targeting agent (PLArg). The process of gene release and activating apoptotic pathway were enhanced by NIR thermal therapy, which could disrupt the electrostatic interactions and release the protein corona and genes from the surface of nanoplatforms. In conclusion, modification of nanoplatforms with targeting agents could alter the composition of corona toward well interaction with cell and deliver the therapeutic agent.


Danish dementia mice suggest that loss of function and not the amyloid cascade causes synaptic plasticity and memory deficits.
According to the prevailing "amyloid cascade hypothesis," genetic dementias such as Alzheimer's disease and familial Danish dementia (FDD) are caused by amyloid deposits that trigger tauopathy, neurodegeneration, and behavioral/cognitive alterations. To efficiently reproduce amyloid lesions, murine models of human dementias invariably use transgenic expression systems. However, recent FDD transgenic models showed that Danish amyloidosis does not cause memory defects, suggesting that other mechanisms cause Danish dementia. We studied an animal knock-in model of FDD (FDD(KI/+)) genetically congruous with human cases. FDD(KI/+) mice present reduced Bri2 levels, impaired synaptic plasticity and severe hippocampal memory deficits. These animals show no cerebral lesions that are reputed characteristics of human dementia, such as tangles or amyloid plaques. Bri2(+/-) mice exhibit synaptic and memory deficits similar to FDD(KI/+) mice, and memory loss of FDD(KI/+) mice is prevented by expression of WT BRI2, indicating that Danish dementia is caused by loss of BRI2 function. Together, the data suggest that clinical dementia in Danish patients occurs via a loss of function mechanism and not as a result of amyloidosis and tauopathy.


A mitotic kinase scaffold depleted in testicular seminomas impacts spindle orientation in germ line stem cells.
Correct orientation of the mitotic spindle in stem cells underlies organogenesis. Spindle abnormalities correlate with cancer progression in germ line-derived tumors. We discover a macromolecular complex between the scaffolding protein Gravin/AKAP12 and the mitotic kinases, Aurora A and Plk1, that is down regulated in human seminoma. Depletion of Gravin correlates with an increased mitotic index and disorganization of seminiferous tubules. Biochemical, super-resolution imaging, and enzymology approaches establish that this Gravin scaffold accumulates at the mother spindle pole during metaphase. Manipulating elements of the Gravin-Aurora A-Plk1 axis prompts mitotic delay and prevents appropriate assembly of astral microtubules to promote spindle misorientation. These pathological responses are conserved in seminiferous tubules from Gravin(-/-) mice where an overabundance of Oct3/4 positive germ line stem cells displays randomized orientation of mitotic spindles. Thus, we propose that Gravin-mediated recruitment of Aurora A and Plk1 to the mother (oldest) spindle pole contributes to the fidelity of symmetric cell division.


Modeling dynamics of isotropic dielectrics in a laminar heterogeneous configuration.
The predictive capabilities of models that satisfy the Weiner bounds and Hashin-Shtrikman (HS) bounds were studied for isotropic dielectrics in a laminar heterogeneous configuration oriented perpendicular to the electric field. The dynamics were investigated isothermally using broadband dielectric relaxation spectroscopy (DRS) in the frequency range of 1 MHz to 100 mHz. The molecules chosen for study were low molecular weight glass formers, glycerol, phenyl salicylate, imidazole, and dimethyl sulfoxide, and macromolecules, polymethylhydrosiloxane, polyvinylpyrrolidone-co-vinyl acetate, poly-dl-lactic acid, and poly l-lactic acid. It was found that none of the models were able to adequately predict in entirety the resultant dynamics. Of the models studied, the most successful were the HS upper bound (HSUB), the complementary universal Weiner equation (CWE), and the Lichtenecker model for the dimensional parameter, ζ = -1/2. The least successful models were the upper Weiner bound (UWB), the Neelakantaswamy, Turkman, and Sarkar (NTS) model for ζ = 1/2, and the Lichtenecker model for ζ = 1/2.


Comparison of different sampling techniques and of different culture methods for detection of group B streptococcus carriage in pregnant women.
Streptococcus agalactiae (group B streptococcus; GBS) is a significant cause of perinatal and neonatal infections worldwide. To detect GBS colonization in pregnant women, the CDC recommends isolation of the bacterium from vaginal and anorectal swab samples by growth in a selective enrichment medium, such as Lim broth (Todd-Hewitt broth supplemented with selective antibiotics), followed by subculture on sheep blood agar. However, this procedure may require 48 h to complete. We compared different sampling and culture techniques for the detection of GBS. A total of 300 swabs was taken from 100 pregnant women at 35-37 weeks of gestation. For each subject, one rectovaginal, one vaginal and one rectal ESwab were collected. Plating onto Columbia CNA agar (CNA), group B streptococcus differential agar (GBSDA) (Granada Medium) and chromID Strepto B agar (CA), with and without Lim broth enrichment, were compared. The isolates were confirmed as S. agalactiae using the CAMP test on blood agar and by molecular identification with tDNA-PCR or by 16S rRNA gene sequence determination. The overall GBS colonization rate was 22%. GBS positivity for rectovaginal sampling (100%) was significantly higher than detection on the basis of vaginal sampling (50%), but not significantly higher than for rectal sampling (82%). Direct plating of the rectovaginal swab on CNA, GBSDA and CA resulted in detection of 59, 91 and 95% of the carriers, respectively, whereas subculturing of Lim broth yielded 77, 95 and 100% positivity, respectively. Lim broth enrichment enabled the detection of only one additional GBS positive subject. There was no significant difference between GBSDA and CA, whereas both were more sensitive than CNA. Direct culture onto GBSDA or CA (91 and 95%) detected more carriers than Lim broth enrichment and subculture onto CNA (77%). One false negative isolate was observed on GBSDA, and three false positives on CA. In conclusion, rectovaginal sampling increased the number GBS positive women detected, compared to vaginal and/or rectal sampling. Direct plating on CA and/or GBSDA provided rapid detection of GBS that was at least as sensitive and specific as the CDC recommended method of Lim broth subcultured onto non chromogenic agar.