Subclinical hypothyroidism is associated with increased risk for all-cause and cardiovascular mortality in adults.
This study sought to evaluate the relationship between subclinical hypothyroidism (SCH) and all-cause and cardiovascular disease (CVD) mortality. SCH may increase the risks of hypercholesterolemia and atherosclerosis. The associations between SCH and all-cause or CVD mortality are uncertain, on the basis of the results of previous studies. A baseline cohort of 115,746 participants without a history of thyroid disease, ≥20 years of age, was recruited in Taiwan. SCH was defined as a serum thyroid-stimulating hormone (TSH) level of 5.0 to 19.96 mIU/l with normal total thyroxine concentrations. Euthyroidism was defined as a serum TSH level of 0.47 to 4.9 mIU/l. Cox proportional hazards regression analysis was used to estimate the relative risks (RRs) of death from all-cause and CVD for adults with SCH during a 10-year follow-up period. There were 3,669 deaths during the follow-up period; 680 deaths were due to CVD. Compared with subjects with euthyroidism, after adjustment for age, sex, body mass index, diabetes, hypertension, dyslipidemia, smoking, alcohol consumption, betel nut chewing, physical activity, income, and education level, the RRs (95% confidence interval) of deaths from all-cause and CVD among subjects with SCH were 1.30 (1.02 to 1.66), and 1.68 (1.02 to 2.76), respectively. Adult Taiwanese with SCH had an increased risk for all-cause mortality and CVD death.


The differentiated networks related to essential tremor onset and its amplitude modulation after alcohol intake.
The dysregulation of endogenous rhythms within brain networks have been implicated in a broad range of motor and non-motor pathologies. Essential tremor (ET), classically the purview of a single aberrant pacemaker, has recently become associated with network-level dysfunction across multiple brain regions. Specifically, it has been suggested that motor cortex constitutes an important node in a tremor-generating network involving the cerebellum. Yet the mechanisms by which these regions relate to tremor remain a matter of considerable debate. We sought to discriminate the contributions of cerebral and cerebellar dysregulation by combining high-density electroencephalography with subject-specific structural MRI. For that, we contrasted ET with voluntary (mimicked) tremor before and after ingestion of alcohol to regulate the tremorgenic networks. Our results demonstrate distinct loci of cortical tremor coherence, most pronounced over the sensorimotor cortices in healthy controls, but more frontal motor areas in ET-patients consistent with a heightened involvement of the supplementary motor area. We further demonstrate that the reduction in tremor amplitude associated with alcohol intake is reflected in altered cerebellar - but not cerebral - coupling with movement. Taken together, these findings implicate tremor emergence as principally associated with increases in activity within frontal motor regions, whereas modulation of the amplitude of established tremor relates to changes in cerebellar activity. These findings progress a mechanistic understanding of ET and implicate network-level vulnerabilities in the rhythmic nature of communication throughout the brain.


Alfvén waves in the lower solar atmosphere.
The flow of energy through the solar atmosphere and the heating of the Sun's outer regions are still not understood. Here, we report the detection of oscillatory phenomena associated with a large bright-point group that is 430,000 square kilometers in area and located near the solar disk center. Wavelet analysis reveals full-width half-maximum oscillations with periodicities ranging from 126 to 700 seconds originating above the bright point and significance levels exceeding 99%. These oscillations, 2.6 kilometers per second in amplitude, are coupled with chromospheric line-of-sight Doppler velocities with an average blue shift of 23 kilometers per second. A lack of cospatial intensity oscillations and transversal displacements rules out the presence of magneto-acoustic wave modes. The oscillations are a signature of Alfvén waves produced by a torsional twist of +/-22 degrees. A phase shift of 180 degrees across the diameter of the bright point suggests that these torsional Alfvén oscillations are induced globally throughout the entire brightening. The energy flux associated with this wave mode is sufficient to heat the solar corona.


Factors associated with suicide after parasuicide in young people.
To determine factors associated with completed suicide in young parasuicide patients. Case-control study. Regional poisoning treatment centre in a teaching general hospital. Patients who, between 1968 and 1985 when aged 15-24 years, were admitted to the regional poisoning treatment centre because of deliberate self poisoning or self injury. Cases (n = 62) consisted of those who by the end of 1985 had died locally from either suicide (n = 41) or possible suicide (n = 21). Controls (n = 124) were patients who were known not to have died locally during the study period. Two controls were selected for each case, matched by sex, age (within two years), and length of follow up. Possible predictors of completed suicide. Univariate analysis (conditional logistic regression) showed that risk of death due to suicide and possible suicide was associated with six factors: social class V (odds ratio 2.7, 95% confidence interval 1.1 to 6.7), unemployment (2.8, 1.4 to 5.8), previous inpatient psychiatric treatment (4.9, 2.2 to 10.9), substance misuse (3.3, 1.6 to 6.8), personality disorder (2.1, 1.03 to 4.4), and previous attempted suicide (2.3, 1.2 to 4.4). Multivariate analysis identified two factors as significantly contributing to the model that best discriminated between the cases and controls: substance misuse (alcohol or drugs, or both) (adjusted odds ratio 3.9) and previous inpatient psychiatric treatment (3.7). These factors seemed to be associated with suicide after attempted suicide in both the short term (less than 12 months) and the long term (one year or more) and were also identified when the analysis was restricted to subjects who definitely died by suicide and their controls. Suicide after parasuicide in young people is associated with substance misuse. This suggests that prevention of suicide in young people who attempt suicide might be improved by close liaison between general hospital services for patients who have attempted suicide and services for young substance misusers and by measures aimed at preventing substance misuse in young people.


Ivermectin reduces alcohol intake and preference in mice.
The high rate of therapeutic failure in the management of alcohol use disorders (AUDs) underscores the urgent need for novel and effective strategies that can deter ethanol consumption. Recent findings from our group showed that ivermectin (IVM), a broad-spectrum anthelmintic with high tolerability and optimal safety profile in humans and animals, antagonized ethanol-mediated inhibition of P2X4 receptors (P2X4Rs) expressed in Xenopus oocytes. This finding prompted us to hypothesize that IVM may reduce alcohol consumption; thus, in the present study we investigated the effects of this agent on several models of alcohol self-administration in male and female C57BL/6 mice. Overall, IVM (1.25-10 mg/kg, intraperitoneal) significantly reduced 24-h alcohol consumption and intermittent limited access (4-h) binge drinking, and operant alcohol self-administration (1-h). The effects on alcohol intake were dose-dependent with the significant reduction in intake at 9 h after administration corresponding to peak IVM concentrations (C(max)) in the brain. IVM also produced a significant reduction in 24-h saccharin consumption, but did not alter operant sucrose self-administration. Taken together, the findings indicate that IVM reduces alcohol intake across several different models of self-administration and suggest that IVM may be useful in the treatment of AUDs.


Direct phosphorylation of IkappaB by IKKalpha and IKKbeta: discrimination between free and NF-kappaB-bound substrate.
A large protein complex mediates the phosphorylation of the inhibitor of kappaB (IkappaB), which results in the activation of nuclear factor kappaB (NF-kappaB). Two subunits of this complex, IkappaB kinase alpha (IKKalpha) and IkappaB kinase beta (IKKbeta), are required for NF-kappaB activation. Purified recombinant IKKalpha and IKKbeta expressed in insect cells were used to demonstrate that each protein can directly phosphorylate IkappaB proteins. IKKalpha and IKKbeta were found to form both homodimers and heterodimers. Both IKKalpha and IKKbeta phosphorylated IkappaB bound to NF-kappaB more efficiently than they phosphorylated free IkappaB. This result explains how free IkappaB can accumulate in cells in which IKK is still active and thus can contribute to the termination of NF-kappaB activation.


MXene Ti3C2: An Effective 2D Light-to-Heat Conversion Material.
MXene, a new series of 2D material, has been steadily advancing its applications to a variety of fields, such as catalysis, supercapacitor, molecular separation, electromagnetic wave interference shielding. This work reports a carefully designed aqueous droplet light heating system along with a thorough mathematical procedure, which combined leads to a precise determination of internal light-to-heat conversion efficiency of a variety of nanomaterials. The internal light-to-heat conversion efficiency of MXene, more specifically Ti3C2, was measured to be 100%, indicating a perfect energy conversion. Furthermore, a self-floating MXene thin membrane was prepared by simple vacuum filtration and the membrane, in the presence of a rationally chosen heat barrier, produced a light-to-water-evaporation efficiency of 84% under one sun irradiation, which is among the state of art energy efficiency for similar photothermal evaporation system. The outstanding internal light-to-heat conversion efficiency and great light-to-water evaporation efficiency reported in this work suggest that MXene is a very promising light-to-heat conversion material and thus deserves more research attention toward practical applications.


Oxidative stress in aging human skin.
Oxidative stress in skin plays a major role in the aging process. This is true for intrinsic aging and even more for extrinsic aging. Although the results are quite different in dermis and epidermis, extrinsic aging is driven to a large extent by oxidative stress caused by UV irradiation. In this review the overall effects of oxidative stress are discussed as well as the sources of ROS including the mitochondrial ETC, peroxisomal and ER localized proteins, the Fenton reaction, and such enzymes as cyclooxygenases, lipoxygenases, xanthine oxidases, and NADPH oxidases. Furthermore, the defense mechanisms against oxidative stress ranging from enzymes like superoxide dismutases, catalases, peroxiredoxins, and GSH peroxidases to organic compounds such as L-ascorbate, α-tocopherol, beta-carotene, uric acid, CoQ10, and glutathione are described in more detail. In addition the oxidative stress induced modifications caused to proteins, lipids and DNA are discussed. Finally age-related changes of the skin are also a topic of this review. They include a disruption of the epidermal calcium gradient in old skin with an accompanying change in the composition of the cornified envelope. This modified cornified envelope also leads to an altered anti-oxidative capacity and a reduced barrier function of the epidermis.


Structural and functional dissection of the Abp1 ADFH actin-binding domain reveals versatile in vivo adapter functions.
Abp1 is a multidomain protein that regulates the Arp2/3 complex and links proteins involved in endocytosis to the actin cytoskeleton. All of the proposed cellular functions of Abp1 involve actin filament binding, yet the actin binding site(s) on Abp1 have not been identified, nor has the importance of actin binding for Abp1 localization and function in vivo been tested. Here, we report the crystal structure of the Saccharomyces cerevisiae Abp1 actin-binding actin depolymerizing factor homology (ADFH) domain and dissect its activities by mutagenesis. Abp1-ADFH domain and ADF/cofilin structures are similar, and they use conserved surfaces to bind actin; however, there are also key differences that help explain their differential effects on actin dynamics. Using point mutations, we demonstrate that actin binding is required for localization of Abp1 in vivo, the lethality caused by Abp1 overexpression, and the ability of Abp1 to activate Arp2/3 complex. Furthermore, we genetically uncouple ABP1 functions that overlap with SAC6, SLA1, and SLA2, showing they require distinct combinations of activities and interactions. Together, our data provide the first structural and functional view of the Abp1-actin interaction and show that Abp1 has distinct cellular roles as an adapter, linking different sets of ligands for each function.


Sunitinib-Induced Elevation of Mean Corpuscular Volume (MCV)-Exploring Its Possible Clinical Relevance in Cancer Patients.
Sunitinib is a broad-spectrum multitargeted tyrosine kinase inhibitor mainly used as second-line therapy for non-resectable gastrointestinal stromal or first-line treatment option of metastatic renal cell carcinoma (mRCC), and as an "off-label" option in pediatric oncology. It has been previously reported that sunitinib elevates the mean corpuscular volume of erythrocytes (MCV) in treated subjects. The aim of this study was to assess time-dependent changes of this effect and evaluate its possible clinical relevance. In this study, 179 adult and 21 pediatric patients with solid tumors treated with sunitinib were retrospectively analyzed. The laboratory and treatment-related data were collected for each treatment period. The regression model with a broken-line relationship was used to fit time dependence of the MCV. In the adult group, the MCV was increasing during the first 21.6 weeks (median) of treatment in a median level of 99.8 fL, where it stabilized. MCV increase was faster in the patients who suffered from treatment-related adverse events (21.3 vs. 24.6 weeks, p = 0.010). In the pediatric cohort, the MCV dynamics were similar to adults. In conclusion, MCV changes during sunitinib treatment in pediatric and adult patients may be of clinical utility in monitoring sunitinib treatment course.


Associations of human crystalline lens retrodots and waterclefts with visual impairment: an observational study.
To investigate the relationships between visual acuity, contrast sensitivity, and 11 clinicopathologic classes of opacity in the human crystalline lens. The Somerset and Avon Eye Study is an observational population study of age-related sight-threatening eye disease, based in Bristol, UK. After excluding eyes with other visually relevant disease, data from 902 individuals aged 55 years or older were analyzed. The associations of lens features (posterior subcapsular cataract, nuclear color, nuclear white scatter, cortical spokes, anterior subcapsular cataract, vacuoles, waterclefts, coronary flakes, focal dots, retrodots, fiber folds), with refracted log minimum angle of resolution (MAR) distance acuity and Pelli-Robson contrast sensitivity, were investigated. Multivariable linear regression models using data from both eyes and taking account of the intraclass correlation between eyes were used for analysis, with the lens features and age included as potential explanatory variables. As anticipated from earlier studies, posterior subcapsular, nuclear, and cortical cataracts were associated with visual impairment. In addition, retrodots were strongly and independently associated in the multivariable models with both impaired visual acuity (P < 0.001) and contrast sensitivity (P < 0.001). Waterclefts were strongly associated with impaired visual acuity (P < 0.001). Retrodots and waterclefts are associated with visual impairment. A causal relationship between these lens features and retinal image degradation is plausible.


Catalytic diesel particulate filters reduce the in vitro estrogenic activity of diesel exhaust.
An in vitro reporter gene assay based on human breast cancer T47D cells (ER-CALUX) was applied to examine the ability of diesel exhaust to induce or inhibit estrogen receptor (ER)-mediated gene expression. Exhaust from a heavy-duty diesel engine was either treated by iron- or copper/iron-catalyzed diesel particulate filters (DPFs) or studied as unfiltered exhaust. Collected samples included particle-bound and semivolatile constituents of diesel exhaust. Our findings show that all of the samples contained compounds that were able to induce ER-mediated gene expression as well as compounds that suppressed the activity of the endogenous hormone 17beta-estradiol (E2). Estrogenic activity prevailed over antiestrogenic activity. We found an overall ER-mediated activity of 1.63 +/- 0.31 ng E2 CALUX equivalents (E2-CEQs) per m(3) of unfiltered exhaust. In filtered exhaust, we measured 0.74 +/- 0.07 (iron-catalyzed DPF) and 0.55 +/- 0.09 ng E2-CEQ m(-3) (copper/iron-catalyzed DPF), corresponding to reductions in estrogenic activity of 55 and 66%, respectively. Our study demonstrates that both catalytic DPFs lowered the ER-mediated endocrine-disrupting potential of diesel exhaust.


Phandango: an interactive viewer for bacterial population genomics.
Fully exploiting the wealth of data in current bacterial population genomics datasets requires synthesizing and integrating different types of analysis across millions of base pairs in hundreds or thousands of isolates. Current approaches often use static representations of phylogenetic, epidemiological, statistical and evolutionary analysis results that are difficult to relate to one another. Phandango is an interactive application running in a web browser allowing fast exploration of large-scale population genomics datasets combining the output from multiple genomic analysis methods in an intuitive and interactive manner. Phandango is a web application freely available for use at www.phandango.net and includes a diverse collection of datasets as examples. Source code together with a detailed wiki page is available on GitHub at https://github.com/jameshadfield/phandango.


Yap, a novel family of eight bZIP proteins in Saccharomyces cerevisiae with distinct biological functions.
Saccharomyces cerevisiae contains eight members of a novel and fungus-specific family of bZIP proteins that is defined by four atypical residues on the DNA-binding surface. Two of these proteins, Yap1 and Yap2, are transcriptional activators involved in pleiotropic drug resistance. Although initially described as AP-1 factors, at least four Yap proteins bind most efficiently to TTACTAA, a sequence that differs at position +/-2 from the optimal AP-1 site (TGACTCA); further, a Yap-like derivative of the AP-1 factor Gcn4 (A239Q S242F) binds efficiently to the Yap recognition sequence. Molecular modeling suggests that the Yap-specific residues make novel contacts and cause physical constraints at the +/-2 position that may account for the distinct DNA-binding specificities of Yap and AP-1 proteins. To various extents, Yap1, Yap2, Yap3, and Yap5 activate transcription from a promoter containing a Yap recognition site. Yap-dependent transcription is abolished in strains containing high levels of protein kinase A; in contrast, Gcn4 transcriptional activity is stimulated by protein kinase A. Interestingly, Yap1 transcriptional activity is stimulated by hydrogen peroxide, whereas Yap2 activity is stimulated by aminotriazole and cadmium. In addition, unlike other yap mutations tested, yap4 (cin5) mutations affect chromosome stability, and they suppress the cold-sensitive phenotype of yap1 mutant strains. Thus, members of the Yap family carry out overlapping but distinct biological functions.


Patchy Micelles with a Crystalline Core: Self-Assembly Concepts, Properties, and Applications.
Crystallization-driven self-assembly (CDSA) of block copolymers bearing one crystallizable block has emerged to be a powerful and highly relevant method for the production of one- and two-dimensional micellar assemblies with controlled length, shape, and corona chemistries. This gives access to a multitude of potential applications, from hierarchical self-assembly to complex superstructures, catalysis, sensing, nanomedicine, nanoelectronics, and surface functionalization. Related to these applications, patchy crystalline-core micelles, with their unique, nanometer-sized, alternating corona segmentation, are highly interesting, as this feature provides striking advantages concerning interfacial activity, functionalization, and confinement effects. Hence, this review aims to provide an overview of the current state of the art with respect to self-assembly concepts, properties, and applications of patchy micelles with crystalline cores formed by CDSA. We have also included a more general discussion on the CDSA process and highlight block-type co-micelles as a special type of patchy micelle, due to similarities of the corona structure if the size of the blocks is well below 100 nm.


Confining the spin between two metal atoms within the carbon cage: redox-active metal-metal bonds in dimetallofullerenes and their stable cation radicals.
Lanthanide-lanthanide bonds are exceptionally rare, and dimetallofullerenes provide a unique possibility to stabilize and study these unusual bonding patterns. The presence of metal-metal bonds and consequences thereof for the electronic properties of M2@C82 (M = Sc, Er, Lu) are addressed by electrochemistry, electron paramagnetic resonance, SQUID magnetometry and other spectroscopic techniques. A simplified non-chromatographic separation procedure is developed for the isolation of Er2@C82 (Cs(6) and C3v(8) cage isomers) and Sc2@C82 (C3v(8) isomer) from fullerene mixtures. Sulfide clusterfullerenes Er2S@C82 with Cs(6) and C3v(8) fullerene cages are synthesized for the first time. The metal-metal bonding orbital of the spd hybrid character in M2@C82 is shown to be the highest occupied molecular orbital, which undergoes reversible single-electron oxidation with a metal-dependent oxidation potential. Sulfide clusterfullerenes with a fullerene-based HOMO have more positive oxidation potentials. The metal-based oxidation of Sc2@C82-C3v is confirmed by the EPR spectrum of the cation radical [Sc2@C82-C3v]+ generated by chemical oxidation in solution. The spectrum exhibits an exceptionally large a(45Sc) hyperfine coupling constant of 199.2 G, indicating a substantial 4s contribution to the metal-metal bonding orbital. The cationic salt [Er2@C82-C3v]+SbCl6- is prepared, and its magnetization behavior is compared to that of pristine Er2@C82-C3v and Er2S@C82-C3v. The formation of the single-electron Er-Er bond in the cation dramatically changes the coupling between magnetic moments of Er ions.


Comparative studies on single-layer reduced graphene oxide films obtained by electrochemical reduction and hydrazine vapor reduction.
The comparison between two kinds of single-layer reduced graphene oxide (rGO) sheets, obtained by reduction of graphene oxide (GO) with the electrochemical method and hydrazine vapor reduction, referred to as E-rGO and C-rGO, respectively, is systematically studied. Although there is no morphology difference between the E-rGO and C-rGO films adsorbed on solid substrates observed by AFM, the reduction process to obtain the E-rGO and C-rGO films is quite different. In the hydrazine vapor reduction, the nitrogen element is incorporated into the obtained C-rGO film, while no additional element is introduced to the E-rGO film during the electrochemical reduction. Moreover, Raman spectra show that the electrochemical method is more effective than the hydrazine vapor reduction method to reduce the GO films. In addition, E-rGO shows better electrocatalysis towards dopamine than does C-rGO. This study is helpful for researchers to understand these two different reduction methods and choose a suitable one to reduce GO based on their experimental requirements.


Amyloid Network Topology Characterizes the Progression of Alzheimer's Disease During the Predementia Stages.
There is increasing evidence showing that the accumulation of the amyloid-β (Aβ) peptide into extracellular plaques is a central event in Alzheimer's disease (AD). These abnormalities can be detected as lowered levels of Aβ42 in the cerebrospinal fluid (CSF) and are followed by increased amyloid burden on positron emission tomography (PET) several years before the onset of dementia. The aim of this study was to assess amyloid network topology in nondemented individuals with early stage Aβ accumulation, defined as abnormal CSF Aβ42 levels and normal Florbetapir PET (CSF+/PET-), and more advanced Aβ accumulation, defined as both abnormal CSF Aβ42 and Florbetapir PET (CSF+/PET+). The amyloid networks were built using correlations in the mean 18F-florbetapir PET values between 72 brain regions and analyzed using graph theory analyses. Our findings showed an association between early amyloid stages and increased covariance as well as shorter paths between several brain areas that overlapped with the default-mode network (DMN). Moreover, we found that individuals with more advanced amyloid accumulation showed more widespread changes in brain regions both within and outside the DMN. These findings suggest that amyloid network topology could potentially be used to assess disease progression in the predementia stages of AD.


Calcimycin potentiates responses of rat hippocampal neurons to N-methyl-D-aspartate.
We examined the effect of elevating intracellular calcium ([Ca2+]i) on responses to iontophoretically applied N-methyl-D-aspartate (NMDA), and quisqualate in CA1 neurons of the hippocampal slice. Topical application of calcimycin (A23187), a calcium ionophore, potentiated responses to NMDA but not to quisqualate. This potentiation was prevented by loading cells with the calcium chelator, BAPTA, suggesting that the action of calcimycin on NMDA receptors was mediated by an elevation of [Ca2+]i in the recorded cell. The potentiation was also recorded in voltage-clamped and in cesium-loaded cells, suggesting that it was not mediated by non-specific changes in voltage or input resistance of the cell that may have resulted from the rise in [Ca2+]i. We propose that intracellular calcium plays a crucial role in regulating the activity of the NMDA subtype of L-glutamate receptor.


Relapsing invasive group B streptococcal infection in adults.
To study recurrent group B streptococcal infection in adults. Patients with more than one reported group B streptococcal infection were identified through active surveillance for this infection. Sterile-site group B streptococcal isolates were evaluated for serotype and molecular subtyping using restriction endonuclease analysis of chromosomal DNA (REAC). All acute-care hospitals in Maryland. Nonpregnant residents of Maryland 18 years of age or older. 22 adults had at least two group B streptococcal episodes that were separated by 2 to 95 weeks (mean, 24 weeks). Of 395 patients with invasive group B streptococcal infection who survived the first episode and were followed for at least 1 year, 17 (4.3% [95% CI, 2.6% to 6.9%]) had more than one episode. Several patients were found to have endocarditis or osteomyelitis during the second episode. Group B streptococcal isolates from both episodes were obtained from 18 of 22 patients. Of the 18 isolate pairs, 13 (72% [CI, 46% to 90%]) had identical REAC patterns; the probability that at least 13 matches would be found by chance alone was less than 0.000001. Among patients with recurrent infection caused by the same strain, the interval between episodes was shorter (mean, 14 weeks) than that among patients with recurrent infection caused by another strain (mean, 43 weeks; P = 0.05). Recurrent group B streptococcal infection is common among adults and in most cases appears to be caused by relapse. The optimal management of adults with a first episode of group B streptococcal infection needs to be further defined to minimize the likelihood of recurrent disease.


The effect of noise exposure on the cervical vestibular evoked myogenic potential.
The purpose of this study was to investigate the effects of noise exposure on the cervical vestibular evoked myogenic potential (cVEMP) in individuals with asymmetric noise-induced sensorineural hearing loss (NIHL). A cross-sectional observational study was used to compare cVEMP characteristics in 43 individuals with a history of noise exposure greater in one ear (e.g., the left ear of a right-handed rifle shooter) and asymmetric sensorineural hearing loss consistent with the history of noise exposure and in 14 age-matched controls. The characteristics of hearing loss were examined further for the noise-exposed participants with abnormal cVEMPs and the noise-exposed participants with normal cVEMPs. Thirty-three percent of the noise-exposed participants had abnormal cVEMPs, whereas cVEMPs were present and symmetrical in 100% of the age-matched controls, and cVEMP threshold was greater in the noise-exposed group than in the control group. Abnormal cVEMPs occurred most often in the ears with poorer hearing (or greater NIHL), and the noise-exposed participants who had abnormal cVEMPs had poorer high-frequency pure-tone thresholds (greater NIHL) and greater interaural high-frequency pure-tone threshold differences than the noise-exposed participants with normal cVEMPs. These findings are consistent with previous studies that suggest that the sacculocollic pathway may be susceptible to noise-related damage. There is emerging evidence that the severity of NIHL is associated with the presence or absence of cVEMPs.


Can axillary reverse mapping avoid lymphedema in node positive breast cancer patients?
Tracing lymphatic drainage of the ipsilateral arm of node positive breast cancer patients, termed "axillary reverse mapping" (ARM), has recently been described in several reports. We analyzed our experience with this new technique in patients scheduled for axillary lymph node dissection (ALND) and evaluated its usefulness for reducing the incidence of lymphedema. Blue dye was injected subcutaneously along the intermuscular groove of the upper inner arm; radioisotope was injected subcutaneously in the interdigital webspace of the hand. All blue and radioactive lymph vessels and lymph nodes were recorded. Only unsuspicious "ARM lymph nodes" located in the lateral part of the axillary basin were preserved. All other level I and II axillary lymph nodes were removed. Resected ARM nodes were immediately separated from all other lymph nodes. ARM was performed in 143 patients subsequently undergoing ALND. ARM lymph nodes were successfully identified in 112 cases (78%). In 55 patients at least one ARM lymph node had to be removed. In 14 of these, tumor involvement was confirmed. In 71 patients one or more ARM nodes were preserved. During a median follow-up time of 19 months no axillary recurrence was noted. 35 of 114 evaluated patients developed lymphedema. Preservation of ARM lymph nodes did not significantly decrease the incidence of lymphedema. ARM is feasible for patients with node positive breast cancer. However, we found no evidence that it reduces the incidence of lymphedema.


Lesions of the perirhinal cortex but not of the frontal, medial prefrontal, visual, or insular cortex block fear-potentiated startle using a visual conditioned stimulus.
The present study is part of an ongoing series of experiments aimed at delineation of the neural pathways that mediate fear-potentiated startle, a model of conditioned fear in which the acoustic startle reflex is enhanced when elicited in the presence of a light previously paired with shock. A number of cortical areas that might be involved in relaying information about the visual conditioned stimulus (the light) in fear-potentiated startle were investigated. One hundred thirty-five rats were given 10 light-shock pairings on each of 2 consecutive days, and 1-2 d later electrolytic or aspiration lesions in various cortical areas were performed. One week later, the magnitude of fear-potentiated startle was measured. Complete removal of the visual cortex, medial prefrontal cortex, insular cortex, or posterior perirhinal cortex had no significant effect on the magnitude of fear-potentiated startle. Lesions of the frontal cortex attenuated fear-potentiated startle by approximately 50%. However, lesions of the anterior perirhinal cortex completely eliminated fear-potentiated startle. The effective lesions included parts of the cortex both dorsal and ventral to the rhinal sulcus and extended from approximately 1.8 to 3.8 mm posterior to bregma. Lesions slightly more posterior (2.3-4.8 mm posterior to bregma) or lesions that included only the perirhinal cortex dorsal to the rhinal sulcus had no effect. The region of the perirhinal cortex in which lesions blocked fear-potentiated startle projects to the amygdala, and thus may be part of the pathway that relays the visual conditioned stimulus information to the amygdala, a structure that is also critical for fear-potentiated startle. In addition, the present findings are in agreement with numerous studies in primates suggesting that the perirhinal cortex may play a more general role in memory.


Is it in a neonate's best interest to enter a randomised controlled trial?
Clinicians are required to act in the best interest of neonates. However, it is not obvious that entry into a randomised controlled trial (RCT) is in a neonate's best interest because such trials often involve additional onerous procedures (such as intramuscular injections) in return for which the neonate receives unproven treatment or a placebo. On the other hand, neonatology needs to develop its evidence base, and RCTs are central to this task. The solution posited here is based on two points. First, "best interest" is not equivalent to "the best possible interest" only to "best interest within a certain realm". The realm of deliberation when asking the title question is the neonate's health. Deliberating in this realm may involve the exclusion from consideration of some factors that might be thought relevant (such as parental wealth). Furthermore, circumstances may dictate the need to deliberate on other factors that might be thought irrelevant (such as health care resources). Second, deciding on a neonate's best interest does not involve "putting oneself in its shoes". Rather, it involves asking in what it has an interest, or stake. These will include some things in which we all, as human beings, have a stake, such as medical progress. Putting these two points together, in the realm of health the answer to whether RCT entry is in a neonate's best interest is usually very finely balanced. Where this is the case, it is reasonable to invoke a broader notion of best interest and include a broader range of elements in which the neonate has a stake, including medical progress. In this way RCT entry can, usually, be said to be in a neonate's best interest.


Arsenic in North Carolina: public health implications.
Arsenic is a known human carcinogen and relevant environmental contaminant in drinking water systems. We set out to comprehensively examine statewide arsenic trends and identify areas of public health concern. Specifically, arsenic trends in North Carolina private wells were evaluated over an eleven-year period using the North Carolina Department of Health and Human Services database for private domestic well waters. We geocoded over 63,000 domestic well measurements by applying a novel geocoding algorithm and error validation scheme. Arsenic measurements and geographical coordinates for database entries were mapped using Geographic Information System techniques. Furthermore, we employed a Bayesian Maximum Entropy (BME) geostatistical framework, which accounts for geocoding error to better estimate arsenic values across the state and identify trends for unmonitored locations. Of the approximately 63,000 monitored wells, 7712 showed detectable arsenic concentrations that ranged between 1 and 806μg/L. Additionally, 1436 well samples exceeded the EPA drinking water standard. We reveal counties of concern and demonstrate a historical pattern of elevated arsenic in some counties, particularly those located along the Carolina terrane (Carolina slate belt). We analyzed these data in the context of populations using private well water and identify counties for targeted monitoring, such as Stanly and Union Counties. By spatiotemporally mapping these data, our BME estimate revealed arsenic trends at unmonitored locations within counties and better predicted well concentrations when compared to the classical kriging method. This study reveals relevant information on the location of arsenic-contaminated private domestic wells in North Carolina and indicates potential areas at increased risk for adverse health outcomes.


The efficacy of mirtazapine in the treatment of cocaine dependence with comorbid depression.
Prior findings concerning the use of mirtazapine in the treatment of a variety of substance use disorders and its antagonistic actions at the serotonin 5-HT(2A) receptor suggest that this drug may have efficacy in the treatment of cocaine dependence in the presence of a depressive disorder. Depressed cocaine-dependent subjects received either mirtazapine (target dose 45 mg daily) or placebo for 12 weeks. Urine concentrations of benzoylecgonine and self-report were used to assess cocaine consumption. Depression and sleep quality were evaluated using the Hamilton Depression Rating Scale (HAM-D) and the Pittsburgh Sleep Quality Index, respectively. Cocaine consumption during the treatment period did not differ significantly between the mirtazapine (n = 11) and placebo (n = 13) groups in this study. In week 4 sleep latency was significantly lower in the active medication than in the placebo group. Positive effects of mirtazapine treatment on early insomnia were suggested by an item analysis of the HAM-D. The results of this study suggest that mirtazapine is superior to placebo in improving sleep in patients with comorbid depression and cocaine dependence, but is not more effective than placebo in reducing cocaine use.


Radiofrequency ablation of hepatic tumors adjacent to the gallbladder: feasibility and safety.
This study was performed to assess the feasibility and safety of radiofrequency ablation of hepatic tumors adjacent to the gallbladder. Of the 83 patients who underwent radiofrequency ablation of hepatic tumors at our institution between December 1997 and August 2000, we identified eight patients--four men and four women who were 42-85 years old (mean age, 67 years)--who had tumors adjacent to the gallbladder. All ablations were performed with curative intent. We reviewed the patients' preablation imaging, radiofrequency ablation parameters, and course after ablation. Follow-up ranged from 3 to 22 months (mean, 8 months). Six patients with colorectal carcinoma and two with hepatocellular carcinoma had a total of 14 tumors adjacent to the gallbladder. Of the 14 tumors, nine (64%) were metastases and five (36%) were hepatocellular carcinoma. Eleven tumors (79%) were located directly adjacent to the gallbladder and three (21%) were located within 1 cm of the gallbladder. Tumor size ranged from 0.9 to 4.5 cm (mean, 3.6 cm). The number of radiofrequency ablations performed on each tumor ranged between one and six (mean, three ablations). Right upper quadrant pain developed in the immediate postablation period (within 7 days after the ablation) in six patients (75%) and ranged in duration from 5 to 21 days (mean, 7 days). Fever developed in four patients (50%), with a mean duration of 5 days. Arthralgia and right shoulder pain developed in one patient (12%). No deaths were noted in the immediate period after ablation. Complete ablation of all tumors visible on CT was achieved in seven patients. Of these, one patient (14%) had local tumor recurrence after 11 months. Radiofrequency ablation of tumors adjacent to the gallbladder is feasible and appears to be safe. Self-limited morbidity after ablation is noted in most patients and is probably related to a mild iatrogenic cholecystitis.


Regulation of IgE responses to inhaled antigen in mice by antigen-specific gamma delta T cells.
Indirect evidence implicates gamma delta T cells in the cross-regulation of CD4 alpha beta T cell responses. Adoptive transfer of small numbers of gamma delta T cells from ovalbumin (OVA)-tolerant mice selectively suppressed TH2-dependent immunoglobulin E (IgE) antibody production without affecting parallel IgG responses. Challenge of these gamma delta T cells in vitro with specific antigen resulted in production of high levels of interferon gamma. The effects of the gamma delta T cells may be mediated by direct inhibition of OVA-specific CD4+ TH2 cell proliferation or selection for specific CD4 TH2 cells.


RNA granules present only in extracellular toxoplasma gondii increase parasite viability.
Toxoplasma gondii is an obligate intracellular parasite. When searching for a new cell to invade, the parasites have to confront the stress of being exposed to the extracellular environment. The mechanisms by which T. gondii survives outside the host cells are poorly understood. In this work we show that extracellular parasites form mRNA aggregates with characteristics of stress granules. Intracellular tachyzoites or bradyzoites do not form mRNA granules. We tested different stimuli that trigger granule formation in vitro and discovered that a buffer that mimics the host cell cytosol ionic composition (high potassium) strongly induces granule formation, suggesting that the granules arise when the parasites come in contact with the host cell cytosol during egress. We examined the importance of granule formation for parasite viability and show that the parasite populations that are able to form granules have a growth advantage, increased invasion, and decreased apoptosis in the extracellular environment. Overall, granule formation improves the fitness of extracellular parasites and increases the efficiency of the lytic cycle.


Cross-sectional association between soda consumption and body mass index in a community-based sample of twins.
Consumption of sugar-sweetened beverages, such as soda, have been shown to play an important role in weight gain. Although soda consumption has been associated with body mass index (BMI) in many studies, it has been difficult to ascertain a true causal relationship between soda consumption and BMI for two reasons. First, findings have been based largely on observational and cross-sectional studies, with much less evidence from randomized controlled trials. Second, the reported relationships may be confounded by genetic and shared environmental factors that affect both soda consumption and BMI. In the present study, we used the twin design to better understand the relationship between soda consumption and BMI by accounting for measured and unmeasured confounds in non-experimental data. Associations from genetically informed tests in twins are considered "quasi-causal," suggesting that our confidence in the causal underpinning of the association between soda consumption and BMI has been strengthened. We hypothesized that the association between soda consumption and BMI would be significant both between and within twins. This was a cross sectional study of 5787 same sex adult twin pairs (18-97 years, 66% female) from the community based Washington State Twin Registry. Structural equation modeling (SEM) was employed to investigate associations between soda consumption and BMI in the population (the phenotypic association between exposure and outcome among all twins treated as individuals) and within pairs of identical and fraternal twins (the quasi-causal association controlling for between pair genetic and environmental confounds). Among all twins, there was a significant phenotypic association between soda consumption and BMI that held when controlling for age, sex, race, annual household income, and education level (P < 0.05). In the quasi-causal model, however, the effect of soda consumption on BMI was greatly reduced and no longer significant, with a large genetic confound in both men and women (P < 0.05). Among a large group of adult twin pairs, increased soda consumption was associated with increased BMI; however, the observed association was mediated by a genetic background common to both.


The neutral self-assembling peptide hydrogel SPG-178 as a topical hemostatic agent.
Conventional self-assembling peptide hydrogels are effective as topical hemostatic agents. However, there is a possibility to harm living tissues due to their low pH. The aim of the present study was to demonstrate the efficacy of SPG-178, a neutral self-assembling peptide hydrogel, as a topical hemostatic agent. First, we measured the bleeding duration of incisions made on rat livers after application of SPG-178 (1.0% w/v), SPG-178 (1.5% w/v), RADA16 (1.0% w/v), and saline (n = 12/group). Second, we observed the bleeding surfaces by transmission electron microscopy immediately after hemostasis. Third, we measured the elastic and viscous responses (G' and G″, respectively) of the hydrogels using a rheometer. Our results showed that bleeding duration was significantly shorter in the SPG-178 group than in the RADA16 group and that there were no significant differences in transmission electron microscopy findings between the groups. The greater the G' value of a hydrogel, the shorter was the bleeding duration. We concluded that SPG-178 is more effective and has several advantages: it is non-biological, transparent, nonadherent, and neutral and can be sterilized by autoclaving.


Spin-chain correlations in the frustrated triangular lattice material CuMnO2.
The Ising triangular lattice remains the classic test-case for frustrated magnetism. Here we report neutron scattering measurements of short range magnetic order in CuMnO2, which consists of a distorted lattice of Mn3+ spins with single-ion anisotropy. Physical property measurements on CuMnO2 are consistent with 1D correlations caused by anisotropic orbital occupation. However the diffuse magnetic neutron scattering seen in powder measurements has previously been fitted by 2D Warren-type correlations. Using neutron spectroscopy, we show that paramagnetic fluctuations persist up to ∼25 meV above T N = 65 K. This is comparable to the incident energy of typical diffractometers, and results in a smearing of the energy integrated signal, which hence cannot be analysed in the quasi-static approximation. We use low energy XYZ polarised neutron scattering to extract the purely magnetic (quasi)-static signal. This is fitted by reverse Monte Carlo analysis, which reveals that two directions in the triangular layers are perfectly frustrated in the classical spin-liquid phase at 75 K. Strong antiferromagnetic correlations are only found along the b-axis, and our results hence unify the pictures seen by neutron scattering and macroscopic physical property measurements.


Decision-making deficits of korsakoff patients in a new gambling task with explicit rules: associations with executive functions.
Decision-making deficits reflected by risky decisions in gambling tasks have been associated with frontal lobe dysfunctions in various neurologic and psychiatric populations. The question remains whether decision-making impairments are related to executive functions. The authors developed a new gambling task, the Game of Dice Task, with explicit and stable rules for reinforcement and punishment, to investigate relations between executive functions and risk-taking behavior in an explicit decision-making situation. A sample of 35 alcoholic Korsakoff patients and 35 healthy controls was examined with the Game of Dice Task and a neuropsychological test battery. Results show that Korsakoff patients are strongly impaired in this explicit decision-making task and that these disturbances are correlated with specific executive functions.


Disruption of the direct perforant path input to the CA1 subregion of the dorsal hippocampus interferes with spatial working memory and novelty detection.
Subregional analyses of the hippocampus suggest CA1-dependent memory processes rely heavily upon interactions between the CA1 subregion and entorhinal cortex. There is evidence that the direct perforant path (pp) projection to CA1 is selectively modulated by dopamine while having little to no effect on the Schaffer collateral (SC) projection to CA1. The current study takes advantage of this pharmacological dissociation to demonstrate that local infusion of the non-selective dopamine agonist, apomorphine (10, 15 microg), into the CA1 subregion of awake animals produces impairments in working memory at intermediate (5 min), but not short-term (10 s) delays within a delayed non-match-to-place task on a radial arm maze. Sustained impairments were also found in a novel context with similar object-space relationships. Infusion of apomorphine into CA1 is also shown here to produce deficits in spatial, but not non-spatial novelty detection within an object exploration paradigm. In contrast, apomorphine produces no behavioral deficits when infused into the CA3 subregion or overlying cortex. These behavioral studies are supported by previous electrophysiological data that demonstrate local infusion of the same doses of apomorphine significantly modifies evoked responses in the distal dendrites of CA1 following angular bundle stimulation, but produces no significant effects in the proximal dendritic layer following stimulation of the SC. These results support a modulatory role for dopamine in EC-CA1, but not CA3-CA1 circuitry, and suggest the possibility of a fundamental role for EC-CA1 synaptic transmission in terms of detection of spatial novelty, and intermediate-term, but not short-term spatial working memory or object-novelty detection.


[Somatic screening in child and adolescent psychiatry: a descriptive pilot study].
Somatic disorders occur more often in psychiatric patients than in the general population. Somatic symptoms can cause or increase psychiatric symptoms. Psychiatric symptoms and their treatment can have an effect on the physical state of the patient. A pilot study involving an adult outpatient population has demonstrated that 62% of the patients studied had new clinically relevant symptoms. So far, no other data are available relating to somatic screening in child and adolescent psychiatry. To assess whether somatic screening of children and adolescents newly referred to a department of child and adolescent psychiatry in the Netherlands gives added value to the diagnosis and treatment policy. In a pilot study 43 newly referred patients aged between 6 and 18 were screened by means of somatic history, a physical examination and blood parameters. On this basis we could calculate the percentage of somatic symptoms and , where necessary, follow-up treatment could be applied. One or more clinically relevant disorders were found in almost 56% of the children and adolescents investigated. The disorders included dysmorphic anomalies, weight and height deviations, raised thyroid hormone levels, dyslipidaemia, anaemia and vitamin D and B12 deficiency. Advice about a healthy lifestyle was given to 44% of the patients. An antipsychotic medication in 25% of the patients was changed, in the case of 16% of the patients a family doctor was contacted about subsequent treatment and 19% of the patients were referred to a medical specialist. Although the results of the pilot study indicate that somatic screening does provide added value, more research is needed in order to optimise the screening procedure.


Differential CARM1 Isoform Expression in Subcellular Compartments and among Malignant and Benign Breast Tumors.
Coactivator-associated arginine methyltransferase 1 (CARM1) is a coactivator for ERα and cancer-relevant transcription factors, and can methylate diverse cellular targets including histones. CARM1 is expressed in one of two alternative splice isoforms, full-length CARM1 (CARM1FL) and truncated CARM1 (CARM1ΔE15). CARM1FL and CARM1ΔE15 function differently in transcriptional regulation, protein methylation, and mediation of pre-mRNA splicing in cellular models. To investigate the functional roles and the prognosis potential of CARM1 alternative spliced isoforms in breast cancer, we used recently developed antibodies to detect differential CARM1 isoform expression in subcellular compartments and among malignant and benign breast tumors. Immunofluorescence in MDA-MB-231 and BG-1 cell lines demonstrated that CARM1ΔE15 is the dominant isoform expressed in the cytoplasm, and CARM1FL is more nuclear localized. CARM1ΔE15 was found to be more sensitive to Hsp90 inhibition than CARM1FL, indicating that the truncated isoform may be the oncogenic form. Clinical cancer samples did not have significantly higher expression of CARM1FL or CARM1ΔE15 than benign breast samples at the level of mRNA or histology. Furthermore neither CARM1FL nor CARM1ΔE15 expression correlated with breast cancer molecular subtypes, tumor size, or lymph node involvement. The analysis presented here lends new insights into the possible oncogenic role of CARM1ΔE15. This study also demonstrates no obvious association of CARM1 isoform expression and clinical correlates in breast cancer. Recent studies, however, have shown that CARM1 expression correlates with poor prognosis, indicating a need for further studies of both CARM1 isoforms in a large cohort of breast cancer specimens.


HSP90 inhibition alters the chemotherapy-driven rearrangement of the oncogenic secretome.
Adaptive resistance to therapy is a hallmark of cancer progression. To date, it is not entirely clear how microenvironmental stimuli would mediate emergence of therapy-resistant cell subpopulations, although a rearrangement of the cancer cell secretome following therapy-induced stress can be pivotal for such a process. Here, by using the highly chemoresistant malignant pleural mesothelioma (MPM) as an experimental model, we unveiled a key contribution of the chaperone HSP90 at assisting a chemotherapy-instigated Senescence-Associated-Secretory-Phenotype (SASP). Thus, administration of a clinical trial grade, HSP90, inhibitor blunted the release of several cytokines by the chemotherapy-treated MPM cells, including interleukin (IL)-8. Reduction of IL-8 levels hampered the FAK-AKT signaling and inhibited 3D growth and migration. This correlated with downregulation of key EMT and chemoresistance genes and affected the survival of chemoresistant ALDHbright cell subpopulations. Altogether, inhibition of HSP90 provoked a switch from a pro-tumorigenic SASP to a pro-apoptotic senescence status, thus resulting in chemosensitizing effects. In mouse xenografts treated with first-line agents, inhibiting HSP90 blunted FAK activation and reduced the expression of ALDH1A3 and the levels of circulating human IL-8, these latter strongly correlating with the effect on tumor growth. We validated the above findings in primary mesothelioma cultures, a more clinically relevant model. We unveiled here a key contribution of the chaperone HSP90 at assisting the secretory stress in chemotherapy-treated cells, which may warrant further investigation in combinatorial therapeutic settings.


RB-mediated tumor suppression of a lung cancer cell line is abrogated by an extract enriched in extracellular matrix.
To examine whether the expression of retinoblastoma (RB) protein could mediate tumor suppression in a lung carcinoma cell line carrying multiple genetic defects, we transfected the Rb gene into a non-small cell lung cancer cell line with absent RB protein. We observed that the stable expression of a functional RB product was associated with a decreased efficiency of soft agar cloning and partial suppression of tumorigenicity in nude mice. The suppression of tumorigenicity was marked when 10(6) cells were injected into the flanks of nude mice but was less prominent when 10(7) cells were injected. RB-mediated tumor suppression, however, was consistently blocked by preincubation of the transfected cells with an extract enriched with an extracellular matrix (Matrigel). Analysis of tumors harvested from nude mice showed that they continued to express detectable levels of human RB protein which retained functional E1A binding activity and nuclear localization. RB-mediated inhibition of soft agar cloning was also blocked in a dose-dependent manner by the addition of Matrigel. These observations demonstrate that the expression of wild-type RB may suppress certain parameters of tumorigenicity in lung carcinoma cells that contain multiple genetic alterations. In addition, the reversal of tumor suppression by an extract enriched in basement membrane components may offer clues for further investigations into the mechanism of RB-mediated tumor suppression.


Sexual healthcare for cancer patients receiving palliative care: a narrative review.
Palliative care aims to improve quality of life (QoL) for patients and families and does so by addressing issues not limited to pathology, but other symptoms that may be debilitating to patient experience and QoL. Despite sexual health being an important aspect of life for many patients, it is often omitted in clinical practice. This review summarizes published primary studies to explore the prevalence and importance of incorporating sexual health in the symptom screening and assessments of palliative patients, to identify current interventions that are implemented to address sexual health issues, and identify the barriers that health care professionals (HCPs) and patients may encounter which may prevent sexual health discussions. A literature review was conducted on Medline and Embase databases using keywords including "cancer", "sexual health", "intimacy", and "palliative care". Eleven papers focusing on the sexual health and intimacy of terminally ill patients in hospice, palliative or terminal care settings were identified for inclusion. Discussions about sexual health, functioning, and intimacy were not common in patient care, despite being a service that both patients and their partners desired. Referrals to sexologists, or discussions with patients and partners about intimacy and sexuality over the course of the disease trajectory were shown to improve QoL as well as alleviate some of the stress of receiving palliative care services. HCPs cited a lack of training, their own life experiences, or discomfort with the topic as barriers to initiating conversations with patients. In conclusion, sexuality and intimacy remain important parts of many people's lives regardless of their health, and should be incorporated into the care of all patients including those in palliative care. There is a need for further research to evaluate different methods or procedures for educating and counselling patients and their partners on sexual health issues. HCPs should have specific training and education in sexual health care to enable them to initiate and direct these discussions.


Simple spatial scaling rules behind complex cities.
Although most of wealth and innovation have been the result of human interaction and cooperation, we are not yet able to quantitatively predict the spatial distributions of three main elements of cities: population, roads, and socioeconomic interactions. By a simple model mainly based on spatial attraction and matching growth mechanisms, we reveal that the spatial scaling rules of these three elements are in a consistent framework, which allows us to use any single observation to infer the others. All numerical and theoretical results are consistent with empirical data from ten representative cities. In addition, our model can also provide a general explanation of the origins of the universal super- and sub-linear aggregate scaling laws and accurately predict kilometre-level socioeconomic activity. Our work opens a new avenue for uncovering the evolution of cities in terms of the interplay among urban elements, and it has a broad range of applications.


Investigation and analysis of a human orf outbreak among people living on the same farm.
Human orf is a viral zoonotic infection caused by Parapoxvirus. The skin lesions of human orf can be misdiagnosed as cutaneous anthrax leading to overtreatment and also fear. This study was conducted to analyze an outbreak which led to deaths among kids and lambs in the same flock, and skin lesions in some persons who were living on the same farm that were initially diagnosed as cutaneous anthrax by a practitioner. Eight patients with skin lesions and eleven persons who had no skin lesion were considered as patients and control groups, respectively. The cultures obtained from the lesions of all patients were negative for Bacillus anthracis. The diagnosis of skin lesions was done by clinical findings, histopathological examination and PCR as human orf. To be under 20 years of age, direct contact with the animals, and contact with flayed skin of sick animals were the risk factors for human orf (Odds Ratio 7.5; 95% Confidence Interval 1.02-54.54, OR 12.25; 95% CI:1.3-100.9, OR 16.67; 95% CI:1.65-148.20, respectively). Orf should be kept in mind in the differential diagnosis of skin lesions resembling anthrax. For control and prevention of orf, transmission routes should be known; good hand hygiene and other personal protective measures have to be implemented.


Do TNF inhibitors reduce the risk of myocardial infarction in psoriasis patients?
To assess whether patients with psoriasis treated with tumor necrosis factor (TNF) inhibitors have a decreased risk of myocardial infarction (MI) compared with those not treated with TNF inhibitors. Retrospective cohort study. Kaiser Permanente Southern California health plan. Patients with at least 3 International Classification of Diseases, Ninth Revision, Clinical Modification, codes for psoriasis (696.1) or psoriatic arthritis (696.0) (without antecedent MI) between January 1, 2004, and November 30, 2010. Incident MI. Of 8845 patients included, 1673 received a TNF inhibitor for at least 2 months (TNF inhibitor cohort), 2097 were TNF inhibitor naive and received other systemic agents or phototherapy (oral/phototherapy cohort), and 5075 were not treated with TNF inhibitors, other systemic therapies, or phototherapy (topical cohort). The median duration of follow-up was 4.3 years (interquartile range, 2.9, 5.5 years), and the median duration of TNF inhibitor therapy was 685 days (interquartile range, 215, 1312 days). After adjusting for MI risk factors, the TNF inhibitor cohort had a significantly lower hazard of MI compared with the topical cohort (adjusted hazard ratio, 0.50; 95% CI, 0.32-0.79). The incidence of MI in the TNF inhibitor, oral/phototherapy, and topical cohorts were 3.05, 3.85, and 6.73 per 1000 patient-years, respectively. Use of TNF inhibitors for psoriasis was associated with a significant reduction in MI risk and incident rate compared with treatment with topical agents. Use of TNF inhibitors for psoriasis was associated with a non-statistically significant lower MI incident rate compared with treatment with oral agents/phototherapy.


A fresh scientific look at transfer and persistence: From a materials science and tribology perspective.
Knowledge of the mechanisms governing transfer, persistence, and recovery of trace evidence, together with background prevalence in the population of interest, and other task relevant information, is key for the forensic interpretation and reconstruction of what happened at the activity level. Up to now, this informational "toolkit" has largely been developed through empirical forensic studies on specific trace materials such as glass, textile fibers, and soil. Combined with the identified systemic siloing between disciplines, while valuable, such research tends to be very material-dependent, introducing specific parameters and interpretations that may have actually impeded the recognition of underlying foundational factors applicable to most material types. In Australia, there has been a renewed interest in developing a discipline-independent framework for the interpretation and/or reconstruction of trace evidence to interpret specific circumstances in casework. In this paper, we present a discipline agnostic "way of thinking" that has been anchored in foundational science underpinning the trace evidence discipline. Physical and mechanical material properties such as material geometry and surface topography, strength, stiffness, and hardness collectively influence contact interactions through underlying friction, wear, and lubrication cause and effect mechanisms. We discuss how these fundamental factors and parameters stemming from materials science and tribology may be adopted and adapted by forensic practitioners and researchers to contribute to a better understanding of transfer, persistence, and recovery mechanisms irrespective of evidence discipline and material type. Examples are provided to demonstrate the practical significance to real-life casework and academic research.


Multiparameter telemetry as a sensitive screening method to detect vaccine reactogenicity in mice.
Refined vaccines and adjuvants are urgently needed to advance immunization against global infectious challenges such as HIV, hepatitis C, tuberculosis and malaria. Large-scale screening efforts are ongoing to identify adjuvants with improved efficacy profiles. Reactogenicity often represents a major hurdle to the clinical use of new substances. Yet, irrespective of its importance, this parameter has remained difficult to screen for, owing to a lack of sensitive small animal models with a capacity for high throughput testing. Here we report that continuous telemetric measurements of heart rate, heart rate variability, body core temperature and locomotor activity in laboratory mice readily unmasked systemic side-effects of vaccination, which went undetected by conventional observational assessment and clinical scoring. Even minor aberrations in homeostasis were readily detected, ranging from sympathetic activation over transient pyrogenic effects to reduced physical activity and apathy. Results in real-time combined with the potential of scalability and partial automation in the industrial context suggest multiparameter telemetry in laboratory mice as a first-line screen for vaccine reactogenicity. This may accelerate vaccine discovery in general and may further the success of vaccines in combating infectious disease and cancer.


Reducing Frequent Utilization of Psychiatric Emergency Services Among Veterans While Maintaining Quality of Care.
Use of psychiatric emergency services in emergency departments (EDs) and inpatient psychiatry units contributes substantially to the cost of mental health care. Among patients who utilize psychiatric emergency services, a small percentage ("high utilizers") contributes a disproportionate share of the total cost, yet little is known about the context of care for these patients. This study employed qualitative methods to identify barriers to and facilitators of reducing use of psychiatric emergency services among high utilizers. Semistructured phone interviews were conducted with 31 directors of mental health services and providers of psychiatric emergency services across 22 Veterans Health Administration medical centers. The Consolidated Framework for Implementation Research was used to guide the interviews to evaluate the context of care for high utilizers. Thematic coding was used to identify barriers to and facilitators of reducing utilization. Barriers emerged at the patient level (for example, treatment nonadherence and transiency), provider level (for example, stigma toward high utilizers and lack of expertise and training in the management of psychiatric issues among ED staff), and system level (for example, lack of specialized services to address short- and long-term care needs). Facilitators included recovery-oriented care; interdisciplinary care coordination and case management, with emphasis on the role of psychiatric social workers; and predictive analytics to flag high utilizers. The findings lay the groundwork for the design of novel approaches to care for high utilizers of psychiatric emergency services while limiting provider burnout, managing costs, and optimizing treatment outcomes.


The gendered effects of foreign investment and prolonged state ownership on mortality in Hungary: an indirect demographic, retrospective cohort study.
Research on the health outcomes of globalisation and economic transition has yielded conflicting results, partly due to methodological and data limitations. Specifically, the outcomes of changes in foreign investment and state ownership need to be examined using multilevel data, linking macro-effects and micro-effects. We exploited the natural experiment offered by the Hungarian economic transition by means of a multilevel study designed to address these gaps in the scientific literature. For this indirect demographic, retrospective cohort study, we collected multilevel data related to Hungary between 1995 and 2004 from the PrivMort database and other sources at the town, company, and individual level to assess the relation between the dominant company ownership of a town and mortality. We grouped towns into three ownership categories: dominant state, domestic private, and foreign ownership. We did population surveys in these towns to collect data on vital status and other characteristics of survey respondents' relatives. We assessed the relation between dominant ownership and mortality at the individual level. We used discrete-time survival modelling, adjusting for town-level and individual-level confounders, with clustered SEs. Of 83 eligible towns identified, we randomly selected 52 for inclusion in the analysis and analysed ownership data from 262 companies within these towns. Additionally, between June 16, 2014, and Dec 22, 2014, we collected data on 78 622 individuals from the 52 towns, of whom 27 694 were considered eligible. After multivariable adjustment, we found that women living in towns with prolonged state ownership had significantly lower odds of dying than women living in towns dominated by domestic private ownership (odds ratio [OR] 0·74, 95% CI 0·61-0·90) or by foreign investment (OR 0·80, 0·69-0·92). Prolonged state ownership was associated with protection of life chances during the post-socialist transformation for women. The indirect economic benefits of foreign investment do not translate automatically into better health without appropriate industrial and social policies. The European Research Council.


Better together: Elements of successful scientific software development in a distributed collaborative community.
Many scientific disciplines rely on computational methods for data analysis, model generation, and prediction. Implementing these methods is often accomplished by researchers with domain expertise but without formal training in software engineering or computer science. This arrangement has led to underappreciation of sustainability and maintainability of scientific software tools developed in academic environments. Some software tools have avoided this fate, including the scientific library Rosetta. We use this software and its community as a case study to show how modern software development can be accomplished successfully, irrespective of subject area. Rosetta is one of the largest software suites for macromolecular modeling, with 3.1 million lines of code and many state-of-the-art applications. Since the mid 1990s, the software has been developed collaboratively by the RosettaCommons, a community of academics from over 60 institutions worldwide with diverse backgrounds including chemistry, biology, physiology, physics, engineering, mathematics, and computer science. Developing this software suite has provided us with more than two decades of experience in how to effectively develop advanced scientific software in a global community with hundreds of contributors. Here we illustrate the functioning of this development community by addressing technical aspects (like version control, testing, and maintenance), community-building strategies, diversity efforts, software dissemination, and user support. We demonstrate how modern computational research can thrive in a distributed collaborative community. The practices described here are independent of subject area and can be readily adopted by other software development communities.


Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum.
Mutations in the POLG gene have emerged as one of the most common causes of inherited mitochondrial diseases in children and adults. This study sequenced the exons and flanking intronic regions of the POLG gene from 2697 unrelated patients with clinical presentations suggestive of POLG deficiency. Informative mutations have been identified in 136 unrelated individuals (5%), including 92 patients with two recessive pathogenic alleles and three patients harbouring a dominant mutation. Twenty-four novel recessive mutations and a novel possible dominant mutation, p.Y951N, were identified. All missense mutations occurred at evolutionarily conserved amino acids within functionally important regions identified by molecular modelling analyses. Oligonucleotide array comparative genomic hybridisation analyses performed on DNA samples from 81 patients with one mutant POLG allele identified a large intragenic deletion in only one patient, suggesting that large deletions in POLG are rare. The 92 patients with two mutant alleles exhibited a broad spectrum of disease. Almost all patients in all age groups had some degree of neuropathy. Seizures, hepatopathy, and lactic acidaemia were predominant in younger patients. By comparison, patients who developed symptoms in adulthood had a higher percentage of myopathy, sensory ataxia, and chronic progressive external ophthalmoplegia (CPEO)/ptosis. In conclusion, POLG mutations account for a broad clinical spectrum of mitochondrial disorders. Sequence analysis of the POLG gene should be considered as a part of routine screening for mitochondrial disorders, even in the absence of apparent mitochondrial DNA abnormalities.


Dissociable psychosocial profiles of adolescent substance users.
Alcohol, tobacco and cannabis use in adolescence is associated with adverse outcomes. Characterizing adolescent substance misusers, however, is difficult due to the wide range of risk and protective factors linked to substance use. The aim of the present study was to examine the role of the Individual, Family, School, Peer, and Social Environment on alcohol (lifetime and risky), tobacco (risky only), and cannabis use (lifetime and riskiness). Data were analyzed from a national sample of 5,680 adolescents, capturing substance use behavior alongside risk and protective factors across Individual, Family, School, Peer and Social domains. We applied a sophisticated machine learning classifier to develop models of alcohol, tobacco and cannabis initiation and misuse. We found highly accurate (area under curve of receiver-operator-characteristic for out-of-sample performance was > .88) and replicable (over multiple iterations and in comparison with permuted outcomes) dissociable psychosocial profiles of alcohol, tobacco and cannabis use. Alongside common predictors (peer relations and externalizing behavior), dissociable risk and resilience factors were observed. Adolescent profiles of alcohol use were distinguished by the contribution of multiple domains. In contrast, tobacco use was characterized by a small number of individual variables, including female gender and poor perceived academic position. Cannabis use was differentiated by the distinct contribution of Individual risk factors, in particular male gender and feelings of anger. Differential associations were also evident, with the strength and direction of association differing substantially across substances. This study indicates that the relationship between the environment and substance use is more complex than previously thought.


Differential effects of extracellular ATP on chloride transport in cortical collecting duct cells.
Extracellular ATP in the cortical collecting duct can inhibit epithelial sodium channels (ENaC) but also stimulate calcium-activated chloride channels (CACC). The relationship between ATP-mediated regulation of ENaC and CACC activity in cortical collecting duct cells has not been clearly defined. We used the mpkCCD(c14) cortical collecting duct cell line to determine effects of ATP on sodium (Na(+)) and chloride (Cl(-)) transport with an Ussing chamber system. ATP, at a concentration of 10(-6) M or less, did not inhibit ENaC-mediated short-circuit current (I(sc)) but instead stimulated a transient increase in I(sc). The macroscopic current-voltage relationship for ATP-inducible current demonstrated that the direction of this ATP response changes from positive to negative when transepithelial voltage (V(te)) is clamped to less than -10 mV. We hypothesized that this negative V(te) might be found under conditions of aldosterone stimulation. We next stimulated mpkCCD(c14) cells with aldosterone (10(-6) M) and then clamped the V(te) to -50 mV, the V(te) of aldosterone-stimulated cells under open-circuit conditions. ATP (10(-6) M) induced a transient increase in negative clamp current, which could be inhibited by flufenamic acid (CACC inhibitor) and BAPTA-AM (calcium chelator), suggesting that ATP stimulates Cl(-) absorption through CACC. Together, our findings suggest that the status of ENaC activity, by controlling V(te), may dictate the direction of ATP-stimulated Cl(-) transport. This interplay between aldosterone and purinergic signaling pathways may be relevant for regulating NaCl transport in cortical collecting duct cells under different states of extracellular fluid volume.


Clinical algorithms for malaria diagnosis lack utility among people of different age groups.
We conducted a study to determine whether clinical algorithms would be useful in malaria diagnosis among people living in an area of moderate malaria transmission within Kilifi District in Kenya. A total of 1602 people of all age groups participated. We took smears and recorded clinical signs and symptoms (prompted or spontaneous) of all those presenting to the study clinic with a history of fever. A malaria case was defined as a person presenting to the clinic with a history of fever and concurrent parasitaemia. A set of clinical signs and symptoms (algorithms) with the highest sensitivity and specificity for diagnosing a malaria case was selected for the age groups </=5 years, 6-14 years and >/=15 years. These age-optimized derived algorithms were able to identify about 66% of the cases among those <15 years of age but only 23% of cases among adults. Were these algorithms to be used as a basis for a decision on treatment among those presenting to the clinic, 16% of children </=5 years, 44% of those 6-14 years of age and 66% of the adults who had a history of fever and parasitaemia >/=5000 parasites/microl of blood would be sent home without treatment. Clinical algorithms therefore appear to have little utility in malaria diagnosis, performing even worse in the older age groups, where avoiding unnecessary use of anti-malarials would make more drugs available to the really needy population of children under 5 years of age.


Late stage functionalization of heterocycles using hypervalent iodine(iii) reagents.
Late stage functionalization (LSF) through direct X-H manipulations (X = C, N) enables synthetic chemists to accelerate the diversification of natural products, agrochemicals and pharmaceuticals allowing rapid access to novel bioactive molecules without resorting to arduous de novo synthesis. LSF does not only allow tapping of the hitherto unexplored chemical space but also renders the synthetic sequence more straightforward, atom economical and cost-effective. In this regard, the recent decade has witnessed the emergence of hypervalent iodine(iii) reagents as a powerful synthetic tool owing to their easy availability, mild reaction conditions, remarkable oxidizing properties and high functional group tolerance. Iodine(iii) reagents have tremendous applications in the regio- and chemo-selective late-stage functionalization of a diverse variety of heterocycles through an exciting range of transformations, such as oxidative amination, cross-dehydrogenative coupling (CDC), fluoroalkylation, azidation, halogenation and oxidation. The present review, classified according to the types of synthetic methods involved, encompasses all these recent developments in the field of transition-metal-free iodine(iii)-catalyzed/mediated direct functionalizations of heterocycles with representative examples and insightful mechanistic discussions.


[Social spending in Brazil: income transfer programs versus social investments].
This paper compares the dynamics of social spending in Brazil, with lower outlays on basic services and more direct monetary transfers through means-test programs, highlighting the fact that as Brazil's social safety net concentrates on cash transfer programs without simultaneously increasing per capita outlays on education, basic sanitation and housing, it is not resolving the issue of inequality. This paper works with secondary data from the National Household Sampling Survey, together with Federal, State and Municipal budgets.


Ethicolegal aspects of genetics in surgical practice.
Genetic medicine can pose ethical and legal dilemmas or both. This short review highlights some of the ethicolegal issues in disclosure of genetic information to family members and considers whether the availability, or not, of a medical intervention is relevant in communication of risk information.


Industrial fungal enzymes: an occupational allergen perspective.
Occupational exposure to high-molecular-weight allergens is a risk factor for the development and pathogenesis of IgE-mediated respiratory disease. In some occupational environments, workers are at an increased risk of exposure to fungal enzymes used in industrial production. Fungal enzymes have been associated with adverse health effects in the work place, in particular in baking occupations. Exposure-response relationships have been demonstrated, and atopic workers directly handling fungal enzymes are at an increased risk for IgE-mediated disease and occupational asthma. The utilization of new and emerging fungal enzymes in industrial production will present new occupational exposures. The production of antibody-based immunoassays is necessary for the assessment of occupational exposure and the development of threshold limit values. Allergen avoidance strategies including personal protective equipment, engineering controls, protein encapsulation, and reduction of airborne enzyme concentrations are required to mitigate occupational exposure to fungal enzymes.


Polysaccharide-Based Systems for Targeted Stem Cell Differentiation and Bone Regeneration.
Bone tissue engineering is an ever-changing, rapidly evolving, and highly interdisciplinary field of study, where scientists try to mimic natural bone structure as closely as possible in order to facilitate bone healing. New insights from cell biology, specifically from mesenchymal stem cell differentiation and signaling, lead to new approaches in bone regeneration. Novel scaffold and drug release materials based on polysaccharides gain increasing attention due to their wide availability and good biocompatibility to be used as hydrogels and/or hybrid components for drug release and tissue engineering. This article reviews the current state of the art, recent developments, and future perspectives in polysaccharide-based systems used for bone regeneration.


Uptake and speciation of selenium in garlic cultivated in soil amended with symbiotic fungi (mycorrhiza) and selenate.
The scope of the work was to investigate the influence of selenate fertilisation and the addition of symbiotic fungi (mycorrhiza) to soil on selenium and selenium species concentrations in garlic. The selenium species were extracted from garlic cultivated in experimental plots by proteolytic enzymes, which ensured liberation of selenium species contained in peptides or proteins. Separate extractions using an aqueous solution of enzyme-deactivating hydroxylamine hydrochloride counteracted the possible degradation of labile selenium species by enzymes (such as alliinase) that occur naturally in garlic. The selenium content in garlic, which was analysed by ICP-MS, showed that addition of mycorrhiza to the natural soil increased the selenium uptake by garlic tenfold to 15 microg g(-1) (dry mass). Fertilisation with selenate and addition of mycorrhiza strongly increased the selenium content in garlic to around one part per thousand. The parallel analysis of the sample extracts by cation exchange and reversed-phase HPLC with ICP-MS detection showed that gamma-glutamyl-Se-methyl-selenocysteine amounted to 2/3, whereas methylselenocysteine, selenomethionine and selenate each amounted to a few percent of the total chromatographed selenium in all garlic samples. Se-allyl-selenocysteine and Se-propyl-selenocysteine, which are selenium analogues of biologically active sulfur-containing amino acids known to occur in garlic, were searched for but not detected in any of the extracts. The amendment of soil by mycorrhiza and/or by selenate increased the content of selenium but not the distribution of detected selenium species in garlic. Finally, the use of two-dimensional HPLC (size exclusion followed by reversed-phase) allowed the structural characterisation of gamma-glutamyl-Se-methyl-selenocysteine and gamma-glutamyl-Se-methyl-selenomethionine in isolated chromatographic fractions by quadrupole time-of-flight mass spectrometry.


Impact of an adherence clinic on behavioral outcomes and virologic response in treatment of HIV infection: a prospective, randomized, controlled pilot study.
The aim of this randomized, controlled pilot study was to examine the impact of a pharmacist operated adherence clinic on adherence to highly active antiretroviral therapy (HAART) and viral suppression in patients with HIV over 28 weeks. Consecutive eligible patients initiating HAART at an indigent-care clinic were randomized to an adherence clinic or to standard care (information provided by physician or nurse practitioner) for education and monitoring. Group assignment was stratified before randomization according to regimen complexity and potential tolerability. Adherence (electronic monitoring and patient self-report) and viral load (reverse-transcription polymerase chain reaction) were assessed at weeks 4, 16, and 28. Thirty-three randomized patients (adherence clinic, n = 16; standard care, n = 17) comprised the intent-to-treat population. The groups were well-matched for demographics and antiretroviral regimen. The median age was 38.0 years in both groups. Most patients were male (85%), had previously used HAART (78%), and had an AIDS diagnosis (79%). Mean (SD) adherence at weeks 4, 16, and 28 was 86% (27%), 77% (28%), and 74% (31%) in the adherence clinic group versus 73% (32%), 56% (39%), and 51% (41%) in the standard care group (week-16 difference, 21% [90% CI, 1%-42%]; week-28 difference, 23% [90% CI, 1%-44%]). Sixty-nine percent of patients in the adherence clinic group took their medication on schedule versus 42% in the standard care group (P = 0.025); mean decline in adherence from weeks 4 to 28 was 12% in the adherence clinic group (P = 0.15) versus 22% in the standard care group (P = 0.002). HIV-1 RNA levels were <400 copies/mL at weeks 4, 16, and 28 in 63%, 100%, and 94% of the adherence clinic group and 29% (P = NS), 71% (P = 0.04), and 65% (P = NS) of the standard care group. In this preliminary trial, an adherence clinic model improved adherence to HAART and virologic response over 28 weeks in the patients studied.


Revenge Pornography: Mental Health Implications and Related Legislation.
Revenge pornography, also known as nonconsensual pornography, is a subtype of cyberharassment/cyberstalking, and a serious problem facing society in the Internet age. Revenge pornography can result in lifelong mental health consequences for victims, damaged relationships, and social isolation. Recently, a growing number of states have recognized the importance of this phenomenon and have enacted legislation that criminalizes it. The technology industry has also taken steps to assist victims of revenge pornography by creating web forms to request removal of links leading to the explicit content. The Cyber Civil Rights Initiative (CCRI) has been instrumental in promoting public awareness of this often overlooked problem and in providing services for victims. Although important steps have been made, greater recognition of the gravity of this problem and the mental health implications of revenge pornography is needed to expand legislation criminalizing such acts. A federal criminal law, in particular, is much overdue. Mental health professionals must understand the dimensions of revenge pornography to be able to identify and address the consequences in both forensic and clinical settings.


Multifaceted prismatic silver nanoparticles: synthesis by chloride-directed selective growth from thiolate-protected clusters and SERS properties.
We describe the synthetic preparation of well-defined symmetric multifaceted prismatic silver nanoparticles with chemically controlled faceting advantageous for strong and tunable surface-enhanced Raman scattering, SERS. These silver nanoparticles, that have been termed nanoflowers, AgNFls for their characteristic morphologies, have been prepared by a one-pot aqueous reaction under ambient conditions. AgNFl faceting is synthetically controlled by selective nanoparticle growth driven by chloride ions. Selective chloride binding to the surface of growing AgNFls results in nanoparticle enlargement predominantly at the points of their highest energy. These growth points are located at the tips of prismatic polygons in precursor prismatic morphologies that have been produced from thiolate-protected silver clusters whose coalescence is triggered with a strong base. For the practical aspects of AgNFl synthesis, concentrations of thiol and a strong base were found to be the key variables reliably controlling the extent of AgNFl faceting, as well as the kinetics of AgNFl formation and their stability. The selective growth of AgNFls progresses slower compared to that of non-faceted prisms: fewer nuclei can form leading to larger AgNFls with the diameter ranging from 130 to 2250 nm and asperity sizes on the order of 20 to 100 nm. Self-assembly of AgNFls yields columnar stacking. AgNFls were demonstrated to function as a promising substrate for surface-enhanced Raman scattering. SERS measurements were performed for a series of AgNFls with variable faceting, where the enhancement factors of 4.6 × 10(8) and 425 have been achieved for dry solid films and aqueous dispersions of non-aggregated AgNFls with single-particle enhancement, respectively. These SERS results are promising, especially in combination with that AgNFl nanoscale asperities can be conveniently tailored synthetically. Overall, AgNFls offer valuable opportunities for a system with synthetically variable nanoscale asperities.


Defining and assessing an anisotropic delineation margin for modern radiotherapy.
Uncertainty in target volume delineation for modern radiotherapy impacts dosimetry and patient outcomes. Delineation uncertainty is generally overlooked in practice as a source of error, potentially since historically, other uncertainties have been the main focus. This work defined and assessed an anisotropic delineation margin in both polar and spherical coordinate systems in order to account for the spatially varying nature of this uncertainty using a whole breast radiotherapy cohort as a proof of concept. A cohort of 21 whole breast radiotherapy patient datasets with clinical target volumes delineated by eight independent observers was utilized. Patients were divided into categories based on target volume and laterality. An anisotropic delineation margin for each category was determined by multiplying the average standard deviation in observer contours in each category by a factor of two. Standard deviation was determined in both polar and spherical coordinates at angular increments. This anisotropic approach was compared to a conventional clinical approach, where the delineation margin was applied in the cardinal directions only. The assessment of the delineation margin was undertaken by comparing the encompassment of the observer volumes by the target volume with added margin. The extra, presumed healthy tissue included in the margin and the malignant tissue missed by the margin were determined. The proposed delineation margin is effective at accounting for inter-observer variation, producing >95% coverage of all CTVs for polar, spherical, and Cartesian margins in 82%, 79%, and 92% of cases, respectively. Additionally, <1% malignant tissue was missed for 65%, 70%, and 91% of cases and <37% healthy tissue was included in 95%, 89%, and 97% of cases. A conventional delineation margin approach is most appropriate for small and gold standard target volumes. However, for large target volumes, an anisotropic margin is necessary, producing significantly greater coverage of CTVs, including significantly less presumed healthy tissue and missing significantly less malignant tissue. All delineation margin methods that account for target volume and laterality proved to be adequate, with appropriate encompassment of interobserver variation and minimal inclusion of extra excess healthy tissue and exclusion of possible malignant tissue. The anisotropic approach was found to be superior to a conventional approach for target volumes >1400 cm3 only with significantly greater encompassment of interobserver variation, less missed malignant tissue and less included healthy tissue. This methodology has been validated for a whole breast radiotherapy cohort as a proof of concept, however could be applied to other anatomical sites.


Flipped scleral flap surgery for reduction of ocular pigmentation in oculodermal melanosis.
To report on surgical reduction of oculodermal melanosis in 6 patients presenting with severe episcleral pigmentation. After informed consent was obtained, surgical reduction of ocular pigmentation with ocular dermal melanosis was performed on 3 children, 2 girls and 1 boy male, who were cosmetically handicapped. After conjunctival peritomy, rectangular scleral free flaps were created using lamellar dissection, usually in the nasal or temporal quadrants. The rectangles extended from just posterior to the rectus muscle insertion. These free flaps were flipped over and reattached to the scleral bed, hiding the episcleral pigmentation internally and resulting in a less pigmented surface being visible. The superficial scleral nevus and the nevus adjacent to the limbus were peeled using a blade. In all cases, episcleral pigmentation was reduced with satisfactory cosmetic improvement, but mild scleral pigmentation and conjunctival scarring remained. During the 37-month mean follow-up period, no complications were observed. Patients with oculodermal melanosis often complain of globe pigmentation as well as face pigmentation. Serial follow-up was needed because some reports indicate development of choroidal melanoma occurs in oculodermal melanosis. To the best of our knowledge, this is the first report of successful surgical reduction of ocular pigmentation in oculodermal melanosis.


Hyperbranched polyesters as biodegradable and antibacterial additives.
Herein, we present novel hyperbranched poly(amino-ester)s functionalized with quaternary ammonium salts (QAS-HPAEs). These materials can be used as antibacterial and biodegradable additives for mixing with non-active polymers. The chemical structure and thermal properties of the HPAEs were studied. All QAS-HPAEs were stable until 192 °C, which makes their thermal blending with other polymers possible. Blending polycaprolactone (PCL) as a biodegradable polymer with QAS-HPAEs improved its surface and bulk hydrophilicity, while partially decreasing its elastic modulus and tensile strength. Mixing 10 wt% of QAS-HPAEs in PCL resulted in a film with high contact-killing activity against E. coli and B. subtilis and faster degradability in the presence and absence of esterase. The activity of esterase was inhibited in the presence of a higher content of QAS-HPAEs (20 wt%).


Enhancement of the antitumor effect by the concurrent use of a monoclonal antibody and the protein-bound polysaccharide PSK in mice bearing a human cancer cell line.
The antitumor effects of a monoclonal antibody against a human cancer cell line and a protein-bound polysaccharide, PSK, obtained from cultured mycelia of Coriolus versicolor in basidiomycetes were examined. The IgG2a monoclonal antibody against the human colon cancer cell line colo 205 induced in vitro antibody-dependent macrophage-mediated cytotoxicity against the cancer cells, but only slightly suppressed the in vivo growth of the cancer cells. Concurrent use of PSK with the antibody enhanced the in vitro antibody-dependent macrophage-mediated cytotoxicity as well as the in vivo antitumor activity. These findings suggest that the combined use of a monoclonal antibody and PSK, which have different modes of action, may be useful in the treatment of cancer.