The optimal use of chlormethine gel for mycosis fungoides: An expert consensus from Germany, Austria and Switzerland (DACH region).
In Europe chlormethine gel is licensed for the management of patients with mycosis fungoides of all stages. However, the optimal regimen regarding frequency and dosing as well as combination and maintenance therapy is not well established. Ten experts experienced in research and management of cutaneous T-cell lymphomas from Germany, Austria, and Switzerland (DACH region) were asked in written form to report on indication for chlormethine gel, frequency of use, monitoring, concomitant therapies, adverse effects, combination therapies in later stages of the disease, maintenance therapy, and adherence to this therapy for mycosis fungoides. The structured answers were discussed in a consensus conference and recommendations were developed. Essential for therapy with chlormethine gel is an individualized and symptom-oriented management. Because of the lack of systemic resorption of topically administered chlormethine gel, systemic adverse events are unlikely. An allergic or irritative-toxic contact dermatitis is common but manageable with adaptation of the regimen, interruption of administration, and symptom-specific supportive measurements. A step-up initial approach with application of chlormethine gel every other day is associated with a better tolerability, especially if it is alternated with topical corticosteroids. The use of chlormethine gel in the management of mycosis fungoides is often limited by a concomitant contact dermatitis. An adequate therapeutic regimen and the management of adverse effects can preclude an unnecessary withdrawal of therapy so that more patients can benefit from this treatment option.


P0 proteins of European beet-infecting poleroviruses display variable RNA silencing suppression activity.
Post-transcriptional gene silencing (PTGS), or RNA silencing, is one of the key mechanisms of antiviral defence used by plants. To counter this defence response, viruses produce suppressor proteins that are able to inhibit the PTGS pathway or to interfere with some of its function. The aim of this study was to evaluate the RNA silencing suppressor (RSS) activity of P0 proteins from selected European isolates of the beet-infecting poleroviruses beet chlorosis virus (BChV) and beet mild yellowing virus (BMYV) using two different experimental systems: (i) agro-infiltration of Nicotiana benthamiana green fluorescent protein-positive plants and (ii) mechanical inoculation of Chenopodium quinoa using a beet necrotic yellow vein virus (BNYVV, genus Benyvirus) RNA3-based replicon. The results demonstrated that P0 of most BMYV isolates exhibited RSS activity, although at various efficiencies among isolates. Conversely, P0 of BChV isolates displayed no RSS activity in either of the two systems under the experimental conditions used. These results are the first reported evidence that P0 proteins of two closely related beet poleroviruses show strain-specific differences in their effects on RNA silencing.


Process control of lightly salted wild and farmed Atlantic cod (Gadus morhua) by brine injection, brining, and freezing--a low field NMR study.
The aim of this study was to use low-field nuclear magnetic resonance (NMR) and traditional chemical methods to investigate the physical and chemical differences in wild and farmed cod processed pre- and postrigor, and how these properties were affected by brine injection, brining, and freezing. In prerigor processed farmed or wild cod, brine injections followed by brining for 2 d, with brine concentrations up to 5.5% and 4%, respectively, were not sufficient to reach a muscle salt concentration of 2% as aimed for, while wild cod processed postrigor had sufficient salt uptake after the same processing. Low-field NMR gave valuable information about the differences in the muscle structure between wild and farmed cod as well as the state of the water in the muscle during brine injection, brining, and during rigor tension. Low-field NMR is, therefore, a valuable tool that can be used to optimize the salting and storing processes of lightly salted cod products from both wild and farmed cod. For farmed cod to be used in the production of lightly salted products further research is needed. Practical Application: Optimal processing of lightly salted cod products is important to the fish industry, due to an increasing market for this product in southern Europe. Farmed cod, which is seen as a potential steady raw material source for this production, differs considerably from its wild counterparts by having other chemical and physical muscle properties, such as lower water content and lower pH. With the processing procedures used today the farmed cod can, therefore, only be used in some of the products, where wild cod is currently used as raw material. It is, therefore, important that the processing of these products is optimized with regard to these differences in the raw material. This study gives a valuable contribution to further studies about optimal combinations of brine injections, brining, and freezing of pre- and postrigor processed farmed compared to wild cod.


Effect of Iron Oxide and Phase Separation on the Color of Blue Jun Ware Glaze.
Based on the traditional Jun ware glaze, the imitated Jun ware glazes were prepared by adding iron oxide and introducing phase separation agent apatite through four-angle-method. The effect of iron oxide contents, phase separation and the firing temperature on the color of Jun ware glazes were investigated by a neutral atmosphere experiment, optical microscope and scanning electronic microscope. The results showed that the colorant, mainly Fe2O3, contributed to the Jun ware glaze blue and cyan colors of Jun ware glaze. The light scatter caused by the small droplets in phase separation structure only influenced the shade of the glaze color, intensify or weaken the color, and thus made the glaze perfect and elegant opal visual effects, but was not the origin of general blue or cyan colors of Jun ware glaze. In addition, the firing temperature and the basic glaze composition affected the glaze colors to some extent.


Adequacy of treatment for child and adolescent mental disorders in Australia: A national study.
Worldwide, little information is available about the extent to which children with mental disorders in the general population receive treatment from health professionals that meets minimal clinical practice guidelines. This study identifies the percentage of 6-17 year olds with mental disorders in the 2013-2014 Australian national survey of mental health who had sufficient contact with health professionals during the 18 months after the survey to have received treatment meeting criteria for minimally adequate treatment (MAT). It also identifies factors associated with children having this level of contact with health professionals. Mental disorders were identified using the Diagnostic Interview Schedule for Children Version IV completed by parents. Health professional attendances and psychotropic medications dispensed were identified from linked national Medicare Benefits Schedule and Pharmaceutical Benefits Scheme records. Only 11.6% (95% confidence interval [CI] [9.1, 14.8]) of children with disorders ( n = 517) had sufficient contact to achieve study criteria for MAT. Furthermore, among children with mental disorders who had severe functional impairment and whose parents perceived that their child needed help ( n = 146), 20.2% (95% CI [14.3, 27.9]) had contact sufficient for MAT, 46.0% (95% CI [37.8, 54.4]) had contact that did not achieve MAT criteria and 33.8% (95% CI [26.1, 42.3]) had no contact with health professionals. In multivariable regression, children with moderate or severe functional impairment were more likely to have had sufficient contact to meet MAT criteria. During the 18 months after being identified with a mental disorder, only a small percentage of children have enough contact with health professionals to allow provision of MAT. This may be contributing to the unchanging high prevalence of childhood mental disorders.


Excision of a congenital laryngeal cyst in a five-month-old dog via a lateral extraluminal approach.
A 5-month-old neutered male Golden Retriever was evaluated because of moderate stridor, exercise intolerance, and dyspnea. The dog had been neutered 3 weeks previously, and the referring veterinarian identified a large fluid-filled swelling on the left lateral aspect of the larynx during anesthetic intubation for that surgery. The referring veterinarian drained fluid from the mass by use of needle centesis via the oral cavity, which resulted in temporary improvement in clinical signs; however, the clinical signs returned soon thereafter. A large, soft, spherical mass was located between the left arytenoid and thyroid cartilages and axial to the left ceratohyoid bone, thus causing partial obstruction of the rima glottidis. Laryngoscopic examination, computed tomography (CT), and cytologic evaluation of aspirates performed before surgery; examination during surgery; and histologic evaluation of tissues following surgical excision confirmed the diagnosis of a laryngeal cyst. Complete surgical excision was successfully performed via a lateral extraluminal approach to the larynx. One week after surgery, the dog coughed only occasionally. Twelve months after surgery, the owner reported that the dog was clinically normal with no recurrence of clinical signs, and laryngoscopic examination revealed no recurrence of the cyst or other pathological changes in the laryngeal region. Congenital laryngeal cysts are rarely reported in domestic animals. The information provided here described the CT appearance of a laryngeal cyst and the use of CT in diagnosis and surgical planning. Congenital laryngeal cysts can be resected via a lateral submucosal approach.


Gene network analysis during early infection of human coronary artery smooth muscle cells by Trypanosoma cruzi and Its gp83 ligand.
Trypanosoma cruzi, the causative agent of Chagas' disease, infects heart and muscle cells leading to cardiac arrest, followed by death. The genetic architectures in the early T. cruzi infection process of human cells are unknown. To understand the genetic architectures of the early invasion process of T. cruzi, we conducted gene transcription microarray analysis, followed by gene network construction of the host cell response in primary human coronary artery smooth muscle (HCASM) cells infected with T. cruzi or exposed to T. cruzi gp83, a ligand used by the trypanosome to bind host cells. Using seven RT-PCR verified up-regulated genes (FOSB, ATF5, INPP1, CCND2, THBS1, LAMC1, and APLP2) as the seed for network construction, we built an interaction network of the early T. cruzi infection process containing 165 genes, connected by 598 biological interactions. This interactome network is centered on the BCL6 gene as a hub. Silencing the expression of two seed genes (THBS1 and LAMC1) by RNAi reduced T. cruzi infection. Overall, our results elucidate the significant and complex process involved in T. cruzi infection of HCASM cells at the transcriptome level. This is the first elucidation into the interactome network in human cells caused by T. cruzi and its gp83 ligand.


Correlated photons in one-dimensional waveguides.
We study two-photon transport in a one-dimensional waveguide with a side-coupled two-level system. Depending on the momentum of the incoming photons, we find that the nature of the scattering process changes considerably. We further show that bunching behavior can be found in the scattered light. As a result, we find that the waveguide dispersion has a strong influence on the photon correlations. By modifying the momentum of the pulse, the nature of the correlations can therefore be altered or optimized.


[Compression syndromes of the axillary nerve and the suprascapular nerve].
We report on seven patients with altogether four paralyses of the axillary and six paralyses of the suprascapular nerve without a singular trauma. In one patient, the paralysis of the axillary nerve developed spontaneously over night after a period of habitual dislocations of the shoulder joint. Another patient developed a paralysis of the suprascapular nerve after prolonged wearing of a rucksack. Three of the remaining five patients developed both an axillary and suprascapular paresis without any preceeding trauma or irritation. In two further patients, an isolated suprascapular paralysis developed without trauma. An analysis of the intraoperative findings in these five patients shows in all cases adhesions of the nerve with the surrounding tissues at the site of the suprascapular notch respectively the quadrilateral space. In all three cases of axillary nerve paralysis there was in addition a narrow quadrilateral space. However only in three of five suprascapular nerve lesions there was a narrow suprascapular notch. In the two remaining cases adhesions alone had caused the paralysis and produced a serpentine deformity of the nerve. It is concluded that inflammatory processes cause the paralysis and the adhesions. Compression in the narrow space and fibrous changes are responsible for maintaining the paralysis after the inflammation has subsided. Macroscopically unchanged nerves underwent external neurolysis. With fibrous changes an epineuriotomy and with more pronounced changes an epineuriectomy were performed. The results are discussed.


Central nervous system infections in the systemic vasculitides.
Central nervous system infections are not uncommon in systemic vasculitides. Being vigilant of central nervous system infections as an alternative consideration, instead of systemic vasculitides per se, could prove to be lifesaving in certain circumstances. Common pathogens, such as tuberculosis, Cryptococcus, and Listeria, still occur commonly as the major causes of central nervous system infection in systemic vasculitides. However, rare pathogens could be responsible among those immunocompromised hosts, and they should not be overlooked. The manifestation of central nervous system infection tends to be atypical among systemic vasculitides patients. History, physical, and cerebrospinal fluid analyses are still time-honored approaches to establishing the correct diagnosis. Newer techniques such as interferon-gamma release assay for tuberculosis, cerebrospinal fluid cytokine, or chemokine profiling need further validation and careful interpretation among such a special patient population. Immune disturbance, mainly due to immunosuppressive therapy, and polymorphism of the innate immune pathway (for example, Toll-like receptor) could be susceptibility factors for certain central nervous system infections. The biologic agents (for example, anti-tumor necrosis factor alpha, and B-cell depletion therapy) represent novel methods for treating systemic vasculitides, but they raise a critical issue owing to their increased likelihood for being associated with opportunistic infections. Despite the recent progress in this special field, the mortality of central nervous system infection in systemic vasculitides is still high, and the prognostic factors are still largely undetermined.


Coarsening and clustering in run-and-tumble dynamics with short-range exclusion.
The emergence of clustering and coarsening in crowded ensembles of self-propelled agents is studied using a lattice model in one dimension. The persistent exclusion process, where particles move at directions that change randomly at a low tumble rate α, is extended allowing sites to be occupied by more than one particle, with a maximum n_{max} per site. Three phases are distinguished. For n_{max}=1 a gas of clusters form, with sizes distributed exponentially and no coarsening takes place. For n_{max}≥3 and small values of α, coarsening takes place and few large clusters appear, with a large fraction of the total number of particles in them. In the same range of n_{max} but for larger values of α, a gas phase where a negligible fraction of particles takes part of clusters. Finally, n_{max}=2 corresponds to a crossover phase. The character of the transitions between phases is studied extending the model to allow n_{max} to take real values and jumps to an occupied site are probabilistic. The transition from the gas of clusters to the coarsening phase is continuous and the mass of the large clusters grows continuously when varying the maximum occupancy, and the crossover found corresponds to values close to the transition. The second transition, from the coarsening to the gaseous phase, can be either continuous or discontinuous depending on the parameters, with a critical point separating both cases.


The effect of pitch, rhythm, and familiarity on working memory and anxiety as measured by digit recall performance.
The purpose of this study was to isolate and quantitatively evaluate the effects of pitch and rhythm of unfamiliar and familiar melodies on working memory and anxiety as measured by sequential digit recall performance. Participants (N = 60) listened to 6 treatment conditions each consisting of 9 randomized monosyllabic digits. The digits were paired with (a) a familiar melody and pitch only, (b) a familiar melody and rhythm only, (c) a familiar melody with both pitch and rhythm, (d) an unfamiliar melody with pitch only, (e) an unfamiliar melody with rhythm only, and (f) an unfamiliar melody with both pitch and rhythm. The 6 different treatments were counterbalanced using a Latin square design in an attempt to control for order effects. Participants rated their state anxiety on a Likert-type scale before, midway through, and after the digits test. No statistically significant order, learning, or practice effects were found. A 3-way repeated-measures ANOVA indicated a statistically significant difference in digit recall performance across musical element conditions and groups. Results indicated that music majors outperformed nonmusic majors on the digit recall task. Participants were able to recall digits from the rhythm condition most accurately while recalling digits from pitch only and both pitch and rhythm conditions the least accurately. Graphic analysis of treatment as a function of sequential position indicated digit recall was best during conditions of primacy and recency. No main effects were found for the familiarity condition. Additionally, no main effects or interactions were found for the anxiety variable. The results of this study are congruent with existing working memory and music literature suggesting that pairing information with rhythm can facilitate recall, music majors outperform non-music majors, and recall accuracy is best in positions of primacy and recency. Implications for practice in therapy and education are made as well as suggestions for future research.


Dental perspectives on the population history of Southeast Asia.
This article uses metric and nonmetric dental data to test the "two-layer" or immigration hypothesis whereby Southeast Asia was initially occupied by an "Australo-Melanesian" population that later underwent substantial genetic admixture with East Asian immigrants associated with the spread of agriculture from the Neolithic period onwards. We examined teeth from 4,002 individuals comprising 42 prehistoric and historic samples from East Asia, Southeast Asia, Australia, and Melanesia. For the odontometric analysis, dental size proportions were compared using factor analysis and Q-mode correlation coefficients, and overall tooth size was also compared between population samples. Nonmetric population affinities were estimated by Smith's distances, using the frequencies of 16 tooth traits. The results of both the metric and nonmetric analyses demonstrate close affinities between recent Australo-Melanesian samples and samples representing early Southeast Asia, such as the Early to Middle Holocene series from Vietnam, Malaysia, and Flores. In contrast, the dental characteristics of most modern Southeast Asians exhibit a mixture of traits associated with East Asians and Australo-Melanesians, suggesting that these populations were genetically influenced by immigrants from East Asia. East Asian metric and/or nonmetric traits are also found in some prehistoric samples from Southeast Asia such as Ban Kao (Thailand), implying that immigration probably began in the early Neolithic. Much clearer influence of East Asian immigration was found in Early Metal Age Vietnamese and Sulawesi samples. Although the results of this study are consistent with the immigration hypothesis, analysis of additional Neolithic samples is needed to determine the exact timing of population dispersals into Southeast Asia.


A metal-bridged tricyclic aromatic system: synthesis of osmium polycyclic aromatic complexes.
Aromaticity is one of the most important concepts in organic chemistry. A variety of metalla-aromatic compounds have been recently prepared and in most of those examples, the metal participates only in a monocyclic ring. In contrast, metal-bridged bicyclic aromatic molecules, in which a metal is shared between two aromatic rings, have been less developed. Herein, we report the first metal-bridged tricyclic aromatic system, in which the metal center is shared by three aromatic five-membered rings. These metalla-aromatics are formed by reaction between osmapentalyne and arene nucleophiles. Experimental results and theoretical calculations reveal that the three five-membered rings around the osmium center are aromatic. In addition, the broad absorption bands in the UV/Vis absorption spectra of these novel aromatic systems cover almost the entire visible region. This straightforward synthetic strategy may be extended to the synthesis of other metal-bridged polycyclic aromatics.


Genome-wide analysis of self-renewal in Drosophila neural stem cells by transgenic RNAi.
The balance between stem cell self-renewal and differentiation is precisely controlled to ensure tissue homeostasis and prevent tumorigenesis. Here we use genome-wide transgenic RNAi to identify 620 genes potentially involved in controlling this balance in Drosophila neuroblasts. We quantify all phenotypes and derive measurements for proliferation, lineage, cell size, and cell shape. We identify a set of transcriptional regulators essential for self-renewal and use hierarchical clustering and integration with interaction data to create functional networks for the control of neuroblast self-renewal and differentiation. Our data identify key roles for the chromatin remodeling Brm complex, the spliceosome, and the TRiC/CCT-complex and show that the alternatively spliced transcription factor Lola and the transcriptional elongation factors Ssrp and Barc control self-renewal in neuroblast lineages. As our data are strongly enriched for genes highly expressed in murine neural stem cells, they are likely to provide valuable insights into mammalian stem cell biology as well.


Peripheral enhancement of breast cancers on contrast-enhanced ultrasound: correlation with microvessel density and vascular endothelial growth factor expression.
There is little evidence of an association between peripheral enhancement on contrast-enhanced ultrasound and histopathologic prognostic factors in breast cancer. The purpose of our study was to investigate the relationship of peripheral enhancement on contrast-enhanced ultrasound with microvessel density, vascular endothelial growth factor (VEGF) expression and other prognostic factors in patients with breast cancer. In 51 patients with BI-RADS (Breast Imaging Reporting and Data System) category 5 lesions scheduled for surgery, contrast-enhanced ultrasound with an 8-4 linear transducer and B-mode pulse inversion harmonic imaging was performed after administration of SonoVue. Forty-three histologically confirmed breast cancers were included in the study and divided into the peripheral enhancement group and non-peripheral enhancement group on the basis of their features on contrast-enhanced ultrasound. The ratio of peripheral to central microvessel density, VEGF expression, tumor size, histopathologic type, stage, lymph node metastasis and expression of estrogen receptor, progesterone receptor, c-erb-B2 and p53 were compared between the two groups. The ratio of peripheral to central microvessel density and a peripherally positive/centrally negative VEGF expression pattern were significantly higher in the peripheral enhancement group than in the non-peripheral enhancement group (t-test, p = 0.023, and χ(2) test, p = 0.035, respectively). There were no significant differences in breast cancer size, histopathologic type, stage, lymph node metastasis or expression of estrogen receptor, progesterone receptor, c-erb-B2 and p53 between the two groups (χ(2) test, p = 0.416, 0.877, 0.543, 0.124, 0.453, 0.554, 0.350 and 0.479 respectively). The peripheral enhancement pattern of breast cancer on contrast-enhanced ultrasound may be valuable in the evaluation of peripheral/central tumor angiogenesis and VEGF expression.


[Comparative analysis of results of revascularization of the first segment of vertebral arteries].
Analysed herein is efficacy of various operations on the first segment of the vertebral artery (VA) during treatment of patients with vertebrobasilar insufficiency (VBI). The study enrolled a total of 194 patients with the clinical pattern of VBI induced by an atherosclerotic lesion of the first segment of the VA (stenosis >70%). All patients prior to admission had been receiving a course of medicamentous therapy under neurologist's supervision for more than 6 months with no significant effect. The patients were divided into two groups: Group A included 129 (66.5%) patients with VA tortuosity, subjected to 'open' operations, Group B was composed of 65 (33.5%) patients without VA tortuosity, subjected to stenting of the first segment of the VA. The main criteria of assessing the results were patency of the reconstructed zone and clinical improvement after surgery. In 189 (97.4%) patients we managed to attain stable clinical improvement which persisted after 1 year in 177 (91.2%) patients and after 3 years in 156 (80.2%). In the group of stenting, excellent immediate results were obtained - 100% technical and clinical success. However, in the remote period, the outcomes of 'open' operations turned out to be better as compared with those of stenting. Thus, 3-year clinical efficacy of 'open' and stenting operations amounted to 79.8% and 73.8%, respectively (p>0.05). After 'open' operations there was a significantly lower rate of restenosis of the reconstruction zone (1.6%) than after stenting - 15.4% (p<0.05). However, after 'open' operations the frequency of thrombosis of the reconstructed zone was higher than after stenting - 5.5 vs 1.5% (p>0.05). The incidence of stroke after open operations and after stenting amounted to 2.3 and 3.1%, respectively (p>0.05). Comparative assessment of relapse-free survival after all analysed methods of operations and interventions showed that the best techniques in the long-term perspective turned out to be 'open' operations, and amongst them the operation of transposition of the VA to the common carotid artery (median - 13 years) and the operation of reimplantation of the VA into its ostium (median not achieved in follow up observations for more than 18 years).


Activated sludge behaviour in a batch reactor in the presence of antibiotics: study of extracellular polymeric substances.
The influence of Erythromycin, Roxithromycin, Amoxicillin, Tetracycline and Sulfamethoxazole on municipal sludge in batch reactors was investigated. The study was focused on extracellular polymeric substances (EPS) as indicator of bacteria sensitivity to toxic agents. The EPS were analysed by UV-Vis and FT-IR spectroscopies and by size exclusion chromatography. It was found that Erythromycin and Roxithromycin induced a significant increase of bound EPS in flocs. This was attributed to a protection mechanism of the bacteria. Erythromycin was the only antibiotic which inhibited COD and nitrogen removal.


A comparison of beclomethasone, salmeterol, and placebo in children with asthma. Canadian Beclomethasone Dipropionate-Salmeterol Xinafoate Study Group.
An inhaled glucocorticoid is currently the medication of choice for long-term control of persistent asthma in children. The role of long-acting beta2-adrenergic-receptor agonists, such as salmeterol, needs to be defined. We conducted a randomized, double-blind, placebo-controlled, parallel-group, one-year study of 241 children (mean [+/-SD] age, 9.3+/-2.4 years) with clinically stable asthma and less than one month of prior glucocorticoid use. We compared inhaled beclomethasone dipropionate (200 microg twice daily) with salmeterol xinafoate (50 microg twice daily) and placebo (lactose). The primary outcome measure, airway responsiveness (as assessed with a methacholine challenge) was evaluated before treatment; after 3, 6, 9, and 12 months of treatment (12 and 36 hours after study medications had been withheld); and 2 weeks after the end of treatment. Spirometry, symptoms, use of rescue medication (200 microg of albuterol inhaled as needed), and adverse effects were also assessed. During months 1 through 12 overall, beclomethasone was associated with significantly less airway hyperresponsiveness than salmeterol (P= 0.003) or placebo (P<0.001). This effect was lost two weeks after treatment had been stopped. As compared with placebo, beclomethasone was associated with less variability between morning and evening in the peak expiratory flow (P=0.002), as was salmeterol (P=0.02). Beclomethasone was also associated with a reduced need for albuterol as rescue therapy (P<0.001) and fewer withdrawals because of asthma exacerbations (P=0.03), but salmeterol was not (P=0.09 and 0.55, respectively). During months 1 through 12, linear growth was 3.96 cm in the children receiving beclomethasone, as compared with 5.40 cm in the salmeterol group (P=0.004) and 5.04 cm in the placebo group (P=0.018). Height was not measured after treatment ended. Beclomethasone was effective in reducing airway hyperresponsiveness and in controlling symptoms of asthma, but it was associated with decreased linear growth. Salmeterol was not as effective as beclomethasone in reducing airway hyperresponsiveness or in controlling symptoms; however, it was an effective bronchodilator and was not associated with rebound airway hyperresponsiveness, masking of symptoms, or adverse effects.


Consideration of postpartum management in HIV-positive Haitian women: an analysis of CD4 decline, mortality, and follow-up after delivery.
A previous study at the GHESKIO HIV clinic confirmed that highly active antiretroviral therapy (HAART) prophylaxis reduced mother-to-child transmission (MTCT) and infant mortality in Haiti. This analysis looks at maternal outcomes in this cohort after delivery. Records of 508 HIV-positive Haitian women who delivered between 1999 and 2005 were analyzed. We examined mortality, loss to follow-up, time to death or HAART initiation, and time of decline of CD4 count to 350 cells/μL. One hundred seventy women reached a CD4 ≤200 or developed clinical AIDS and were started on long-term HAART. The median CD4 count at HAART initiation was 178 (interquartile range, 106-227). CD4 decline was stratified by CD4 at delivery to project the mean months to a CD4 of 350. With an initial CD4 of 350-499 cells/μL, it was 19 months (95% confidence interval: 14 to 28) while with a CD4 >500 cells/μL, it was 71 months (95% confidence interval: 59 to 88). At study close, 257 women remained in follow-up, with loss to follow-up 3 times less in those on HAART (3.2/100 person-years) than those not on HAART (9.8/100 person-years). The threshold for starting treatment was often missed in HIV-infected women after delivery. Success of follow-up of women after delivery was favorably influenced by being on HAART. Women with high (>500) initial CD4 counts had a protracted time (5-7 years) before they reach a threshold CD4 count, in contrast to those with CD4 <500 cells/μL. Strategies for postpartum treatment of women should be informed by the speed with which they are likely to progress.


Passive protection against Pseudomonas aeruginosa infection in an experimental leukopenic mouse model.
An experimental leukopenic mouse model was used to evaluate the protective capacities of immunoglobulin G (IgG) fractions directed against toxin A (AT-IgG), elastase (AE-IgG), and lipopolysaccharide (ALPS-IgG) against fatal Pseudomonas aeruginosa infection. Statistically significant protection, as measured by long-term survival, was observed only when mice were treated with serotype-specific ALPS-IgG. The mean lethal dose for P. aeruginosa could be increased by as much as 6,600-fold for mice given ALPS-IgG as compared to mice which received only normal rabbit IgG. ALPS-IgG afforded high levels of protection, even when administered up to 6 h postchallenge. Experiments designed to monitor the growth and spread of a locally administered challenge showed that ALPS-IgG prevented bacteremia and organ colonization, which were pronounced in control animals. The effectiveness of combined antibiotic and immune therapy was tested. Gentamicin alone or in combination with AT-IgG or AE-IgG provided no detectable protection. However, its use with ALPS-IgG afforded substantially higher levels of protection than ALPS-IgG alone.


Density discrimination with occlusions in 3D clutter.
We examined how well human observers can discriminate the density of surfaces in two halves of a rotating three-dimensional cluttered sphere. The observer's task was to compare the density of the front versus back half or the left versus right half. We measured how the bias and sensitivity in judging the denser half depended on the level of occlusion and on the area and density of the surfaces in the clutter. When occlusion level was low, observers in the front-back task were biased to judge the back as denser, and when occlusion level was high they were biased to judge the front as denser. Weber fractions decreased as density increased for both the front-back and left-right tasks, consistent with previous findings for two-dimensional density discrimination. Weber fractions did not vary significantly with area for the front-back task, but increased with area for the left-right task, and we attribute this difference to occlusions that have different effects in the two tasks. We also ran model observers that compared the image occupancies of the two halves against a known expected difference. As the occlusion level increased, this expected difference followed a similar trend as the biases of the human observers, with a roughly constant offset between them. Weber fractions for human and model observers followed some similar trends, but there were discrepancies as well that can be partly explained by the information available to human versus model observers in carrying out their respective tasks.


Akkermansia muciniphila suppressing nonalcoholic steatohepatitis associated tumorigenesis through CXCR6+ natural killer T cells.
Gut microbiota plays a crucial role in the development and progression of nonalcoholic steatohepatitis (NASH) and associated hepatocellular carcinoma (HCC). Akkermansia muciniphila was reported to inhibit inflammation-associated cancer in the intestine. The anti-NASH ability of A. muciniphila has recently been found. Thus, we were to investigate whether supplementation of A. muciniphila could prevent NASH-associated HCC. In a model we called STAM, male C57BL/6J mice were subcutaneously injected with 200 µg streptozotocin at 4 days after birth, and fed with high-fat diet at 4 weeks of age to induce NASH-associated HCC. Faeces from mice and patients with NASH-related HCC were collected for 16S rRNA sequencing. STAM mice were orally administered either saline or A. muciniphila twice a day starting at 4 or 10 weeks of age. The effects of A. muciniphila on the immune responses were also evaluated. Patients and mice with NASH-related HCC showed significantly reduced gut A. muciniphila in comparison to healthy controls. Administration of breast milk-isolated A. muciniphila (AM06) but not feces-isolated A. muciniphila (AM02) could improve NASH severity. Interestingly, breast milk-isolated A. muciniphila treatment suppressed the progression of NASH to HCC, accompanied with an increased hepatic CXCR6+ natural killer T (NKT) cell and decreased macrophage infiltration. The antitumor ability of A. muciniphila was not evident in NKT cell-deficient mice (CD1d-/- and CXCR6-/-). In vitro, A. muciniphila promoted the killing of hepG2 cells by NKT cells. Our study will provide the rationale for the application of A. muciniphila to treat NASH and for the prevention of its progression to HCC.


Food advertising and television exposure: influence on eating behavior and nutritional status of children and adolescents.
This study aimed to evaluate the influence of food advertising and television exposure on eating behaviour and nutritional status of children and adolescents. It was a cross sectional study developed among 116 students from a private school in Brazil. Socio-demographic and health conditions were evaluated. Anthropometric data, food consumption, physical activity, television viewing habits and behaviour in relation to food advertising were also investigated. Among the results, a 1:2 relationship was identified between the number of televisions and residents per household. Excessive weight was present in 25.8% of subjects and 66.4% of children watched television while eating. Children were exposed to television for a median of 3.0 hours daily (95% CI: 2.9 to 3.6). There was a direct association between attraction to foods advertised and purchasing the product (p < 0.001) and a positive relationship between the number of televisions per household and body weight (r = 0.246, p = 0.015) and the amount of liquid consumed during meals (r = 0.277, p = 0.013). Findings also highlighted the association between watching television while eating and the reduced probability of fruit consumption (p = 0.032), contrasted with a greater likelihood of daily artificial juice intake (p = 0.039). In conclusion, watching television is associated with lower probability of daily consumption of fruits and the number of television at household is positively related to BMI in children and adolescents.


The protonation state of Glu181 in rhodopsin revisited: interpretation of experimental data on the basis of QM/MM calculations.
The structure and spectroscopy of rhodopsin have been intensely studied in the past decade both experimentally and theoretically; however, important issues still remain unresolved. Of central interest is the protonation state of Glu181, where controversial and contradictory experimental evidence has appeared. While FTIR measurements indicate this residue to be unprotonated, preresonance Raman and UV-vis spectra have been interpreted in favor of a protonated Glu181. Previous computational approaches were not able to resolve this issue, providing contradicting data as well. Here, we perform hybrid QM/MM calculations using DFT methods for the electronic ground state, MRCI methods for the electronically excited states, and a polarization model for the MM part in order to investigate this issue systematically. We constructed various active-site models for protonated as well as unprotonated Glu181, which were evaluated by computing NMR, IR, Raman, and UV-vis spectroscopic data. The resulting differences in the UV-vis and Raman spectra between protonated and unprotonated models are very subtle, which has two major consequences. First, the common interpretation of prior Raman and UV-vis experiments in favor of a neutral Glu181 appears questionable, as it is based on the assumption that a charge at the Glu181 location would have a sizable impact. Second, also theoretical results should be interpreted with care. Spectroscopic differences between the structural models must be related to modeling uncertainties and intrinsic methodological errors. Despite a detailed comparison of various rhodopsins and mutants and consistently favorite results with charged Glu181 models, we find merely weak evidence from UV-vis and Raman calculations. On the contrary, difference FTIR and NMR chemical shift measurements on Rh mutants are indicative of the protonation state of Glu181. Supported by our results, they provide strong and independent evidence for a charged Glu181.


Vaccination with antioxidant enzymes confers protective immunity against challenge infection with Schistosoma mansoni.
Schistosoma mansoni, an intravascular parasite, lives in a hostile environment in close contact with host humoral and cellular cytotoxic factors. To establish itself in the host, the parasite has evolved a number of immune evasion mechanisms, such as antioxidant enzymes. Our laboratory has demonstrated that the expression of antioxidant enzymes is developmentally regulated, with the highest levels present in the adult worm, the stage least susceptible to immune elimination, and the lowest levels in the larval stages, the most susceptible to immune elimination. Vaccination of mice with naked DNA constructs containing Cu/Zn cytosolic superoxide dismutase (CT-SOD), signal-peptide containing SOD or glutathione peroxidase (GPX) showed significant levels of protection compared to a control group. We have further shown that vaccination with SmCT-SOD but not SmGPX results in elimination of adult worms. Anti-oxidant enzyme vaccine candidates offer an advance over existing vaccine strategies that all seem to target the larval developmental stages in that they target adult worms and thus may have therapeutic as well as prophylactic value. To eliminate the potential for cross-reactivity of SmCT-SOD with human superoxide dismutase, we identified parasite-specific epitope-containing peptides. Our results serve as a basis for developing a subunit vaccine against schistosomiasis.


Transient factor VIII inhibitor in a hemophilia patient after staphylococcal septic shock syndrome.
We report a transient type I factor VIII inhibitor that arose in a 30-year-old hemophilia patient just after staphylococcal septicemia. This situation usually occurs early in the course of substitution therapy with factor VIII concentrate in hemophilia patients. Although disseminated intravascular coagulation and acute respiratory distress syndrome developed after septic shock, the patient recovered following intravenous administration of antibiotics (meropenem and gentamycin), an antithrombin preparation, high-dose methylprednisolone, and recombinant factor VIII concentrate (rFVIII). During this therapy, however, activated partial thromboplastin time gradually lengthened. On the seventh day of hospitalization, intracranial hemorrhage occurred with right hemiplegia, even though the substitution therapy had continued at the same dosage (30 U/kg per day) of rFVIII. At that point, 4 Bethesda units of the type I inhibitor against factor VIII were detected in the plasma. Increased amounts (46 U/kg per day) of rFVIII and prednisolone were administered, and hypothermic therapy was initiated. Following these treatments, the patient's general condition gradually improved, and within 25 days the inhibitor titer dropped to undetectable levels and did not recur during treatment. These clinical findings suggest that the staphylococcal septic shock may have acted as a trigger in the development of transient factor VIII inhibitor in this patient.


Relationship between proportion and composition of albumins, and in vitro protein digestibility of raw and cooked pea seeds (Pisum sativum L.).
Peas provide an excellent plant protein resource for human diets, but their proteins are less readily digestible than animal proteins. To identify the relationship between composition and in vitro digestibility of pea protein, eight pea varieties with a wide range of protein content (157.3-272.7 g kg(-1)) were determined for the proportion of albumins and globulins, their compositions using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and in vitro protein digestibility (IVPD) before and after heat treatment using a multi-enzyme (trypsin, chymotrypsin and peptidase) method. The proportion of albumins based on total seed protein content decreased from 229 to 147 g kg(-1) as seed protein content increased from 157.3 to 272.7 g kg(-1), while the proportion of globulins increased from 483 to 590 g kg(-1). The IVPDs of eight raw pea seeds were 79.9-83.5%, with significant varietal variations, and those were improved to 85.9-86.8% by cooking. Albumins, including (pea albumins 2) PA2, trypsin inhibitor, lectin and lipoxygenase, were identified as proteolytic resistant proteins. Globulins were mostly digested by protease treatment after heating. The quantitative ratio of albumins and globulins, and the quantitative variations of albumin protein components, including lipoxygenase, PA2, lectins and trypsin inhibitors, appear to influence the protein digestibility of both raw and cooked pea seeds.


The Associations of Hospital Volume, Surgeon Volume, and Surgeon Experience with Complications and 30-Day Rehospitalization after Free Tissue Transfer: A National Population Study.
Greater provider volume is associated with better outcomes. There is, however, a paucity of evidence on volume-outcome associations for surgical complications and 30-day all-cause rehospitalization after free tissue transfer or free flap surgery. Surgical complications and frequent rehospitalization are important quality indicators that substantially hinder appropriate health care spending. The authors hypothesized that increased provider volume and surgeon experience are associated with lower complication and hospital readmission rates. The authors conducted a retrospective cohort study of adults aged 18 to 64 years who underwent free tissue transfer. They examined 100 percent of all free tissue transfers between 2001 and 2012 using Taiwan's national data, and used regression modeling to examine associations between volume and outcome. All models were adjusted for patient, surgeon, and hospital characteristics. Seventeen percent of free tissue transfer operations (4201 of 25,327) had complications. Infection was the most prevalent after free tissue transfer (70 percent), and the 30-day rehospitalization rate was approximately 20 percent. Hospital volume was associated with a small decrease in complications (OR, 0.99; 95 percent CI, 0.99 to 0.99; p < 0.01). For surgeons, years of experience and not annual case volume decreased surgical complications (OR, 0.98; 95 percent CI, 0.97 to 0.99; p = 0.01). The authors did not find any association between hospital or surgeon volume, or surgeon's years of experience and 30-day rehospitalization. Higher-volume hospitals and more experienced surgeons were shown to have a lower likelihood of postsurgery complications. Hospital process and structure affect outcomes and reduce surgical complications. Reducing 30-day rehospitalization may require payment reform, as it demands coordinated care before and after hospital discharge. Therapeutic, III.


Psychosocial evaluation of heart transplant candidates: an international survey of process, criteria, and outcomes.
Heart transplant programs were surveyed regarding psychosocial evaluation process, criteria, and outcomes. There was considerable disagreement among programs when a patient is rejected on psychosocial grounds with regard to the use of second opinions and how often patients are informed of the reasons. Wide discrepancies in criteria used and rates of patients refused on psychosocial grounds were discovered. More than 70% of all programs excluded patients for transplantation on the grounds of dementia, active schizophrenia, current suicidal ideation, history of multiple suicide attempts, severe mental retardation, current heavy alcohol use, and current use of addictive drugs. Lack of consensus was found for some exclusion criteria (cigarette smoking, obesity, noncompliance, recent alcohol or drug abuse, criminality, personality disorder, mild mental retardation, controlled schizophrenia, and affective disorder). The proportion of patients rejected for transplantation on psychosocial grounds ranged from 0% to 37%, with an average rate of 5.6% in the United States and 2.5% in non-U.S. programs. This survey thus supports the need for research on the validity and reliability of psychosocial selection criteria.


Lactobacillus plantarum TWK10 Supplementation Improves Exercise Performance and Increases Muscle Mass in Mice.
Lactobacillus plantarum (L. plantarum) is a well-known probiotic among the ingested-microorganism probiotics (i.e., ingested microorganisms associated with beneficial effects for the host). However, few studies have examined the effects of L. plantarum TWK10 (LP10) supplementation on exercise performance, physical fatigue, and gut microbial profile. Male Institute of Cancer Research (ICR) strain mice were divided into three groups (n = 8 per group) for oral administration of LP10 for six weeks at 0, 2.05 × 10⁸, or 1.03 × 10⁹ colony-forming units/kg/day, designated the vehicle, LP10-1X and LP10-5X groups, respectively. LP10 significantly decreased final body weight and increased relative muscle weight (%). LP10 supplementation dose-dependently increased grip strength (p < 0.0001) and endurance swimming time (p < 0.001) and decreased levels of serum lactate (p < 0.0001), ammonia (p < 0.0001), creatine kinase (p = 0.0118), and glucose (p = 0.0151) after acute exercise challenge. The number of type I fibers (slow muscle) in gastrocnemius muscle significantly increased with LP10 treatment. In addition, serum levels of albumin, blood urea nitrogen, creatinine, and triacylglycerol significantly decreased with LP10 treatment. Long-term supplementation with LP10 may increase muscle mass, enhance energy harvesting, and have health-promotion, performance-improvement, and anti-fatigue effects.


Endovascular management of acute subarachnoid haemorrhage in the elderly.
The objective of this study was to analyse the technical and clinical outcome in elderly patients receiving endovascular treatment for acutely ruptured intracranial aneurysms. The case notes and angiograms of 14 patients over the age of 69 years undergoing endovascular treatment for subarachnoid haemorrhage within the Interventional Neuroradiology Unit, Royal Perth Hospital over a period of 6 years were retrospectively reviewed. The degree of angiographic occlusion achieved, and periprocedural, short-term and long-term clinical outcome were retrospectively assessed. Greater than 90% occlusion was obtained in 92% of cases. 82% of patients with Hunt and Hess grade I and II had an excellent clinical outcome. We conclude that endovascular coiling is an effective means of treating acute subarachnoid haemorrhage in grade I and II elderly patients.


Kir6.1/K-ATP channel in astrocytes is an essential negative modulator of astrocytic pyroptosis in mouse model of depression.
Rationale: Astrocyte dysfunction is one of the important pathological mechanisms of depression. Stress contributes to the onset of depression. As metabolic stress sensor, Kir6.1-contaning K-ATP channel (Kir6.1/K-ATP) is prominently expressed in astrocytes. However, the involvement of Kir6.1/K-ATP channel in depression remains obscure. Methods: Astrocyte-specific Kir6.1 knockout mice were used to prepare two mouse models of depression to explore the role of astrocytic Kir6.1/K-ATP channel in depression. Primary astrocytes were cultured to reveal the underlying mechanism for Kir6.1-regulated astrocytic pyroptosis. Results: We identified that chronic stress reduced the astrocytic Kir6.1 expression in hippocampus of mice. We further observed astrocyte-specific knockout of Kir6.1 induced depressive-like behaviors in mice. Moreover, we found that astrocytic Kir6.1 deletion increased NLRP3-mediated astrocytic pyroptosis in response to stress. Mechanistically, Kir6.1 associated with NLRP3, and this interaction prevented the assembly and activation of NLRP3 inflammasome, thereby inhibition of astrocytic pyroptosis. More importantly, VX-765, an effective and selective inhibitor for NLRP3 inflammasome, could reverse the astrocytic pyroptosis and rescue the deterioration of behaviors in astrocytic Kir6.1 knockout mice. Conclusions: Our findings illustrate that Kir6.1/K-ATP channel in astrocytes is an essential negative modulator of astrocytic pyroptosis and plays a crucial role in depression and suggest that astrocytic Kir6.1/K-ATP channel may be a promising therapeutic target for depression.


Fully protected glycosylated zinc (II) phthalocyanine shows high uptake and photodynamic cytotoxicity in MCF-7 cancer cells.
Phthalocyanine photosensitizers are effective in anticancer photodynamic therapy (PDT) but suffer from limited solubility, limited cellular uptake and limited selectivity for cancer cells. To improve these characteristics, we synthesized isopropylidene-protected and partially deprotected tetra β-glycosylated zinc (II) phthalocyanines and compared their uptake and accumulation kinetics, subcellular localization, in vitro photocytotoxicity and reactive oxygen species generation with those of disulfonated aluminum phthalocyanine. In MCF-7 cancer cells, one of the compounds, zinc phthalocyanine {4}, demonstrated 10-fold higher uptake, 5-fold greater PDT-induced cellular reactive oxygen species concentration and 2-fold greater phototoxicity than equimolar (9 μm) disulfonated aluminum phthalocyanine. Thus, isopropylidene-protected β-glycosylation of phthalocyanines provides a simple method of improving the efficacy of PDT.


Microminiaturized immunoassays using quantum dots as fluorescent label by laser confocal scanning fluorescence detection.
An immunoassay readout method based on fluorescent imaging analysis with laser confocal scanning is described. The ZnS-coated CdSe quantum dots (ZnS/CdSe QDs) were linked to a detection antibody. Immunoassay was carried out on a glass chip using a sandwich assay approach, where antibody covalently bound to a glass chip was allowed to capture antigen specially. Afterwards, the detection antibody labeled with QD was allowed to bind selectively to the captured antigen. The fluorescent signals of the sandwich conjugate were detected by a laser confocal scanner. A diode laser was used to excite efficiently the fluorescent signals while bovine serum albumin was used to eliminate nonspecific binding sites. The detection limit of this approach was up to 10(-9) M under current experimental conditions. The specificity of the QDs-labeled immunoglobulin (IgG) was tested by an experiment using goat IgG and human IgG samples. The result was consistent with the binding specificity in a sandwich-type assay. The potential of this method to function as a simple and efficient readout strategy for immunoassay in biochip is discussed.


Consequences of increased systolic blood pressure in patients with osteoarthritis and rheumatoid arthritis.
To estimate the potential effect on cardiovascular event occurrence and treatment costs associated with increases in systolic blood pressure (SBP) among patients with osteoarthritis (OA) and rheumatoid arthritis (RA). We used cardiovascular risk prediction models from the Framingham Heart Study and data on risk factors from the Third National Health and Nutrition Examination Survey (NHANES III) to estimate occurrences of ischemic heart disease and stroke over one year among US adults with OA/RA. Separate analyses were conducted for treated hypertensive patients, and untreated hypertensive and normotensive patients, respectively. Published estimates were used to assign costs to these events and to follow care. The effect of incremental increases in SBP on events and costs was then assessed. Monte Carlo simulation was undertaken to assess the range of event occurrence and costs associated with alternative assumptions regarding the distribution of increased SBP in the at-risk population. Of the estimated 30 million adults in the US aged > or = 35 years with OA and RA, roughly 11.8 million (39%) receive pharmacologic treatment for hypertension. Increases in SBP of 1-5 mm Hg were associated with 7,100-35,700 additional ischemic heart disease and stroke events over one year, with corresponding costs (year 2000 USD) of 114-569 million year 2000 USD. A 20 mm Hg increase in SBP experienced by 15% of the at-risk population (equivalent to a population-average 3 mm Hg increase) is associated with about 21,700 additional events (95% CI 19,120, 24,221) and 346 million year 2000 USD (95% CI 305 year 2000 USD, 387 million) in associated costs. Relatively small changes in SBP associated with use of common arthritis medications can have a significant effect on the cardiovascular risk profile. It is important that clinicians who treat patients with OA/RA accurately weigh the potential risks of these medications against their benefits.


Observations on vascular accidents in the central nervous system of neonatal foals.
A technique for the subarachnoid perfusion-fixation of the central nervous system was developed to help identify various significant vascular accidents (SVAs) in the central nervous system (CNS) of 24 neonatal foals submitted for necropsy. SVAs, comprising subarachnoid, parenchymal and nerve root haemorrhages, and oedema and necrosis, occurred in 17 foals, more frequently in the spinal cord than the brain. They occurred as frequently in premature foals as in those born at full term, in foals born dead as in foals born alive, and in foals born following dystocia with an assisted delivery as in foals born unassisted. Eight of the live foals showed neurological signs. Those with syndromes of cerebral disease tended to have brain SVAs, whilst all 3 with signs of spinal cord disease had SVAs restricted to the spinal cord. No association between the SVAs and other specific disease processes was detected in these foals although 2 premature foals born dead with equine herpesvirus-1 infection did have spinal cord SVAs only. A similar distribution of brain and/or spinal cord SVAs was detected in the foals born dead as in the live foals, but the lesions were more severe. It is concluded that the birth process itself may be a major factor in the development of SVAs and that some affected foals may exhibit a syndrome referable to spinal cord involvement.


Patient safety culture shapes presenteeism and absenteeism: a cross-sectional study among Croatian healthcare workers.
Healthcare workers have high rates of injuries and illnesses at the workplace, and both their absence from work due to illness (absenteeism) or working ill (presenteeism) can compromise patient safety and the quality of health care delivered. Following this premise, we wanted to determine whether presenteeism and absenteeism were associated with patient safety culture (PSC) and in what way. Our sample consisted of 595 Croatian healthcare workers (150 physicians and 445 nurses) who answered the short-form WHO Health and Work Performance Questionnaire and the Hospital Survey on Patient Safety Culture. The results have confirmed the association with both presenteeism and absenteeism in several PSC dimensions, but not as we expected based on the premise from which we started. Opposite to our expectations, lower job performance (as a measure of presenteeism) was associated with higher PSC instead of lower PSC. Absenteeism, in turn, was associated with lower PSC, just as we expected. These findings suggest that it is the PSC that shapes presenteeist and absenteeist behaviour and not the other way around. High PSC leads to presenteeism, and low PSC to absenteeism. We also believe that the presenteeism questionnaires should be adjusted to health care and better define what lower performance means both quantitatively and qualitatively in a hospital setting.


[Epigenetic variability induced by nicotinic acid in Triticum aestivum L].
The effect of nicotinic acid (NA) on hereditary traits of spring common wheat cultivar Kazakhstanskaya 126 (K.126) were studied under the laboratory and field conditions. Treatment of seeds and vegetating plants with 0.01-0.1% NA (aqueous solution) induced heritable epigenetic changes in wheat. As a result, strong tall plants with the long productive spike, large seeds, and several quantitative and qualitative characters other than in the original cultivar were obtained in the second and further generations after treatment. Crosses of changed plants with each other did not result in segregation with respect to leaf downiness or anthocyan stem color in F2-F4, suggesting the same epigenetic state of genes responsible for changed characters. In crosses with the original cultivar, characters of the changed plants always dominated in F1. Basing on the current views, the changes were attributed to a transition of the hl1 and pc recessive marker genes into new, dominant epiallelic states Hl1 and Pc, which respectively determine downy leaves and the colored stem. The NA effect was specific, since only one type of the variation was observed. The changed characters were stable, and no reversion to the original phenotype was detected in 57 generations.


Genetic diversity and Wolbachia infection of the Drosophila parasitoid Leptopilina clavipes in western Europe.
Wolbachia are maternally transmitted bacteria that alter their arthropod hosts' reproduction in various ways, including parthenogenesis induction (PI). Wolbachia-induced parthenogenesis can have drastic effects on the genetic structure of its host because it potentially reduces populations to clones without genetic exchange. However, Wolbachia-induced parthenogenesis does not inevitably result in a reduction of genetic variation of infected populations vs. uninfected populations, because the parthenogenetic populations are initially derived from uninfected populations and can thus show similar genetic variation. Here we investigate these issues in infected and uninfected populations of the Drosophila parasitoid Leptopilina clavipes in western Europe. Wasps from 19 sites in the Netherlands, France and northern Spain were screened for Wolbachia and analysed using amplified fragment length polymorphism (AFLP) markers. All the populations from the Netherlands and mid-France were infected with the same two strains of Wolbachia, whereas populations from the Pyrenees were not infected. The infected and uninfected populations show identical levels of genetic variation, but have clearly diverged genetically, indicating the presence of a barrier that prevents gene flow. Within the infected wasps two distinct genotypes were found at multiple localities, indicating the coexistence of multiple clones. The conditions promoting clonal coexistence in L. clavipes are discussed.


Loss, Psychosis, and Chronic Suicidality in a Korean American Immigrant Man: Integration of Cultural Formulation Model and Multicultural Case Conceptualization.
Culture shapes the nature, experience, and expression of psychopathology and help-seeking behavior across ethnically diverse groups. Although the study of psychopathology among Asian Americans has advanced, clinicians remain in need of culturally appropriate tools for the assessment and diagnosis of severe mental disorders including psychotic symptoms among Asian Americans. In this article, we present a brief overview of two culturally relevant conceptual tools: a) the Cultural Formulation Model, and b) the Multicultural Case Conceptualization approach. We use a case scenario to illustrate the integration of these two approaches in providing culturally responsive clinical conceptualization, assessment and treatment of a Korean American immigrant suffering from prominent psychiatric symptoms. We intend this discussion to engender further empirical work to advance our knowledge of the manifestation and experience of severe mental illness including psychotic disorders among Asian Americans, and contribute to culturally competent prevention and intervention of chronic and persistent mental illness within this group.


Diagnostic and prognostic relevance of autoantibodies in uranium miners.
Uranium miners exposed to silica dust have a higher risk of developing systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). Sera of 1976 former uranium miners were analysed for autoantibodies typical of connective tissue disease. The frequency of some of these antibodies (anti-centromere, -topoisomerase I, -nucleolar, -dsDNA, -Ro/SSA, -La-SSB and U1-RNP antibodies) was significantly higher compared to a gender- and age-matched control group and was associated with the intensity of exposure as well as with clinical symptoms of SSc or SLE. It was also shown that SSc-associated autoantibodies may serve as an early indicator of disease development. Some differences in the autoantibody production between silica-dust-associated and idiopathic SLE/SSc were observed that might be caused by environmental factors in the population of uranium miners.


Genetic linkage of snowflake vitreoretinal degeneration to chromosome 2q36.
To identify the chromosomal location of the gene causing snowflake vitreoretinal degeneration (SVD), an autosomal dominant retinal degeneration characterized by small yellow-white dots in the retina, fibrillar anomaly of the vitreous humor, and retinal detachment. Clinical data were collected on 31 family members by history and examination. Thirteen family members underwent prospective examination. Genotyping was performed using microsatellite markers spaced at approximately 10 cM intervals. Two-point and multipoint linkage analysis was performed (FASTLINK version of the MLINK program and the VITESSE algorithm, both available at http://linkage.rockefeller.edu/soft/list.html). Direct DNA sequencing of amplified genomic DNA and mRNA was performed for candidate gene analysis. The SVD locus was linked to markers in a region of chromosome 2q36 defined by D2S2158 and D2S2202, based on meiotic breakpoint mapping of affected individuals. A maximum two-point lod score of 5.5 was obtained with marker D2S172 at theta; = 0 within this region. Direct DNA sequencing of all 52 exons of the COL4A3 gene revealed no potentially pathogenic coding sequence variation or evidence for deletion. The genetic locus for SVD lies in a 9 Mb region flanked by D2S2158 and D2S2202. Localization of SVD to a genomic region distinct from both Wagner disease and the Stickler syndromes indicates that SVD is a distinct genetic entity. The absence of coding sequence variation in the only collagen gene within the disease-region, suggests a novel pathogenesis for vitreoretinal degeneration. Snowflake vitreoretinal degeneration should be considered in the differential diagnosis of families with fibrillar anomaly of the vitreous.


A New Homozygous Frameshift Mutation in the HSD3B2 Gene in an Apparently Nonconsanguineous Italian Family.
3β-Hydroxysteroid dehydrogenase (3β-HSD) deficiency is a rare cause of congenital adrenal hyperplasia (CAH) caused by inactivating mutations in the HSD3B2 gene. We report the molecular and structural analysis of the HSD3B2 gene in a 46,XY child born to apparently nonconsanguineous parents and presenting ambiguous genitalia and salt wasting. The steroid profile showed elevated concentrations of 17-hydroxyprogesterone, androstenedione, ACTH and plasma renin, but normal values of cortisol and dehydroepiandrosterone sulfate. Unexpectedly, plasma aldosterone was high. For structural and functional analyses, the three-dimensional structure of 3β-HSD2 was modeled using the crystal structure of the short-chain dehydrogenase Gox2253 from Gluconobacter oxydans as a template. The direct DNA sequence of the child revealed a new homozygous frameshift mutation in exon 4 of the HSD3B2 gene, a single nucleotide deletion at codon 319 [GTC(Val)x2192;GC], yielding premature stop codon in position 367. Molecular homology modeling and secondary structure predictions suggested that the variant sequence might both alter the substrate-binding cleft and compromise the overall stability of the enzyme. We have described the first HSD3B2 gene mutation in the Italian population and analyzed its effect in the context of the 3β-HSD2 structure and function.


[Pain-specific diagnosis patterns in claims data - Identification by means of classification and regression trees (CART)].
The identification of beneficiaries with persistent, recurrent or chronic pain in claims data by means of individual diagnoses or analgesic prescription is not sufficient and reliable. By using CLASSIFICATION AND REGRESSION TREES (CART) it was possible to identify specific diagnosis patterns for patients suffering from pain. Diagnosis patterns are considered as specific if they occur more frequently among beneficiaries with at least two opioid prescriptions within one year compared with beneficiaries who did not receive any analgesic therapy. Diagnosis and prescription data of 2006 were provided by the German sickness fund DAK. As a result, 65 diagnosis patterns occurred more frequently among beneficiaries treated with opioids than among the control group. These 65 patterns can be classified as follows: cancer-related pain (4), specific back pain/osteoporosis (8), spine-related pain (6), arthritis-related pain/rheumatoid arthritis (22), pain after traumatic fractures (5), pain in multimorbid, dependent patients (3), neuropathic pain (7), headache (5), non-specific back pain (5). The derived diagnosis patterns showed high predictive values (sensitivity: 78%, specificity: 66%) and are suitable for the identification of beneficiaries suffering from pain - the first step towards health services research in pain-based on claims data.


Perspectives on the use of melatonin to reduce cytotoxic and genotoxic effects of methacrylate-based dental materials.
Melatonin (5-methoxy-N-acetyltryptamine), an indoleamine produced in the pineal gland and many other organs, displays a wide spectrum of protective effects against cell injury of various origins. Contemporary dental restorative materials mainly consist of methacrylate polymers with some additives. However, because of the incompleteness of polymerization process in situ as well as mechanical shearing and enzymatic degradation, methacrylate monomers are released from the restoration into the oral cavity and the pulp, from where they gain access to other tissues and organs. Such monomers have displayed toxic properties in many in vivo and in vitro studies, including cytotoxicity and genotoxicity and a considerable portion of these effects is underlined by the oxidative action of these compounds. As melatonin shows biocompatibility with the oral cavity and displays antioxidative properties, it may be considered as a protective agent against harmful effects of methacrylate monomers derived from dental restorations. Melatonin decreases cytotoxic and genotoxic effects of methacrylate monomers used in dentistry, and it does not influence the bond strength of dental composites. This opens a new possible application of melatonin to improve properties of biomaterials used in dentistry.


[Interpersonal psychotherapy (IPT) in depressions].
Evidence-based medicine gains more importance within psychotherapy as well, although some problems occur in trying to follow the principles of evidence-based-medicine in the field of psychotherapy very strictly. The Interpersonal Psychotherapy (IPT) for depression, which has been developed more than 30 years ago may be taken as an example for evidence-based-psychotherapy: the concept was built on empirical observations and manualised. Further on it was evaluated in many clinical trails that showed the good efficacy and later effectiveness. IPT reaches a high level of evidence and is to be seen as well-established psychotherapy. Psychotherapy research tries to point out the effectiveness for different subtypes of depressive disorders. Moreover it is investigated which connection exist between therapy outcome and neurobiological changes in the central nervous system.


Factors affecting starch digestibility and the glycemic response with special reference to legumes.
Large differences exist in the degree to which different starch containing foods affect the blood glucose levels of both normal volunteers and diabetics. These differences appear to relate to the digestibility of the starch and the factors determining this, including: the interaction of starch with fiber, antinutrients (eg, phytate) and protein in the food, together with the nature of the starch itself and its physical form (eg, raw or cooked, ground or whole). In this respect legumes exemplify a class of foods, high in fiber, protein and antinutrients, with a starch which is digested slowly in vitro. They also produce relatively small blood glucose rises after consumption by both normals and diabetics and in the longterm result in improved diabetic control. Identification of more such foods and further understanding of factors determining starch digestibility will allow greater therapeutic use of diet in the management of diabetics and disorders of carbohydrate metabolism.


Fractional Exhalation Nitric Oxide (FeNO) changes in cystic fibrosis patients induced by compound honey syrup: a pretest-posttest clinical trial.
To evaluate the effect of Persian medicine Syrup 'compound honey syrup (CHS)' on fractional exhalation nitric oxide (FENO) changes in patients with cystic fibrosis (CF). We conducted a before-after clinical trial on 70 CF patients. All patients received classical treatments for CF along with CHS (including honey, Ginger, cinnamon, saffron, cardamom and galangal), 5-10 cc (depending on the age and weight of patients) in 100 cc of warm boiled water twice a day, 30 min after meals. In this clinical trial, before and 12 weeks after the start of the CHS, FeNO test was evaluated. From 70 patients were enrolled, 44 patients completed this 12-week course of treatment. At the end of the study, changes in FeNO was significantly different before and after treatment (P-value < 0.05). At the end of the study, no dangerous side effects of CHS was reported. This study revealed that CHS can be effective as a complementary and safe drug in the medication of CF patients.


Progress in the Systemic Treatment of Advanced Soft-Tissue Sarcomas.
BACKGROUND: Despite the plethora of chemotherapeutic remedies for advanced soft-tissue sarcomas, little evidence has developed to indicate that these efforts have been curative. No controlled comparison has yet proven that patients receiving multidrug regimens survive longer than those receiving doxorubicin alone. METHODS: The authors review current systemic treatments and then discuss some investigational efforts now in progress. Also, they seek to demonstrate how the therapies currently available can be integrated with surgery and radiation therapy to accomplish more than might be anticipated from chemotherapy alone. RESULTS: While working to develop better systemic therapies for advanced soft-tissue sarcomas, the integrated use of our best chemotherapy regimens in combination with selected surgical and radiotherapy efforts may provide patients with the best available therapy. Some recent observations involving the use of molgramostim plus chemotherapy have been intriguing. CONCLUSIONS: Progress in the systemic treatment of advanced soft-tissue sarcomas may be gradual, but it is real. Our daily challenge is to be certain that we offer each patient the best available multimodality treatment applicable to his or her clinical situation. Molgramostim should be made available for further study with chemotherapy in controlled clinical trials.


No effect of folic acid on markers of endothelial dysfunction or inflammation in patients with type 2 diabetes mellitus and mild hyperhomocysteinaemia.
Mild hyperhomocysteinaemia is a cardiovascular risk factor in patients with type 2 diabetes mellitus. Homocysteine may exert its detrimental effects through induction of endothelial dysfunction and/or chronic inflammation. In this study, we examined the effects of homocysteine-lowering therapy with folic acid on biochemical markers of endothelial dysfunction and low-grade inflammation in patients with type 2 diabetes mellitus and mild hyperhomocysteinaemia (> or = 14 micromol/l). In a randomised, double-blind, controlled trial, patients were treated with folic acid 5 mg or placebo for six months. At 0 and 6 months, albuminuria, von Willebrand factor, soluble cellular adhesion molecules, C-reactive protein, interleukin-6 and tumour necrosis factor-alpha were determined. Forty-one patients completed the study (folic acid 23, placebo 18). Baseline hyperhomocysteinaemia (median 17 micromol/l, range 14 to 30 micromol/l) was reduced by 29% in the folic-acid-treated group, and remained unchanged in patients receiving placebo. On average, folic acid treatment did not significantly affect any of the endothelial (e.g. von Willebrand factor: difference folic acid minus placebo +1%, confidence interval -3 to +16%) or inflammation (e.g. C-reactive protein: difference folic acid minus placebo +13%, confidence interval -42 to +52%) markers studied. Multiple regression analyses without and with adjustment for baseline differences in cardiovascular disease and ethnicity confirmed these results. An apparent beneficial effect of folic acid on albuminuria in crude analysis was attenuated by multiple adjustment (difference folic acid minus placebo -35%, confidence interval -178 to +32%, p=0.08, adjusted 0.26). The data indicate that, in this group of patients with type 2 diabetes mellitus and mild hyperhomocysteinaemia, lowering homocysteine with folic acid for six months does not improve biochemical markers of endothelial dysfunction or low-grade inflammation.


Biomarkers for Early Detection of Colorectal Cancer: The Early Detection Research Network, a Framework for Clinical Translation.
Early detection by screening significantly reduces mortality from colorectal cancer, but 40% of guideline-eligible patients are not screened as recommended in the United States. Novel strategies to improve screening uptake overall and efforts to deploy best practices to underserved populations are a high priority for health care. This review focuses on existing biomarkers in practice and those in development with clinical relevance to early detection of colorectal neoplasia, with an emphasis on those developed by investigators of the NCI's Early Detection Research Network. Aberrantly methylated DNA markers (blood and stool), stool-based markers (including fecal immunochemical test-DNA), and a variety of blood-based marker assays in development (protein markers, glycoproteins including mucins, and cell-free DNA tests) are reviewed. Individual markers and biomarker panels, sample resources, and barriers to translating biomarkers to clinical practice are discussed.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."


Improving bitter pit prediction by the use of X-ray fluorescence (XRF): A new approach by multivariate classification.
Bitter pit (BP) is one of the most relevant post-harvest disorders for apple industry worldwide, which is often related to calcium (Ca) deficiency at the calyx end of the fruit. Its occurrence takes place along with an imbalance with other minerals, such as potassium (K). Although the K/Ca ratio is considered a valuable indicator of BP, a high variability in the levels of these elements occurs within the fruit, between fruits of the same plant, and between plants and orchards. Prediction systems based on the content of elements in fruit have a high variability because they are determined in samples composed of various fruits. With X-ray fluorescence (XRF) spectrometry, it is possible to characterize non-destructively the signal intensity for several mineral elements at a given position in individual fruit and thus, the complete signal of the mineral composition can be used to perform a predictive model to determine the incidence of bitter pit. Therefore, it was hypothesized that using a multivariate modeling approach, other elements beyond the K and Ca could be found that could improve the current clutter prediction capability. Two studies were carried out: on the first one an experiment was conducted to determine the K/Ca and the whole spectrum using XRF of a balanced sample of affected and non-affected 'Granny Smith' apples. On the second study apples of three cultivars ('Granny Smith', 'Brookfield' and 'Fuji'), were harvested from two commercial orchards to evaluate the use of XRF to predict BP. With data from the first study a multivariate classification system was trained (balanced database of healthy and BP fruit, consisting in 176 from each group) and then the model was applied on the second study to fruit from two orchards with a history of BP. Results show that when dimensionality reduction was performed on the XRF spectra (1.5 - 8 KeV) of 'Granny Smith' apples, comparing fruit with and without BP, along with K and Ca, four other elements (i.e., Cl, Si, P, and S) were found to be deterministic. However, the PCA revealed that the classification between samples (BP vs. non-BP fruit) was not possible by univariate analysis (individual elements or the K/Ca ratio).Therefore, a multivariate classification approach was applied, and the classification measures (sensitivity, specificity, and balanced precision) of the PLS-DA models for all cultivars evaluated ('Granny Smith', 'Fuji' and 'Brookfield') on the full training samples and with both validation procedures (Venetian and Monte Carlo), ranged from 0.76 to 0.92. The results of this work indicate that using this technology at the individual fruit level is essential to understand the factors that determine this disorder and can improve BP prediction of intact fruit.


CXCL12 mediates immunosuppression in the lymphoma microenvironment after allogeneic transplantation of hematopoietic cells.
Clinical studies indicate a role of allogeneic hematopoietic cell transplantation (alloHCT) for patients with refractory or recurrent B-cell lymphoma (BCL) indicative of a graft-versus-tumor effect. However, the relevance of local immunosuppression in the BCL microenvironment by donor-derived regulatory T cells (Treg) after alloHCT is unclear. Therefore, we studied Treg recruitment after alloHCT in different murine BCL models and the impact of lymphoma-derived chemoattractive signals. Luciferase transgenic Tregs accumulated in murine BCL microenvironment and microarray-based analysis of BCL tissues revealed increased expression of CXCL9, CXCL10, and CXCL12. In vivo blocking identified the CXCR4/CXCL12 axis as being critical for Treg attraction toward BCL. In contrast to Tregs, effector T cells displayed low levels of CXCR4 and were not affected by the pharmacologic blockade. Most important, blocking CXCR4 not only reduced Treg migration toward tumor tissue but also enhanced antitumor responses after alloHCT. CXCL12 production was dependent on antigen-presenting cells (APC) located in the lymphoma microenvironment, and their diphtheria-toxin receptor (DTR)-based depletion in CD11c.DTR-Tg mice significantly reduced Treg accumulation within BCL tissue. CXCL12 was also detected in human diffuse, large BCL tissues indicative of its potential clinical relevance. In conclusion, we demonstrate that Tregs are recruited toward BCL after alloHCT by infiltrating host APCs in a CXCL12-dependent fashion. Blocking CXCR4 enhanced antitumor effects and prolonged survival of tumor-bearing mice by reducing local Treg accumulation, indicating that CXCR4 is a potential target to interfere with tumor escape after alloHCT.


Challenges to biobanking in LMICs during COVID-19: time to reconceptualise research ethics guidance for pandemics and public health emergencies?
Biobanking can promote valuable health research that may lead to significant societal benefits. However, collecting, storing and sharing human samples and data for research purposes present numerous ethical challenges. These challenges are exacerbated when the biobanking efforts aim to facilitate research on public health emergencies and include the sharing of samples and data between low/middle-income countries (LMICs) and high-income countries (HICs). In this article, we explore ethical challenges for COVID-19 biobanking, offering examples from two past infectious disease outbreaks in LMICs where biobanking activities contributed to the perpetuation of global inequities. We focus on how the ethical imperative to promote the common good during public health emergencies can conflict with protecting the interests of biobank participants. We discuss how conducting biobank research under a waiver of informed consent during public health emergencies is ethically permissible, provided guidance is in place to prevent biopiracy and exploitation of vulnerable communities. We also highlight the need for biobank collaborations between LMICs and HICs to promote capacity building and benefit sharing. Finally, we offer guidance to promote the ethical oversight of biobanks and biobank research during the COVID-19 pandemic or other future public health emergencies.


Targeting the endothelin axis as a therapeutic strategy for oral cancer metastasis and pain.
Metastasis reduces survival in oral cancer patients and pain is their greatest complaint. We have shown previously that oral cancer metastasis and pain are controlled by the endothelin axis, which is a pathway comprised of the endothelin A and B receptors (ETAR and ETBR). In this study we focus on individual genes of the pathway, demonstrating that the endothelin axis genes are methylated and dysregulated in cancer tissue. Based on these findings in patients, we hypothesize that ETAR and ETBR play dichotomous roles in oral carcinogenesis and pain, such that ETAR activation and silenced ETBR expression result in increased carcinogenesis and pain. We test a treatment strategy that targets the dichotomous functions of the two receptors by inhibiting ETAR with macitentan, an ETAR antagonist approved for treatment of pulmonary hypertension, and re-expressing the ETBR gene with adenovirus transduction, and determine the treatment effect on cancer invasion (i.e., metastasis), proliferation and pain in vitro and in vivo. We demonstrate that combination treatment of macitentan and ETBR gene therapy inhibits invasion, but not proliferation, in cell culture and in a mouse model of tongue cancer. Furthermore, the treatment combination produces an antinociceptive effect through inhibition of endothelin-1 mediated neuronal activation, revealing the analgesic potential of macitentan. Our treatment approach targets a pathway shown to be dysregulated in oral cancer patients, using gene therapy and repurposing an available drug to effectively treat both oral cancer metastasis and pain in a preclinical model.


Mortality after infection with methicillin-resistant Staphylococcus aureus (MRSA) diagnosed in the community.
Outbreak reports suggest that community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections can be life-threatening. We conducted a population based cohort study to assess the magnitude of mortality associated with MRSA infections diagnosed in the community. We used the United Kingdom's General Practice Research Database (GPRD) to form a cohort of all patients with MRSA diagnosed in the community from 2001 through 2004 and up to ten patients without an MRSA diagnosis. The latter were frequency-matched with the MRSA patients on age, GPRD practice and diagnosis date. All patients were older than 18 years, had no hospitalization in the 2 years prior to cohort entry and medical history information of at least 2 years prior to cohort entry. The cohort was followed up for 1 year and all deaths and hospitalizations were identified. Hazard ratios of all-cause mortality were estimated using the Cox proportional hazards model adjusted for patient characteristics. The cohort included 1439 patients diagnosed with MRSA and 14,090 patients with no MRSA diagnosis. Mean age at cohort entry was 70 years in both groups, while co-morbid conditions were more prevalent in the patients with MRSA. Within 1 year, 21.8% of MRSA patients died as compared with 5.0% of non-MRSA patients. The risk of death was increased in patients diagnosed with MRSA in the community (adjusted hazard ratio 4.1; 95% confidence interval: 3.5-4.7). MRSA infections diagnosed in the community are associated with significant mortality in the year after diagnosis.


Clinical, functional and quality of life changes after balneokinesis with sulphurous water in patients with varicose veins.
Purpose of this study was to assess the effects of thermal hydrotherapy (balneokinesis) with a sulphurous water on clinical symptoms, quality of life and some functional parameters in patients with varicose veins. 70 patients with primary or secondary symptomatic varicosis were enrolled and submitted to elastic compression therapy. Patients were then randomized to receive (50 pts, group A) or not receive (20 pts, group B) balneokinetic treatment for 12 days "on top" of elastic compression. Clinical symptoms, quality of life and functional parameters obtained with light reflex plethysmography (PPG) and laser Doppler fluxmetry (LDF) were assessed after 3 and 6 months. Scores for subjective symptoms as pain, edema, and venous claudication were decreased after 6 months in both groups, but more evidently in group A submitted to balneokinesis. Some parameters related to quality of life evaluation as "bodily pain" and "emotional role" were improved only in patients undergoing balneokinesis. Regarding functional parameters, with PPG venous refilling time after foot exercise moderately increased in both groups. With LDF a significant improvement in the veno-arteriolar reflex was seen in the group treated with balneokinesis. These results show additional benefits of balneokinetic treatment in patients with symptomatic varices submitted to elastic compression. In fact, clinical and quality of life improvements were observed. The associated amelioration in the veno-arteriolar reflex may support these subjective benefits.


Brain ventricular volume and cerebrospinal fluid biomarkers of Alzheimer's disease.
The frequent co-occurrence of Alzheimer's disease (AD) pathology in patients with normal pressure hydrocephalus suggests a possible link between ventricular dilation and AD. If enlarging ventricles serve as a marker of faulty cerebrospinal fluid (CSF) clearance mechanisms, then a relationship may be demonstrable between increasing ventricular volume and decreasing levels of amyloid-beta peptide (Abeta) in CSF in preclinical and early AD. CSF biomarker data (Abeta, tau, and phosphorylated tau) as well as direct measurements of whole brain and ventricular volumes were obtained from the Alzheimer's Disease Neuroimaging Initiative dataset. The ratio of ventricular volume to whole brain volume was derived as a secondary independent measure. Baseline data were used for the group analyses of 288 subjects classified as being either normal (n=87), having the syndrome of mild cognitive impairment (n=136), or mild AD (n=65). Linear regression models were derived for each biomarker as the dependent variable, using the MRI volume measures and age as independent variables. For controls, ventricular volume was negatively associated with CSF Abeta in APOE epsilon4 positive subjects. A different pattern was seen in AD subjects, in whom ventricular volume was negatively associated with tau, but not Abeta in epsilon4 positive subjects. Increased ventricular volume may be associated with decreased levels of CSF Abeta in preclinical AD. The basis for the apparent effect of APOE epsilon4 genotype on the relationship of ventricular volume to Abeta and tau levels is unknown, but could involve altered CSF-blood-brain barrier function during the course of disease.


Nonprofit drugs as the salvation of the world's healthcare systems: the case of Antabuse (disulfiram).
The effort to repurpose old drugs for new uses is not sufficient; even drugs that have been used clinically for decades must undergo expensive clinical trials. This process requires the pharmaceutical industry to fund the repatenting of old drugs. Because inexpensive drugs are necessary for people around the world, attempts should be made to develop nonprofit drugs through clinical trials of generic drugs that are funded by governments and charities. Evidence supports the use the old anti-alcoholic drug Antabuse as a new nonprofit drug for cancer.


Borderline personality features and integration of positive and negative thoughts about significant others.
Taking the bad with the good is a necessity of life, and people who readily integrate thoughts of their loved one's flaws with thoughts of their more positive attributes maintain more stable, satisfying relationships. Borderline personality disorder, however, is often characterized by interpersonal perceptions that fluctuate between extremes of good and bad. We used a timed judgment task to examine information processing about significant others in individuals high in borderline personality features relative to healthy individuals and those high in avoidant personality features. In Study 1, when judging traits of a liked significant other, same-valence facilitation by negative primes (judging negative traits faster than positive traits after a negative prime) was significantly stronger in the borderline features group than the other two groups, and was inversely associated with self-reports of integrated thoughts about significant others. In contrast, same-valence facilitation by positive primes (judging positive traits faster than negative traits after a positive prime) was significantly stronger in the avoidant features group than the other two groups, and inversely associated with self-esteem. No between-group differences in same-valence facilitation were statistically significant when participants judged traits of disliked significant others, liked foods, and disliked foods. In Study 2, same-valence facilitation by negative primes when judging traits of a liked significant other was significantly associated with less integrated positive/negative thoughts about that person in a 12-day diary. These results identify an implicit information-processing pattern relevant to interpersonal difficulties in borderline personality disorder. (PsycINFO Database Record


Household Structure and Children's Educational Attainment: A Perspective on Coresidence with Grandparents.
Children from alternative households complete fewer years of schooling. Yet little is known about the implications of coresidence with grandparents for educational attainment. Using data from the National Longitudinal Study of Adolescent Health (N = 10,083), this study found that extended households with two biological parents were not detrimental to high school completion or college enrollment. Although coresidence with grandparents did not compensate for not living with two biological parents, it seemed to be beneficial for the educational attainment of youth from single-mother households. In contrast, skipped-generation households were associated with a persistent disadvantage for educational attainment. Limited socioeconomic resources partially accounted for the adverse effects of alternative households, whereas parenting quality did not explain these effects. Interactions of gender by household structure suggested that stepfather households could have negative consequences for high school completion and college enrollment only for girls.


Co-Design of a Virtual Reality Multiplayer Adventure Game for Adolescents With Autism Spectrum Disorder: Mixed Methods Study.
Virtual reality (VR) adventure games can offer ideal technological solutions for training social skills in adolescents with autism spectrum disorder (ASD), leveraging their support for multisensory and multiplayer interactions over distance, which may lower barriers to training access and increase user motivation. However, the design of VR-based game environments for social skills training is still understudied and deserves the deployment of an inclusive design approach to ensure its acceptability by target users. We aimed to present the inclusive design process that we had followed to develop the Zentastic VR adventure game to foster social skills training in adolescents with ASD and to investigate its feasibility as a training environment for adolescents. The VR game supports multiplayer training sessions involving small groups of adolescents and their therapists, who act as facilitators. Adolescents with ASD and their therapists were involved in the design and in an explorative acceptability study of an initial prototype of the gaming environment, as well as in a later feasibility multisession evaluation of the VR game final release. The feasibility study demonstrated good acceptability of the VR game by adolescents and an enhancement of their social skills from baseline to posttraining. The findings provide preliminary evidence of the benefits that VR-based games can bring to the training of adolescents with ASD and, potentially, other neurodevelopmental disorders.