First Report of Ginseng (Panax ginseng) as a Natural Host of Dodder (Cuscuta japonica) in China.
Ginseng (Panax ginseng C.A. Meyer) belongs to the Araliaceae family and is a high-value medicinal herb grown mainly in Jilin Province, China. China is the world's oldest and largest producer of ginseng. Annual yield and exports account for more than 78 and 60% for the world, respectively. In July 2009 and August 2010, dodder (Cuscuta sp.), a parasitic seed plant, was observed on 4- and 5-year-old plants that were being cultivated on raised beds under artificial shading in three separate locations approximately 200 kilometers apart in Jilin Province. The infested area was approximately one-third of the field (300 m2 of 10,000 m2), which was previously planted with pine trees and herbaceous plants. Initially, there were no obvious symptoms on ginseng plants, but later, symptoms consisted of poor growth, chlorosis, and wilting, eventually followed by death in large areas throughout the field. One typical representative of 10 samples collected was identified as Cuscuta japonica based on several morphological characteristics, including yellow stems with purplish spots with branches 1.2 to 2.5 mm in diameter. Inflorescences were spicate and measured 3 cm with broadly ovate, scale-like bracts. Flowers were sessile with deeply divided calyxes. The parasite had purplish, ovate sepals with pink or greenish white corollas. The plant had five stamens with yellow, ovate-circular anther. Ovaries were globose and smooth. Capsules contained three to four pale yellow or brown ovate seeds measuring 1.9 to 2.7 mm (3,4). The internal transcribed spacer (ITS) region of rDNA of the representative samples was amplified using primers ITS4/ITS5 (2) and sequenced. BLASTn analysis of the 650-bp amplicon (GenBank Accession No. JF431541) showed 99% sequence identity with C. japonica (Accession Nos. DQ924571 and EU330320). Phylogenetic trees constructed by utilizing the neighbor-joining method with software MEGA 4.0 (1) placed the dodder specimens and C. japonica (DQ924571 and EU330320) into one group. The reported hosts of C. japonica include plants belonging to the Leguminosae, Salicaceae, Polygonaceae, and Compositae. Therefore, to our knowledge, this is the first report of C. japonica naturally infecting P. ginseng in the world. Reference: (1) K. Tamura et al. Mol. Biol. Evol. 24:1596, 2007. (2) T. J. White et al. Page 315 in: PCR Protocols: A Guide to Methods and Applications. Academic Press, San Diego, 1990. (3) Z. Y. Wu. Flora Reipublicae Popularis Sinicae 64:147, 1979. (4) L. P. Yin. Plant Quarantine (in Chinese) 9:292, 1995.


Impact of Systemic Therapy and Recurrence Pattern on Survival Outcome after Radiofrequency Ablation for Colorectal Liver Metastases.
Background: Most patients undergoing radiofrequency ablation (RFA) of colorectal liver metastasases (CLM) develop disease recurrence, but little is known about the effect of recurrence patterns and/or systemic therapy on outcome. In this study, we examined the recurrence patterns and survival after systemic therapy plus RFA in patients with unresectable CLM without extrahepatic disease. The aims were to analyze the effect of recurrence patterns on survival and to assess the relative benefit contributed by systemic therapy and local ablation to disease control and patient outcome. Methods: From January 2002 to December 2012, 113 patients underwent RFA of liver-limited CLM after systemic therapy. Univariate and multivariate analyses for associations between clinical and/or treatment-related variables, recurrence-free survival (RFS), recurrence patterns, and overall survival (OS) were carried out. Results: Of 113 patients, 105 (92.8%) had disease recurrence (median RFS: 6.1 months). Lower post-recurrence OS was observed after early (≤6 months) than after late recurrence (8.5 versus 24.0 months, p < 0.001). Recurrence sites were RFA-sites only (4.8%), liver-only (57.1%), lung-only (10.5%), or multiple (27.6%); the corresponding post-recurrence OS was 21, 19, 39, and 7 months (p < 0.001), respectively. Response to pre-RFA systemic therapy was the strongest predictor for OS (hazard ratio [HR] 5.28), RFS (HR 3.30), early (odds ratio [OR] 6.34) and multiple-site recurrence (OR 3.83) (p < 0.01), respectively; only responders achieved 5-year OS and RFS (29% and 12% versus 0% and 0% for non-responders, p < 0.001, respectively). Conclusions: Survival after RFA for liver-limited CLM is strongly linked to the timing and pattern of non-local disease recurrence. Local ablation efficacy is necessary but not sufficient to obtain long-term disease control. Effective pre-RFA systemic therapy does favourably affect the incidence, timing and patterns of recurrence and long-term survival and appears essential for the tailoring of RFA application to maximize patient benefit.


How individual cells develop from a syncytium: merogony in Theileria parva (Apicomplexa).
The central problem for Theileria parva during merogony is how to form numerous individual, uninucleate merozoites from a syncytial schizont so that each merozoite contains a single nucleus and a prescribed assortment of organelles. The way T. parva packages all the requisite organelles into free merozoites is by binding these organelles to the nuclear envelope, which in turn becomes associated, both directly and through the rhoptry complex, with the schizont plasma membrane. Formation of the merozoites occurs in a synchronous manner by a budding process. The merozoites develop with the rhoptry complex at the apical end by the progressive, outward evagination of the schizont plasma membrane. This evagination of the plasma membrane is associated with, and presumably induced by, the development of an orderly array of tubules that originate from the apical end and progressively form a longitudinal basket enclosing first the rhoptry complex, then the mitochondria and ribosomes, and finally the nucleus. The process of merogony is compared to sporogony within the tick salivary gland and with the differentiation of the intra-erythrocytic piroplasm stage. Because all three processes occur by a morphologically similar mechanism, the possibility that the parasite uses a single cassette of genes to perform each of these similar processes is discussed.


Health-promoting effects of green tea.
Green tea is manufactured from the leaves of the plant Camellia sinensis Theaceae and has been regarded to possess anti-cancer, anti-obesity, anti-atherosclerotic, anti-diabetic, anti-bacterial, and anti-viral effects. Many of the beneficial effects of green tea are related to the activities of (-)-epigallocatechin gallate (EGCG), a major component of green tea catechins. For about 20 years, we have engaged in studies to reveal the biological activities and action mechanisms of green tea and EGCG. This review summarizes several lines of evidence to indicate the health-promoting properties of green tea mainly based on our own experimental findings.


Viral antigen mediated NKp46 activation of NK cells results in tumor rejection via NK-DC crosstalk.
Natural killer (NK) cells play a critical role in antitumor immunity, their activation being regulated through NK cell receptors. Although the endogenous ligands for these receptors are largely unknown, viral ligands have been identified. We investigated the ability of an activating NK receptor ligand derived from the mumps virus, haemagglutinin-neuraminidase (HN) to enhance NK activation against tumor cells. HN-expressing B16.OVA tumor cells induced stronger activation of NK cells compared with B16.OVA cells and also promoted dendritic cell (DC) activation toward a DC1 phenotype, in vitro. Moreover, incubation of DCs, NK cells and HN-expressing B16-OVA cells further enhanced NK cell activation through the NK-DC crosstalk, in a cell-to-cell contact- and IL-12-dependent fashion. Immunization of mice with HN-expressing B16-OVA cells resulted in > 85% survival rate after subsequent challenge with parental B16 or B16.OVA tumor cells. Tumor rejection was dependent on both NK and CD8+ T cells but not on CD4+ T cells, demonstrating induction of an effective adaptive immune response through innate immune cell activation. Our data indicate the potential of using robust NK cell activation, which through the NK-DC crosstalk stimulates effective antitumor responses, providing an alternate vaccine strategy.


Sialylation of IgG Fc domain impairs complement-dependent cytotoxicity.
IgG molecules exert both pro- and antiinflammatory effector functions based on the composition of the fragment crystallizable (Fc) domain glycan. Sialylated IgG Fc domains have antiinflammatory properties that are attributed to their ability to increase the activation threshold of innate effector cells to immune complexes by stimulating the upregulation of the inhibitory Fcγ receptor IIB (FcγRIIB). Here, we report that IgG Fc sialylation of human monoclonal IgG1 molecules impairs their efficacy to induce complement-mediated cytotoxicity (CDC). Fc sialylation of a CD20-targeting antibody had no impact on antibody-dependent cellular cytotoxicity and did not change the affinity of the antibody for activating Fcγ receptors. In contrast, the presence of sialic acid abrogated the increased binding of C1q to Fc-galactosylated IgG1 and resulted in decreased levels of C3b deposition on the cell surface. Similar to monoclonal antibodies, sialic acid inhibited the increased C1q binding to galactosylated Fc fragments in human polyclonal IgG. In sera derived from patients with chronic inflammatory demyelinating polyneuropathy, an autoimmune disease of the peripheral nervous system in which humoral immune responses mediate tissue damage, induction of IgG Fc sialylation was associated with clinical disease remission. Thus, impairment of CDC represents an FcγR-independent mechanism by which Fc-sialylated glycovariants might limit proinflammatory IgG effector functions.


Transport risk index of physiologic stability: a practical system for assessing infant transport care.
To develop and validate a practical, physiology-based system for assessment of infant transport care. Transport teams prospectively collected data, before and after transport, from 1723 infants at 8 neonatal intensive care units (NICUs) from 1996 to 1997. We used logistic regression to derive a prediction model for mortality within 7 days of NICU admission and develop the Transport Risk Index of Physiologic Stability (TRIPS). We validated TRIPS for prediction of 7-day mortality, total NICU mortality (until discharge), and severe (> or =grade 3) intraventricular hemorrhage. TRIPS comprises 4 empirically weighted items (temperature, blood pressure, respiratory status, and response to noxious stimuli). TRIPS discriminated 7-day NICU mortality and total NICU mortality from survival with receiver operating characteristic areas of 0.83 and 0.76, respectively. There was good calibration across the full range of TRIPS scores and gestational age groups. Increase and decrease in TRIPS scores after transport were associated with increased and decreased mortality, respectively. The receiver operating characteristic area for TRIPS prediction of severe intraventricular hemorrhage was 0.74. Addition of TRIPS improved performance of prediction models in which gestational age and baseline population risk variables were used. TRIPS is validated for infant transport assessment.


Proliferative suppression by CDK4/6 inhibition: complex function of the retinoblastoma pathway in liver tissue and hepatoma cells.
Hepatocellular carcinoma is the third leading cause of cancer mortality worldwide; current chemotherapeutic interventions for this disease are largely ineffective. The retinoblastoma tumor suppressor (RB) is functionally inactivated at relatively high frequency in hepatocellular carcinoma and hepatoma cell lines. Here, we analyzed the ability of CDK4/6 inhibition to inhibit hepatocyte proliferation and the effect of RB status on this process. Hepatoma cell lines and xenograft models harboring RB knockdown and mice harboring liver-specific Rb deletion were used to define the role of RB function in response to CDK4/6 inhibition. Our study shows that CDK4/6-dependent cell cycle progression in hepatoma cells was readily arrested by inhibition of CDK4/6 by PD-0332991 or p16ink4a irrespective of RB status. Interestingly, upon CDK4/6 inhibition, p107 protein stability was dramatically increased as a function of RB loss. This engagement of compensatory mechanisms was critical for cell cycle inhibition in the absence of RB, because both the E1A oncoprotein and overexpression of E2F proteins were capable of overcoming the effect of CDK4/6 inhibition. These findings were recapitulated in xenograft models. Furthermore, to determine how these findings relate to hepatocyte proliferation in vivo, mice were exposed to carbon tetrachloride to induce liver regeneration followed by treatment with PD-0332991. This treatment significantly inhibited hepatocyte proliferation. Strikingly, this facet of PD-0332991 function was retained even in RB-deficient livers. These data show that CDK4/6 inhibition is a potent mediator of cytostasis and that RB loss can be readily compensated for in the context of both hepatoma cell lines and liver tissue.


Depression and acitretin: a true association or a class labeling?
The potential relationship between systemic retinoids used in dermatology and affective disorders is controversial. Acitretin, which is widely used in the treatment of psoriasis is part of this controversy secondary to its chemical relation to isotretinoin, a drug which has been associated with a large number of anecdotal case reports of depression and suicidal ideation. Moreover, an FDA package insert precaution regarding acitretin's association with depression and suicide has elevated the level of concern for patient safety. The objective of this article is to review the evidence in the literature regarding acitretin's association with affective disorders. After 12 years of worldwide use only two cases involving acitretin have been reported in the literature. In addition, despite many anecdotal cases involving isotretinoin, there have been no clinical studies that have proven a causal relationship between isotretinoin and depression or suicidal ideation. For acitretin there have been no systematic clinical studies that examine such a relationship. Moreover, it is notable that the FDA precaution regarding depression and suicide on the package insert of acitretin predates the publication of the aforementioned two cases. This suggests that a relationship between acitretin and affective disorders is a class labeling rather than a scientifically proven association.


[Current epidemiological situation of trichinosis in Chile. 1991-2000].
Human and animal trichinosis has been recorded in Chile since the late XIX century and is irregularly distributed along the country. From high rates of infection in the early 1900, the frequency of this parasitosis in man has progressively decreased. To describe and discuss the epidemiological situation of trichinosis in Chile during the decade 1991-2000. Human infection was assessed using annual incidence and lethality reports provided by the Ministry of Health, periodic photostrichinoscopies in corpses of non selected individuals autopsied at the Medico Legal Service and periodic national serologic surveys. The advise of one of the authors in an epidemic that occurred in 1999 in the VIII Region was also used. Animal infection was assessed using the annual prevalence of infection in pigs slaughtered in abattoirs, furnished by the Ministry of Health. A total of 631 clinical cases with 4 deaths (0.6%) was recorded. A decline in the incidence, from 0.7 x 100,000 in 1991 to 0.2 x 100,000 in 2000 was recorded. The higher frequency of the parasitosis was observed in the Metropolitan, VI, VIII and X regions. Although human trichinosis has been observed in all seasons, its frequency increases in close relation with the higher pork consumption in cold seasons (45.8% in winter and 37.5% in spring). There has been a decrease of infection rates in pigs from 0.17@1000 in 1991 to 0.04@1000 in 1998-2000. The incidence and prevalence of trichinosis shows a constant decline in Chile. Considering the geographical characteristics of Chile, it is possible that an undetermined number of pigs are home reared and butchered without veterinary control, constituting an important source of human trichinosis.


Hereditary lipo-muscular atrophy with joint contracture, skin eruptions and hyper-gamma-globulinemia: a new syndrome.
We previously reported two siblings with decreased subcutaneous adipose tissue, muscular atrophy, joint contractures, recurrent skin eruptions, hyper-gamma-globulinemia, and reduced natural killer cell activity. Some of their clinical features are similar to those of partial lipodystrophy, but they are distinct in that muscular atrophy, joint contractures and recurrent skin eruptions are not found in patients with partial lipodystrophy. Thirteen other Japanese patients with similar clinical manifestations have been reported. We propose that such cases should be considered a distinct clinical entity.


Overcoming the challenges of drug discovery for neglected tropical diseases: the A·WOL experience.
Neglected tropical diseases (NTDs) are a group of 17 diseases that typically affect poor people in tropical countries. Each has been neglected for decades in terms of funding, research, and policy, but the recent grouping of them into one unit, which can be targeted using integrated control measures, together with increased advocacy has helped to place them on the global health agenda. The World Health Organization has set ambitious goals to control or eliminate 10 NTDs by 2020 and launched a roadmap in January 2012 to guide this global plan. The result of the launch meeting, which brought together representatives from the pharmaceutical industry, donors, and politicians, was the London Declaration: a series of commitments to provide more drugs, research, and funds to achieve the 2020 goals. Drug discovery and development for these diseases are extremely challenging, and this article highlights these challenges in the context of the London Declaration, before focusing on an example of a drug discovery and development program for the NTDs onchocerciasis and lymphatic filariasis (the anti-Wolbachia consortium, A·WOL).


Recent advances in the development of anti-infective peptoids.
In the search for new sources of antimicrobials many researchers have investigated antimicrobial peptides (AMPs) as templates for the design of innovative therapeutics. However, efforts to develop AMPs in this area has been severely hampered by their inherent susceptibility to enzymatic degradation. Given this only a handful of AMPs are currently in clinical trials. Peptide mimetics such as peptoids have emerged as highly promising alternatives to AMPs as they are inherently stable to enzymatic degradation and display potent antimicrobial properties. This feature article highlights the progress that has been made towards the development of novel anti-infective peptoids.


Four new species of Acoela from Chile.
Acoels are with few exceptions marine worms and a common component of the interstitial meiofauna. In this study we present new species to science belonging to Isodiametridae and Solenofilomorphidae. The new species, Isodiametra finkei n. sp., Postaphanostoma nilssoni n. sp., Pseudaphanostoma hyalinorhabdoida n. sp. and Solenofilomorpha pellucida n. sp. were all collected in Chile during March 2012. Nucleotide sequences for the ribosomal genes 18S rDNA and 28S rDNA as well as COI mtDNA have been determined for the new species and used in a maximum likelihood analysis to further support their classification.


A Novel Joint Brain Network Analysis Using Longitudinal Alzheimer's Disease Data.
There is well-documented evidence of brain network differences between individuals with Alzheimer's disease (AD) and healthy controls (HC). To date, imaging studies investigating brain networks in these populations have typically been cross-sectional, and the reproducibility of such findings is somewhat unclear. In a novel study, we use the longitudinal ADNI data on the whole brain to jointly compute the brain network at baseline and one-year using a state of the art approach that pools information across both time points to yield distinct visit-specific networks for the AD and HC cohorts, resulting in more accurate inferences. We perform a multiscale comparison of the AD and HC networks in terms of global network metrics as well as at the more granular level of resting state networks defined under a whole brain parcellation. Our analysis illustrates a decrease in small-worldedness in the AD group at both the time points and also identifies more local network features and hub nodes that are disrupted due to the progression of AD. We also obtain high reproducibility of the HC network across visits. On the other hand, a separate estimation of the networks at each visit using standard graphical approaches reveals fewer meaningful differences and lower reproducibility.


Crucial neuroprotective roles of the metabolite BH4 in dopaminergic neurons.
Dopa-responsive dystonia (DRD) and Parkinson's disease (PD) are movement disorders caused by the dysfunction of nigrostriatal dopaminergic neurons. Identifying druggable pathways and biomarkers for guiding therapies is crucial due to the debilitating nature of these disorders. Recent genetic studies have identified variants of GTP cyclohydrolase-1 (GCH1), the rate-limiting enzyme in tetrahydrobiopterin (BH4) synthesis, as causative for these movement disorders. Here, we show that genetic and pharmacological inhibition of BH4 synthesis in mice and human midbrain-like organoids accurately recapitulates motor, behavioral and biochemical characteristics of these human diseases, with severity of the phenotype correlating with extent of BH4 deficiency. We also show that BH4 deficiency increases sensitivities to several PD-related stressors in mice and PD human cells, resulting in worse behavioral and physiological outcomes. Conversely, genetic and pharmacological augmentation of BH4 protects mice from genetically- and chemically induced PD-related stressors. Importantly, increasing BH4 levels also protects primary cells from PD-affected individuals and human midbrain-like organoids (hMLOs) from these stressors. Mechanistically, BH4 not only serves as an essential cofactor for dopamine synthesis, but also independently regulates tyrosine hydroxylase levels, protects against ferroptosis, scavenges mitochondrial ROS, maintains neuronal excitability and promotes mitochondrial ATP production, thereby enhancing mitochondrial fitness and cellular respiration in multiple preclinical PD animal models, human dopaminergic midbrain-like organoids and primary cells from PD-affected individuals. Our findings pinpoint the BH4 pathway as a key metabolic program at the intersection of multiple protective mechanisms for the health and function of midbrain dopaminergic neurons, identifying it as a potential therapeutic target for PD.


Social pathways to health: On the mediating role of the social network in the relation between socio-economic position and health.
Good health is one of the key qualities of life, but opportunities to be and remain healthy are unequally distributed across socio-economic groups. The beneficial health effects of the social network are well known. However, research on the social network as potential mediator in the pathway from socio-economic position (SEP) to health is scarce, while there are good reasons to expect a socio-economical patterning of networks. We aim to contribute to our understanding of socio-economic inequalities in health by examining the mediating role of structural and functional characteristics of the social network in the SEP-health relationship. Data were from the second wave of the Norwegian study on the life course, aging and generation study (NorLAG) and comprised 4534 men and 4690 women aged between 40 and 81. We applied multiple mediation models to evaluate the relative importance of each network characteristic, and multiple group analysis to examine differences between middle-aged and older men and women. Our results indicated a clear socio-economical patterning of the social network for men and women. People with higher SEP had social networks that better protect against loneliness, which in turn lead to better health outcomes. The explained variance in health in older people by the social network and SEP was only half of the explained variance observed in middle-aged people, suggesting that other factors than SEP were more important for health when people age. We conclude that it is the function of the network, rather than the structure, that counts for health.


Sound production by North Atlantic right whales (Eubalaena glacialis) in surface active groups.
The surface active group (SAG) is the most commonly observed surface social behavior of North Atlantic right whales. Recordings were made from 52 SAGs in the Bay of Fundy, Canada between July and September, from 1999 to 2002. The call types recorded from these groups were similar to those described previously for Southern right whales (Eubalaena australis), with six major call types being termed scream, gunshot, blow, upcall, warble, and downcall. The percentage of total calls of each call type depended on the group size and composition. The most common call type recorded was the scream call. The scream calls were produced by the focal female in a SAG. Production of other sound types can be attributed to whales other than the focal female, with gunshot and upcalls produced by males, and warble calls produced by female calves. The source levels for these sounds range from 137 to 162 dB rms re 1 ,tPa-m for tonal calls and 174 to 192 dB rms for broadband gunshot sounds.


The Facultative Symbiont Rickettsia Protects an Invasive Whitefly against Entomopathogenic Pseudomonas syringae Strains.
Facultative endosymbionts can benefit insect hosts in a variety of ways, including context-dependent roles, such as providing defense against pathogens. The role of some symbionts in defense may be overlooked, however, when pathogen infection is transient, sporadic, or asymptomatic. The facultative endosymbiont Rickettsia increases the fitness of the sweet potato whitefly (Bemisia tabaci) in some populations through mechanisms that are not yet understood. In this study, we investigated the role of Rickettsia in mediating the interaction between the sweet potato whitefly and Pseudomonas syringae, a common environmental bacterium, some strains of which are pathogenic to aphids. Our results show that P. syringae multiplies within whiteflies, leading to host death, and that whiteflies infected with Rickettsia show a decreased rate of death due to P. syringae. Experiments using plants coated with P. syringae confirmed that whiteflies can acquire the bacteria at a low rate while feeding, leading to increased mortality, particularly when the whiteflies are not infected with Rickettsia. These results suggest that P. syringae may affect whitefly populations in nature and that Rickettsia can ameliorate this effect. This study highlights the possible importance of interactions among opportunistic environmental pathogens and endosymbionts of insects.


Association of Fc receptor-like 5 (FCRL5) with Graves' disease is secondary to the effect of FCRL3.
The Fc receptor-like 3 (FCRL3) molecule, involved in controlling B-cell signalling, may contribute to the autoimmune disease process. Recently, a genome-wide screen detected association of neighbouring gene FCRL5 with Graves' disease (GD). To determine whether FCRL5 represents a further independent B-cell signalling GD susceptibility loci, we screened 12 tag SNPs, capturing all known common variation within FCRL5, in 5192 UK Caucasian GD index cases and controls. A case-control association study investigating twelve tag SNPs within FCRL5 which captured the majority of known common variation within this gene region. A data set comprising 2504 UK Caucasian patients with GD and 2688 geographically matched controls taken from the 1958 British Birth cohort. We used the chi-squared test and haplotype analysis to investigate the association between the tag SNPs and GD before performing logistic regression analysis to determine whether association at FCRL5 was independent of the known FCRL3 association. Three of the FCRL5 tag SNPs, rs6667109, rs3811035 and rs6692977 showed association with GD (P = 0·015-0·001, OR = 1·15-1·16). Logistic regression performed on all FCRL5 and, previously screened, FCRL3 tag SNPs revealed that association with FCRL5 was secondary to linkage disequilibrium with the FCRL3, rs11264798 and rs10489678 SNPs. FCRL5 does not appear to be exerting an independent effect on the development of GD in the UK. Fine mapping of the entire FCRL region is required to determine the exact location of the aetiological variant/s present.


Associative dreaming: reverie and active imagination.
The idea of countertransference has expanded beyond its original meaning of a neurotic reaction to include all reactions of the therapist: affective, bodily, and imaginal. Additionally, Jung's fundamental insight in 'The psychology of the transference' was that a 'third thing' is created in the analysis, but he failed to demonstrate how this third is experienced and utilized in analysis. This 'analytic third', as Ogden names it, is co-created by analyst and analysand in depth work and becomes the object of analysis. Reverie, as developed by Bion and clinically utilized by Ogden, provides a means of access to the unconscious nature of this third. Reverie will be placed on a continuum of contents of mind, ranging from indirect to direct associative forms described as associative dreaming. Active imagination, as developed by Jung, provides the paradigm for a mode of interaction with these contents within the analytic encounter itself. Whether the analyst speaks from or about these contents depends on the capacity of the patient to dream. Classical amplification can be understood as an instance of speaking about inner contents. As the ego of the analyst, the conscious component, relates to unconscious contents emerging from the analytic third, micro-activations of the transcendent function constellate creating an analytic compass.


High sense of mastery reduces psychological distress for African American women but not African American men.
Recent research has suggested that relative to Whites, African Americans (AAs) may be at a systemic disadvantage regarding the health effects of socioeconomic position (SEP) indicators as well as psychological assets (e.g., sense of mastery). However, less is known about how these diminished returns differ between AA men and women. This study tested whether AA men and women differ in the mental health effects of high sense of mastery. The National Survey of American Life (NSAL, 2003) recruited 3570 AA adults who were either female (n = 2299) or male (n = 1271). Dependent variable was psychological distress. Independent variable was sense of mastery. Gender was the focal moderator. Age and educational attainment were the covariates. Multiple linear regression model was applied for statistical analysis. Overall, high sense of mastery was associated with lower psychological distress. Significant interaction was found between gender and sense of mastery on psychological distress suggestive of a stronger association for AA women compared to men. A smaller mental health gain of high sense of mastery for AA men compared to AA women is indicative of within race heterogeneity regarding diminished returns. Racism and discrimination may be why high sense of mastery does not translate to mental health gain for AA men.


Increase in excitatory amino acid concentration and transporters expression in osteoarthritic knees of anterior cruciate ligament transected rabbits.
The present study aimed to determine the role of excitatory amino acids (EAAs) and EAA transporters (EAATs) in an osteoarthritis (OA) model of rabbit knees. OA was induced in New Zealand white male rabbits by anterior cruciate ligament transection (ACLT) in one knee of one hind limb; the other knee left unoperated. Rabbits that received ACLT of knee were assigned to the ACLT group (n=6), while a sham-operated group (n=6) underwent arthrotomy with no ACLT. Six naïve rabbits that received no surgery were used as normal control. The width of the knee joint was measured to determine the severity of joint inflammation. Before operation and at 10, 20, and 30 weeks after operation, knee joint dialysates were collected by microdialysis and assayed for EAAs by high-performance liquid chromatography. Gross morphology and histopathology and EAATs glutamate/aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) expression in the articular cartilage of the knees were evaluated by immunohistochemistry and western blot analysis. In the ACLT knees, a significant increase in the joint width was observed (5.3+/-0.9 mm, P<0.05) at 30 weeks after operation, while the sham-operated and naïve knees showed no difference as compared with the basal values. The concentrations (microM) of aspartate and glutamate in knee dialysates at 30 weeks after ACLT in naïve, sham, and ACLT were 0.36+/-0.07 and 4.5+/-1.10; 0.38+/-0.09 and 4.61+/-1.11; 0.67+/-0.18 and 9.71+/-2.89, respectively. Levels of glutamate and aspartate in the dialysates obtained from the ACLT knees increased by 213.3+/-29.6% and 187.5+/-33.8% (P<0.05) when compared to those in the sham-operated knees. Both naïve and ACLT chondrocytes were positively stained by antibodies against GLAST and GLT-1. GLAST and GLT-1 protein expressions were significantly increased in the ACLT knees (P<0.05). Our findings indicate an involvement of EAAs and EAATs in the pathogenesis of OA in ACLT rabbits.


A polysaccharide fraction from medicinal herb Prunella vulgaris downregulates the expression of herpes simplex virus antigen in Vero cells.
Herpes simplex viruses (HSV) are pathogenic. With the emergence of drug-resistant strains of HSV, new antiviral agents, especially those with different modes of action, are urgently needed. Prunella vulgaris L. (Labiatae), a perennial plant commonly found in China and Europe, has long been used as a folk medicine to cure ailments. In this study, a polysaccharide fraction was prepared from Prunella vulgaris (PPV), and its effects on the expressions of HSV-1 and HSV-2 antigens in their host Vero cells were investigated with flow cytometry. The HSV antigen increased time-dependently in the infected cells, and PPV reduced its expression. The effective concentrations of PPV with 50% reductions of the HSV-1 and HSV-2 antigens were 20.6 and 20.1 microg/ml, respectively. The novelty of PPV is that it also reduces the antigen expression of acyclovir-resistant strain of HSV-1. After incubations with 25-100 microg/ml of PPV the HSV antigen-positive cells were reduced by 24.8-92.6%, respectively, showing that this polysaccharide fraction has a different mode of anti-HSV action from acyclovir. Results from this study show that PPV is effective against both the HSV-1 and HSV-2 infections, and flow cytometry offers a quantitative and highly reproducible anti-HSV drug-susceptibility assay.


Towards a differentiated understanding of active travel behaviour: using social theory to explore everyday commuting.
Fostering physical activity is an established public health priority for the primary prevention of a variety of chronic diseases. One promising population approach is to seek to embed physical activity in everyday lives by promoting walking and cycling to and from work ('active commuting') as an alternative to driving. Predominantly quantitative epidemiological studies have investigated travel behaviours, their determinants and how they may be changed towards more active choices. This study aimed to depart from narrow behavioural approaches to travel and investigate the social context of commuting with qualitative social research methods. Within a social practice theory framework, we explored how people describe their commuting experiences and make commuting decisions, and how travel behaviour is embedded in and shaped by commuters' complex social worlds. Forty-nine semi-structured interviews and eighteen photo-elicitation interviews with accompanying field notes were conducted with a subset of the Commuting and Health in Cambridge study cohort, based in the UK. The findings are discussed in terms of three particularly pertinent facets of the commuting experience. Firstly, choice and decisions are shaped by the constantly changing and fluid nature of commuters' social worlds. Secondly, participants express ambiguities in relation to their reasoning, ambitions and identities as commuters. Finally, commuting needs to be understood as an embodied and emotional practice. With this in mind, we suggest that everyday decision-making in commuting requires the tactical negotiation of these complexities. This study can help to explain the limitations of more quantitative and static models and frameworks in predicting travel behaviour and identify future research directions.


SU-E-T-266: Shielding Measurements for a Proton Therapy Facility.
This paper is a follow up on the analytical calculations for the Roberts Proton Therapy Center with empirical data to determine the precision of the calculations from Avery, et al. Neutrak dosimeters were placed in two sets around the facility while it was in operation at points of interest examined in Avery, et al. The doses to these dosimeters were recorded over one month for one set and two months for the other. Dosimeters that both recorded a dose and could be practically examined were compared to the doses predicted via the analytical method of Avery, et al. at their point of placement. Two points showed a less than 10% difference to the calculated doses. One point shielded by both concrete and pre-cast blocks and one point shielded by both concrete and the facility's cyclotron were not as precise. The analytical calculation method explored in Avery, et al. is fairly precise in describing the dose at various points in the facility shielded only by concrete. for materials other than concrete, such as the make-up of the cyclotron or varying wall material, it warrants follow up calculations using the same method.


Modified mRNA Vaccines Protect against Zika Virus Infection.
The emergence of ZIKV infection has prompted a global effort to develop safe and effective vaccines. We engineered a lipid nanoparticle (LNP) encapsulated modified mRNA vaccine encoding wild-type or variant ZIKV structural genes and tested immunogenicity and protection in mice. Two doses of modified mRNA LNPs encoding prM-E genes that produced virus-like particles resulted in high neutralizing antibody titers (∼1/100,000) that protected against ZIKV infection and conferred sterilizing immunity. To offset a theoretical concern of ZIKV vaccines inducing antibodies that cross-react with the related dengue virus (DENV), we designed modified prM-E RNA encoding mutations destroying the conserved fusion-loop epitope in the E protein. This variant protected against ZIKV and diminished production of antibodies enhancing DENV infection in cells or mice. A modified mRNA vaccine can prevent ZIKV disease and be adapted to reduce the risk of sensitizing individuals to subsequent exposure to DENV, should this become a clinically relevant concern.


A bedtime milk snack does not impact RMR, substrate utilisation and appetite the following morning in mildly overweight males.
Nighttime eating is often associated with a negative impact on weight management and cardiometabolic health. However, data from recent acute metabolic studies have implicated a benefit of ingesting a bedtime snack for weight management. The present study compared the impact of ingesting a milk snack containing either 10 (BS10) or 30 g (BS30) protein with a non-energetic placebo (BS0) 30 min before bedtime on next morning metabolism, appetite and energy intake in mildly overweight males (age: 24·3 (sem 0·8) years; BMI: 27·4 (sem 1·1) kg/m2). Next morning measurements of RMR, appetite and energy intake were measured using indirect calorimetry, visual analogue scales and an ad libitum breakfast, respectively. Bedtime milk ingestion did not alter next morning RMR (BS0: 7822 (sem 276) kJ/d, BS10: 7482 (sem 262) kJ/d, BS30: 7851 (sem 261) kJ/d, P=0·19) or substrate utilisation as measured by RER (P=0·64). Bedtime milk ingestion reduced hunger (P=0·01) and increased fullness (P=0·04) during the evening immediately after snack ingestion, but elicited no effect the next morning. Next morning breakfast (BS0: 2187 (sem 365) kJ, BS10: 2070 (sem 336) kJ, BS30: 2582 (sem 384) kJ, P=0·21) and 24 h post-trial (P=0·95) energy intake was similar between conditions. To conclude, in mildly overweight adults, compared with a non-energetic placebo, a bedtime milk snack containing 10 or 30 g of protein does not confer changes in next morning whole-body metabolism and appetite that may favour weight management.


Post-traumatic stress disorder (PTSD) is not a contraindication to gastric bypass in veterans with morbid obesity.
The veteran population is routinely screened for post-traumatic stress disorder (PTSD). The prevalence of obesity in this population continues to increase. We examined whether weight loss outcomes in veterans with PTSD is comparable to results in veterans who do not suffer from PTSD, after gastric bypass. We also examined the effect of bariatric surgery on PTSD symptoms. This retrospective review of prospective data compares veterans with and without PTSD who underwent laparoscopic gastric bypass. Differences between the means of age, initial BMI, and percent excess weight loss were compared between the groups using a Student's t test. Pearson's chi(2) was used to evaluate the relationship between a diagnosis of PTSD, major depressive disorder (MDD), and other Axis I psychiatric disorders. A similar analysis was done to assess for a relationship between PTSD and obesity-related comorbidities, including diabetes mellitus (DM), hypertension (HTN), hyperlipidemia, and GERD. We identified 24 patients who had gastric bypass and a diagnosis of PTSD before surgery and compared them to those without PTSD. Both groups had a similar mean age and initial BMI. There was no significant difference between the percent excess weight lost after 1 year follow-up between the PTSD group (66%) and the non-PTSD group (72%) (p = 0.102). In assessing comorbid conditions, we found a significant association between the diagnosis of PTSD and MDD (p = 0.002), PTSD and other Axis I disorders (p = 0.004), and PTSD and GERD (p = 0.002). However, we saw no significant association between PTSD and DM (p = 0.977), HTN (p = 0.332), and obstructive sleep apnea (OSA) (p = 0.676). The severity of PTSD symptoms fluctuated in the postoperative period. Veterans with PTSD have comparable weight loss to those without PTSD after gastric bypass. In addition, surgery does not seem to have an adverse effect on PTSD symptoms, although PTSD symptomatology tends to fluctuate over time. Further study in this patient population is warranted.


Development of a 20-item food frequency questionnaire to assess a 'prudent' dietary pattern among young women in Southampton.
To develop a short food frequency questionnaire (FFQ) that can be used among young women in Southampton to assess compliance with a prudent dietary pattern characterized by high consumption of wholemeal bread, fruit and vegetables, and low consumption of sugar, white bread, and red and processed meat. Diet was assessed using a 100-item interviewer-administered FFQ in 6129 non-pregnant women aged 20-34 years. In total, 94 of these women were re-interviewed 2 years later using the same FFQ. Subsequently, diet was assessed in 378 women attending SureStart Children's Centres in the Nutrition and Well-being Study (NWS) using a 20-item FFQ. The 20 foods included were those that characterized the prudent dietary pattern. The 20-item prudent diet score was highly correlated with the full 100-item score (r=0.94) in the Southampton Women's Survey (SWS). Both scores were correlated with red blood cell folate (r=0.28 for the 100-item score and r=0.25 for the 20-item score). Among the women re-interviewed after 2 years, the change in prudent diet score was correlated with change in red cell folate for both the 20-item (r(S)=0.31) and 100-item scores (r(S)=0.32). In the NWS a strong association between the 20-item prudent diet score and educational attainment (r=0.41) was observed, similar to that seen in the SWS (r=0.47). The prudent diet pattern describes a robust axis of variation in diet. A 20-item FFQ based on the foods that characterize the prudent diet pattern has clear advantages in terms of time and resources, and is a helpful tool to characterize the diets of young women in Southampton.


5-Amino-4-imidazolecarboxamide riboside potentiates the metabolism and anti-human immunodeficiency virus activity of 2',3'-dideoxyinosine.
The antiviral activity of the purine dideoxynucleosides 2',3'-dideoxyadenosine (ddA) and 2',3'-dideoxyinosine (ddI) is dependent on their conversion into ddA triphosphate in vivo. 5-Amino-4-imidazolecarboxamide riboside (AICA riboside), a natural metabolite in purine biosynthetic pathways, is converted into IMP, a substrate for the biosynthesis of adenine and guanine nucleotides, and enhances the intracellular purine nucleotide pools. Because IMP also serves as a phosphate donor in the anabolic phosphorylation of ddI (and ddA) into ddI monophosphate by the cytosolic enzyme 5'-nucleotidase, we investigated the effects of AICA riboside on the phosphorylation and antiretroviral activity of these purine nucleoside analogs. At an AICA riboside concentration of 0.5 mM, there was a approximately 2-fold increase in the intracellular ATP and GTP levels, whereas a nearly 8-fold increase was observed for the phosphorylation of ddA (or ddI). A marked reduction in intracellular pools of the pyrimidine nucleotides CTP and UTP was observed in AICA riboside-treated cells and inhibited cell proliferation. However, this growth inhibition was prevented by the addition of uridine to the cultures. Cells pretreated with AICA riboside and ddI were less susceptible to human immunodeficiency virus (HIV) infection and synthesized reduced levels of HIV proviral DNA. A 10-fold potentiation of the effectiveness of ddI against both wild-type HIV (HIVIIIB) and a ddI-resistant variant HIV was observed in the presence of 0.5 mM AICA riboside. These results show that AICA riboside modulates the anabolism and antiviral activity of ddI, and they have implications for possible therapies with dideoxynucleosides.


Morinda citrifolia (Noni) Juice Augments Mammary Gland Differentiation and Reduces Mammary Tumor Growth in Mice Expressing the Unactivated c-erbB2 Transgene.
Morinda citrifolia (noni) is reported to have many beneficial properties, including on immune, inflammatory, quality of life, and cancer endpoints, but little is known about its ability to prevent or treat breast cancer. To test its anticancer potential, the effects of Tahitian Noni Juice (TNJ) on mammary carcinogenesis were examined in MMTV-neu transgenic mice. Mammary tumor latency, incidence, multiplicity, and metastatic incidence were unaffected by TNJ treatment, which suggests that it would not increase or decrease breast cancer risk in women taking TNJ for its other benefits. However, noni may be useful to enhance treatment responses in women with existing HER2/neu breast cancer since TNJ resulted in significant reductions in tumor weight and volume and in longer tumor doubling times in mice. Remarkably, its ability to inhibit the growth of this aggressive form of cancer occurred with the mouse equivalent of a recommended dose for humans (<3 oz/day). A 30-day treatment with TNJ also induced significant changes in mammary secondary ductule branching and lobuloalveolar development, serum progesterone levels, and estrous cycling. Additional studies investigating TNJ-induced tumor growth suppression and modified reproductive responses are needed to characterize its potential as a CAM therapy for women with and without HER2(+) breast cancer.


Molecular identification, genotyping, and drug susceptibility of the basidiomycetous yeast pathogen Trichosporon isolated from Turkish patients.
Deep-seated infections due to Trichosporon species are emerging mycoses that have a very poor prognosis in patients with persistent neutropenia. This study elucidated the mycological characteristics of Trichosporon strains obtained from deep-seated infections in Turkish patients and identified by DNA sequence analysis of intergenic spacer (IGS) region 1 of the rDNA locus. In addition, we genotyped the major causative agent, T. asahii, and evaluated the in vitro drug susceptibility of the isolates. While 87 (81.3%) of the 107 isolates were T. asahii, the remaining 20 were T. faecale (14.0%), T. asteroids (0.9%), T. coremiiforme (0.9%), T. japonicum, (0.9%), T. lactis (0.9%), and a new species (0.9%). In addition to the eight known T. asahii genotypes, one novel genotype was identified. The distribution of the T. asahii genotypes in this study were genotype 1 (79.3%), followed by 5 (8.0%), 3 (6.9%), 6 (3.4%), 4 (1.1%), and 9 (1.1%). Turkish isolates showed low susceptibility to amphotericin B, 5-flucytosine, and fluconazole. Although relatively low minimum inhibitory concentrations (MICs) were found with all drugs, voriconazole appeared to be the most active. The MICs of the non-Trichosporon asahiiTrichosporon species were similar to those of the T. asahii strains. Our findings suggest that Trichosporon species isolated from Turkish patients are more diverse than those reported from other countries.


Seaweed intake and blood pressure levels in healthy pre-school Japanese children.
Few studies have examined whether dietary factors might affect blood pressure in children. We purposed to investigate whether seaweed intake is associated with blood pressure level among Japanese preschool children. The design of the study was cross-sectional and it was conducted in autumn 2006. Subjects were healthy preschoolers aged 3-6 years in Aichi, Japan. Blood pressure and pulse were measured once by an automated sphygmomanometer, which uses oscillometric methods. Dietary data, including seaweed intake, were assessed using 3-day dietary records covering 2 consecutive weekdays and 1 weekend day. Of a total of 533 children, 459 (86.1 percent) agreed to be enrolled in our study. Finally, blood pressure measurement, complete dietary records and parent-reported height and weight were obtained for 223 boys and 194 girls. When we examined Spearman's correlation coefficients, seaweed intake was significantly negatively related to systolic blood pressure in girls (P = 0.008). In the one-way analysis of covariance for blood pressure and pulse after adjustments for age and BMI, the boys with the lowest, middle and highest tertiles of seaweed intake had diastolic blood pressure readings of 62.8, 59.3 and 59.6 mmHg, respectively (P = 0.11, trend P = 0.038). Girls with higher seaweed intake had significantly lower systolic blood pressure readings (102.4, 99.2 and 96.9 mmHg for girls with the lowest, middle and highest tertiles of seaweed intake, respectively; P = 0.037, trend P = 0.030). Our study showed that seaweed intake was negatively related to diastolic blood pressure in boys and to systolic blood pressure in girls. This suggests that seaweed might have beneficial effects on blood pressure among children.


Value of the revised Atlanta classification (RAC) and determinant-based classification (DBC) systems in the evaluation of acute pancreatitis.
Since increasing acute pancreatitis (AP) severity is significantly associated with mortality, accurate and rapid determination of severity is crucial for effective clinical management. This study investigated the value of the revised Atlanta classification (RAC) and the determinant-based classification (DBC) systems in stratifying severity of acute pancreatitis. This retrospective observational cohort study included 480 AP patients. Patient demographics and clinical characteristics were recorded. The primary outcome was mortality, and secondary outcomes were admission to intensive care unit (ICU), duration of ICU stay, and duration of hospital stay. Based on the RAC classification, there were 295 patients with mild AP (MAP), 146 patients with moderate-to-severe AP (MSAP), and 39 patients with severe AP (SAP). Based on the DBC classification, there were 389 patients with MAP, 41 patients with MSAP, 32 patients with SAP, and 18 patients with critical AP (CAP). ROC curve analysis showed that the DBC system had a significantly higher accuracy at predicting organ failure compared to the RAC system (p < .001). Multivariate regression analysis showed that age and ICU stay were independent risk factors of mortality. The DBC system had a higher accuracy at predicting organ failure. Age and ICU stay were significantly associated with risk of death in AP patients. A classification of CAP by the DBC system should warrant close attention, and rapid implementation of effective measures to reduce mortality.


Aromatic cross-links in insect cuticle: detection by solid-state 13C and 15N NMR.
Cross-polarization magic-angle-spinning nuclear magnetic resonance spectroscopy has been used to determine insect cuticle composition and cross-link structure during sclerotization or tanning. Unsclerotized cuticle from newly ecdysed pupae of the tobacco hornworm, Manduca sexta L., had a high protein content with lesser amounts of lipid and chitin. Concentrations of chitin, protein, and catechol increased substantially as dehydration and sclerotization progressed. Analysis of intact cuticle specifically labeled with carbon-13 and nitrogen-15 revealed direct covalent linkages between ring nitrogens of protein histidyl residues and ring carbons derived from the catecholamine dopamine. This carbon-nitrogen adduct was present in chitin isolated from cuticle by alkaline extraction and is probably bound covalently to chitin. These data support the hypothesis that the stiffening of insect cuticle during sclerotization results primarily from the deposition of protein and chitin polymers and their crosslinking by quinonoid derivatives of catecholamines.


Identifying Small-Molecule Binding Sites for Epigenetic Proteins at Domain-Domain Interfaces.
Epigenetics is a rapidly growing field in drug discovery. Of particular interest is the role of post-translational modifications to histones and the proteins that read, write, and erase such modifications. The development of inhibitors for reader domains has focused on single domains. One of the major difficulties of designing inhibitors for reader domains is that, with the notable exception of bromodomains, they tend not to possess a well-enclosed binding site amenable to small-molecule inhibition. As many of the proteins in epigenetic regulation have multiple domains, there are opportunities for designing inhibitors that bind at a domain-domain interface which provide a more suitable interaction pocket. Examination of X-ray structures of multiple domains involved in recognising and modifying post-translational histone marks using the SiteMap algorithm identified potential binding sites at domain-domain interfaces. For the tandem plant homeodomain-bromodomain of SP100C, a potential inter-domain site identified computationally was validated experimentally by the discovery of ligands by X-ray crystallographic fragment screening.


Gender-specific psychological and social impact of COVID-19 in Pakistan.
COVID-19 has rapidly spread across the world. Women may be especially vulnerable to depression and anxiety as a result of the pandemic. This study attempted to assess how gender affects risk perceptions, anxiety levels and behavioural responses to the COVID-19 pandemic in Pakistan, to recommend gender-responsive health policies. A cross-sectional online survey was conducted. Participants were asked to complete a sociodemographic data form, the Hospital Anxiety and Depression Scale, and questions on their risk perceptions, preventive behaviour and information exposure. Multiple logistic regression analysis was used to assess the effects of factors such as age, gender and household income on anxiety levels. Of the 1391 respondents, 478 were women and 913 were men. Women considered their chances of survival to be relatively lower than men (59% v. 73%). They were also more anxious (62% v. 50%) and more likely to adopt precautionary behaviour, such as avoiding going to the hospital (78% v. 71%), not going to work (72% v. 57%) and using disinfectants (93% v. 86%). Men were more likely to trust friends, family and social media as reliable sources of COVID-19 information, whereas women were more likely to trust doctors. Women experience a disproportionate burden of the psychological and social impact of the pandemic compared with men. Involving doctors in healthcare communication targeting women might prove effective. Social media and radio programmes may be effective in disseminating COVID-19-related information to men.


Protein and nucleic acid analysis of influenza B viruses isolated in Italy in 1984.
Genomic and phenotypic analysis of 30 influenza B viruses, isolated in Italy in 1984, antigenically closely related to the B/USSR/100/83 prototype virus, was carried out using T1-oligonucleotide fingerprinting of total RNA and one-dimensional peptide mapping. The results of fingerprinting analysis indicated an oligonucleotide spot homology of 90-96%, corresponding to a nucleotide sequence variation of only 0.75-0.3%. All the strains appear to belong to the same evolutionary line. Nevertheless, heterogeneity was found at the structural and antigenic level, when the viruses were compared by peptide mapping and monoclonal antibody analysis. No correlation between the biochemical variability of the viruses and the epidemiological characteristics of the different strains was established, which is consistent with the hypothesis that distinct variants, arisen at different times from a parental strain, co-circulate during an epidemic, although the additional occurrence of random mutations during the evolution of the epidemic cannot be excluded.


Modeling spinal muscular atrophy in Drosophila.
Spinal Muscular Atrophy (SMA), a recessive hereditary neurodegenerative disease in humans, has been linked to mutations in the survival motor neuron (SMN) gene. SMA patients display early onset lethality coupled with motor neuron loss and skeletal muscle atrophy. We used Drosophila, which encodes a single SMN ortholog, survival motor neuron (Smn), to model SMA, since reduction of Smn function leads to defects that mimic the SMA pathology in humans. Here we show that a normal neuromuscular junction (NMJ) structure depends on SMN expression and that SMN concentrates in the post-synaptic NMJ regions. We conducted a screen for genetic modifiers of an Smn phenotype using the Exelixis collection of transposon-induced mutations, which affects approximately 50% of the Drosophila genome. This screen resulted in the recovery of 27 modifiers, thereby expanding the genetic circuitry of Smn to include several genes not previously known to be associated with this locus. Among the identified modifiers was wishful thinking (wit), a type II BMP receptor, which was shown to alter the Smn NMJ phenotype. Further characterization of two additional members of the BMP signaling pathway, Mothers against dpp (Mad) and Daughters against dpp (Dad), also modify the Smn NMJ phenotype. The NMJ defects caused by loss of Smn function can be ameliorated by increasing BMP signals, suggesting that increased BMP activity in SMA patients may help to alleviate symptoms of the disease. These results confirm that our genetic approach is likely to identify bona fide modulators of SMN activity, especially regarding its role at the neuromuscular junction, and as a consequence, may identify putative SMA therapeutic targets.


Evaluation of potentially common adverse events associated with the first and second doses of measles-mumps-rubella vaccine.
In 1989, the American Academy of Pediatrics and the Advisory Committee on Immunization Practices recommended that school children receive 2 doses of measles-mumps-rubella vaccine. With measles and rubella eliminated from the United States, measles-mumps-rubella vaccine adverse events have come under scrutiny, but no study has compared the reactogenicity of the first (measles-mumps-rubella vaccine dose 1) and second (measles-mumps-rubella vaccine dose 2) doses at the most common ages of administration in the United States. From a health maintenance organization, 3 groups of children were recruited: (1) toddlers aged 12 to 24 months receiving measles-mumps-rubella vaccine dose 1; (2) kindergartners aged 4 to 6 years receiving measles-mumps-rubella vaccine dose 2; and (3) middle schoolers aged 10 to 12 years receiving measles-mumps-rubella vaccine dose 2. From 2 weeks before measles-mumps-rubella vaccine administration until 4 weeks afterward, families recorded in diaries the occurrence of potentially common symptoms. Postvaccination symptom rates were compared with the prevaccination baseline, with significance assessed by testing incidence rate ratios estimated by Poisson regression. Of 2173 children enrolled, 373 (17%) were lost to attrition, producing a study population of 1800. Compared with the prevaccination baseline, rates of fever, diarrhea, and rash were significantly elevated postvaccination among 535 toddlers receiving measles-mumps-rubella vaccine dose 1. An estimated net 95 (18%) experienced measles-mumps-rubella vaccine-associated events (median onset 5-10 days postvaccination, duration 2-5 days), with high fever (temperature > or = 39.5 degrees C) occurring in 33 (6%). None required medical attention. For 633 kindergartners and 632 middle schoolers, symptom rates were not significantly elevated after measles-mumps-rubella vaccine dose 2 compared with baseline. Vaccination-associated adverse events occur in approximately 1 of every 6 toddlers receiving measles-mumps-rubella vaccine dose 1, with high fever occurring in 1 of 20. Adverse events are infrequent for measles-mumps-rubella vaccine dose 2 administered to school-aged children.


Mood disorders in long-term survivors of stroke: associations with brain lesion location and volume.
Sixty surviving patients from a community-based stroke register who had CT scan evidence of a single brain lesion and neurological signs appropriate to it were interviewed three to five years following their first-ever stroke. Mood disorder (anxiety and depression), physical disability, and intellectual impairment were assessed using standardized measures. The position and volume of the brain lesion was determined from CT scans performed soon after the stroke. The prevalence of depressive disorder was lower in this sample than that reported in previous studies (DSM-IIIR major depression 8.3%; all DSM-IIIR depressive disorders 18.3%). Reports by other workers for an association of depressive disorder either with left-sided brain lesions, or with anteriorly placed lesions in the left cerebral hemisphere, were not supported. Neither was there evidence of a correlation between symptom score and proximity of the lesion to the anterior pole of the left cerebral hemisphere. Psychiatric symptom scores were however greater with larger volume brain lesions. Anxiety disorders, especially agoraphobia, were relatively common (20% if diagnosed in the presence of depressive disorder), but were not related to lesion location or volume.


Simultaneous release of sulfide with Fe, Mn, Ni and Zn in marine harbour sediment measured using a combined metal/sulfide DGT probe.
The technique of DGT (Diffusive Gradients in Thin Films) was further developed to allow simultaneous measurement of sulfide and trace metals at the same location in sediment. The new combined DGT probe consisted of a layer of gel impregnated with AgI, overlain by (1) a layer of gel containing Chelex, (2) a layer of gel and (3) a filter membrane. Diffusion of sulfide was controlled by layers (1) to (3), while diffusion of metals was controlled by layers (2) and (3). The Chelex gel trapped metals that were measured after elution with acid. The AgI gel trapped sulfide through the formation of Ag2S. This was then measured densitometrically as the colour changed from pale yellow to grey. Experiments demonstrated that concentrations of metal or sulfide measured by the combined device were no different to the concentrations measured by more conventional devices. The presence of Chelex in the gel did not impede the diffusion of sulfide. Deployment of a combined probe in marine sediment revealed simultaneous remobilisation of metals and sulfide at the same location. Solubility calculations indicated that some precipitation of amorphous FeS was probably occurring at the maxima in sulfide concentrations. There was general undersaturation with respect to NiS, but ZnS was supersaturated at all locations. There appeared to be localised active zones of organic matter decomposition, where reduction of manganese oxides, iron oxides and sulfate occurred simultaneously. Mass balance calculations indicated that Ni could not be supplied by release from decomposing organic matter. Manganese oxides were the most likely source, but supply from reductive dissolution of iron oxides could not be entirely discounted. Supply from either Fe or Mn oxides could account for the Zn maxima. Application of the newly developed combined probe provides new information that helps understanding of the complex nature of trace metal and sulfur chemistry in sediments.


Electroanatomical characteristics of idiopathic left ventricular tachycardia and optimal ablation target during sinus rhythm: significance of preferential conduction through Purkinje fibers.
We hypothesized that Purkinje potential and their preferential conduction to the left ventricle (LV) posteroseptum during sinus rhythm (SR) are part of reentrant circuits of idiopathic left ventricular tachycardia (ILVT) and reentry anchors to papillary muscle. In 14 patients with ILVT (11 men, mean age 31.5±11.1 years), we compared Purkinje potential and preferential conduction during SR with VT by non-contact mapping (NCM). If clear Purkinje potential(SR) was observed in the LV posteroseptum and the earliest activation site (EA) of preferential conduction at SR (EA(SR)) was well matched with that of VT (EA(VT)), EA(SR) was targeted for radiofrequency catheter ablation (RFCA). Also, the anatomical locations of successful ablation sites were evaluated by echocardiography in five additional patients. 1) All induced VTs exhibited clear Purkinje potential(VT) and preferential conduction in the LV posteroseptum. The Purkinje potential(VT) and EA(VT) was within 5.8±8.2 mm of EA(SR). However, the breakout sites of VT were separated by 30.2±12.6 mm from EA(VT) to the apical side. 2) Purkinje potential(SR) demonstrated a reversed polarity to Purkinje potential(VT), and the interval of Purkinje potential(SR)-QRS was longer than the interval of Purkinje potential(VT)-QRS (p<0.02) 3) RFCA targeting EA(SR) eliminated VT in all patients without recurrence within 23.3±7.5 months, and the successful ablation site was discovered at the base of papillary muscle in the five additional (100%) patients. NCM-guided localization of EA(SR) with Purkinje potential(SR) matches well with EA(VT) with Purkinje potential(VT) and provides an effective target for RFCA, potentially at the base of papillary muscle in patients with ILVT.


Fabrication of Worm-Like Nanorods and Ultrafine Nanospheres of Silver Via Solid-State Photochemical Decomposition.
Worm-like nanorods and nanospheres of silver have been synthesized by photochemical decomposition of silver oxalate in water by UV irradiation in the presence of CTAB and PVP, respectively. No external seeds have been employed for the synthesis of Ag nanorods. The synthesized Ag colloids have been characterized by UV-visible spectra, powder XRD, HRTEM, and selected area electron diffraction (SAED). Ag nanospheres of average size around 2 nm have been obtained in the presence of PVP. XRD and TEM analyses revealed that top and basal planes of nanorods are bound with {111} facets. Williamson-Hall plot has revealed the presence of defects in the Ag nanospheres and nanorods. Formation of defective Ag nanocrystals is attributed to the heating effect of UV-visible irradiation.


Innate immune response of human alveolar macrophages during influenza A infection.
Alveolar macrophages (AM) are one of the key cell types for initiating inflammatory and immune responses to influenza virus in the lung. However, the genome-wide changes in response to influenza infection in AM have not been defined. We performed gene profiling of human AM in response to H1N1 influenza A virus PR/8 using Affymetrix HG-U133 Plus 2.0 chips and verified the changes at both mRNA and protein levels by real-time RT-PCR and ELISA. We confirmed the response with a contemporary H3N2 influenza virus A/New York/238/2005 (NY/238). To understand the local cellular response, we also evaluated the impact of paracrine factors on virus-induced chemokine and cytokine secretion. In addition, we investigated the changes in the expression of macrophage receptors and uptake of pathogens after PR/8 infection. Although macrophages fail to release a large amount of infectious virus, we observed a robust induction of type I and type III interferons and several cytokines and chemokines following influenza infection. CXCL9, 10, and 11 were the most highly induced chemokines by influenza infection. UV-inactivation abolished virus-induced cytokine and chemokine response, with the exception of CXCL10. The contemporary influenza virus NY/238 infection of AM induced a similar response as PR/8. Inhibition of TNF and/or IL-1β activity significantly decreased the secretion of the proinflammatory chemokines CCL5 and CXCL8 by over 50%. PR/8 infection also significantly decreased mRNA levels of macrophage receptors including C-type lectin domain family 7 member A (CLEC7A), macrophage scavenger receptor 1 (MSR1), and CD36, and reduced uptake of zymosan. In conclusion, influenza infection induced an extensive proinflammatory response in human AM. Targeting local components of innate immune response might provide a strategy for controlling influenza A infection-induced proinflammatory response in vivo.


Prevalence of malaria and clinical profile of febrile HIV infected patients in three HIV clinics in Ivory Coast.
To determine the prevalence and clinical profile of malaria among febrile HIV-infected patients followed up in three HIV clinics in Ivory Coast. A cross-sectional multicentre study was conducted between 2009 and 2010 in the Pneumology Department of Cocody Teaching Hospital in Abidjan, Medical Esperance Centre and the Regional Hospital in San-Pedro. Patients of all ages presenting with fever (rectal or axillary temperature >37,5°C) or a medical history of fever within 72 hrs prior to consultation were included. Parasitological diagnostic methods used were microscopy by blood smear (BS) for search malaria parasite and parasite density. Haemoglobin levels were assessed to assess anaemia. Over the study period, 530 people living with HIV consulted for fever. The 476 patients included were predominantly female (n=280, 59%), with a median age of 34 (range 3-74 yrs), a mean of 38 ± 8.3 (SD) yrs, infected with HIV-1 (n=409, 86%), on antiretroviral therapy (n=376, 79%), and cotrimoxazole prophylaxis (n=381, 80%). Only 73 (15%) patients were using LLINs. Malaria prevalence was 10% (n=47). Plasmodium falciparum was the only species identified with a mean density of 15 900 trophozoites/μl. Malaria was more common among patients with a CD4 count of <200/mm3 (p<0.001) neither on cotrimoxazole prophylaxis (p<0.001) nor on antiretroviral therapy (ART) (p<0.001). Uncomplicated malaria accounted for 32 (68%) of the cases. The signs of severe malaria (n=15, 32%,) were dominated by severe anaemia (n= 12, 25.5%). Our study revealed that malaria prevalence appears to be low in HIV clinics for people living with HIV on HAART and cotrimoxazole prophylaxis. Uncomplicated malaria is predominant when consultation is early. Signs of severe malaria were dominated by severe anaemia.


Racial and Ethnic Differences in Disability Transitions Among Older Adults in the United States.
Racial and ethnic differences in disability persist and are possibly widening in recent years, but evidence is limited for racial and ethnic differences in disability progression through the entire disablement process and potential influential factors. The objective of this study is to examine racial and ethnic differences in patterns of late-life disability transitions, using a new disability spectrum that incorporates successful accommodation with assistive devices in response to capacity limitations to prolong independence. The study cohort consisted of a nationally representative sample of Medicare beneficiaries aged 65 and older in the United States who were enrolled in the 2011 National Health and Aging Trends Study and followed up annually until 2015 (n = 6,198). First-order Markov transition models were used to determine racial/ethnic differences in transitions among three stages of self-care and mobility limitations (fully able, successful accommodation, difficulty/assistance) and death. After adjustment for age and sex, non-Hispanic Black and Hispanic respondents had higher probabilities of unfavorable transitions and lower probabilities of remaining in the successful accommodation stage than non-Hispanic White respondents. The racial and ethnic differences in probabilities of maintaining successful accommodation remained statistically significant after adjustment for socioeconomic and health factors (Black: 0.56, 95% CI = 0.52-0.60; Hispanic: 0.53, 95% CI = 0.44-0.61; White: 0.63, 95% CI = 0.61-0.65). Successful accommodation with assistive devices may provide possibilities for implementing interventions to enhance older adults' capacities and reducing racial/ethnic differences in late-life disability.


A genome-wide analysis identifies genetic variants in the RELN gene associated with otosclerosis.
Otosclerosis is a common form of progressive hearing loss, characterized by abnormal bone remodeling in the otic capsule. The etiology of the disease is largely unknown, and both environmental and genetic factors have been implicated. To identify genetic factors involved in otosclerosis, we used a case-control discovery group to complete a genome-wide association (GWA) study with 555,000 single-nucleotide polymorphisms (SNPs), utilizing pooled DNA samples. By individual genotyping of the top 250 SNPs in a stepwise strategy, we were able to identify two highly associated SNPs that replicated in two additional independent populations. We then genotyped 79 tagSNPs to fine map the two genomic regions defined by the associated SNPs. The region with the strongest association signal, p(combined) = 6.23 x 10(-10), is on chromosome 7q22.1 and spans intron 1 to intron 4 of reelin (RELN), a gene known for its role in neuronal migration. Evidence for allelic heterogeneity was found in this region. Consistent with the GWA data, expression of RELN was confirmed in the inner ear and in stapes footplate specimens. In conclusion, we provide evidence that implicates RELN in the pathogenesis of otosclerosis.


Sextortion Among Adolescents: Results From a National Survey of U.S. Youth.
Sextortion is the threatened dissemination of explicit, intimate, or embarrassing images of a sexual nature without consent, usually for the purpose of procuring additional images, sexual acts, money, or something else. Despite increased public interest in this behavior, it has yet to be empirically examined among adolescents. The current study fills this gap by exploring the prevalence of sextortion behaviors among a nationally representative sample of 5,568 U.S. middle and high school students. Approximately 5% of students reported that they had been the victim of sextortion, while about 3% admitted to threatening others who had shared an image with them in confidence. Males and nonheterosexual youth were more likely to be targeted, and males were more likely to target others. Moreover, youth who threatened others with sextortion were more likely to have been victims themselves. Implications for future research, as well as the preventive role that youth-serving professionals can play, are discussed.


Effect of hyperparathyroidism on coagulation: a global assessment by modified rotation thromboelastogram (ROTEM)
Hyperparathyroidism is an endocrine disorder characterized by hypercalcemia. Because of calcium's effects on parathyroid glands, bone, intestines, and kidneys, it has an important place in homeostasis. The results of studies regarding hyperparathyroidism hemostasis are conflicting. Thromboelastography helps to evaluate all steps of hemostatic system. Our aim in this study was to investigate the possible role of hemostatic mechanisms in the development of thrombosis in hyperparathyroid patients with the modified rotation thromboelastogram (ROTEM). Twenty-two patients with primary hyperparathyroidism (PHPT) and 20 healthy controls were involved. This study was conducted in Eskisehir Osmangazi University Faculty of Medicine, Endocrinology and Hematology clinics for 2 years. The complete blood count, fibrinogen, D-dimer levels, prothrombin time, activated prothrombin time, and ROTEM parameters [clot formation time (CFT), clotting time (CT), and maximum clot formation (MCF)] were determined by two activated tests, INTEM and EXTEM analyses. A thromboelastographic evaluation was performed in the preoperative and postoperative (3 months after surgery) periods. In INTEM assay, the CT (p = 0.012) and CFT (p = 0.07) values were increased in preoperative PHPT patients compared with the control group. Although there was a decrease in the postoperative CT and CFT values, no statistical difference was found. The prolongation of the CT and CFT values were consistent with a hypocoagulable state in patients with PHPT. Hyperparathyroidism causes a hypocoagulable state that can be successfully assessed by ROTEM. Hemostatic changes, do not seem to have an effect on increased cardiovascular mortality.


In vitro and in vivo comparison of transport media for detecting nasopharyngeal carriage of Streptococcus pneumoniae.
As a standard method for pneumococcal carriage studies, the World Health Organization recommends nasopharyngeal swabs be transported and stored at cool temperatures in a medium containing skim-milk, tryptone, glucose and glycerol (STGG). An enrichment broth used for transport at room temperature in three carriage studies performed in Norway may have a higher sensitivity than STGG. We therefore compared the media in vitro and in vivo. For the in vitro component, three strains (serotype 4, 19F and 3) were suspended in STGG and enrichment broth. Recovery was compared using latex agglutination, quantification of bacterial loads by real-time PCR of the lytA gene, and counting colonies from incubated plates. For the in vivo comparison, paired swabs were obtained from 100 children and transported in STGG at cool temperatures or in enrichment broth at room temperature. Carriage was identified by latex agglutination and confirmed by Quellung reaction. In vitro, the cycle threshold values obtained by PCR did not differ between the two media (p = 0.853) and no clear difference in colony counts was apparent after incubation (p = 0.593). In vivo, pneumococci were recovered in 46% of swabs transported in STGG and 51% of those transported in enrichment broth (Kappa statistic 0.90, p = 0.063). Overall, no statistical differences in sensitivity were found between STGG and enrichment broth. Nevertheless, some serotype differences were observed and STGG appeared slightly less sensitive than enrichment broth for detection of nasopharyngeal carriage of pneumococci by culturing. We recommend the continued use of STGG for transport and storage of nasopharyngeal swabs in pneumococcal carriage studies for the benefit of comparability between studies and settings, including more resource-limited settings.


Pitch change in male-to-female transsexuals: has phonosurgery a role to play?
Male-to-female transsexuals, who have undergone gender reassignment surgery, may continue to have low pitched voices. Voice therapy may assist them to use their voice in a manner more likely to be perceived as female but, if this approach is unsuccessful, a laryngeal framework operation may be necessary to raise vocal pitch. This study assessed the effects of crico-thyroid approximation surgery in 14 transsexuals. Modal pitch was significantly increased by surgery but with substantial variation across speakers. Modal pitch was significantly correlated with judgements of gender by speech and language therapists who listened to tapes of the subjects. The results suggest that crico-thyroid approximation may be used to raise the pitch of voices of male-to-female transsexuals. Further research is needed to clarify the reasons for the variability in outcome, to monitor the longer-term changes in voice and the impact for clients of their modified voice in real life situations.


Risk of obesity and type 2 diabetes with tumor necrosis factor-α 308G/A gene polymorphism in metabolic syndrome and coronary artery disease subjects.
Tumor Necrosis Factor-alpha (TNF-α) has been implicated in the pathogenesis of insulin resistance and obesity. The increased expression of TNF-α in adipose tissue is known to induce insulin resistance, and a polymorphism at position -308 in the promoter region of TNF-α gene may lead to its increased transcription in adipocytes. The objective of this work was to determine the role of TNFα-308G/A gene polymorphism in metabolic syndrome (MetS) and coronary artery disease (CAD) with obesity and type 2 diabetes mellitus (T2DM). A total of 250 MetS and 224 CAD patients and 214 controls were studied. TNFα-308G/A polymorphism was detected from the whole blood genomic DNA using PCR-amplification refractory mutation system. The 2 × 2 contingency tables and multiple regression analysis were used for determining the association of genotypes with obesity and type 2 diabetes mellitus (T2DM) in MetS and CAD subjects. In CAD subjects with T2DM, the AG genotypes showed a very strong association (P < 0.0001; OR 0.194, 95%CI 0.103-0.365). In CAD subjects with obesity, the AA (P = 0.049; OR 2.449) and AG genotypes showed a strong association (P < 0.0001; OR 0.206). In both males and females, AG genotype and G allele (P < 0.0001) showed a strong association with T2DM. In MetS subjects with T2DM, there was a strong association with AG (P = 0.002; OR 4.483) as well as AA+AG genotypes (P = 0.002; OR 4.255). The AA and AG genotype (P = 0.001; OR 5.497) in males showed a strong 4.6- and 5.4-fold risks, respectively, with obesity. In females, only AG genotype showed a strong 4.5-fold risk with obesity (P = 0.001). In MetS subjects with obesity, the AA genotype (P = 0.043; OR 3.352) as well as AG showed a very strong association (P = 0.001; OR 5.011). The AG genotypes showed a high 3.5-fold risk with T2DM in females (P = 0.011). In CAD subjects, AG genotype showed a protective effect in both obese males and females (P < 0.0001). Heterozygous TNFα-308G/A gene variant may be an important risk factor for MetS with T2DM and obesity in both males and females, but may have a protective role in CAD subjects with obesity and T2DM. A allele may be an important risk factor for MetS and CAD with obesity as well as CAD subjects with T2DM.


Integrative functional genomics decodes herpes simplex virus 1.
The predicted 80 open reading frames (ORFs) of herpes simplex virus 1 (HSV-1) have been intensively studied for decades. Here, we unravel the complete viral transcriptome and translatome during lytic infection with base-pair resolution by computational integration of multi-omics data. We identify a total of 201 transcripts and 284 ORFs including all known and 46 novel large ORFs. This includes a so far unknown ORF in the locus deleted in the FDA-approved oncolytic virus Imlygic. Multiple transcript isoforms expressed from individual gene loci explain translation of the vast majority of ORFs as well as N-terminal extensions (NTEs) and truncations. We show that NTEs with non-canonical start codons govern the subcellular protein localization and packaging of key viral regulators and structural proteins. We extend the current nomenclature to include all viral gene products and provide a genome browser that visualizes all the obtained data from whole genome to single-nucleotide resolution.


Vascular alterations in the sprague-dawley rat mandible during intravenous bisphosphonate therapy.
Long-term use of intravenous bisphosphonates, such as zoledronic acid (zoledronate), has been linked to bisphosphonate-related osteonecrosis of the jaw (BRONJ). Invasive dental surgery seems to trigger the bone necrosis in most cases. To determine the effects of zoledronic acid on the vascular structure of the rat mandible. Extracted of the mandibular first molar in rats that received 2 IV injections of zoledronate (20 μg/kg), 4 weeks apart. Zoledronate-treated rats (n = 18) were then compared to a control group of untreated rats (n = 18). At the fourth, eighth, and 12th week after molar extraction, 8 rat mandibles from each group were perfused with 35% radiopaque triphenylbismuth in methyl methacrylate via carotid artery perfusion. Mandibles were harvested and examined by micro-CT to assess the spatial and dimensional changes of the vasculature as a result of zoledronate treatment. The micro-CT analysis showed that zoledronic acid-treated rats had blood vessels that were thicker, less connected, and less ordered than control rats that were not exposed to zoledronic acid. This study demonstrated that treatment with zoledronic acid in rats is associated with vascular changes in alveolar bone. Further studies are underway to explore whether these vascular changes contribute to the pathogenesis of BRONJ.


Going big versus going small: Lithic miniaturization in hominin lithic technology.
Lithic miniaturization was one of our Pleistocene ancestors' more pervasive stone tool production strategies and it marks a key difference between human and non-human tool use. Frequently equated with "microlith" production, lithic miniaturization is a more complex, variable, and evolutionarily consequential phenomenon involving small backed tools, bladelets, small retouched tools, flakes, and small cores. In this review, we evaluate lithic miniaturization's various technological and functional elements. We examine archeological assumptions about why prehistoric stoneworkers engaged in processes of lithic miniaturization by making small stone tools, small elongated tools, and small retouched and backed tools. We point to functional differences that motivate different aspects of lithic miniaturization and several instances where archeological systematics have possibly led archeologists to false negative findings about lithic miniaturization. Finally, we suggest productive avenues by which archeologists can move closer to understanding the complex evolutionary forces driving variability in lithic miniaturization.


Predictors of diagnosis in Huntington disease.
Subtle signs and symptoms of Huntington disease (HD) are often present before impairments reach a point where the neurologic disease is manifest and a diagnosis must be considered. The objective is to examine the prognostic significance of these early clinical signs and symptoms regarding time until unequivocal clinical HD diagnosis. We analyzed longitudinal data from 218 at-risk but healthy participants in the Huntington Study Group database who had either normal motor examination results or minimal soft motor signs at first observation. This group was followed periodically in HD clinics for up to 4.5 years. We used survival analysis to examine predictors of time until HD diagnosis. Diagnostic prediction was significantly improved using specific, nonredundant items from the Unified Huntington's Disease Rating Scale. When a movement disorder specialist initially had a global impression of "soft signs" present, cumulative relative risk of diagnosis was 4.68 times greater at 1.5 years of follow-up and 3.58 at 3 years. A neuropsychological test pattern with psychomotor speed 1 SD worse than a semantic knowledge measure increased cumulative risk by 1.99 times at 1.5 years and 1.81 at 3 years. Finally, reports of various subjective HD symptoms increased 3-year relative risk by 2.6 to 3.4. Findings demonstrate that neuropsychological performance and both the clinician rating and the patient subjective perception of motor difficulties contribute nonredundantly to a prediction of Huntington disease diagnosis. These findings may have implications for prognostic assessment of persons at risk and eventually assist with early interventions.


The ultrastructure of the Z disc in skeletal muscle.
This electron microscopic study deals with the structure of the Z disc of frog's skeletal muscle, with special regard to the I filaments-whether they pass through the Z disc or terminate at it. In most longitudinal sections the I filaments terminate as rod-like projections on either side of the Z disc, one I filament on one side lying between two I filaments on the opposite side. This indicates that the I filaments are not continuous through the Z disc. The rod-like projections are often seen to consist of filaments (denoted as Z filaments) which meet at an angle. In cross-sections through the Z region the I filaments and Z filaments form tetragonal patterns. The I filaments are situated in the corners of the squares; the oblique Z filaments form the sides of squares. The tetragonal pattern formed by the Z filaments is rotated 45 degrees with respect to the tetragons formed by the I filaments on both sides of Z. This structural arrangement is interpreted to indicate that each I filament on one side of the Z disc faces the center of the space between four I filaments on the opposite side of Z and that the interconnection is formed by four Z filaments.


The impact of stratospheric ozone recovery on the Southern Hemisphere westerly jet.
In the past several decades, the tropospheric westerly winds in the Southern Hemisphere have been observed to accelerate on the poleward side of the surface wind maximum. This has been attributed to the combined anthropogenic effects of increasing greenhouse gases and decreasing stratospheric ozone and is predicted to continue by the Intergovernmental Panel on Climate Change/Fourth Assessment Report (IPCC/AR4) models. In this paper, the predictions of the Chemistry-Climate Model Validation (CCMVal) models are examined: Unlike the AR4 models, the CCMVal models have a fully interactive stratospheric chemistry. Owing to the expected disappearance of the ozone hole in the first half of the 21st century, the CCMVal models predict that the tropospheric westerlies in Southern Hemisphere summer will be decelerated, on the poleward side, in contrast with the prediction of most IPCC/AR4 models.


An outbreak of severe infections with community-acquired MRSA carrying the Panton-Valentine leukocidin following vaccination.
Infections with community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) are emerging worldwide. We investigated an outbreak of severe CA-MRSA infections in children following out-patient vaccination. We carried out a field investigation after adverse events following immunization (AEFI) were reported. We reviewed the clinical data from all cases. S. aureus recovered from skin infections and from nasal and throat swabs were analyzed by pulse-field gel electrophoresis, multi locus sequence typing, PCR and microarray. In May 2006, nine children presented with AEFI, ranging from fatal toxic shock syndrome, necrotizing soft tissue infection, purulent abscesses, to fever with rash. All had received a vaccination injection in different health centres in one District of Ho Chi Minh City. Eight children had been vaccinated by the same health care worker (HCW). Deficiencies in vaccine quality, storage practices, or preparation and delivery were not found. Infection control practices were insufficient. CA-MRSA was cultured in four children and from nasal and throat swabs from the HCW. Strains from children and HCW were indistinguishable. All carried the Panton-Valentine leukocidine (PVL), the staphylococcal enterotoxin B gene, the gene complex for staphylococcal-cassette-chromosome mec type V, and were sequence type 59. Strain HCM3A is epidemiologically unrelated to a strain of ST59 prevalent in the USA, although they belong to the same lineage. We describe an outbreak of infections with CA-MRSA in children, transmitted by an asymptomatic colonized HCW during immunization injection. Consistent adherence to injection practice guidelines is needed to prevent CA-MRSA transmission in both in- and outpatient settings.


I-J-restricted interactions in the generation of azobenzenearsonate-specific suppressor T cells.
The genetic restrictions of the activation of third-order suppressor cells (Ts3) were studied in mice, using two different types of anti-azobenzenearsonate (ABA)-immune responses, namely delayed-type hypersensitivity (DTH) and cytotoxic T lymphocyte (CTL) generation. Ts2 cells were induced in several different strains of mice by injecting monoclonal T hybridoma molecules or first-order suppressor factors (TsF1) originating in A/J (H-2a, Igh-1e) mice and then testing the TsF2 molecules derived from these Ts2 in A/J and A.By (H-2b, Igh-1e) or (A/J X A.By)F1 (H-2a/b, Igh-1e) and (C57Bl/6 X A/J)F1 (H-2b/a, Igh-1e) mice. It was shown that the activity of TsF2 was restricted to the I-J of the strain in which Ts2 was induced. By genetic analysis, restriction was shown to be due to the requirement of H-2 identity between ABA-coupled cells used for Ts3 activation and the strain of the TsF2 origin. Moreover, by using H-2-congenic ABA-coupled cells, we were also able to precisely map and demonstrate that ABA-coupled cells I-J identical to TsF2 induced in various strains were necessary for effective suppression to occur. This selective activation of Ts3 suggested the existence of I-J-related antigen presentation for suppression as the counterpart of I-A or I-A-I-E-restricted antigen presentation for positive immune responses.


Probability-based model of protein-protein interactions on biological timescales.
Simulation methods can assist in describing and understanding complex networks of interacting proteins, providing fresh insights into the function and regulation of biological systems. Recent studies have investigated such processes by explicitly modelling the diffusion and interactions of individual molecules. In these approaches, two entities are considered to have interacted if they come within a set cutoff distance of each other. In this study, a new model of bimolecular interactions is presented that uses a simple, probability-based description of the reaction process. This description is well-suited to simulations on timescales relevant to biological systems (from seconds to hours), and provides an alternative to the previous description given by Smoluchowski. In the present approach (TFB) the diffusion process is explicitly taken into account in generating the probability that two freely diffusing chemical entities will interact within a given time interval. It is compared to the Smoluchowski method, as modified by Andrews and Bray (AB). When implemented, the AB & TFB methods give equivalent results in a variety of situations relevant to biology. Overall, the Smoluchowski method as modified by Andrews and Bray emerges as the most simple, robust and efficient method for simulating biological diffusion-reaction processes currently available.


Virological investigation of hand, foot, and mouth disease in a tertiary care center in South India.
Hand, foot, and mouth disease (HFMD) remains a common problem in India, yet its etiology is largely unknown as diagnosis is based on clinical characteristics. There are very few laboratory-based molecular studies on HFMD outbreaks. The aim of this study was to characterize HFMD-related isolates by molecular techniques. Between 2005 and 2008, during two documented HFMD outbreaks, 30 suspected HFMD cases presented at the Outpatient Unit of the Department of Dermatology, Christian Medical College (CMC), Vellore. Seventy-eight clinical specimens (swabs from throat, mouth, rectum, anus, buttocks, tongue, forearm, sole, and foot) were received from these patients at the Department of Clinical Virology, CMC, for routine diagnosis of hand, foot, and mouth disease. Samples from these patients were cultured in Vero and rhabdomyosarcoma (RD) cell lines. Isolates producing enterovirus-like cytopathogenic effect (CPE) in cell culture were identified by a nested reverse transcription-based polymerase chain reaction (RT-PCR) and sequenced. The nucleotide sequences were analyzed using the BioEdit sequence program. Homology searches were performed using the Basic Local Alignment Search Tool (BLAST) algorithm. The statistical analysis was performed using Epi Info version 6.04b and Microsoft Excel 2002 (Microsoft Office XP). Of the 30 suspected HFMD cases, only 17 (57%) were laboratory confirmed and Coxsackievirus A16 (CVA16) was identified as the etiological agent in all these cases. Coxsackievirus A16 (CVA16) was identified as the virus that caused the HFMD outbreaks in Vellore between 2005 and 2008. Early confirmation of HFMD helps to initiate control measures to interrupt virus transmission. In the laboratory, classical diagnostic methods, culture and serological tests are being replaced by molecular techniques. Routine surveillance systems will help understand the epidemiology of HFMD in India.