Efficient condensed-phase production of perdeuterated soluble and membrane proteins.
Protein perdeuteration approaches have tremendous value in protein NMR studies, but are limited by the high cost of perdeuterated media. Here, we demonstrate that E. coli cultures expressing proteins using either the condensed single protein production method (cSPP), or conventional pET expression plasmids, can be condensed prior to protein expression, thereby providing high-quality (2)H, (13)C, (15)N-enriched protein samples at 2.5-10% the cost of traditional methods. As an example of the value of such inexpensively-produced perdeuterated proteins, we produced (2)H, (13)C, (15)N-enriched E. coli cold shock protein A (CspA) and EnvZb in 40x condensed phase media, and obtained NMR spectra suitable for 3D structure determination. The cSPP system was also used to produce (2)H, (13)C, (15)N-enriched E. coli plasma membrane protein YaiZ and outer membrane protein X (OmpX) in condensed phase. NMR spectra can be obtained for these membrane proteins produced in the cSPP system following simple detergent extraction, without extensive purification or reconstitution. This allows a membrane protein's structural and functional properties to be characterized prior to reconstitution, or as a probe of the effects of subsequent purification steps on the structural integrity of membrane proteins. We also provide a standardized protocol for production of perdeuterated proteins using the cSPP system. The 10-40 fold reduction in costs of fermentation media provided by using a condensed culture system opens the door to many new applications for perdeuterated proteins in spectroscopic and crystallographic studies.


Stage-specific effects of fibroblast growth factor 2 on the differentiation of dental pulp cells.
Dentinogenesis is a complex and multistep process, which is regulated by various growth factors, including members of the fibroblast growth factor (FGF) family. Both positive and negative effects of FGFs on dentinogenesis have been reported, but the underlying mechanisms of these conflicting results are still unclear. To gain a better insight into the role of FGF2 in dentinogenesis, we used dental pulp cells from various transgenic mice, in which fluorescent protein expression identifies cells at different stages of odontoblast differentiation. Our results showed that the continuous exposure of pulp cells to FGF2 inhibited mineralization and revealed both the stimulatory and inhibitory effects of FGF2 on the expression of markers of dentinogenesis and various transgenes. During the proliferation phase of in vitro growth, FGF2 increased the expression of markers of dentinogenesis and the percentages of dentin matrix protein 1/green fluorescent protein (DMP1-GFP)-positive functional odontoblasts and dentin sialophosphoprotein (DSPP)-Cerulean-positive odontoblasts. Additional exposure to FGF2 during the differentiation/mineralization phase of in vitro growth decreased the extent of mineralization and the expression of markers of dentinogenesis and of the DMP1-GFP and DSPP-Cerulean transgenes. Recovery experiments showed that the inhibitory effects of FGF2 on dentinogenesis were related to the blocking of the differentiation of cells into mature odontoblasts. These observations together showed the stage-specific effects of FGF2 on dentinogenesis by dental pulp cells, and they provide critical information for the development of improved treatments for vital pulp therapy and dentin regeneration.


Programmable RNA-binding protein composed of repeats of a single modular unit.
The ability to monitor and perturb RNAs in living cells would benefit greatly from a modular protein architecture that targets unmodified RNA sequences in a programmable way. We report that the RNA-binding protein PumHD (Pumilio homology domain), which has been widely used in native and modified form for targeting RNA, can be engineered to yield a set of four canonical protein modules, each of which targets one RNA base. These modules (which we call Pumby, for Pumilio-based assembly) can be concatenated in chains of varying composition and length, to bind desired target RNAs. The specificity of such Pumby-RNA interactions was high, with undetectable binding of a Pumby chain to RNA sequences that bear three or more mismatches from the target sequence. We validate that the Pumby architecture can perform RNA-directed protein assembly and enhancement of translation of RNAs. We further demonstrate a new use of such RNA-binding proteins, measurement of RNA translation in living cells. Pumby may prove useful for many applications in the measurement, manipulation, and biotechnological utilization of unmodified RNAs in intact cells and systems.


Macrophages eliminate circulating tumor cells after monoclonal antibody therapy.
The use of monoclonal antibodies (mAbs) as therapeutic tools has increased dramatically in the last decade and is now one of the mainstream strategies to treat cancer. Nonetheless, it is still not completely understood how mAbs mediate tumor cell elimination or the effector cells that are involved. Using intravital microscopy, we found that antibody-dependent phagocytosis (ADPh) by macrophages is a prominent mechanism for removal of tumor cells from the circulation in a murine tumor cell opsonization model. Tumor cells were rapidly recognized and arrested by liver macrophages (Kupffer cells). In the absence of mAbs, Kupffer cells sampled tumor cells; however, this sampling was not sufficient for elimination. By contrast, antitumor mAb treatment resulted in rapid phagocytosis of tumor cells by Kupffer cells that was dependent on the high-affinity IgG-binding Fc receptor (FcγRI) and the low-affinity IgG-binding Fc receptor (FcγRIV). Uptake and intracellular degradation were independent of reactive oxygen or nitrogen species production. Importantly, ADPh prevented the development of liver metastases. Tumor cell capture and therapeutic efficacy were lost after Kupffer cell depletion. Our data indicate that macrophages play a prominent role in mAb-mediated eradication of tumor cells. These findings may help to optimize mAb therapeutic strategies for patients with cancer by helping us to aim to enhance macrophage recruitment and activity.


Avoidable factors contributing to death after head injury.
We reviewed 116 patients, known to have talked before dying after head injury, to discover factors which had contributed to death but which might have been avoided. All the patients were admitted to a neurosurgical unit and had a neuropathological post-mortem examination. One or more avoidable factors were identified in 86 patients (74%); an avoidable factor was judged certainly to have contributed to death in 63 patients (54%). The most common avoidable factor was delay in the treatment of an intracranial haematoma; others included poorly controlled epilepsy, meningitis, hypoxia, and hypotension. Changes in the management of patients with head injuries which reduce the incidence of avoidable factors should decrease mortality from this condition.


Flow Cytometric Measurement of Blood Cells with BCR-ABL1 Fusion Protein in Chronic Myeloid Leukemia.
Chronic myeloid leukemia (CML) is characterized in the majority of cases by a t(9;22)(q34;q11) translocation, also called the Philadelphia chromosome, giving rise to the BCR-ABL1 fusion protein. Current treatment with tyrosine kinase inhibitors is directed against the constitutively active ABL1 domain of the fusion protein, and minimal residual disease (MRD) after therapy is monitored by real-time quantitative PCR (RQ-PCR) of the fusion transcript. Here, we describe a novel approach to detect and enumerate cells positive for the BCR-ABL1 fusion protein by combining the in situ proximity ligation assay with flow cytometry as readout (PLA-flow). By targeting of the BCR and ABL1 parts of the fusion protein with one antibody each, and creating strong fluorescent signals through rolling circle amplification, PLA-flow allowed sensitive detection of cells positive for the BCR-ABL1 fusion at frequencies as low as one in 10,000. Importantly, the flow cytometric results correlated strongly to those of RQ-PCR, both in diagnostic testing and for MRD measurements over time. In summary, we believe this flow cytometry-based method can serve as an attractive approach for routine measurement of cells harboring BCR-ABL1 fusions, also allowing simultaneously assessment of other cell surface markers as well as sensitive longitudinal follow-up.


Fish oil delays lymphoma progression in the TLL mouse.
The objective was to investigate the effects of omega-3 fatty acids, known for their anti-inflammatory effects, on time to lymphoma progression and survival in the TLL mouse, a strain genetically prone to developing aggressive T-cell lymphoma. Compared to mice fed a standard diet, TLL mice fed omega-3 (menhaden fish oil) experienced a significant delay in disease progression and were more likely to remain alive and symptom free during the first 8 months of the study. In contrast, omega-6 supplementation (corn oil) did not significantly affect lymphoma progression. Irrespective of diet, all mice eventually progressed, and 1-year survival was not different between the groups. Immunological analysis demonstrated a significantly altered B-cell compartment and fewer NK cells in healthy C57Black6 mice fed omega-3, compared to controls. In conclusion, a diet rich in omega-3 fatty acids delays lymphoma development in the TLL mouse possibly by mechanisms that include complex effects on immune function.


Activation of the BMP4/Smad1 Pathway Promotes Retinal Ganglion Cell Survival and Axon Regeneration.
We investigate if the BMP4/Smad1 intracellular signaling pathway is neuroprotective and axogenic in adult rodent retinal ganglion cells (RGC) in vivo and in vitro. Adult retinal cultures were prepared from intact and after optic nerve crush (ONC) injured rats that have been stimulated to survive and regenerate using an intravitreal peripheral nerve (PN) graft. Laser capture microdissection (LCM) then was used to isolate RGC with and without neurites. Quantitative RT-PCR determined changes in BMP4/Smad1 signaling pathway mRNA. Immunohistochemistry confirmed localization of BMP4 and activation of Smad1 in ONC+PN-stimulated RGC in vivo. BMP4 peptide was used to stimulate RGC survival and neurite/axon regeneration in vitro and in vivo. Finally, the rapamycin sensitivity of the effects was determined in BMP4-stimulated RGC in vitro and in vivo. In retinal cultures prepared from intact and ONC+PN-stimulated rats, RGC with neurites had upregulated regeneration-related and BMP4/Smad1 signaling pathway mRNA levels, while low levels of these mRNAs were present in RGC isolated without neurites. An optimal dose of 200 ng/mL BMP4 peptide in vitro promoted approximately 30% RGC survival and disinhibited RGC neurite outgrowth, despite the presence of inhibitory CNS myelin extracts. BMP4 also promoted approximately 30% RGC survival in vivo and stimulated significant RGC axon regeneration at 100, 200, and 400 μm beyond the lesion site. Finally, the response of RGC to BMP4 treatment in vitro and in vivo was rapamycin-insensitive. Activation of the BMP4/Smad1 pathway promotes survival and axon regeneration independent of mTOR and, therefore, may be of therapeutic interest.


Electrostatic interactions between charged dielectric particles in an electrolyte solution: constant potential boundary conditions.
The problem of electrostatic interactions between colloidal particles in an electrolyte solution has been solved within the Debye-Hückel approximation using the boundary condition of constant potential. The model has been validated in two independent ways - by considering the limiting cases obtained from DLVO theory and comparison with the available experimental data. The presented methodology provides the final part of a complete theory of pairwise electrostatic interactions between spherical colloidal particles; one that embraces all possible chemical scenarios within the boundary conditions of constant potential and constant charge.


Vulnerability and resilience after early institutional care: The Greek Metera study.
The aim of the study was to examine possible influences on individual differences in adolescence in response to early institutional care in infancy not involving either generalized privation or subnutrition. Fifty-two adopted adolescents aged 13 years who received institutional care in infancy at the Metera Babies Centre and 36 adolescents of the same age who were raised in their biological families participated in the study. Adolescents' attachment relationships, cognition, behavioral adjustment and use of psychological services were assessed. Marked heterogeneity in outcomes was found. No predictive effects were found for preinstitutional features or for adoptive circumstances. By contrast a large effect was found for institutional care extending beyond the age of 2 years and for quality of institutional care as experienced at an individual level. There was a close association between prolonged institutional care and disorganized attachment while in the institution, but the main institutional effect derived from the length of time in the institution.


Novel deep eutectic solvent-functionalized carbon nanotubes adsorbent for mercury removal from water.
Due to the interestingly tolerated physicochemical properties of deep eutectic solvents (DESs), they are currently in the process of becoming widely used in many fields of science. Herein, we present a novel Hg2+ adsorbent that is based on carbon nanotubes (CNTs) functionalized by DESs. A DES formed from tetra-n-butyl ammonium bromide (TBAB) and glycerol (Gly) was used as a functionalization agent for CNTs. This novel adsorbent was characterized using Raman spectroscopy, Fourier transform infrared (FTIR) spectroscopy, XRD, FESEM, EDX, BET surface area, and Zeta potential. Later, Hg2+ adsorption conditions were optimized using response surface methodology (RSM). A pseudo-second order model accurately described the adsorption of Hg2+. The Langmuir and Freundlich isotherm models described the absorption of Hg2+ on the novel adsorbent with acceptable accuracy. The maximum adsorption capacity was found to be 177.76mg/g.


Acute hyperammonemia after L-asparaginase administration in a dog.
To describe a previously unreported and potentially fatal complication of L-asparaginase (L-asp) administration in a dog. A 7-year-old, 6.6 kg, female spayed Beagle presented with a 1-week history of progressive inappetance and lethargy. Diagnostic tests identified the presence of stage Vb lymphoma and liver dysfunction. The dog was treated with L-asp at 400 IU/kg, corticosteroids, and IV fluids. Within 12 hours the dog became depressed, vomited, and developed abdominal pain. Within 24 hours, the dog's mentation progressed from obtunded to comatose; subsequently the dog developed a "decerebrate posture." Blood ammonia concentrations exceeded 1,000 μmol/L (1,700 μg/dL). Treatment with broad-spectrum antimicrobials, lactulose enemas, and continuous renal replacement therapy were initiated without response and the dog suffered cardiopulmonary arrest. The purpose of this report is to describe the development of severe hyperammonemia after L-asp therapy in a dog, which has not been previously reported in the literature. Given the rapid progression and fatal outcome observed in this case, early recognition may be crucial for management and treatment of this complication.


A novel technique of tangential, circumferential, scleral tunnel in 20-gauge transconjunctival sutureless vitrectomy: optical coherence tomography-aided analysis of wound integrity and clinical outcome.
To describe a novel technique of sclerotomy construction to facilitate 20-gauge transconjunctical sutureless vitrectomy (TSV) along with the evaluation of the wound integrity. The surgical technique is described. One hundred consecutive patients who underwent TSV were evaluated for wound leaks, postoperative hypotony, endophthalmitis and any other complication related to surgery. The sclerotomies of eight patients (24 ports) were analysed by imaging with anterior segment optical coherence tomography immediately after surgery, and on the first postoperative day and after the first postoperative month. 104 eyes of 100 patients were evaluated with a mean follow-up of 9.6 months. All cases underwent surgery with standard 20-gauge instrumentation and vitrectomy techniques. Five sclerotomies were found to leak at the end of surgery, requiring a suture. Anterior segment optical coherence tomography images were obtained from eight eyes with good apposition of the tunnel noted in all the cases. Mean intraocular pressure was 18.7 mm Hg on the first postoperative day. One patient had hypotony without leak and this patient had pre-existing hypotony due to chronic panuveitis. There was no instance of postoperative endophthalmitis. This technique of 20-gauge TSV achieves good wound apposition with a low incidence of complications while using standard 20-gauge instrumentation and vitrectomy techniques.


15-Deoxy-Delta12,14-prostaglandin J(2) induces death receptor 5 expression through mRNA stabilization independently of PPARgamma and potentiates TRAIL-induced apoptosis.
15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), the terminal derivative of the PGJ series, is emerging as a potent antineoplastic agent among cyclopentenone prostaglandins derivatives and also known as the endogenous ligand of peroxisome proliferator-activated receptor gamma (PPARgamma). On the other hand, death receptor 5 (DR5) is a specific receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is one of the most promising candidates for new cancer therapeutics. Here, we report that 15d-PGJ(2) induces DR5 expression at both mRNA and protein levels, resulting in the synergistic sensitization of TRAIL-induced apoptosis in human neoplastic cells, such as Jurkat human leukemia cells or PC3 human prostate cancer cells. 15d-PGJ(2) significantly increased DR5 mRNA stability, whereas it did not activate DR5 promoter activity. Synthetic PPARgamma agonists, such as pioglitazone or rosiglitazone, did not mimic the DR5-inducing effects of 15d-PGJ(2), and a potent PPARgamma inhibitor GW9662 failed to block DR5 induction by 15d-PGJ(2), suggesting PPARgamma-independent mechanisms. Cotreatment with 15d-PGJ(2) and TRAIL enhanced the sequential activation of caspase-8, caspase-10, caspase-9, caspase-3, and Bid. DR5/Fc chimera protein, zVAD-fmk pancaspase inhibitor, and caspase-8 inhibitor efficiently blocked the activation of these apoptotic signal mediators and the induction of apoptotic cell death enhanced by cotreatment with 15d-PGJ(2) and TRAIL. Moreover, a double-stranded small interfering RNA targeting DR5 gene, which suppressed DR5 up-regulation by 15d-PGJ(2), significantly attenuated apoptosis induced by cotreatment with 15d-PGJ(2) and TRAIL. These results suggest that 15d-PGJ(2) is a potent sensitizer of TRAIL-mediated cancer therapeutics through DR5 up-regulation.


2-Amino-6-chloro-N-methyl-benzamide.
In the title compound, C8H9ClN2O, the dihedral angle between the benzene ring and the methyl-amide substituent is 68.39 (11)°. In the crystal, mol-ecules are linked by N-H⋯O hydrogen bonds, forming layers parallel to the ab plane.


Genetic reconstitution of the human adenovirus type 2 temperature-sensitive 1 mutant defective in endosomal escape.
Human adenoviruses infect the upper and lower respiratory tracts, the urinary and digestive tracts, lymphoid systems and heart, and give rise to epidemic conjunctivitis. More than 51 human serotypes have been identified to-date, and classified into 6 species A-F. The species C adenoviruses Ad2 and Ad5 (Ad2/5) cause upper and lower respiratory disease, but how viral structure relates to the selection of particular infectious uptake pathways is not known. An adenovirus mutant, Ad2-ts1 had been isolated upon chemical mutagenesis in the past, and shown to have unprocessed capsid proteins. Ad2-ts1 fails to package the viral protease L3/p23, and Ad2-ts1 virions do not efficiently escape from endosomes. It had been suggested that the C22187T point mutation leading to the substitution of the conserved proline 137 to leucine (P137L) in the L3/p23 protease was at least in part responsible for this phenotype. To clarify if the C22187T mutation is necessary and sufficient for the Ad2-ts1 phenotype, we sequenced the genes encoding the structural proteins of Ad2-ts1, and confirmed that the Ad2-ts1 DNA carries the point mutation C22187T. Introduction of C22187T to the wild-type Ad2 genome in a bacterial artificial chromosome (Ad2-BAC) gave Ad2-BAC46 virions with the full Ad2-ts1 phenotype. Reversion of Ad2-BAC46 gave wild-type Ad2 particles indicating that P137L is necessary and sufficient for the Ad2-ts1 phenotype. The kinetics of Ad2-ts1 uptake into cells were comparable to Ad2 suggesting similar endocytic uptake mechanisms. Surprisingly, infectious Ad2 or Ad5 but not Ad2-ts1 uptake required CALM (clathrin assembly lymphoid myeloid protein), which controls clathrin-mediated endocytosis and membrane transport between endosomes and the trans-Golgi-network. The data show that no other mutations than P137L in the viral protease are necessary to give rise to particles that are defective in capsid processing and endosomal escape. This provides a basis for genetic analyses of distinct host requirements for Ad endocytosis and escape from endosomes.


The ecology of the microbiome: Networks, competition, and stability.
The human gut harbors a large and complex community of beneficial microbes that remain stable over long periods. This stability is considered critical for good health but is poorly understood. Here we develop a body of ecological theory to help us understand microbiome stability. Although cooperating networks of microbes can be efficient, we find that they are often unstable. Counterintuitively, this finding indicates that hosts can benefit from microbial competition when this competition dampens cooperative networks and increases stability. More generally, stability is promoted by limiting positive feedbacks and weakening ecological interactions. We have analyzed host mechanisms for maintaining stability-including immune suppression, spatial structuring, and feeding of community members-and support our key predictions with recent data.


Support person interventions to increase use of quitline services among racially diverse low-income smokers: A pilot study.
Social support from nonsmokers may have a role in prompting smokers to use evidence-based cessation treatment. Prior studies found that an intervention for nonsmoking support persons (SPs) was effective for promoting smokers' use of free, state quitline services. This pilot study adapted and assessed feasibility of this intervention for a racially diverse, low-income population. Single group, non-randomized design enrolling SP-smoker dyads with low income status enrolled in one of three study "waves" of 10 pairs each. Participants were recruited using flyers and in-person outreach methods. The SP intervention included a 1-session coaching call and written materials; study waves 2 and 3 also included text messaging and a monetary incentive for smokers who used quitline services. Using content analysis, the intervention was iteratively adapted based on SP feedback. Baseline measures assessed socio-demographics, dyad and tobacco use characteristics. Follow-up assessments were conducted among SPs at 1-month follow-up and among smokers at 3-months follow-up. Feasibility indicators were recruitment, retention, and SP intervention acceptability and adherence. Secondary outcomes were smokers' use of any quitline service verified by quitline staff and 7-day, point prevalence, biochemically verified smoking abstinence at 3 months. Recruitment of 30 dyads was feasible; in-person recruitment methods were the most successful. SPs who completed follow-up assessments found the intervention acceptable, suggesting only minor content modifications, and they perceived the quitline information as novel. But the study had some feasibility challenges (e.g., SP coaching call completion: 60% and SP study retention: 53%). At 3 months, 2 smokers (7%) had used any quitline service and 13% were biochemically confirmed smoking abstinent. This pilot study demonstrated feasibility of recruiting SP-smoker dyads from diverse, low-income communities. While the intervention was well received, its delivery was not feasible in this population. Results suggest that further consumer adaptation of the intervention is needed among both SPs and smokers.


Viral load in tissues during the early and chronic phase of non-pathogenic SIVagm infection.
African green monkeys (AGMs) persistently infected with SIVagm do not develop AIDS, although their plasma viremia levels can reach those reported for pathogenic HIV-1 and SIVmac infections. In contrast, the viral burden in lymph nodes in SIVagm-infected AGMs is generally lower in comparison with HIV/SIVmac pathogenic infections, at least during the chronic phase of SIVagm infection. We searched for the primary targets of viral replication, which might account for the high viremias in SIVagm-infected AGMs. We evaluated for the first time during primary infection SIVagm dissemination in various lymphoid and non-lymphoid tissues. Sixteen distinct organs at a time point corresponding to maximal virus production were analyzed for viral RNA and DNA load. At days 8 and 9 p.i., viral RNA could be detected in a wide range of tissues, such as jejunum, spleen, mesenteric lymph nodes, thymus and lung. Quantification of viral DNA and RNA as well as of productively infected cells revealed that viral replication during this early phase takes place mainly in secondary lymphoid organs and in the gut (5 x 10(4)-5 x 10(8) RNA copies/10(6) cells). By 4 years p.i., RNA copy numbers were below detection level in thymus and lung. Secondary lymphoid organs displayed 6 x 10(2)-2 x 10(6) RNA copies/10(6) cells, while some tissue fragments of ileum and jejunum still showed high viral loads (up to 10(9) copies/10(6) cells). Altogether, these results indicate a rapid dissemination of SIVagm into lymphoid tissues, including the small intestine. The latter, despite showing marked regional variations, most likely contributes significantly to the high levels of viremia observed during SIVagm infection.


Taxonomy and phylogeny of industrial solvent-producing clostridia.
We performed a systematic study of 55 solvent-producing clostridial strains, the majority of which are currently classified as Clostridium acetobutylicum strains, by using a combination of biotyping and DNA fingerprint analysis. The biotyping procedures used included rifampin susceptibility testing, bacteriocin typing, and bacteriophage typing. The 55 strains examined exhibited a good correlation between their biotypes and DNA fingerprints, which allowed us to divide them into nine groups. The DNA fingerprints of the nine groups differed markedly, but within each group the DNA fingerprints exhibited a high level of similarity. To determine the phylogenetic relationships of the nine groups, we performed a 16S rRNA gene sequence analysis. The results of a comparative analysis of the partial sequence corresponding to positions 830 to 1383 (Escherichia coli numbering) of the 16S rRNA gene indicated that the nine biotype groups could be assembled into four taxonomic groups. The complete 16S rRNA sequences of strains representing these groups were determined. Our phylogenetic analysis revealed that the amylolytic type strain C. acetobutylicum ATCC 824 (taxonomic group I) was only distantly related to the saccharolytic strains belonging to taxonomic groups II, III, and IV (levels of sequence similarity, 90 to 90.5%). The strains belonging to taxonomic groups II, III, and IV, represented by C. acetobutylicum NCP 262, "Clostridium saccharoperbutylacetonicum" N1-4, and C. acetobutylicum NCIMB 8052T (T = type strain), respectively, were closely related (levels of sequence similarity, 98.2 to 98.9%). C. acetobutylicum NCIMB 8052T exhibited a level of similarity of 100% with the type strain of Clostridium beijerinckii. Reclassification of the saccharolytic solvent-producing strains is necessary, and possible names for the four taxonomic groups are discussed.


Stereotactic heavy-charged-particle Bragg-peak radiation for intracranial arteriovenous malformations.
Heavy-charged-particle radiation has several advantages over protons and photons for the treatment of intracranial lesions; it has an improved physical distribution of the dose deep in tissue, a small angle of lateral scattering, and a sharp distal falloff of the dose. We present detailed clinical and radiologic follow-up in 86 patients with symptomatic but surgically inaccessible cerebral arteriovenous malformations that were treated with stereotactic helium-ion Bragg-peak radiation. The doses ranged from 8.8 to 34.6 Gy delivered to volumes of tissue of 0.3 to 70 cm3. Two years after radiation treatment, the rate of complete obliteration of the lesions, as detected angiographically, was 94 percent for lesions smaller than 4 cm3, 75 percent for those of 4 to 25 cm3, and 39 percent for those larger than 25 cm3. After three years, the rates of obliteration were 100, 95, and 70 percent, respectively. Major neurologic complications occurred in 10 patients (12 percent), of whom 8 had permanent deficits. All these complications occurred in the initial stage of the protocol, before the maximal dose of radiation was reduced to 19.2 Gy. In addition, hemorrhage occurred in 10 patients from residual malformations between 4 and 34 months after treatment. Seizures and headaches were less severe in 63 percent of the 35 and 68 percent of the 40 patients, respectively, who had them initially. Given the natural history of these inaccessible lesions and the high risks of surgery, we conclude that heavy-charged-particle radiation is an effective therapy for symptomatic, surgically inaccessible intracranial arteriovenous malformations. The current procedure has two disadvantages: a prolonged latency period before complete obliteration of the vascular lesion and a small risk of serious neurologic complications.


Phylogenetic analysis of the GST family in Anopheles (Nyssorhynchus) darlingi.
Anopheles darlingi Root, 1926 and Anopheles gambiae (Diptera: Culicidae) are the most important human malaria vectors in South America and Africa, respectively. The two species are estimated to have diverged 100 million years ago. Studies on the phylogenetics and evolution of gene sequences, such as glutathione S-transferase (GST) in disease-transmitting mosquitoes are scarce. The sigma class GST (KC890767) from the transcriptome of An. darlingi captured in the Brazilian Amazon was studied by in silico hybridization, and mapped to chromosome 3 of An. gambiae. The sigma class GST of An. darlingi was used for phylogenetic analyses to understand the GST base composition of the most recent common ancestor between An. darlingi, Anopheles gambiae, Aedes aegypti and Culex quinquefasciatus. The GST (KC890767) of An. darlingi was studied to generate the main divergence branches using a Neighbor-Joining and bootstrapping approaches to confirm confidence levels on the tree nodes that separate the An. darlingi and other mosquito species. The results showed divergence between An. gambiae, Ae. Aegypti, Cx. quinquefasciatus, and Phlebotomus papatasi as outgroup, and the homology relationship between sigma class GST of An. darlingi and GSTS1_1 gene of An. gambiae was valuable for phylogenetic and evolutionary studies.


Evolution of Laparoscopic Surgery for Colorectal Cancer: The Impact of the Clinical Outcomes of Surgical Therapy Group Trial.
The Clinical Outcomes of Surgical Therapy Group (COST) Trial established laparoscopic procedures offer short-term benefits while preserving the same oncologic outcomes in colorectal cancer (CRC) patients compared with open procedures. The aim of this study was to evaluate the trend of laparoscopic resection for CRC before and after the publication of the COST Trial. Retrospective study of surgically treated CRC patients was conducted from January 2000 to December 2009. Surveillance, Epidemiology, and End Results Program and Medicare. Between 2000 and 2009, 147,388 patients underwent resection for CRC, 9,901 resections were performed laparoscopically. In 2000, 1.0 per cent of colorectal resections were performed laparoscopically. There was a dramatic increase in laparoscopic resections in 2009 to 30.4 per cent. During this time period, rates of laparoscopic resections increased for all tumor stages. Right colectomies and early stage tumors had the most significant rise from 3.1 per cent (2004) to 38.7 per cent (2009) and 4.41 per cent (2004) to 39.17 per cent (2009), respectively; whereas, rectal and later stage tumors resection rates were more modest from 2.1 per cent (2004) to 13.2 per cent (2009) and 1.41 per cent (2004) to 17.10 per cent (2009), respectively. This study demonstrates the COST Trial had a significant impact on utilization of laparoscopic colorectal resection for CRC. Although laparoscopic colorectal resections have been accepted for all types of CRCs, more difficult procedures are being adopted at slower rates.


Alkyl chain length effects on double-deck assembly at a liquid/solid interface.
Controlled double-deck packing is an appealing means to expand upon conventional 2D self-assembly which is critical in crystal engineering, yet it is rare and poorly understood. Herein, we report the first systematic study of double-deck assembly in a series of alkylated aminoquinone derivatives at the liquid-solid interface. The competition between the fraction of alkyl chains adsorbed on the surface and the optimal conformation of the alkyl chains near the head group leads to a stepwise structural transformation ranging from complete double-deck packing to complete monolayer packing. Alkyl chains on the bottom or top layer of the double-deck assemblies were selectively visualized by carefully tuning the scanning tunneling microscopy settings. A method to easily identify mirror image domains was discovered based on the coincidence of domain boundaries with a graphite main axis. The effect of molecular symmetry and metal complexation on the formation of the double-deck assembly was also explored. Based on 2D crystal engineering principles, this bottom-up double-deck assembly can potentially provide an essential toehold for constructing precise 3D hierarchical structures.


Greenhouse Effects due to Man-Mad Perturbations of Trace Gases.
Nitrous oxide, methane, ammonia, and a number of other trace constituents in the earth's atmosphere have infrared absorption bands in the spectral region 7 to 14 microm and contribute to the atmospheric greenhouse effect. The concentrations of these trace gases may undergo substantial changes because of man's activities. Extensive use of chemical fertilizers and combustion of fossil fuels may perturb the nitrogen cycle, leading to increases in atmospheric N(2)O, and the same perturbing processes may increase the amounts of atmospheric CH(4) and NH(3). We use a one-dimensional radiative-convective model for the atmospheric thermal structure to compute the change in the surface temperature of the earth for large assumed increases in the trace gas concentrations; doubling the N(2)O, CH(4), and NH(3) concentrations is found to cause additive increases in the surface temperature of 0.7 degrees , 0.3 degrees , and 0.1 degrees K, respectively. These systematic effects on the earth's radiation budget would have substantial climatic significance. It is therefore important that the abundances of these trace gases be accurately monitored to determine the actual trends of their concentrations.


Lack of expression of surface immunoglobulin light chains in B-cell non-Hodgkin lymphomas.
We describe 10 cases of B-cell non-Hodgkin lymphoma (NHL) that did not express immunoglobulin kappa or lambda light chains by dual-color flow cytometry. Cases were identified from 298 consecutive cases of B-cell NHL and included follicular center cell lymphoma, diffuse large B-cell lymphoma, small noncleaved cell lymphoma, and small lymphocytic lymphoma. One case did not express any immunoglobulin heavy chain (IgH) as well; however, isolated expression of IgG heavy chain was seen in another case. Immunoglobulin heavy chains were not part of the lymphoma panel in other cases. All 3 cases in which gene rearrangement studies were performed showed rearrangement of IgH genes, including the case that did not express surface IgH chains. Immunoglobulin kappa light chain genes were rearranged in 2 of 3 cases and were in germline configuration in the third. All 147 cases of benign lymph nodes analyzed by flow cytometry showed polyclonal expression of immunoglobulin kappa and lambda light chains. Because of the absence of surface immunoglobulin light chains, these tumors must be distinguished from precursor B-cell acute lymphoblastic leukemia, plasma cell tumors, and rare cases of florid follicular hyperplasia that do not express surface immunoglobulins. The absence of immunoglobulin expression on malignant B cells can result from defects at any level from gene transcription to translocation of fully assembled proteins to the cell surface.


Attenuation of the formation of DNA-repair foci containing RAD51 in Fanconi anaemia.
The role of the Fanconi anaemia genes in DNA repair was examined by a quantitative analysis of nuclear DNA repair foci in FA primary fibroblasts after ionising irradiation using antibodies directed against RAD51, MRE11 and BRCA1 for visualisation. IR induced foci detected with anti-RAD51, but not those detected with anti-MRE11, are reduced in fibroblasts of all eight FA complementation groups in comparison to control cells. Correction of FA-A, FA-C and FA-G cells by retroviral cDNA transfer specifically corrected the RAD51-foci response but did not affect formation of foci containing BRCA1 or MRE11. Since all FA cells, except FA-D1, lack the monoubiquitinated FANCD2-L protein, this isoform is likely to be involved in the formation of nuclear foci containing RAD51 in diploid FA cells. FA-D1 cells show the same attenuation in RAD51 foci formation, suggesting that the unknown FANCD1 protein is similarly involved in RAD51 foci formation, either independently or as a subsequent step in the FANCD2 pathway. These findings indicate that Fanconi anaemia cells have an impairment in the RAD51-dependent homologous recombination pathway for DNA repair, explaining their chromosomal instability and extreme sensitivity to DNA cross-linking agents.


A model for paired-multinomial data and its application to analysis of data on a taxonomic tree.
In human microbiome studies, sequencing reads data are often summarized as counts of bacterial taxa at various taxonomic levels specified by a taxonomic tree. This article considers the problem of analyzing two repeated measurements of microbiome data from the same subjects. Such data are often collected to assess the change of microbial composition after certain treatment, or the difference in microbial compositions across body sites. Existing models for such count data are limited in modeling the covariance structure of the counts and in handling paired multinomial count data. A new probability distribution is proposed for paired-multinomial count data, which allows flexible covariance structure and can be used to model repeatedly measured multivariate count data. Based on this distribution, a test statistic is developed for testing the difference in compositions based on paired multinomial count data. The proposed test can be applied to the count data observed on a taxonomic tree in order to test difference in microbiome compositions and to identify the subtrees with different subcompositions. Simulation results indicate that proposed test has correct type 1 errors and increased power compared to some commonly used methods. An analysis of an upper respiratory tract microbiome data set is used to illustrate the proposed methods.


Comparing methods of analyzing fMRI statistical parametric maps.
Approaches for the analysis of statistical parametric maps (SPMs) can be crudely grouped into three main categories in which different philosophies are applied to delineate activated regions. These being type I error control thresholding, false discovery rate (FDR) control thresholding and posterior probability thresholding. To better understand the properties of these main approaches, we carried out a simulation study to compare the approaches as they would be used on real data sets. Using default settings, we find that posterior probability thresholding is the most powerful approach, and type I error control thresholding provides the lowest levels of type I error. False discovery rate control thresholding performs in between the other approaches for both these criteria, although for some parameter settings this approach can approximate the performance of posterior probability thresholding. Based on these results, we discuss the relative merits of the three approaches in an attempt to decide upon an optimal approach. We conclude that viewing the problem of delineating areas of activation as a classification problem provides a highly interpretable framework for comparing the methods. Within this framework, we highlight the role of the loss function, which explicitly penalizes the types of errors that may occur in a given analysis.


Current and future perspectives on functional molecular imaging in nephro-urology: theranostics on the horizon.
In recent years, a paradigm shift from single-photon-emitting radionuclide radiotracers toward positron-emission tomography (PET) radiotracers has occurred in nuclear oncology. Although PET-based molecular imaging of the kidneys is still in its infancy, such a trend has emerged in the field of functional renal radionuclide imaging. Potentially allowing for precise and thorough evaluation of renal radiotracer urodynamics, PET radionuclide imaging has numerous advantages including precise anatomical co-registration with CT images and dynamic three-dimensional imaging capability. In addition, relative to scintigraphic approaches, PET can allow for significantly reduced scan time enabling high-throughput in a busy PET practice and further reduces radiation exposure, which may have a clinical impact in pediatric populations. In recent years, multiple renal PET radiotracers labeled with 11C, 68Ga, and 18F have been utilized in clinical studies. Beyond providing a precise non-invasive read-out of renal function, such radiotracers may also be used to assess renal inflammation. This manuscript will provide an overview of renal molecular PET imaging and will highlight the transformation of conventional scintigraphy of the kidneys toward novel, high-resolution PET imaging for assessing renal function. In addition, future applications will be introduced, e.g. by transferring the concept of molecular image-guided diagnostics and therapy (theranostics) to the field of nephrology.


Traumatic grief in Kenyan bereaved parents following the Kyanguli School fire tragedy.
Following the death of 67 boys in a fire tragedy at Kyanguli School in rural Kenya, the level of traumatic grief was assessed in a sample of 164 parents and guardians whose sons died in the fire. The study was cross-sectional. Counseling services were offered to all the bereaved parents soon after the tragedy. The subjects were interviewed using the Traumatic Grief Scale. A group of 92 parents/guardians was interviewed 2 months after the event, while the other group of 72 was assessed 7 days later. The second group of bereaved parents also completed the Self Rating Questionnaire (SRQ) and the Ndetei-Othieno-Kathuku scale (NOK). Over 90% of parents from both groups had a yearning for the departed and found themselves searching for him quite often. There was no much difference in terms of symptoms profile or intensity between the two groups. It appears that the counseling offered had minimal impact on the levels of distress.


Agarose coated spherical micro resonator for humidity measurements.
A new type of fiber optic relative humidity (RH) sensor based on an agarose coated silica microsphere resonator is proposed and experimentally demonstrated. Whispering gallery modes (WGMs) in the micro resonator are excited by evanescent coupling using a tapered fiber with ~3.3 µm waist diameter. A change in the relative humidity of the surrounding the resonator air induces changes in the refractive index (RI) and thickness of the Agarose coating layer. These changes in turn lead to a spectral shift of the WGM resonances, which can be related to the RH value after a suitable calibration. Studies of the repeatability, long-term stability, measurement accuracy and temperature dependence of the proposed sensor are carried out. The RH sensitivity of the proposed sensor depends on the concentration of the agarose gel which determines the initial thickness of the deposited coating layer. Studies of the micro- resonators with coating layers fabricated from gels with three different Agarose concentrations of 0.5%, 1.125% and 2.25 wt./vol.% showed that an increase in the initial thickness of the coating material results in an increase in sensitivity but also leads to a decrease of quality factor (Q) of the micro resonator. The highest sensitivity achieved in our experiments was 518 pm/%RH in the RH range from 30% to 70%. The proposed sensor offers the advantages of a very compact form factor, low hysteresis, good repeatability, and low cross sensitivity to temperature.


Development of encorafenib for BRAF-mutated advanced melanoma.
To describe the pharmacological properties, preclinical and clinical data of the novel V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF)-inhibitor encorafenib (LGX818) and to compare these with established BRAF-inhibitors in the treatment of locally advanced or metastatic melanoma. Encorafenib has shown improved efficacy in the treatment of metastatic melanoma in comparison with vemurafenib. Combination with the MEK inhibitor (MEKi) binimetinib allows for higher dose intensities of encorafenib further improving response rates (RRs). Combination therapy with BRAF and MEKi has evolved as a standard of care in the treatment of locally advanced or metastatic BRAF-mutated melanoma. Despite compelling initial RRs, development of treatment resistance eventually leads to tumor progression in the majority of BRAF/MEK-inhibitor treated patients. Moreover, treatment-related adverse events are frequent, resulting in a substantial proportion of dose modifications and/or treatment discontinuations. The second-generation BRAF inhibitor encorafenib has been developed aiming at improved efficacy and tolerability through modifications in pharmacological properties. Clinical phase 3 data show improved progression-free survival both for encorafenib monotherapy and combination therapy with binimetinib compared with vemurafenib. Overall survival data and regulatory approval of this novel substance are eagerly awaited.


Functional expression of the new gap junction gene connexin47 transcribed in mouse brain and spinal cord neurons.
A new mouse gap junction gene that codes for a protein of 46,551 Da has been identified and designated connexin47 (Cx47). It mapped as a single-copy gene to mouse chromosome 11. In human HeLa cells and Xenopus oocytes, expression of mouse Cx47 or a fusion protein of Cx47 and enhanced green fluorescent protein induced intercellular channels that displayed strong sensitivity to transjunctional voltage. Tracer injections in Cx47-transfected HeLa cells revealed intercellular diffusion of neurobiotin, Lucifer yellow, and 4',6-diamidino-2-phenylindole. Recordings of single channels yielded a unitary conductance of 55 pS main state and 8 pS substate. Cx47 mRNA expression was high in spinal cord and brain but was not found in retina, liver, heart, and lung. A low level of Cx47 expression was detected in ovaries. In situ hybridizations demonstrated high expression in alpha motor neurons of the spinal cord, pyramidal cells of the cortex and hippocampus, granular and molecular layers of the dentate gyrus, and Purkinje cells of the cerebellum as well as several nuclei of the brainstem. This expression pattern is distinct from, although partially overlapping with, that of the neuronally expressed connexin36 gene. Thus, electrical synapses in adult mammalian brain are likely to consist of different connexin proteins depending on the neuronal subtype.


Promoting tobacco cessation and smoke-free workplaces through community outreach partnerships in Puerto Rico.
Puerto Rico (PR) has a lower smoking prevalence than the United States (14.8% vs. 21.2%, respectively); nevertheless, the five leading causes of death are associated with smoking. There is a need to implement evidence-based tobacco control strategies in PR. The Outreach Pilot Program (OPP) was designed to engage communities, health professionals, and researchers in a network to advance health promotion activities and research to increase the use of the PR Quitline (PRQ) among smokers and promoting policies in support of smoke-free workplaces. Using community-based participatory research (CBPR) methods, the OPP mobilized a network of community and academic partners to implement smoking cessation activities including referrals to the PRQ, adoption of evidence-based smoking cessation programs, and promotion of smoke-free legislation. Eighty organizations participated in the OPP. Collaborators implemented activities that supported the promotion of the PRQ and smoke-free workplaces policy and sponsored yearly trainings, including tobacco control conferences. From 2005 to 2008, physician referrals to the PRQ increased from 2.6% to 7.2%. The number of annual smokers receiving cessation services through the PRQ also increased from 703 to 1,086. The OPP shepherded a rigorous smoke-free law through participation in the development, promotion, and implementation of the smoke-free workplaces legislation as well as the creation of the PR Tobacco Control Strategic Plan, launched in 2006. This project demonstrates the feasibility of developing a successful and sustainable community-based outreach program model that enlists the participation of academic researchers, community organizations, and health care providers as partners to promote tobacco control.


Risks of cognitive detriments after low dose heavy ion and proton exposures.
Purpose: Heavy ion and proton brain irradiations occur during space travel and in Hadron therapy for cancer. Heavy ions produce distinct patterns of energy deposition in neuron cells and brain tissues compared to X-rays leading to large uncertainties in risk estimates. We make a critical review of findings from research studies over the last 25 years for understanding risks at low dose. Conclusions: A large number of mouse and rat cognitive testing measures have been reported for a variety of particle species and energies for acute doses. However, tissue reactions occur above dose thresholds and very few studies were performed at the heavy ion doses to be encountered on space missions (<0.04 Gy/y) or considered dose-rate effects, such that threshold doses are not known in rodent models. Investigations of possible mechanisms for cognitive changes have been limited by experimental design with largely group specific and not subject specific findings reported. Persistent oxidative stress and activated microglia cells are common mechanisms studied, while impairment of neurogenesis, detriments in neuron morphology, and changes to gene and protein expression were each found to be important in specific studies. Future research should focus on estimating threshold doses carried out with experimental designs aimed at understating causative mechanisms, which will be essential for extrapolating rodent findings to humans and chronic radiation scenarios, while establishing if mitigation are needed.


Microbial Diversity and Cyanobacterial Production in Dziani Dzaha Crater Lake, a Unique Tropical Thalassohaline Environment.
This study describes, for the first time, the water chemistry and microbial diversity in Dziani Dzaha, a tropical crater lake located on Mayotte Island (Comoros archipelago, Western Indian Ocean). The lake water had a high level of dissolved matter and high alkalinity (10.6-14.5 g L-1 eq. CO32-, i.e. 160-220 mM compare to around 2-2.5 in seawater), with salinity up to 52 psu, 1.5 higher than seawater. Hierarchical clustering discriminated Dziani Dzaha water from other alkaline, saline lakes, highlighting its thalassohaline nature. The phytoplankton biomass was very high, with a total chlorophyll a concentration of 524 to 875 μg chl a L-1 depending on the survey, homogeneously distributed from surface to bottom (4 m). Throughout the whole water column the photosynthetic biomass was dominated (>97% of total biovolume) by the filamentous cyanobacteria Arthrospira sp. with a straight morphotype. In situ daily photosynthetic oxygen production ranged from 17.3 to 22.2 g O2 m-2 d-1, consistent with experimental production / irradiance measurements and modeling. Heterotrophic bacterioplankton was extremely abundant, with cell densities up to 1.5 108 cells mL-1 in the whole water column. Isolation and culture of 59 Eubacteria strains revealed the prevalence of alkaliphilic and halophilic organisms together with taxa unknown to date, based on 16S rRNA gene analysis. A single cloning-sequencing approach using archaeal 16S rDNA gene primers unveiled the presence of diverse extremophilic Euryarchaeota. The water chemistry of Dziani Dzaha Lake supports the hypothesis that it was derived from seawater and strongly modified by geological conditions and microbial activities that increased the alkalinity. Dziani Dzaha has a unique consortium of cyanobacteria, phytoplankton, heterotrophic Eubacteria and Archaea, with very few unicellular protozoa, that will deserve further deep analysis to unravel its uncommon diversity. A single taxon, belonging to the genus Arthrospira, was found responsible for almost all photosynthetic primary production.


A long-term study on female mice fed on a genetically modified soybean: effects on liver ageing.
Liver represents a suitable model for monitoring the effects of a diet, due to its key role in controlling the whole metabolism. Although no direct evidence has been reported so far that genetically modified (GM) food may affect health, previous studies on hepatocytes from young female mice fed on GM soybean demonstrated nuclear modifications involving transcription and splicing pathways. In this study, the effects of this diet were studied on liver of old female mice in order to elucidate possible interference with ageing. The morpho-functional characteristics of the liver of 24-month-old mice, fed from weaning on control or GM soybean, were investigated by combining a proteomic approach with ultrastructural, morphometrical and immunoelectron microscopical analyses. Several proteins belonging to hepatocyte metabolism, stress response, calcium signalling and mitochondria were differentially expressed in GM-fed mice, indicating a more marked expression of senescence markers in comparison to controls. Moreover, hepatocytes of GM-fed mice showed mitochondrial and nuclear modifications indicative of reduced metabolic rate. This study demonstrates that GM soybean intake can influence some liver features during ageing and, although the mechanisms remain unknown, underlines the importance to investigate the long-term consequences of GM-diets and the potential synergistic effects with ageing, xenobiotics and/or stress conditions.


Effect of Cast Modification on Denture Base Adaptation Following Maxillary Complete Denture Processing.
To investigate the effect of cast modifications on denture base adaptation in coronal and sagittal projections following maxillary complete denture processing. A total of 60 edentulous maxillary casts (n = 10) were distributed among six groups. Group 1 was the control group with no modification, groups 2 through 6 included a butterfly postdam preparation, groups 3 and 4 also included a 10-mm wide/4-mm deep box with addition of four round holes in group 4, and groups 5 and 6 also included a 20-mm wide/4-mm deep box with addition of four round holes in group 6. The boxes were prepared at the mid-heel area of the casts. Two layers of baseplate wax (1 mm each) were used to standardize denture base thickness across the groups. A standard technique was used to replicate the denture tooth set-up, and standardized processing was done for all the groups. Following deflasking, casts with the dentures were sectioned in the coronal and sagittal directions. Microscopic pictures were taken at preselected points. Data were organized in tables, and statistical analyses were performed using repeated measure ANOVA, Tukey post hoc tests, and post hoc comparison tests set at 5% level of significance. Maximum gaps were measured at the mid-palatal area followed by nearby areas and the areas near ridge crests in both coronal and sagittal projections. The analyses revealed significant differences between the groups in coronal projection (1/2, 3/4, 5/6) and sagittal projection (1, 2, 3/4, 5/6) without significant differences within the pairs. The groups were ranked from the highest group 1 to the lowest group 6 relative to the gap means. Post hoc comparisons showed that points 1C and 2A had the highest gap means across the study groups. Within the limitations of this study, it can be extrapolated that the denture base adaptation can be effectively increased with the box preparation at the mid-heel aspect of the casts. Significant reduction of gaps was seen when the box size increased from 10 to 20 mm in coronal and sagittal projections; however, the addition of four holes had no significant effect on gap size alterations.


Orphanin FQ/nociceptin suppresses motor activity through an action along the mesoaccumbens axis in rats.
Intracerebroventricular administration of orphanin FQ/nociceptin (OFQ/N), the endogenous agonist ligand of the opioid receptor-like (ORL-1) receptor, decreases extracellular levels of dopamine and suppresses motor activity. The presence of the ORL-1 receptor on mesoaccumbal and nigrostriatal dopaminergic neurons raises the possibility that an action along these pathways may be one means by which OFQ/N produces motor suppression. Thus, the present study used local administration of OFQ/N into the ventral tegmental area (VTA), the substantia nigra, the nucleus accumbens and the striatum to determine the contribution of cell-body regions and terminal fields of the dopaminergic neurons to the motor-suppressant effect of OFQ/N. Rats were implanted bilaterally with guide cannulae into one of the brain regions and tested 4 days later. First, the effect of a single dose of OFQ/N (30 microg/0.5 microL per side) on motor activity was determined after direct injection into the VTA, substantia nigra, nucleus accumbens or striatum. Rats were habituated to activity chambers for 1 hour and then injected with either artificial cerebrospinal fluid or OFQ/N into one of the brain regions, and motor activity was recorded for a further 1 hour. Next, the dose-response effect of intra-VTA or intranigral OFQ/N (3 microg or 30 microg/0.5 microL per side) on motor activity was examined. Finally, the effect of intra-VTA OFQ/N (3 microg or 30 microg/0.5 microL per side) on motor activity was determined in the presence of J-113397, an ORL-1 receptor antagonist. OFQ/N suppressed motor activity when injected into the VTA and to a lesser extent after direct injection into the nucleus accumbens. However, OFQ/N failed to attenuate motor activity significantly after injection into the substantia nigra or the striatum. Subsequent dose-response studies showed that OFQ/N suppressed motor activity even at a 10-fold-lower dose after intrategmental but not intranigral administration. The motor-suppressant action of intra-VTA OFQ/N was attenuated by J-113397 (1.5 microg/0.5 microL per side) administered into the VTA 10 minutes before administration of OFQ/N. Our results indicate that OFQ/N suppresses motor activity through activation of the ORL-1 receptor primarily through an action in the VTA.


Risk factors for anthroponotic cutaneous Leishmaniasis at the household level in Kabul, Afghanistan.
Kabul, Afghanistan, is the largest focus of anthroponotic cutaneous leishmaniasis (ACL) in the world. ACL is a protozoan disease transmitted to humans by the bite of phlebotomine sand flies. Although not fatal, ACL can lead to considerable stigmatization of affected populations. Using data from a standardized survey of 872 households in 4 wards of Kabul, Afghanistan, univariate and multivariate logistic regression analyses tested associations between presence of active ACL and ACL scars with 15 household-level variables. Univariate analyses showed that active ACL was positively associated with household member's age, ACL prevalence, and brick wall type, but negatively associated with household number of rooms, bednet use, and proportion of windows with screens. Multivariate analysis showed a positive association between active ACL and household member's age, ACL prevalence, and brick wall type, and a negative association with household proportion of windows with screens. Household-level characteristics were shown to be risk factors for ACL. Monitoring a selected number of household characteristics could assist in rapid assessments of household-level variation in risk of ACL. ACL prevention and control programs should consider improving house construction, including smoothing of walls and screening of windows.


Childhood adversity, mental health and suicide (CHASE): a methods protocol for a longitudinal case-control linked data study.
Suicide is a tragic outcome with devastating consequences. In 2018, Scotland experienced a 15% increase in suicide from 680 to 784 deaths. This was marked among young people, with an increase of 53% in those aged 15-24, the highest since 2007. Early intervention in those most at risk is key, but identification of individuals at risk is complex, and efforts remain largely targeted towards universal suicide prevention strategies with little evidence of effectiveness.Recent evidence suggests childhood adversity is a predictor of subsequent poor social and health outcomes, including suicide. This protocol reports on methodology for harmonising lifespan hospital contacts for childhood adversity, mental health, and suicidal behaviour. This will inform where to 1) focus interventions, 2) prioritise trauma-informed approaches, and 3) adapt support avenues earlier in life for those most at risk. This study will follow a case-control design. Scottish hospital data (physical health SMR01; mental health SMR04; maternity/birth record SMR02; mother's linked data SMR01, SMR04, death records) from 1981 to as recent as available will be extracted for people who died by suicide aged 10-34, and linked on Community Health Index unique identifier. A randomly selected control population matched on age and geography at death will be extracted in a 1:10 ratio. International Classification of Disease (ICD) codes will be harmonised between ICD9-CM, ICD9, ICD10-CM and ICD10 for childhood adversity, mental health, and suicidal behaviour. ICD codes for childhood adversity from four key studies are reported in two categories, 1) Maltreatment or violence-related codes, and 2) Codes suggestive of maltreatment. 'Clinical Classifications Software' ICD codes to operationalise mental health codes are also reported. Harmonised lifespan ICD categories were achieved semi-automatically, but required labour-intensive supplementary manual coding. Cross-mapped codes are reported. There is a dearth of evidence about touchpoints prior to suicide. This study reports methods and harmonised ICD codes along the lifespan to understand hospital contact patterns for childhood adversity, which come to the attention of hospital practitioners. Childhood Adversity, Adverse Childhood Experiences, Mental Health, Self-harm, Suicide, Suicidality, Violence, Hospital episodes, Routine Data, Data Linkage, Study Protocol.


Impact of sexual assault nurse examiners on the evaluation of sexual assault in a pediatric emergency department.
Nearly 44% of sexual assault victims in the United States are younger than 18 years. These victims often present to emergency departments for care after the assault. To date, the effectiveness of sexual assault nurse examiners (SANEs) on the evaluation and management of pediatric and adolescent sexual assault victims in a pediatric emergency department (PED) has not been evaluated. To evaluate whether the use of SANEs in a PED improves the medical care of pediatric and adolescent sexual assault victims. Medical records of patients who presented to an urban PED with a history of sexual assault and required forensic evaluation (rape kit) from December 2004 to December 2006 were reviewed in a retrospective, blinded fashion for the following documentation: (1) the genitourinary (GU) examination and if a GU injury was present; (2) evaluation for sexually transmitted infections (STIs) (Neisseria gonorrhoeae and Chlamydia trachomatis), and serologies for hepatitis B and C, HIV, and VDRL; (3) prescription of prophylaxis for STIs, HIV, and pregnancy; (4) evaluation by a PED social worker; and (5) referral to sexual assault crisis services. Patients were grouped as to whether a SANE had been involved in their care. The assignment of a patient to a SANE was random, as SANEs in the PED of this institution do not take call from home and are present in the PED as part of their routine nursing shift. To examine the differences between groups, chi analysis or Fisher exact test was used. Of the 114 patients whose medical records were reviewed, 60 had been evaluated by a SANE (SANE), and 54 patients had not (SANE); 98% of patients were girls. There were no differences between the 2 patient groups with respect to time of day when they presented to the PED, time after assault to presentation to the PED, sex, age, or race. All medical records had the history of the sexual assault documented in the medical record. Patients evaluated by a SANE were more likely to have the GU examination documented (71% vs 41%; P < 0.001) and to have GU injury documented (21% vs 0%; P = 0.024). Eligible patients were more likely to have testing for N. gonorrhoeae and C. trachomatis (98% vs 76%; P < or = 0. 001), and serologies for hepatitis B and C (95% vs 80%%; P = 0.03) and HIV (93% vs 72%; P = 0.03) when a SANE had been involved in their care. There were no significant differences between groups with respect to obtaining serology for VDRL. There were no significant differences between groups with respect to provision of prophylaxis for N. gonorrhoeae, C. trachomatis, or HIV. Significantly more patients were prescribed prophylaxis for pregnancy by a SANE (85% vs 64%; P = 0.025). Although there were no significant differences between groups with respect to an evaluation by a PED social worker, significantly more patients in the SANE group were referred to the Rape Crisis Center for support and counseling (98% vs 30%; P < 0.001). Many more patients who had been sexually assaulted received STI testing, pregnancy prophylaxis, and referrals to the Rape Crisis Center when a SANE was present for the evaluation in the PED. Even with a SANE providing medical care, not all eligible patients had medical record documentation of the GU examination or that they received appropriate STI testing or STI and HIV prophylaxis. Ongoing quality assurance in programs that use SANEs is needed to ensure optimal medical evaluation of children and adolescents with sexual assault.


Clerodendron glandulosum.Coleb leaf extract attenuates in vitro macrophage differentiation and expression of VCAM-1 and P-selectin in thoracic aorta of atherogenic diet fed rats.
Present inventory evaluates the anti-atherogenic potential of C. glandulosum.Coleb leaf extract (CG) using in vivo and in vitro experimental models. Serum markers of low density lipoprotein (LDL-C) oxidation, cholesterol, triglycerides, lipoproteins, auto-antibody titer, ex vivo LDL-C oxidation, LDL-C aggregation, aortic lipids, histopathological evaluations and immunolocalization of macrophage surface marker (F4/80), vascular cell adhesion molecule-1 (VCAM-1) and P-selectin were performed in CON [rats treated with single dose of saline (i.p.) and fed with laboratory chow], ATH [rats treated with single dose of vitamin D3 (600,000 IU, i.p) and fed with atherogenic diet] and ATH+CG [rats treated with single dose of vitamin D3 (600,000 IU, i.p.) and fed with atherogenic diet and simultaneously treated with 200 mg/kg CG extract, p.o.] for 8 weeks. CG extract supplementation to atherogenic diet fed rats significantly prevented increment in serum cholesterol, triglycerides, and lipoproteins, markers of LDL-C oxidation, auto-antibody titer and aortic lipids. Also, LDL-C isolated from ATH+CG rats recorded mimimal aggregation and susceptibility to undergo ex vivo LDL-C oxidation. Microscopic evaluation of thoracic aorta of ATH+CG rats reveled prevention of atheromatous plaque formation, accumulation of lipid laden macrophages, calcium deposition, distortion/defragmentation of elastin, accumulation of macrophages and, down regulation of cell adhesion molecules (VCAM-1 and P-selectin) expression. Further, in vitro monocyte to macrophage differentiation was significantly attenuated in presence of CG extract (200 µg/mL). It can be concluded from the present study that, CG extract is capable of controlling induction of experimental atherosclerosis and warrants further scrutiny at the clinical level as a possible therapeutic agent.


The ParaHox gene cluster is an evolutionary sister of the Hox gene cluster.
Genes of the Hox cluster are restricted to the animal kingdom and play a central role in axial patterning in divergent animal phyla. Despite its evolutionary and developmental significance, the origin of the Hox gene cluster is obscure. The consensus is that a primordial Hox cluster arose by tandem gene duplication close to animal origins. Several homeobox genes with high sequence identity to Hox genes are found outside the Hox cluster and are known as 'dispersed' Hox-like genes; these genes may have been transposed away from an expanding cluster. Here we show that three of these dispersed homeobox genes form a novel gene cluster in the cephalochordate amphioxus. We argue that this 'ParaHox' gene cluster is an ancient paralogue (evolutionary sister) of the Hox gene cluster; the two gene clusters arose by duplication of a ProtoHox gene cluster. Furthermore, we show that amphioxus ParaHox genes have co-linear developmental expression patterns in anterior, middle and posterior tissues. We propose that the origin of distinct Hox and ParaHox genes by gene-cluster duplication facilitated an increase in body complexity during the Cambrian explosion.


Bowing, kneeling and 'prostration': athlete's collapse patterns during sudden cardiac arrhythmia/arrest on the field of play.
Sudden cardiac arrest (SCA) on the field of play remains one of the most tragic and challenging events for a team physician. Even with robust regular preparticipation cardiac screening we cannot prevent all cases of SCA. Ability to recognise imminent cardiac arrest occurring on the field of play remains an important step in managing this condition without delay. You Tube was searched for video clips clearly depicting the sequence of an athlete's collapse of cardiac origin. A pattern of collapse was subsequently analysed. 13 cases were available for public viewing on You Tube and demonstrated the final position of collapse. 12 collapses had full video footage of athlete's fall. All athletes were men. 84.6% (11) cases were from football (soccer). 15.4% (2) of cases were from martial arts. In 10 out of 12 cardiac event cases (83.3%) bowing and/or kneeling were followed by decubitus position. 58.3% (7) of cases demonstrated bowing at the beginning of collapse. 58.3% (7) cases had kneeling as an element of collapse. 61.5% (8 out of 13 cases) of casualties adopted position of 'prostration' (ie, prone) as final stage of collapse. When on the field of play, in the absence of head injury, athletes displaying bowing and/or kneeling positions followed by collapse should be assumed to have a life-threatening cardiac event. Final position of 'prostration' was adopted in over half of cardiogenic collapses. A sports medicine professional should bear this in mind and target his/her assessment and treatment accordingly. When attending such casualties, a defibrillator must be taken to the collapsed player.


Community-Based Interventions to Improve and Sustain Antiretroviral Therapy Adherence, Retention in HIV Care and Clinical Outcomes in Low- and Middle-Income Countries for Achieving the UNAIDS 90-90-90 Targets.
Little is known about the effect of community versus health facility-based interventions to improve and sustain antiretroviral therapy (ART) adherence, virologic suppression, and retention in care among HIV-infected individuals in low- and middle-income countries (LMICs). We systematically searched four electronic databases for all available randomized controlled trials (RCTs) and comparative cohort studies in LMICs comparing community versus health facility-based interventions. Relative risks (RRs) for pre-defined adherence, treatment engagement (linkage and retention in care), and relevant clinical outcomes were pooled using random effect models. Eleven cohort studies and eleven RCTs (N = 97,657) were included. Meta-analysis of the included RCTs comparing community- versus health facility-based interventions found comparable outcomes in terms of ART adherence (RR = 1.02, 95 % CI 0.99 to 1.04), virologic suppression (RR = 1.00, 95 % CI 0.98 to 1.03), and all-cause mortality (RR = 0.93, 95 % CI 0.73 to 1.18). The result of pooled analysis from the RCTs (RR = 1.03, 95 % CI 1.01 to 1.06) and cohort studies (RR = 1.09, 95 % CI 1.03 to 1.15) found that participants assigned to community-based interventions had statistically significantly higher rates of treatment engagement. Two studies found community-based ART delivery model either cost-saving or cost-effective. Community- versus facility-based models of ART delivery resulted in at least comparable outcomes for clinically stable HIV-infected patients on treatment in LMICs and are likely to be cost-effective.


[The effects of indomethacin spray on the pain of stomatitis in the patients for hematopoietic stem cell transplantation].
We studied the effects of 0.25% indomethacin (IM) spray as an in-hospital preparation on the pain of stomatitis after hematopoietic stem cell transplantation in 9 patients with various types of leukemia by measuring the change in pain and the decrease in morphine dose. Stomatitis above grade 2 (painful erythema, edema, or ulcers but can eat or swallow) appeared in all patients as white blood cell (WBC) counts declined after transplantation, and clockwise hysteresis was observed between WBC counts and the grade of stomatitis. When the patients used IM spray for the pain of stomatitis and were judged the grade of pain using a face scale of five grades (0-4) before and after the use of this spray, the mean grades of pain at the maximal pain during the appearance of stomatitis declined from 3.4 to 1.8 (n = 5). Furthermore, the concurrent intravenous dose of morphine markedly decreased during IM spray use. There was no complaint concerning the taste and convenience of IM spray by patients. The risk of systemic adverse effects was considered relatively low based on the small amounts of IM applied to the mouth mucosa. In conclusion, it is suggested that IM spray is effective for the relief of stomatitis pain in patients who have undergone hematopoietic stem cell transplantation and is a useful preparation for immediate self-medication upon the appearance of stomatitis pain. We considered that the application of IM spray will contribute to the improvement of patient quality of life.


Learning Categories From Few Examples With Multi Model Knowledge Transfer.
Learning a visual object category from few samples is a compelling and challenging problem. In several real-world applications collecting many annotated data is costly and not always possible. However, a small training set does not allow to cover the high intraclass variability typical of visual objects. In this condition, machine learning methods provide very few guarantees. This paper presents a discriminative model adaptation algorithm able to proficiently learn a target object with few examples by relying on other previously learned source categories. The proposed method autonomously chooses from where and how much to transfer information by solving a convex optimization problem which ensures to have the minimal leave-one-out error on the available training set. We analyze several properties of the described approach and perform an extensive experimental comparison with other existing transfer solutions, consistently showing the value of our algorithm.


Does daily dietary intake affect diabetic retinopathy progression? 10-year results from the 45 and Up Study.
To evaluate the associations of dietary consumption with the 10-year incidence of diabetic retinopathy (DR) progression in working-aged Australians with diabetes. We obtained longitudinal data of all diabetic subjects aged 45-65 years from the baseline of the 45 and Up Study and linked this data with Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Scheme claims until 2016. Retinal photocoagulation (RPC), as determined based on the MBS data, was used as a proxy measure of DR progression. Dietary measurements were assessed via self-reported consumption of meat, dairy products, whole-meal bread, breakfast cereal, vegetables, fruit and fruit juice using a self-administered questionnaire at baseline. Cox regression was used to assess the association between dietary consumption and incident RPC during the follow-up period. A total of 8122 participants were included in the current analysis with a mean age of 57.2±5.2 years. During a mean follow-up of 8.6 years, 314 participants (3.8% of baseline) received RPC. Higher consumption of cheese and whole-meal bread was associated with a lower risk of incident RPC, with the HRs of the highest quartiles versus the lowest being 0.58 (95% CI 0.41 to 0.83; test for trend, p=0.007) and 0.64 (0.46 to 0.89; p=0.04), respectively. Body mass index, insulin treatment and gender were significant modifiers for the association between cheese/whole-meal bread and RPC. Consumption of cheese and whole-meal bread could reduce the risk of DR progression among the working-aged Australian population with diabetes.


Bivalirudin versus heparin in percutaneous coronary intervention-a systematic review and meta-analysis of randomized trials stratified by adjunctive glycoprotein IIb/IIIa strategy.
Bivalirudin has been shown to be associated with less major bleeding than heparin in patients undergoing percutaneous coronary intervention (PCI); but the confounding effect of concomitant glycoprotein IIb/IIIa inhibitors (GPI) limits meaningful comparison. We performed a systematic review and meta-analysis to compare bivalirudin to heparin, with and without adjunctive GPI in PCI. We searched PubMed, Cochrane, EMBASE, CINAHL and WOS from January 2000 to December 2017 for clinical trials comparing bivalirudin to heparin, with and without adjunctive GPI during PCI. Cochrane's Q statistics were used to determine heterogeneity. Random effects model was used. Twenty-six comparison groups (22 original studies and 4 subgroup analyses) with 53,364 patients were included. Mean follow-up was 192±303 days. There was no difference between the two groups in all-cause mortality [risk ratio (RR: 0.93; 95% CI: 0.82-1.05, P=0.260), target vessel revascularization (TVR) (RR: 1.17; 95% CI: 0.93-1.46, P=0.174) or stroke (RR: 0.91; 95% CI: 0.71-1.18, P=0.490). Major bleeding was lower in the bivalirudin group with concomitant GPI in one or both arms (RR: 0.64; 95% CI: 0.53-0.77, P<0.001) and without (RR: 0.71; 95% CI: 0.51-0.99, P=0.041) provisional or routine GPIs. Bivalirudin appeared to have a higher risk of stent thrombosis (RR: 1.32; 95% CI: 1.04-1.68, P=0.022) and a trend towards more myocardial infarction (RR: 1.12; 95% CI: 0.98-1.28, P=0.098) though without statistical significance. However, exclusion of studies with GPI showed no difference in stent thrombosis or myocardial infarction with bivalirudin. Bivalirudin is associated with less major bleeding compared to heparin, regardless of GPI use. The lower anticoagulant effect of bivalirudin is linked with higher stent thrombosis and a trend towards more MI, however a confounding effect of GPI use in the heparin arm cannot be excluded.


A molecular perspective on nonaqueous biocatalysis: contributions from simulation studies.
The technological value of nonaqueous enzymology has been recognized for more than thirty years. A detailed understanding of the molecular determinants of enzyme behaviour in nonaqueous media is essential to explore their potential. Computer simulations have provided valuable contributions to this field, having elucidated how the solvent affects the structural and dynamic properties of enzymes, as well as their activity and enantioselectivity. They have also helped to shed light on the effect of hydration and the role of counterions. In this perspective, we describe the major challenges and achievements of molecular simulations of enzymes in different types of nonaqueous solvents, including organic solvents, ionic liquids and supercritical fluids.


Transient obstruction of the internal carotid artery during angiography.
While performing carotid angiography in a 76-year-old man, we found that the right internal carotid artery repeatedly opened and closed during the examination. The patient experienced no related neurologic events. The explanation, confirmed at surgery, was that a flap associated with an atherosclerotic plaque had acted as a ball valve.


Prospectively assessed neurodevelopmental outcomes in studies of anaesthetic neurotoxicity in children: a systematic review and meta-analysis.
Whether exposure to a single general anaesthetic (GA) in early childhood causes long-term neurodevelopmental problems remains unclear. PubMed/MEDLINE, Embase, CINAHL, Web of Science, and the Cochrane Library were searched from inception to October 2019. Studies evaluating neurodevelopmental outcomes and prospectively enrolling children exposed to a single GA procedure compared with unexposed children were identified. Outcomes common to at least three studies were evaluated using random-effects meta-analyses. Full-scale intelligence quotient (FSIQ); the parentally reported Child Behavior Checklist (CBCL) total, externalising, and internalising problems scores; and Behavior Rating Inventory of Executive Function (BRIEF) scores were assessed. Of 1644 children identified, 841 who had a single exposure to GA were evaluated. The CBCL problem scores were significantly higher (i.e. worse) in exposed children: mean score difference (CBCL total: 2.3 [95% confidence interval {CI}: 1.0-3.7], P=0.001; CBCL externalising: 1.9 [95% CI: 0.7-3.1], P=0.003; and CBCL internalising problems: 2.2 [95% CI: 0.9-3.5], P=0.001). Differences in BRIEF were not significant after multiple comparison adjustment. Full-scale intelligence quotient was not affected by GA exposure. Secondary analyses evaluating the risk of these scores exceeding predetermined clinical thresholds found that GA exposure was associated with increased risk of CBCL internalising behavioural deficit (risk ratio [RR]: 1.47; 95% CI: 1.08-2.02; P=0.016) and impaired BRIEF executive function (RR: 1.68; 95% CI: 1.23-2.30; P=0.001). Combining results of studies utilising prospectively collected outcomes showed that a single GA exposure was associated with statistically significant increases in parent reports of behavioural problems with no difference in general intelligence.


Physical Assault in the Psychiatry Emergency Room.
Previous studies of physical assaults in hospitals focused primarily on inpatient psychiatric units, leaving unanswered questions about the extent to which findings generalize to psychiatric emergency rooms. Assault incident reports and electronic medical records from one psychiatric emergency room and two inpatient psychiatric units were reviewed. Qualitative methods were used to identify precipitants. Quantitative methods were used to describe characteristics of each event, as well as demographic and symptom profiles associated with incidents. During the five-year study period, there were 60 incidents in the psychiatric emergency room and 124 incidents on the inpatient units. Precipitating factors, incident severity, means of assault, and interventions were similar in both settings. Among patients in the psychiatric emergency room, a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder with manic symptoms (Adjusted Odds Ratio (AOR) 27.86) and presenting with thoughts to harm others (AOR 10.94) were associated with an increased likelihood of having an assault incident report. Similarities between assaults in the psychiatric emergency room and inpatient psychiatric units suggest that the broader literature from inpatient psychiatry can be generalized to the psychiatric emergency room setting, although some differences exist. Reprinted from J Am Acad Psychiatry Law 2020; 48:484-495, with permission from The American Academy of Psychiatry and the Law. Copyright © 2020.


Sexual function and gonadal hormones in patients taking antipsychotic treatment for schizophrenia or schizoaffective disorder.
To determine rates of sexual dysfunction and hypogonadism and establish the relationship between gonadal hormone levels and sexual function in patients taking antipsychotic treatment for schizophrenia or schizoaffective disorder. We studied 103 patients with schizophrenia or schizoaffective disorder (mean age = 46.2 (SD = 12.9) years; 51.5% male) from October 2003 through March 2005. Sexual function was assessed using the Sexual Functioning Questionnaire (SFQ) and compared with (1) normal controls (N = 62; mean age = 36.1 (SD = 9.6) years; 55% male) recruited from primary care attendees and (2) sexually dysfunctional controls recruited from a local sexual dysfunction clinic (N = 57; mean age = 39.1 (SD = 10.7) years; 79% male). Prolactin, sex hormone-binding globulin, testosterone, estradiol, progesterone, follicle-stimulating hormone, and luteinizing hormone levels; psychopathology; and side effects were measured. Mean (SD) total SFQ scores were significantly greater in patients (women = 9.9 [5.3]; men = 7.8 [4.9]) compared with normal controls (women = 4.1 [2.9]; men = 4.09 [2.95]), and similar to the scores of sexual dysfunction clinic attendees (women = 7.2 [2.9]; men = 9.9 [4.5]). The odds ratios of patients having sexual dysfunction compared with normal controls were 15.2 for women and 3.7 for men. Hypogonadism was common (in premenopausal women, 79% showed hypoestrogenism and 92% showed low progesterone levels, and 28% of men showed hypotestosteronism). There was no association between total SFQ scores and prolactin or gonadal hormone levels. Patients receiving treatment for schizophrenia or schizoaffective disorder show high rates of sexual dysfunction and hypogonadism. Sexual functioning was not related to prolactin or gonadal hormone levels.


A kinetic Monte Carlo analysis for the production of singularly tethered carbon nanotubes.
Nanoparticles that possess a single covalent tether to either another particle or a surface play an increasingly important role in nanotechnology, serving as a foundation for aggregation-based plasmonic sensors, chemically assembled framework structures, and scanning probe tips. Using a theoretical approach, we explore the reaction conditions necessary to maximize singular tethering for several cases of homogeneously dispersed nanoparticles, with a particular focus on single-walled carbon nanotubes. In the limit of particles of monodisperse size and equal site reactivity, the number of tethers versus the reaction conversion is statistically described by the well-known binomial distribution, with a variance that is minimal for the single tether case. However, solutions of nanoparticles often deviate from this ideal, and reaction events can introduce steric hindrance to neighboring sites or alter particle electronic properties, both of which can influence local reactivity. In order to study these cases we use the electron transfer reactions of single-walled carbon nanotubes. We find that the distribution in the number of monofunctional tubes, as a function of conversion, is largely dependent on the distribution of nanotube rate constants, and therefore tube chiralities, in the initial solution. As a contemporary example, we examine the implications of this result on the metallic-semiconductor separation of carbon nanotubes using electron transfer chemistry.


Quality of meal and appetite sensation.
The scope of this review is to summarize recent studies assessing the role of meal composition on appetite sensation. Currently, data confirm a positive effect on appetite sensations following protein-rich meals, suggesting that at least 25-30-g protein/meal provide potential improvements on appetite, but further long-term studies are required to confirm the results. A greater interest has been showed in the interaction between short-chain fatty acids produced by gut microbiota, following dietary fiber consumption, and appetite sensation, but research is ongoing. Finally, as reflected in the recent literature, new systematic reviews should be carried out to assess the effect of dietary fibers on appetite sensation. Meal composition, in terms of nutrients, widely differs in the ability to affect appetite sensation. This mostly depends on the content of protein and dietary fibers in a meal. The effect of higher protein intake on appetite sensation has been well documented with positive results, whereas dietary fibers, although the majority of evidence suggests positive results, still show inconsistent data because of various methodological approaches. Generally, more research both in the short and long term is required to investigate the underlying mechanism associated with appetite sensation.


A conservative femoral replacement for total hip arthroplasty. A prospective study.
Between 1985 and 1993, 146 patients (162 hips) had total hip replacement (THR) using a conservative uncemented femoral component. The mean age of the patients was 50.8 years and the mean follow-up was 6.2 years (2 to 13). One patient was lost to follow-up, one died within two years of surgery and one had a revision procedure after a fracture sustained in a road-traffic accident. For the remaining 159, Kaplan-Meier survival analysis was calculated for the incidence of revision because of mechanical loosening or osteolysis. Survival without mechanical loosening at both five and ten years was 98.2%. Survival without osteolysis was 99% at five and 91% at ten years. The Harris hip score improved from a mean of 66.3 before to 90.4 at follow-up. Of particular note is the lack of thigh pain in this group. Radiological analysis showed that 139 stems (88%) had no measurable subsidence, 8 (5%) had less than 2 mm and 12 (7%) had more than 2 mm. Two of the eight and one of the 12 were revised for mechanical loosening. Nine hips were revised for late loosening associated with osteolysis. No reaming of the femoral canal was associated with statistically significant less blood loss compared with a comparable control group of uncemented implants (p < 0.0001). Our study suggests that using a conservative femoral implant does not protect against wear debris but the reliable mechanical stability (98.2%) makes this an attractive design of implant particularly for young patients.


SU-E-T-576: Investigation of Combining Modulated Electron Beams with Intensity Modulated Photons for Radiation Therapy of Breast Cases.
Modulated electron radiation therapy (MERT) can offer significant advantages for breast treatments over conventional radiotherapy in terms of sparing distal critical structures. While intensity modulated radiation therapy (IMRT) has the advantage of achieving better dose homogeneity inside the target combining both MERT and IMRT will be the ideal scenario. The Aim of the present study is to investigate the possibility of further improving breast radiation therapy using combined MERT/IMRT treatment technique. Accurate modeling of a prototype motorized electron multileaf collimator was verified in a separate study. In this work treatment planning was performed by an in house Monte Carlo based inverse planning system. Dose deposition coefficients were calculated using MCPLAN and utilizing real patients CTs. Optimization is then conducted based on an equivalent uniform dose objective function. MERT and IMRT plans were created for different patients. The clinical beneficial outcome for MERT either alone or combined with IMRT was investigated based on isodose distributions and dose volume histograms. It is shown that MERT can give similar dose distributions as IMRT in some cases. For some cases, MERT could be advantageous whenever more skin dose was required. In some cases MERT can be identified as the best option. It was found that MERT compared to IMRT could introduce hot spots inside the target. However this was resolved in combined MERT/IMRT treatment. Dose uniformity can be restored with a reduction in the maximum lung and heart received dose. MERT can improve treatment plan quality for many breast patients. In some cases better results can be obtained with a combined MERT/IMRT treatment, where a homogeneous dose in the target can be achieved with an improvement in the DVH of critical structures. This work has been supported by a UICC American Cancer Society Beginning Investigators Fellowship funded by the American Cancer Society.


The Ease of Language Understanding (ELU) model: theoretical, empirical, and clinical advances.
Working memory is important for online language processing during conversation. We use it to maintain relevant information, to inhibit or ignore irrelevant information, and to attend to conversation selectively. Working memory helps us to keep track of and actively participate in conversation, including taking turns and following the gist. This paper examines the Ease of Language Understanding model (i.e., the ELU model, Rönnberg, 2003; Rönnberg et al., 2008) in light of new behavioral and neural findings concerning the role of working memory capacity (WMC) in uni-modal and bimodal language processing. The new ELU model is a meaning prediction system that depends on phonological and semantic interactions in rapid implicit and slower explicit processing mechanisms that both depend on WMC albeit in different ways. It is based on findings that address the relationship between WMC and (a) early attention processes in listening to speech, (b) signal processing in hearing aids and its effects on short-term memory, (c) inhibition of speech maskers and its effect on episodic long-term memory, (d) the effects of hearing impairment on episodic and semantic long-term memory, and finally, (e) listening effort. New predictions and clinical implications are outlined. Comparisons with other WMC and speech perception models are made.


Terahertz lens made out of natural stone.
Terahertz (THz) time-domain spectroscopy probes the optical properties of naturally occurring solid aggregates of minerals, or stones, in the THz frequency range. Refractive index and extinction coefficient measurement reveals that most natural stones, including mudstone, sandstone, granite, tuff, gneiss, diorite, slate, marble, and dolomite, are fairly transparent for THz frequency waves. Dolomite in particular exhibits a nearly uniform refractive index of 2.7 over the broad frequency range from 0.1 to 1 THz. The high index of refraction allows flexibility in lens designing with a shorter accessible focal length or a thinner lens with a given focal length. Good agreement between the experiment and calculation for the THz beam profile confirms that dolomite has high homogeneity as a lens material, suggesting the possibility of using natural stones for THz optical elements.


Serial Recall Predicts Vocoded Sentence Recognition Across Spectral Resolutions.
Purpose The goal of this study was to determine how various aspects of cognition predict speech recognition ability across different levels of speech vocoding within a single group of listeners. Method We tested the ability of young adults (N = 32) with normal hearing to recognize Perceptually Robust English Sentence Test Open-set (PRESTO) sentences that were degraded with a vocoder to produce different levels of spectral resolution (16, eight, and four carrier channels). Participants also completed tests of cognition (fluid intelligence, short-term memory, and attention), which were used as predictors of sentence recognition. Sentence recognition was compared across vocoder conditions, predictors were correlated with individual differences in sentence recognition, and the relationships between predictors were characterized. Results PRESTO sentence recognition performance declined with a decreasing number of vocoder channels, with no evident floor or ceiling performance in any condition. Individual ability to recognize PRESTO sentences was consistent relative to the group across vocoder conditions. Short-term memory, as measured with serial recall, was a moderate predictor of sentence recognition (ρ = 0.65). Serial recall performance was constant across vocoder conditions when measured with a digit span task. Fluid intelligence was marginally correlated with serial recall, but not sentence recognition. Attentional measures had no discernible relationship to sentence recognition and a marginal relationship with serial recall. Conclusions Verbal serial recall is a substantial predictor of vocoded sentence recognition, and this predictive relationship is independent of spectral resolution. In populations that show variable speech recognition outcomes, such as listeners with cochlear implants, it should be possible to account for the independent effects of spectral resolution and verbal serial recall in their speech recognition ability. Supplemental Material https://doi.org/10.23641/asha.12021051.