"What is the score?" A review of football-based public mental health interventions.
Football exercise as an intervention for people with severe mental health problems has seen an increasing interest in the past years. To date, there is, however, no comprehensive review of the empirical evidence regarding the effectiveness of these interventions. In this review, the authors have comprised the research findings from the peer-review literature as well as the theoretical approaches to football exercise as an adjunct treatment. This overview will be informative to everybody who is planning to develop a football intervention for this population as well as to the people who are preparing evaluation studies that measure the effectiveness of such interventions. The paper aims to discuss these issues. The authors identified research papers in the peer-review literature that feature empirical findings on "football interventions" that aim at improving mental and/or physical well-being in participants with mental health problems. The authors are using the term "football intervention" here in the sense that the participants actively took part in football exercise, so the authors excluded studies in which the participants only watched football or used football as a metaphor to discuss mental health problems. In a table, the authors indicate the definition of the target group, targeted outcomes, measured outcomes, form and frequency of the intervention as well as the research method(s). The authors identified 16 studies on 15 projects. The majority of studies were qualitative and had positive findings in which the participants reported increased well-being and connectedness, elevation of symptoms and improved physical well-being. The outcomes of the quantitative studies, however, were mixed with some results suggesting that not all intended goals were achieved. There seems to be a need for more quantitative studies to triangulate the qualitative findings. Interestingly, most interventions take place in the UK. Many studies fail to give detailed methodological information and often the aims of the interventions are vague or not stated at all. Due to the heterogeneity of the studies and relative scarcity of evaluation projects on football interventions for people with mental health problems, the authors could not conduct an in-depth systematic review. Furthermore, the information on methods was often unsatisfying and despite efforts to get more detailed input from the authors of cited papers, those gaps could not always be filled. Instead of coming up with a crystal-clear summary of whether and how football interventions work for everybody, topics were identified that need to be addressed in the planning of interventions, in evaluation studies, in implementation efforts and in the theoretical discourse. This paper constitutes a helpful overview for everybody who is interested in the theoretical background of football interventions for people with mental health problems, for people who are planning to develop respective interventions, for researchers who engage in evaluation projects that look into the effectiveness of football interventions (or similar exercise interventions) as well as for the people who are interested in how football interventions can be implemented. This paper is likely to make a contribution to the advancement of alternative exercise interventions that aim at improving mental, physical and social health in people with mental health problems. This paper will help putting the topic of football interventions (and similar, alternative exercise interventions) further up on the public health agenda by providing an overview of the empirical evidence at hand and by specifying advantages of the approach as well as pointing out actions that need to be taken to make football a recognised, evidence based and viable option for adjunct mental health treatment that is attractive to potential participants as well as funders as well as to the potential participants. There is no comprehensive summary to date that provides a (reasonably) systematic overview of empirical findings for football interventions for people with MH problems. Furthermore, the literature on the theoretical background of these interventions has been somewhat patchy and heterogonous. This paper aims at filling both these gaps and identifies the issues that need to be covered in the planning of respective interventions and evaluations. This paper will be useful to everybody who is developing football interventions (or similar alternative adjunct exercise interventions), who is conducting evaluation research in this area and who is interested in the implementation of football interventions.


Novel pharmacotherapy: NNI-362, an allosteric p70S6 kinase stimulator, reverses cognitive and neural regenerative deficits in models of aging and disease.
Aging is known to slow the neurogenic capacity of the hippocampus, one of only two mammalian adult neurogenic niches. The reduction of adult-born neurons with age may initiate cognitive decline progression which is exacerbated in chronic neurodegenerative disorders, e.g., Alzheimer's disease (AD). With physiologic neurogenesis diminished, but still viable in aging, non-invasive therapeutic modulation of this neuron regeneration process remains possible. The discovery of truly novel neuron regenerative therapies could be identified through phenotypic screening of small molecules that promote adult-born neurons from human neural progenitor cells (hNPCs). By identifying neuron-generating therapeutics and potentially novel mechanism of actions, therapeutic benefit could be confirmed through in vivo proof-of-concept studies. The key aging and longevity mTOR/p70S6 kinase axis, a commonly targeted pathway, is substrate for potential selective kinase modulators to promote new hippocampal neurons from NPCs. The highly regulated downstream substrate of mTOR, p70S6 kinase, directly controls pleiotropic cellular activities, including translation and cell growth. Stimulating this kinase, selectively in an adult neurogenic niche, should promote NPC proliferation, and cell growth and survival in the hippocampus. Studies of kinase profiling and immunocytochemistry of human progenitor neurogenesis suggest that the novel small molecule NNI-362 stimulates p70S6 kinase phosphorylation, which, in turn, promotes proliferation and differentiation of NPCs to neurons. NNI-362 promoted the associative reversal of age- and disease-related cognitive deficits in aged mice and Down syndrome-modeled mice. This oral, allosteric modulator may ultimately be beneficial for age-related neurodegenerative disorders involving hippocampal-dependent cognitive impairment, specifically AD, by promoting endogenous hippocampal regeneration.


Congruence of individual responsiveness to dietary cholesterol and to saturated fat in humans.
Previous experiments have shown that differences between humans in the response of serum cholesterol to dietary cholesterol are at least partly reproducible and stable over a prolonged period. In this study it was investigated whether enhanced sensitivity to dietary cholesterol and saturated fat go together. The subjects had also participated in three or four experiments dealing with the reproducibility of the effect on blood cholesterol of either adding cholesterol to the diet in normal subjects (NORM-EGG group; n = 23) or of cessation of egg consumption in subjects with a high habitual egg intake (HAB-EGG group; n = 24). In the present experiment the NORM-EGG subjects were fed a mixed natural diet providing 21% of energy as polyunsaturated and 11% as saturated fat (P/S2 ratio, 1.9) for 3 weeks, and one providing 5% of energy as polyunsaturated fat and 23% as saturated fat (P/S ratio, 0.2) for the next 3 weeks. The HAB-EGG group was fed the same diets in reverse order. The serum cholesterol concentrations were higher on the low P/S diet than on the high P/S diet (on average 23% in normal subjects and 16% in habitual egg eaters). The correlation coefficient between each subject's serum cholesterol response to fatty acids and his or her average response to dietary cholesterol in the dietary cholesterol experiments was 0.62 for the normal subjects (P less than 0.01) and 0.15 for the HAB-EGG group. We conclude that modest differences in responsiveness of serum cholesterol to dietary saturated fat do exist in humans, and that, in people of normal cholesterol intake, responsiveness to dietary cholesterol and to saturated fat tend to go together.


[Clinical effect of ligustrazine in patients with benign paroxysmal positional vertigo].
The therapeutic effect of Ligustrazine was studied in patients with benign paroxysmal positional vertigo (BPPV). 11 cases were given Ligustrazine 100 mg daily (iv. or im.), another 11 cases were given Valium and Diphenidol as the control group. The results were as follows: In Ligustrazine group, the average curative time was 37 days. In the control group, the average curative time was 72 days. This result suggests that Ligustrazine is a useful drug in the treatment of BPPV. It is believed that the cause of BPPV is due to the occlusion of the anterior vestibular artery. Ligustrazine has the effect of improving microcirculation of the cochlea.


Effect of deuterium irradiation on graphite boronized in the NSTX-U tokamak.
Boronization has been used in the National Spherical Torus-Upgrade (NSTX-U) as first wall conditioning technique. The technique decreased the oxygen impurities in the plasma and the O% on the Plasma Facing Components (PFC) as measured with an in-vacuo probe. Samples were extracted from tiles removed from the tokamak for post-mortem and controlled studies. Ex-vessel low energy and fluence D2+ and Ar+ irradiations were characterized in-situ to elucidate surface evolution of a cored graphite sample with an intrinsic concentration of boron from a tokamak environment. In addition, quadrupole mass spectrometer measurements of emitted D-containing species during irradiation, indicate potential retention of D by the boronized graphite interface and correlated back to the surface chemistry evolution. Classical Molecular Dynamics (CMD) simulations were used to investigate the chemistry of the B-C-O-D system. The results suggest that boron coatings retain oxygen by forming oxidized boron states in the presence of deuterium plasmas and corroborate empirical findings. A four times increase in the O% of the boron coatings was observed following in-situ deuterium exposures, in contrast with a reduction of equal magnitude observed after Ar irradiations. These results illustrate the complex chemistry driven by energetic ions at the edge of tokamaks plasmas on the PFCs.


Primary Stability of Cylindrical and Conical Dental Implants in Relation to Insertion Torque-A Comparative Ex Vivo Evaluation.
The aim of this ex vivo study was to investigate the influence of different insertion torques on primary stability of a conical and a cylindrical implant system. Thirty-two dental implants (Astra Tech OsseoSpeed 5.0 S × 11 mm cylindrical [n = 16] and 5.0 × 11 mm conical [n = 16]) were inserted with 20, 30, 40, and 45 N·cm into fresh porcine bone of mixed trabecular-cortical quality. Before insertion, bone quality was assessed via cone beam tomography. After insertion, resonance frequency analysis was reported using the implant stability quotient (ISQ). Implant insertion depths were evaluated, and the implants were pushed out of the bone by force (measured in N). All experiments were done with n = 4 per group. The highest ISQ (mean 78.25 ± 2.9) and pushout values (mean 675 N ± 5.8) were measured for the cylindrical implant after insertion using 30 N·cm. The conical implant showed the highest primary stability by means of ISQ (mean 76.25 ± 2.2) and pushout force (mean 502.5 N ± 9.6) after an insertion torque of 40 N·cm. If more insertion force was used, primary stability was reduced in all cases. The data indicate that different forms of an implant system need different insertion torques to obtain an optimal primary stability. These results have to be verified clinically.


Interaction of excitation and inhibition in processing of pure tone and amplitude-modulated stimuli in the medial superior olive of the mustached bat.
1. In mammals with good low-frequency hearing, the medial superior olive (MSO) processes interaural time or phase differences that are important cues for sound localization. Its cells receive excitatory projections from both cochlear nuclei and are thought to function as coincidence detectors. The response patterns of MSO neurons in most mammals are predominantly sustained. In contrast, the MSO in the mustached bat is a monaural nucleus containing neurons with phasic discharge patterns. These neurons receive projections from the contralateral anteroventral cochlear nucleus (AVCN) and the ipsilateral medial nucleus of the trapezoid body (MNTB). 2. To further investigate the role of the MSO in the bat, the responses of 252 single units in the MSO to pure tones and sinusoidal amplitude-modulated (SAM) stimuli were recorded. The results confirmed that the MSO in the mustached bat is tonotopically organized, with low frequencies in the dorsal part and high frequencies in the ventral part. The 61-kHz region is overrepresented. Most neurons tested (88%) were monaural and discharged only in response to contralateral stimuli. Their response could not be influenced by stimulation of the ipsilateral ear. 3. Only 11% of all MSO neurons were spontaneously active. In these neurons the spontaneous discharge rate was suppressed during the stimulus presentation. 4. The majority of cells (85%) responded with a phasic discharge pattern. About one-half (51%) responded with a level-independent phasic ON response. Other phasic response patterns included phasic OFF or phasic ON-OFF, depending on the stimulus frequency. Neurons with ON-OFF discharge patterns were most common in the 61-kHz region and absent in the high-frequency region. 5. Double tone experiments showed that at short intertone intervals the ON response to the second stimulus or the OFF response to the first stimulus was inhibited. 6. In neuropharmacological experiments, glycine applied to MSO neurons (n = 71) inhibited any tone-evoked response. In the presence of the glycine antagonist strychnine the response patterns changed from phasic to sustained (n = 35) and the neurons responded to both tones presented in double tone experiments independent of the intertone interval (n = 5). The effects of strychnine were reversible. 7. Twenty of 21 neurons tested with sinusoidally amplitude-modulated (SAM) signals exhibited low-pass or band-pass filter characteristics. Tests with SAM signals also revealed a weak temporal summation of inhibition in 13 of the 21 cells tested.(ABSTRACT TRUNCATED AT 400 WORDS)


Sox9 and programming of liver and pancreatic progenitors.
Recent advances in developmental biology have greatly expanded our understanding of progenitor cell programming and the fundamental roles that Sox9 plays in liver and pancreas organogenesis. In the last 2 years, several studies have dissected the behavior of the Sox9+ duct cells in adult organs, but conflicting results have left unanswered the long-standing question of whether physiologically functioning progenitors exist in adult liver and pancreas. On the other hand, increasing evidence suggests that duct cells function as progenitors in the tissue restoration process after injury, during which embryonic programs are sometimes reactivated. This article discusses the role of Sox9 in programming liver and pancreatic progenitors as well as controversies in the field.


Synthesis of a family of amphiphilic glycopolymers via controlled ring-opening polymerization of functionalized cyclic carbonates and their application in drug delivery.
Polymers bearing pendant carbohydrates have a variety of biomedical applications especially in the area of targeted drug delivery. Here we report the synthesis of a family of amphiphilic block glycopolymers containing d glucose, d galactose and d mannose via metal-free organocatalyzed ring-opening polymerization of functional cyclic carbonates generating narrowly dispersed products of controlled molecular weight and end-group fidelity, and their application in drug delivery. These glycopolymers self-assemble into micelles having a high density of sugar molecules in the shell, a size less than 100 nm with narrow size distribution even after drug loading, and little cytotoxicity, which are important for drug delivery. Using galactose-containing micelles as an example, we demonstrate their strong targeting ability towards ASGP-R positive HepG2 liver cancer cells in comparison with ASGP-R negative HEK293 cells although the galactose is attached to the carbonate monomer at 6-position. The enhanced uptake of DOX-loaded galactose-containing micelles by HepG2 cells significantly increases cytotoxicity of DOX as compared to HEK293. This new family of amphiphilic block glycopolymers has great potential as carriers for targeted drug delivery.


Zebrafish smarcc1a mutants reveal requirements for BAF chromatin remodeling complexes in distinguishing the atrioventricular canal from the cardiac chambers.
Essential patterning processes transform the heart tube into a compartmentalized organ with distinct chambers separated by an atrioventricular canal (AVC). This transition involves the refinement of expression of genes that are first found broadly throughout the heart tube and then become restricted to the AVC. Despite the importance of cardiac patterning, we do not fully understand the mechanisms that limit gene expression to the AVC. We show that the zebrafish gene smarcc1a, encoding a BAF chromatin remodeling complex subunit homologous to mammalian BAF155, is critical for cardiac patterning. In smarcc1a mutants, myocardial differentiation and heart tube assembly appear to proceed normally. Subsequently, the smarcc1a mutant heart fails to exhibit refinement of gene expression patterns to the AVC, and the persistence of broad gene expression is accompanied by failure of chamber expansion. In addition to their cardiac defects, smarcc1a mutants lack pectoral fins, indicating similarity to tbx5a mutants. However, comparison of smarcc1a and tbx5a mutants suggests that perturbation of tbx5a function is not sufficient to cause the smarcc1a mutant phenotype. Our data indicate an important role for Smarcc1a-containing chromatin remodeling complexes in regulating the changes in gene expression and morphology that distinguish the AVC from the cardiac chambers.


[Elongation of mouse spinal cord axons in isogenic grafts of the sciatic nerve, skeletal muscle and submaxillary gland].
Isografts of sciatic nerve, skeletal muscle, submaxillary gland and, as control experiments, of optice nerve, were transplanted into the non transected spinal cord of young albino mice, through a punctiform pial aperture. Under these conditions, local cellular reactions were reduced and the sensori motor behavior of the operated animals remained apparently undisturbed throughout the experimental period. Within a few days, axonal sprouts issuing mainly from the terminal clubs of intraspinal nerve fibres severed by the grafting procedure were seen elongating and growing into--and presumably throughout--the nervous as well as the muscular and glandular transplants. The Schwann cells of these grafts, either sedentary or migrating towards the cord and intermingling with host reactive glial cells, appeared to guide the growth of the axonal sprouts they ensheathed (from day 3 to day 10) and generally myelinated (as early as day 6). Optic nerve transplants, lacking Schwann cells, were never reinnervated. Furthermore, in control microinjuries without grafting, limited growth of axonal sprouts was observed only when a few host Schwann cells were present. Mouse spinal neurons, therefore, demonstrate a marked capacity for regrowth when minimal damage to the spinal cord is associated with an adequate supply of Schwann cells. In contrast, host as well as transplanted glial cells, were unable, at least when they were not associated with Schwannian elements, to promote regenerative expression of these central neurons.


Poliovirus antigenic hybrids simultaneously expressing antigenic determinants from all three serotypes.
We have constructed six hybrid polioviruses (PVs) modified to express PV type 2 and type 3 antigenic determinants on a PV type 1 (Mahoney) capsid. The hybrids were modified in neutralizing antigenic site (NAg) I and/or NAgII. They were viable, but impaired for growth in comparison to PV1 (Mahoney). Some hybrids modified to express type 2 and type 3 NAgI determinants simultaneously displayed some type 2 but no type 3 antigenicity (in addition to type 1 antigenicity associated with other antigenic sites). Hybrids modified to express a type 2 NAgI determinant and a type 3 NAgII determinant, or vice versa, displayed antigenic characteristics of all three serotypes, although expression of the modified NAgII determinant was weak. We conclude that it is possible to construct a viable hybrid PV simultaneously modified in NAgI and NAgII which expresses antigenic determinants of all three serotypes.


Structure of human Fe-S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP-ISD11 interactions.
In eukaryotes, sulfur is mobilized for incorporation into multiple biosynthetic pathways by a cysteine desulfurase complex that consists of a catalytic subunit (NFS1), LYR protein (ISD11), and acyl carrier protein (ACP). This NFS1-ISD11-ACP (SDA) complex forms the core of the iron-sulfur (Fe-S) assembly complex and associates with assembly proteins ISCU2, frataxin (FXN), and ferredoxin to synthesize Fe-S clusters. Here we present crystallographic and electron microscopic structures of the SDA complex coupled to enzyme kinetic and cell-based studies to provide structure-function properties of a mitochondrial cysteine desulfurase. Unlike prokaryotic cysteine desulfurases, the SDA structure adopts an unexpected architecture in which a pair of ISD11 subunits form the dimeric core of the SDA complex, which clarifies the critical role of ISD11 in eukaryotic assemblies. The different quaternary structure results in an incompletely formed substrate channel and solvent-exposed pyridoxal 5'-phosphate cofactor and provides a rationale for the allosteric activator function of FXN in eukaryotic systems. The structure also reveals the 4'-phosphopantetheine-conjugated acyl-group of ACP occupies the hydrophobic core of ISD11, explaining the basis of ACP stabilization. The unexpected architecture for the SDA complex provides a framework for understanding interactions with acceptor proteins for sulfur-containing biosynthetic pathways, elucidating mechanistic details of eukaryotic Fe-S cluster biosynthesis, and clarifying how defects in Fe-S cluster assembly lead to diseases such as Friedreich's ataxia. Moreover, our results support a lock-and-key model in which LYR proteins associate with acyl-ACP as a mechanism for fatty acid biosynthesis to coordinate the expression, Fe-S cofactor maturation, and activity of the respiratory complexes.


Clinical presentation and urachal remnant pathology: implications for treatment.
Symptomatic pediatric urachal remnants are frequently excised but to our knowledge it is unknown whether incidentally identified urachal remnants require removal. Urachal remnant excision in childhood is advocated to avoid future malignancy. Urachal anomalies that contain fibrostromal tissue without epithelium may have lower malignant potential and not require excision. In contrast, lesions with epithelium may have increased potential to undergo malignant transformation. We examined whether incidentally identified urachal remnants would be less likely to contain epithelial elements and not require removal. At our institution 29 patients underwent surgical excision of a urachal anomaly from 1999 to 2008. We retrospectively investigated the presentation mode, radiographic findings, associated genitourinary abnormalities, operative approach, tissue pathology, complications and followup in each patient. The male-to-female ratio was 1.2:1. Patient presentation was incidental (5) or symptomatic (24). Symptomatic presentations included umbilical discharge without omphalitis in 13 cases, umbilical discharge with omphalitis in 7, omphalitis without umbilical discharge in 3 and urinary tract infection in 1. The epithelial types identified were transitional, gastrointestinal, squamous, metaplastic and mixed. Epithelium was present on pathological analysis in 3 of 5 patients who presented incidentally and in 17 of 24 who presented symptomatically. Statistical analysis showed no association between presentation mode and pathology (p = 0.63). Five patients 4 weeks to 2.5 months old had vesicoureteral reflux on voiding cystourethrogram for urachal remnant evaluation. Analysis of 29 patients with urachal anomalies showed no association between incidental presentation and fibrostromal pathology. Patients presenting without symptoms were as likely to have epithelial elements in the urachal remnant as those presenting with symptoms. We could not define treatment recommendations for incidentally identified urachal remnants based on predicting the histopathological composition.


Surveillance for seasonal influenza virus prevalence in hospitalized children with lower respiratory tract infection in Guangzhou, China during the post-pandemic era.
Influenza A(H1N1)pdm09, A(H3N2) and B viruses have co-circulated in the human population since the swine-origin human H1N1 pandemic in 2009. While infections of these subtypes generally cause mild illnesses, lower respiratory tract infection (LRTI) occurs in a portion of children and required hospitalization. The aim of our study was to estimate the prevalence of these three subtypes and compare the clinical manifestations in hospitalized children with LRTI in Guangzhou, China during the post-pandemic period. Children hospitalized with LRTI from January 2010 to December 2012 were tested for influenza A/B virus infection from their throat swab specimens using real-time PCR and the clinical features of the positive cases were analyzed. Of 3637 hospitalized children, 216 (5.9%) were identified as influenza A or B positive. Infection of influenza virus peaked around March in Guangzhou each year from 2010 to 2012, and there were distinct epidemics of each subtype. Influenza A(H3N2) infection was more frequently detected than A(H1N1)pdm09 and B, overall. The mean age of children with influenza A virus (H1N1/H3N2) infection was younger than those with influenza B (34.4 months/32.5 months versus 45 months old; p<0.005). Co-infections of influenza A/ B with mycoplasma pneumoniae were found in 44/216 (20.3%) children. This study contributes the understanding to the prevalence of seasonal influenza viruses in hospitalized children with LRTI in Guangzhou, China during the post pandemic period. High rate of mycoplasma pneumoniae co-infection with influenza viruses might contribute to severe disease in the hospitalized children.


An immunohistochemical and ultrastructural study of an unusual case of multiple non-X histiocytoma.
An immunohistochemical and ultrastructural study of an atypical case of multiple non-X histiocytoma was done. There was involvement of the skin, lungs, and liver in a 3-month-old male infant. Microscopic examination of the cutaneous tumors revealed a dense infiltration of cells with polymorphous large nuclei and abundant eosinophilic cytoplasm in the entire dermis. Both immunohistochemical and electron microscopic studies suggested that the tumors were non-X histiocytomas. The patient's condition deteriorated with dyspnea due to rapid enlargement of tumor masses in the liver and lungs. However, at 5 months of age, the cutaneous nodules and pulmonary and hepatic lesions showed a tendency to involute. Furthermore, at 12 months of age, they were no longer detectable. The patient at 24 months of age was well with normal development. To date, no recurrence of the disease has been observed.


Mycosis fungoides. Electron beam therapy.
The most effective treatment of late mycosis fungoides is total skin electron beam therapy. The beam at the Hammersmith Hospital in London has been adapted to treat these patients. Patients with advanced disease who have failed more conservative methods of treatment are irradiated. The electron beam is modified by the use of carbon and copper scatterers to produce an 80 percent depth dose at 5.5, 8 and 11.5 millimeters below the skin surface. The dose achieved in most patients is between 1500 rads and 2600 rads given in 10 to 13 treatments over 5-7 weeks. Recently the higher dose range has been employed and lithium flouride studies have shown that giving these doses from each of 4 fields, the dose achieved on the skin is approximately twice the given dose. The management of patients and the effects of treatment are discussed.


Functional mapping of genotype-environment interactions for soybean growth by a semiparametric approach.
Functional mapping is a powerful approach for mapping quantitative trait loci (QTLs) that control biological processes. Functional mapping incorporates mathematical aspects of growth and development into a general QTL mapping framework and has been recently integrated with composite interval mapping to build up a so-called composite functional mapping model, aimed to separate multiple linked QTLs on the same chromosomal region. This article reports the principle of using composite functional mapping to estimate the effects of QTL-environment interactions on growth trajectories by parametrically modeling the tested QTL in a marker interval and nonparametrically modeling the markers outside the interval as co-factors. With this new model, we can characterize the dynamic patterns of the genetic effects of QTLs governing growth trajectories, estimate the global effects of the underlying QTLs during the course of growth and development, and test the differentiation in the shapes of QTL genotype-specific growth curves between different environments. By analyzing a real example from a soybean genome project, our model detects several QTLs that cause significant genotype-environment interactions for plant height growth processes. The model provides a basis for deciphering the genetic architecture of trait expression adjusted to different biotic and abiotic environments for any organism.


Constraints on transport and kinetics in hydrothermal systems from zoned garnet crystals.
Zonation of oxygen isotope ratios, fluorine, and rare earth element abundances across garnet crystals from the Permian Oslo Rift reflect temporal variation of the hydrothermal system in which the garnets grew. A sharp rimward decrease in the (18)O/(16)O ratio (of 5 per mil) across the interface between aluminum-rich garnet cores and iron-rich rims indicates influx of meteoric fluids to a system initially dominated by magmatic fluids. This influx may record the transition from ductile to brittle deformation of the hydrothermally altered rocks. In contrast, fluorine and light rare earth element concentrations increase at the core-rim interface. These data may reflect enhanced advective transport and notable kinetic control on trace element uptake by the garnets during brittle deformation.


Intellectual Disability and Behavioral Deficits Linked to CYFIP1 Missense Variants Disrupting Actin Polymerization.
15q11.2 deletions and duplications have been linked to autism spectrum disorder, schizophrenia, and intellectual disability. Recent evidence suggests that dysfunctional CYFIP1 (cytoplasmic FMR1 interacting protein 1) contributes to the clinical phenotypes observed in individuals with 15q11.2 deletion/duplication syndrome. CYFIP1 plays crucial roles in neuronal development and brain connectivity, promoting actin polymerization and regulating local protein synthesis. However, information about the impact of single nucleotide variants in CYFIP1 on neurodevelopmental disorders is limited. Here, we report a family with 2 probands exhibiting intellectual disability, autism spectrum disorder, spastic tetraparesis, and brain morphology defects and who carry biallelic missense point mutations in the CYFIP1 gene. We used skin fibroblasts from one of the probands, the parents, and typically developing individuals to investigate the effect of the variants on the functionality of CYFIP1. In addition, we generated Drosophila knockin mutants to address the effect of the variants in vivo and gain insight into the molecular mechanism that underlies the clinical phenotype. Our study revealed that the 2 missense variants are in protein domains responsible for maintaining the interaction within the wave regulatory complex. Molecular and cellular analyses in skin fibroblasts from one proband showed deficits in actin polymerization. The fly model for these mutations exhibited abnormal brain morphology and F-actin loss and recapitulated the core behavioral symptoms, such as deficits in social interaction and motor coordination. Our findings suggest that the 2 CYFIP1 variants contribute to the clinical phenotype in the probands that reflects deficits in actin-mediated brain development processes.


Critique of interpretation of high levels of heteroplasmy in the human mitochondrial DNA hypervariable region I from hair.
The phenomenon known as heteroplasmy can be operationally observed in some human mitochondrial DNA (mtDNA) samples. Typically, heteroplasmy manifests itself in an individual presenting two mtDNA species that differ at a single base. Heteroplasmy at two, and even possibly three sites, also may occur, but at very low rates. A recent report (Grzybowski, 2000, see ref. [13]) suggests that much higher levels of mtDNA (point substitution) heteroplasmy can occur in hair. This observation is contrary to the experience of the forensic mtDNA community. There are several explanations for the unusual findings of high levels of heteroplasmy. First, the template quantities of DNA are approximately three orders of magnitude higher than required for mtDNA sequencing, and an excessive number of amplification cycles were used. Thus, the protocol used did not follow routine practices by the forensic community. Second, there are misidentifications and tabular errors that call into question the reliability of the findings. Third, by comparing the natural human mtDNA variation with a reference sample population with that observed in the heteroplasmy in hair study, the data are inconsistent with population genetic expectations. The observation of high levels of heteroplasmy may be due to contamination of the samples and/or possibly the amplification of nuclear pseudogenes. The results observed in the heteroplasmy in hair study do not apply to other methods of mtDNA analysis and cannot be used to question the reliability of the current forensic mtDNA practices.


Analysis of factors that influence the maximum number of repetitions in two upper-body resistance exercises: curl biceps and bench press.
The purpose of this study was to analyze the influence of exercise type, set configuration, and relative intensity load on relationship between 1 repetition maximum (1RM) and maximum number of repetitions (MNR). Thirteen male subjects, experienced in resistance training, were tested in bench press and biceps curl for 1RM, MNR at 90% of 1RM with cluster set configuration (rest of 30s between repetitions) and MNR at 70% of 1RM with traditional set configuration (no rest between repetitions). A lineal encoder was used for measuring displacement of load. Analysis of variance analysis revealed a significant effect of load (p<0.01) and a tendency in exercise factor (p=0.096), whereas the interaction effect was not significant. MNR at 70% of 1RM was lower for biceps curl (16.31+/-2.59 vs. 8.77+/-3 in bench press and biceps curl, respectively; p<0.05) and at 90% of 1RM (21.85+/-11.06 vs. 18.54+/-12.84 in bench press and biceps curl, respectively; p>0.05). Correlation between 1RM and MNR was significant for medium-intensity in biceps curl (r=-0.574; p<0.05) and between MNR and 1RM/body mass (r=-0.574; p<0.05). Neither 1RM nor 1RM/body mass correlated with velocity along set, so velocity seems to be similar at a same relative intensity for subjects with differences in maximum strength levels. From our results, we suggest the employment of MNR rather than % of 1RM for training monitoring. Furthermore, we suggest the introduction of cluster set configuration for upper-body assessment of MNR and for upper-body muscular endurance training at high-intensity loads, as it seems an efficient approach in looking for sessions with greater training volumes. This could be an interesting approach for such sports as wrestling or weightlifting.


Effect of 10 Minutes of Prewarming and Prewarmed Intravenous Fluid Administration on the Core Temperature of Patients Undergoing Transurethral Surgery under General Anesthesia.
Background: Patients undergoing transurethral urologic procedures using bladder irrigation are at increased risk of perioperative hypothermia. Thirty minutes of prewarming prevents perioperative hypothermia. However, its routine application is impractical. We evaluated the effect of 10 minutes of prewarming combined with the intraoperative administration of warmed intravenous fluid on patients' core temperature. Methods: Fifty patients undergoing transurethral bladder or prostate resection under general anesthesia were included in this study and were randomly allocated to either the control group or the prewarming group. Patients in the prewarming group were warmed for 10 minutes before anesthesia induction with a forced-air warming device and received warmed intravenous fluid during operations. The patients in control group did not receive preoperative forced-air warming and were administered room-temperature fluid. Participants' core body temperature was measured on arrival at the preoperative holding area (T0), on entering the operating room, immediately after anesthesia induction, and in 10-minute intervals from then on until the end of the operation (Tend), on entering PACU, and in 10-minute intervals during the postanesthesia care unit stay. The groups' incidence of intraoperative hypothermia, change in core temperature (T0 - Tend), and postoperative thermal comfort were compared. Results: The incidence of hypothermia was 64% and 29% in the control group and prewarming group, respectively (P = 0.015). Change in core temperature was 0.93 ± 0.3 °C and 0.55 ± 0.4 °C in the control group and prewarming group, respectively (P = 0.0001). Thermal comfort was better in the prewarming group (P = 0.004). Conclusions: Ten minutes of prewarming combined with warmed intravenous fluid significantly decreased the incidence of intraoperative hypothermia and resulted in better thermal comfort in patients undergoing transurethral urologic surgery under general anesthesia.


Sexuality, aging, and dementia.
Sexuality in later life and its relationship to dementia is a neglected topic: greater understanding of the area has the potential to contribute to the quality of life of people with dementia, their family members, and formal carers. We review current knowledge about sexuality, aging, and dementia. We undertook a review of the recent literature to examine of the following areas: what is known about sexuality and aging, and about attitudes to sexuality and aging; what is known about the relevance of sexuality and aging to people living with dementia and their care; and the management of sexual behaviors causing concern to others. Sexual activity decreases in frequency with increasing age but many older people remain sexually active; there is no age limit to sexual responsiveness; and sexuality is becoming more important to successive cohorts of older people, including people living with dementia and gay, lesbian, bisexual, and transgendered elderly people. Attitudes and beliefs toward sexuality and aging are strongly influenced by stereotypes and myths, not only among the general public but also among those working in health and social care. Professional bodies should include sexuality, aging, and dementia in their training curricula. More work is needed on the impact of environmental issues, particularly in group living situations, on older adults' sexuality, and on consent issues. Ethical decision-making frameworks can be useful in practice. Organizations should investigate how to support staff in avoiding a problem-orientated approach and focus on providing holistic person-centered care.


Molecules of natural origin, semi-synthesis and synthesis with anti-inflammatory and anticancer utilities.
The development of new drugs that can be valuable for the evolution of diseases' treatment is a goal for different areas of research, namely natural products chemistry, molecular biology and biochemistry, pharmacology, medicinal chemistry, synthetic organic chemistry and analytical chemistry. Nature is the main source of compounds for pharmaceutical purposes, either by providing the natural organic chemical compounds of interest or as a source of inspiration for the design of new drugs. The known anti-inflammatory and anticancer agents belong to a great diversity of structural skeletons since inflammatory and cancer processes involve many different biological targets. Their origins extend to plants, fungi, bacteria, and marine organisms, besides those produced by semi-synthesis and total synthesis. The tasks of the organic chemist are the screening, the structure assignment, and the semi and total syntheses of active molecules. Herein the screening and assignment of new active structures is addressed, together with other aspects, namely the improvements, both in availability and in effectiveness of action that can be achieved from new derivatives by synthetic or semi-synthetic strategies. Some aspects of drug delivery of anti-inflammatory and anticancer agents are considered. The bibliography presented is far from being exhaustive due to the prodigious number of published works. Instead, the most significant contributions in the scope of this review are described. The active compounds are organised by their biosynthetic origins as terpenoids; macrolides, polyketides and ansamycins; phenolics; alkaloids; peptides; glycoconjugates; other compounds, and food compounds.


Intravitreal bevacizumab combined with plaque brachytherapy reduces melanoma tumor volume and enhances resolution of exudative detachment.
The purpose of this study was to evaluate intravitreal bevacizumab as an adjuvant treatment to plaque brachytherapy in the treatment of choroidal melanoma. This was a retrospective, consecutive study of 124 patients treated from 2007 to 2009 for choroidal melanoma with plaque brachytherapy. Patients were treated with I-125 plaque brachytherapy with 2 mm margins and 85 Gy to the tumor apex. Consecutive patients were injected intravitreally with 2.5 mg/0.1 mL bevacizumab at a site away from the primary tumor and immediately following plaque removal. Choroidal melanomas were observed using indirect ophthalmoscopy, wide-angle photography, and ultrasound. The main outcome measures were tumor volume, resolution of exudative retinal detachment, and visual acuity. One hundred and twenty-four patients met our inclusion criteria and were included in the analysis. The mean patient age was 65.7 years, and the mean apical tumor height was 4.0 ± 2.7 mm and basal diameter was 12.7 ± 3.0 mm. Mean follow-up was 24 months. Prior to treatment, 100% of tumors had exudative retinal detachment, and pretreatment visual acuity was 20/55 (median 20/40). Tumor control was 100%, metastasis was 0% at last follow-up, and 89.8% had complete resolution of exudative retinal detachment, with a mean time to resolution of 3.36 months. At one month, 43% had complete resolution of exudative retinal detachment, which increased to 73% at 4 months. Visual acuity was 20/62 (median 20/40) at 4 months, with stabilization to 20/57 (median 20/40) at 8 months, 20/56 (median 20/30) at 12 months, and 20/68 (median 20/50) at 24 months. Tumor volume following combined therapy was shown to be reduced by 22.2% at 3 months, 28.9% at 6 months, 39.3% at 12 months, and 52.2% at 24 months (all P < 0.001). All patients tolerated the procedure well without systemic side effects. Intravitreal bevacizumab may be used as an adjuvant agent following plaque brachytherapy. Treated choroidal melanomas show reduction in tumor volume as well as resolution of exudative retinal detachments.


Incidence of nonmelanoma skin cancer in New Brunswick, Canada, 1992 to 2001.
Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), collectively referred to as nonmelanoma skin cancer (NMSC), cause significant morbidity and generate a substantial cost to the health care system. Canadian data on the incidence of NMSC are lacking. To study the incidence and characteristics of NMSC in New Brunswick, Canada (population 729,498 people in 2001), by using the Provincial Cancer Registry. Data were obtained from 1992 to 2001 from the New Brunswick Provincial Cancer Registry, to which reporting of all cancers is mandatory. Multiple tumors of a given histologic type are recorded only once in the registry per individual per lifetime. A descriptive analysis of incidence rates of BCC and invasive SCC of the skin was performed in relation to gender, age, and anatomic location. The main outcome measures were the age- and sex-specific incidence rates of BCC and SCC. Age standardization was performed using the Canadian, US, and world standard populations. When adjusted to the world standard population, the age-standardized incidence rates (ASIRs) per 100,000 population for BCC from 1992 through 2001 were 87 for males and 68 for females. For invasive SCC, the ASIRs per 100,000 population were 34 for males and 16 for females. There was an increasing incidence trend for both BCC and invasive SCC over the 10-year study period, with minimal change in the incidence of SCC in women. The overall ratio of BCC to invasive SCC in the population was 2.8 to 1. The approximate lifetime probabilities of developing BCC and invasive SCC were 13% and 5%, respectively. The incidence of NMSC in the province of New Brunswick is similar to that reported from 1973 through 1987 in the province of British Columbia, higher than those reported in most parts of Europe, and lower than all published rates in the United States and Australia. Owing to the inability of the registry to account for tumor multiplicity, the actual annual number of all NMSC lesions in this population is likely much higher.


PRediction of infarct size by enzymatic techniques: modification of a method and clinical application.
In an attempt to develop improved methods of prediction of infarct size by enzymatic methods, Shell's original algorithm has been critically evaluated in an unselected series of patients. Poor performance of the model is partly the result of a systematic source of error associated with its mathematical formulation. A new model devoid of such limitations has therefore been developed. Residual deviations between predicted and observed CK release seem to be related to frequent and unpredictable extensions of infarction which could be verified by independent clinical, electrocardiographic, and enzymatic criteria. The modified model may possibly be applied to the evaluation of agents aimed at limiting the spread of irreversible injury.


Systematic mapping of global research on climate and health: a machine learning review.
The global literature on the links between climate change and human health is large, increasing exponentially, and it is no longer feasible to collate and synthesise using traditional systematic evidence mapping approaches. We aimed to use machine learning methods to systematically synthesise an evidence base on climate change and human health. We used supervised machine learning and other natural language processing methods (topic modelling and geoparsing) to systematically identify and map the scientific literature on climate change and health published between Jan 1, 2013, and April 9, 2020. Only literature indexed in English were included. We searched Web of Science Core Collection, Scopus, and PubMed using title, abstract, and keywords only. We searched for papers including both a health component and an explicit mention of either climate change, climate variability, or climate change-relevant weather phenomena. We classified relevant publications according to the fields of climate research, climate drivers, health impact, date, and geography. We used supervised and unsupervised machine learning to identify and classify relevant articles in the field of climate and health, with outputs including evidence heat maps, geographical maps, and narrative synthesis of trends in climate health-related publications. We included empirical literature of any study design that reported on health pathways associated with climate impacts, mitigation, or adaptation. We predict that there are 15 963 studies in the field of climate and health published between 2013 and 2019. Climate health literature is dominated by impact studies, with mitigation and adaptation responses and their co-benefits and co-risks remaining niche topics. Air quality and heat stress are the most frequently studied exposures, with all-cause mortality and infectious disease incidence being the most frequently studied health outcomes. Seasonality, extreme weather events, heat, and weather variability are the most frequently studied climate-related hazards. We found major gaps in evidence on climate health research for mental health, undernutrition, and maternal and child health. Geographically, the evidence base is dominated by studies from high-income countries and China, with scant evidence from low-income counties, which often suffer most from the health consequences of climate change. Our findings show the importance and feasibility of using automated machine learning to comprehensively map the science on climate change and human health in the age of big literature. These can provide key inputs into global climate and health assessments. The scant evidence on climate change response options is concerning and could significantly hamper the design of evidence-based pathways to reduce the effects on health of climate change. In the post-2015 Paris Agreement era of climate solutions, we believe much more attention should be given to climate adaptation and mitigation options and their effects on human health. Foreign, Commonwealth & Development Office.


Neural correlates of maintenance working memory, as well as relevant structural qualities, are associated with earlier antiretroviral treatment initiation in vertically transmitted HIV.
There is evidence of HIV affecting cognitive functioning across age groups, with adult studies showing related deficits in frontostriatal and hippocampal regional activity. Additionally, delayed initiation of antiretroviral treatment (ART) has been associated with poorer cognitive outcomes in HIV-infected youth. Little is known, however, of the neural correlates underlying such cognitive deficits in youth populations. We investigated maintenance working memory-related brain activity in South African HIV-infected youth and controls, and the effect of ART initiation age on underlying structures. Sixty-four perinatally infected youth (ages 9-12) and 20 controls (ages 9-13) underwent functional magnetic resonance imaging (fMRI) while completing 1-back and 0-back blocks of the N-back task. At an uncorrected p value threshold of 0.001, the HIV-infected group showed decreased activation in the left superior temporal gyrus, pre- and postcentral gyri, insula, and putamen as well as bilateral hippocampus, and mid cingulum. The HIV patients with delayed ART initiation showed less activation during processing conditions in the mid cingulum; left inferior parietal gyrus; and right inferior frontal, bilateral thalamic, and superior temporal regions. When these regions were tested for structural differences, the mid cingulum and right inferior frontal gyrus, insula, and thalamus were found to have less cortical thickness, surface area, or volume in the group with delayed ART initiation. Regional differences between HIV-infected youth and controls noted in the N-back task are consistent with impairments in structures involved in maintenance working memory. These data support earlier ART initiation in perinatally infected individuals.


Co-release of substance P and neurokinin A from the Atlantic cod stomach.
The function of tachykinins in the control of gastric motility in the cod, Gadus morhua, was studied using native cod substance P ([Lys1, Arg3, Ile3]SP) and cod neurokinin A ([Ile3, Asn4]NKA). Both cod SP and NKA produced contractions of the vascularly perfused cod stomach, SP being almost 6 times more potent than NKA (pD2-values 7.05 +/- 0.06 and 6.28 +/- 0.09, respectively). The release of tachykinins from the cod stomach was measured in radioimmunoassay, using specific antibodies for the two cod tachykinins. Stimulation of the stomach motility by electrical stimulation of the vagus nerve or infusion of acetylcholine increased the amounts of SP and NKA released into the vascular perfusate. The results suggest that both tachykinins are involved in the excitatory response of the cod stomach produced by vagal and cholinergic stimulation.


[Effects of adaptation to periodic hypoxia on bioelectric activity of cardiomyocytes of isolated heart in ischemia and reperfusion].
Experiments on isolated Wistar rat heart perfused according to Langendorff showed that preliminary adaptation of rats to intermittent hypobaric hypoxia limited the fall of values of the resting potential and the amplitude and duration of action potential characteristic for ischemia. Under similar conditions, adaptation considerably reduced the increased time of impulse conduction along the myocardium. In reperfusion, the parameters enumerated restored much more efficiently in hearts from adapted animals than in controls. The role of these changes in the antiarrhythmic effect of adaptation to intermittent hypoxia is under discussion.


Preferences for berries among consumers in southern Chile: blueberries are produced but are they consumed?
Blueberry plantations in Chile are oriented exclusively towards exports to northern hemisphere countries; however, this fruit has recently been introduced into the domestic market due to the increased supply and a fall in export market prices. Based on the previously mentioned, the objectives of the present study were to evaluate consumer preferences for 3 species of berries (blueberries, strawberries, and raspberries), sold loose (unpackaged) as opposed to packaged and branded, at different prices, in one of the principal blueberry producing areas of Chile; and to distinguish consumer segments by their preferences. To do this a survey was applied to 400 people in the Araucanía Region of southern Chile, who were responsible for purchasing fruit for their households. Conjoint analysis showed a preference for raspberries and strawberries over blueberries, packaged and branded, at the lowest price. Total of 2 principal segments were distinguished by cluster analysis: "price sensitive" (42.7%), who preferred strawberries, and "sensitive to species of berry" (47.5%), who preferred raspberries and strawberries. The segments presented different profiles in their demographic make-up and fruit consumption behavior. Strategies are discussed that might reverse the low acceptance of blueberries in the Chilean domestic market. This study presents information on the introduction of new fresh foods into the market.


Clinical outcomes of definitive intensity-modulated radiation therapy with fluorodeoxyglucose-positron emission tomography simulation in patients with locally advanced cervical cancer.
This study aimed to evaluate the toxicity and clinical outcomes for cervical cancer patients treated definitively with intensity-modulated radiation therapy (IMRT) compared with non-IMRT treatment. This prospective cohort study included 452 patients with newly diagnosed cervical cancer treated with curative intent (135 IMRT and 317 non-IMRT). Treatment involved external irradiation and brachytherapy, and 85% of patients received concurrent chemotherapy. All IMRT patients underwent an F-18 fluorodeoxyglucose positron emission tomography (FDG-PET/CT) simulation. A 3-month post-therapy PET was obtained to evaluate treatment response. Toxicity was scored by the Common Terminology Criteria for Adverse Events Version 3.0. The IMRT and non-IMRT groups had similar stage distribution and histology. For all patients, the post-therapy FDG-PET response correlated with overall recurrence risk (p < 0.0001) and cause-specific survival (p < 0.0001). Post-treatment FDG-PET findings were not significantly different between the IMRT and non-IMRT patients (p = 0.9774). The mean follow-up for all patients alive at the time of last follow-up was 52 months (72 months non-IMRT, 22 months IMRT). At last follow-up, 178 patients (39 IMRT, 139 non-IMRT) had developed a recurrence. The difference in recurrence-free survival between the two groups did not reach statistical significance (p = 0.0738), although the IMRT group showed better overall and cause-specific survivals (p < 0.0001). Of the patients, 62 patients (8 IMRT and 54 non-IMRT) developed Grade 3 or greater bowel or bladder complications, and by cumulative hazard function analysis the risk was significantly less for patients treated with IMRT (p = 0.0351). Cervical cancer patients treated with FDG-PET/CT-guided IMRT have improved survival and less treatment-related toxicity compared with patients treated with non-IMRT radiotherapy.


Top-ranking drugs out of 3312 drug-induced liver injury cases evaluated by the Roussel Uclaf Causality Assessment Method.
A list presenting a valid ranking of drugs most commonly implicated is hardly to be found. Areas covered: Published cases of drug-induced liver injury (DILI) with verified causality using RUCAM (Roussel Uclaf Causality Assessment Method) were used for a ranking of drugs most commonly implicated in causing DILI. Expert opinion: RUCAM-based DILI cases were retrieved from 15 reports published by six international databases of DILI registries and three large medical centers, which provided 3312 cases. Overall 48 drugs with the highest number of DILI cases were listed. Among the top 10 ranking drugs implicated in causing DILI were, in decreasing order: amoxicillin-clavulanate, flucloxacilllin, atorvastatin, disulfiram, diclofenac, simvastatin, carbamazepine, ibuprofen, erythromycin, and anabolic steroids as bodybuilding agents. For these 10 drugs, respective DILI case numbers were highest for Amoxicillin-clavulanate (n=333) and lowest for anabolic steroids (n=26). The author classifies the databases of national DILI registries and large medical centers as best sources of drugs implicated in DILI. Presently discouraged is the use of the LiverTox website because many cases were derived from published cases of poor quality and could previously not be classified as DILI, calling for the inclusion of DILI cases with established causality by the updated RUCAM.


Fano profiles induced by near-field coupling in heterogeneous dimers of gold and silver nanoparticles.
The near-field coupling between a gold and a silver spherical nanoparticle is investigated theoretically. Fano profiles are observed in the absorption cross section of the gold nanoparticle due to the coupling between the spectrally localized surface plasmon resonance of the silver nanoparticle and the continuum of interband transitions of the gold one. The effect of dimer internal characteristics (particle sizes and distance), surrounding medium (through the refractive index), and external excitation (polarization and propagation directions) are addressed. In particular, it is shown that the near-field coupling can be tuned from the weak to the strong regime by rotating the polarization direction, and that the Fano profiles are sensitive to the shadowing effect even for small particle sizes.


Utility of Ovarian Reserve Screening with Anti-Müllerian Hormone for Reproductive Age Women Deferring Pregnancy.
Ovarian reserve (OR) testing with serum anti-Müllerian hormone (AMH) can provide information about a woman's fertility potential. The aim of this study was to assess interest and knowledge about OR testing and investigate the utility of measuring AMH in women of reproductive age deferring pregnancy. Women ages 27-37 years currently delaying childbearing were invited to take a survey regarding attitudes and knowledge about OR testing before and after an AMH measurement with explanation of their results. Of 121 women who took the pre-test survey, 96% believed OR testing was beneficial. The median AMH of the 97 women who underwent testing was 3.3 ng/mL (IQR 1.9-5.4 ng/mL). Nineteen percent of women had AMH <10th percentile for age and 3% had an undetectable AMH. Although 83% of these women were using hormonal contraception, none had known risk factors for diminished ovarian reserve. Seventy-eight percent of women with low AMH levels for age planned to seek fertility preservation or pregnancy, while those with AMH levels within established age normograms were reassured. On the post-test survey, 100% reported benefit in knowing their AMH level. Follow-up testing, 6-8 months after the initial measurement, showed stable AMH levels for most participants. Women are interested in OR testing. Most women will be reassured by knowing their AMH level, whereas those with a lower AMH can be counseled on fertility preservation options or may attempt pregnancy earlier.


Sustainable and eco-friendly dyeing of traditional grass cloth with a reactive dye in palm oil medium.
Traditional grass cloth has been used in China for a long time for the manufacturing of various household furnishing textiles and ladieswear. However, traditionally the grass cloth is dyed with reactive dyes in an aqueous medium, but the dyeing process is not sustainable because of high energy and water usage and the production of coloured effluent. In this work, the possibility of palm oil/water dual-phase dyeing of traditional grass cloth with a reactive dye, C.I. Reactive Blue 194 (Reactive Blue 194), was explored. The grass cloth soaked in an alkaline solution with 80-140% pick-up was dyed in a palm oil dyebath containing dye powder dispersed in a palm oil medium. The initial study confirmed that the pre-treatment of the fabric with an alkaline solution with 140% pick-up was beneficial for the uniform distribution of the dye in the fibres. The dyeing process parameters (e.g., fixation temperature, solution pH, and fixation time) for the grass cloth dyeing with the Reactive Blue 194 were optimised by using the Taguchi method. The pH of the alkali pre-treatment solution was found to be the most influential factor, as confirmed by the analysis of variance in terms of the percentage of contribution (94.41%), which was statistically significant (P < 0.05). The confirmation tests were carried out under optimal settings, and a higher K/S (24.06) was found compared with the initial condition (21.51). X-ray diffraction analysis indicated that the dyeing process did not affect the crystallinity of the grass cloth fibres. Furthermore, the recovery of palm oil from the spent dyebath was around 99%, and up to five times recycling and reuse of palm oil were studied for the dyeing of grass cloth. The colour strength of the grass cloths dyed in the palm oil recycled up to five times was similar to the cloth dyed in fresh palm oil. The results show that palm oil can be used as a dyeing medium for the sustainable dyeing of grass cloth with effluent reduction, which can be extended to the dyeing of other textile fibres.


Cumulative strain-based metrics for predicting subconcussive head impact exposure-related imaging changes in a cohort of American youth football players.
Youth football athletes are exposed to repetitive subconcussive head impacts during normal participation in the sport, and there is increasing concern about the long-term effects of these impacts. The objective of the current study was to determine if strain-based cumulative exposure measures are superior to kinematic-based exposure measures for predicting imaging changes in the brain. This prospective, longitudinal cohort study was conducted from 2012 to 2017 and assessed youth, male football athletes. Kinematic data were collected at all practices and games from enrolled athletes participating in local youth football organizations in Winston-Salem, North Carolina, and were used to calculate multiple risk-weighted cumulative exposure (RWE) kinematic metrics and 36 strain-based exposure metrics. Pre- and postseason imaging was performed at Wake Forest School of Medicine, and diffusion tensor imaging (DTI) measures, including fractional anisotropy (FA), and its components (CL, CP, and CS), and mean diffusivity (MD), were investigated. Included participants were youth football players ranging in age from 9 to 13 years. Exclusion criteria included any history of previous neurological illness, psychiatric illness, brain tumor, concussion within the past 6 months, and/or contraindication to MRI. A total of 95 male athletes (mean age 11.9 years [SD 1.0 years]) participated between 2012 and 2017, with some participating for multiple seasons, resulting in 116 unique athlete-seasons. Regression analysis revealed statistically significant linear relationships between the FA, linear coefficient (CL), and spherical coefficient (CS) and all strain exposure measures, and well as the planar coefficient (CP) and 8 strain measures. For the kinematic exposure measures, there were statistically significant relationships between FA and RWE linear (RWEL) and RWE combined probability (RWECP) as well as CS and RWEL. According to area under the receiver operating characteristic (ROC) curve (AUC) analysis, the best-performing metrics were all strain measures, and included metrics based on tensile, compressive, and shear strain. Using ROC curves and AUC analysis, all exposure metrics were ranked in order of performance, and the results demonstrated that all the strain-based metrics performed better than any of the kinematic metrics, indicating that strain-based metrics are better discriminators of imaging changes than kinematic-based measures. Studies relating the biomechanics of head impacts with brain imaging and cognitive function may allow equipment designers, care providers, and organizations to prevent, identify, and treat injuries in order to make football a safer activity.


Reactive, Proactive, and Inductive Agents: An Evolutionary Path for Biological and Artificial Spiking Networks.
Complex environments provide structured yet variable sensory inputs. To best exploit information from these environments, organisms must evolve the ability to anticipate consequences of new stimuli, and act on these predictions. We propose an evolutionary path for neural networks, leading an organism from reactive behavior to simple proactive behavior and from simple proactive behavior to induction-based behavior. Based on earlier in-vitro and in-silico experiments, we define the conditions necessary in a network with spike-timing dependent plasticity for the organism to go from reactive to proactive behavior. Our results support the existence of specific evolutionary steps and four conditions necessary for embodied neural networks to evolve predictive and inductive abilities from an initial reactive strategy.


Relationship between cancer and oral pemphigoid patients with antibodies to alpha6-integrin.
Mucous membrane pemphigoid is an autoimmune mucocutaneous blistering disease. A subset, known as anti-epiligrin cicatricial pemphigoid is associated with a high risk for malignancy. Oral pemphigoid (OP) is limited to the oral cavity. The purpose of this study was to determine the association between malignancy and patients with OP with antibodies to alpha6-integrin subunit. We determined the incidence of cancer in 72 patients with OP and compared it to the expected incidence using age and sex-specific rates of malignancy in the National Cancer Institute's Surveillance, Epidemiology, and End Results (NCI SEER) Registry. During a mean observation period of 9.1 years (range: 2.8-40), for 70, three OP patients developed malignancies. The expected number of cancers based on the NCI SEER Registry was 8.83. The relative risk for cancer in OP patients, with autoantibodies to alpha6-integrin, was 0.34 (95% CI, 0.07-0.99, P < 0.05). It appears that patients with OP, with antibodies to alpha6, may have a possible reduced relative risk for developing cancer.


Rocky Mountain Spotted Fever Associated With Cardiac Arrhythmias.
Rickettsial infection, known as Rocky Mountain spotted fever, is a challenging diagnosis as early clinical manifestations are difficult to distinguish from viral illnesses. Symptoms at presentation depend on the organs involved, ranging from a skin rash as evidence of vascular damage to prerenal azotemia, respiratory failure, hepatic injury, or encephalitis. We report an unusual case of an otherwise healthy 83-year-old female whose serologies tested positive for Rickettsia rickettsii, which led to cardiac dysrhythmia, i.e., the new onset of atrial fibrillation associated with conversion pauses. The patient was treated with antibiotics and ultimately underwent permanent pacemaker placement with resolution. This case highlights cardiac dysrhythmia as a late and severe manifestation in patients diagnosed with rickettsial illness.


[Case of recurrent delayed radiation myelopathy with 5-year remission interval].
We report a 47-year-old woman with relapsed delayed radiation myelopathy (DRM), occurring 5 years and 10 years after radiation therapy for nasopharyngeal carcinoma at 37 years old. Sensations of pain and temperature had been disturbed in the right leg since 42 years old. MRI showed Gadolinium-enhanced lesion as a ring-like-enhancement of the spinal cord at C1-2 on T1-weighted image (T1WI), with high signal area and swelling of the spinal cord at the upper C1 to C6 areas on T2-weighted image. We diagnosed her as having DRM after considering the differential diagnosis, e.g., multiple sclerosis, spinal tumor and other neurological diseases. Her sensory symptoms quickly improved following therapy with prednisolone and warfarin. Although she remained healthy for a few years, dysesthesia of the neck on the right side appeared 5 years later after the first clinical occurrence. At this time, MRI demonstrated Gadolinium-enhanced lesion as a ring-like enhancement of the spinal cord at C2 on T1WI. but the area also differed from that of previous lesion; a high signal area and swelling of the spinal cord was also seen on FLAIR image of the medulla and upper C1 to C6. For recurrence of DRM, we administered prednisolone and warfarin. Thereafter, the patient recovered and the spinal cord lesion on MRI decreased markedly. The clinical course demonstrated that administration of prednisolone and warfarin might be effective for relapsed DRM.


A study of flotation-REST (restricted environmental stimulation therapy) as an insomnia treatment.
Flotation-REST is a treatment for deep relaxation, where a person is contained in a stimuli-restricted environment and floats in water with high salt content. The aim was to investigate the effects from flotation-REST on people with insomnia diagnosis, as previous studies of flotation-REST have demonstrated some effects on sleep but have limitations regarding sample selections and sleep measures. Six participants were recruited through an outpatient psychiatry clinic and posters on a university campus. All participants fulfilled criteria for insomnia diagnosis and four fulfilled criteria for major depressive disorder. Using a single case experimental design, daily changes were investigated on sleep logs regarding sleep onset latency (SOL), wake after sleep onset (WASO), total sleep time (TST), and sleep efficiency over the course of 12 sessions consisting of 45 min of flotation-REST. No other treatments were offered simultaneously. Questionnaire data on insomnia severity (the ISI) and depressive severity (the MADRS) were also collected. Three participants improved on their most salient insomnia symptom (long SOL or WASO), and two improved on sleep efficiency. The improvements were maintained 2 months after treatment. Insomnia severity decreased for three patients, whereas depressive severity decreased for five. No changes in TST were found and two patients did not improve on any sleep measure. The two participants who benefitted the most were students in their 20s. The results were mixed. Flotation-REST may be beneficial for young adults with sleep-onset insomnia but more research is warranted.


Oral health literacy among clients visiting a rural dental college in North India-a cross-sectional study.
Limited health literacy among adults is one of the many barriers to better oral health outcomes. It is not uncommon to find people who consider understanding oral health information a challenge. Therefore, the present study assessed oral health literacy among clients visiting Gian Sagar Dental College and Hospital, Rajpura. A cross-sectional study was conducted on 450participants who visited the Out Patient Department (OPD) of Gian Sagar Dental College and Hospital for a period of two months (Nov-Dec, 2013). A questionnaire was given to each of the participants. Oral health literacy was graded on a 12-point Likert scale based on the total score. Oral Health Literacy of the participants was assessed as low, medium and high on the basis of responses. Statistical analysis was done using SPSS-15 statistical package. ANOVA and Student t-test were used to do comparisons between groups. Low oral health literacy scores were reported in 60.2% (271) participants. More than 60% of the study participants had knowledge about dental terms such as 'dental caries,' and 'oral cancer.' Only 22% of the graduates had a high literacy score. Mean oral health literacy score according to educational qualification was statistically significant (p<0.05), whereas there was no significant difference in terms of age and gender (p>0.05). The majority of the participants had low literacy scores. There is a need to address these problems especially among rural population by health care providers and the government.


Differences in systemic oxidative stress based on race and the metabolic syndrome: the Morehouse and Emory Team up to Eliminate Health Disparities (META-Health) study.
Classification schema such as metabolic syndrome may underestimate cardiovascular disease (CVD) risk in African Americans, despite a higher burden of CVD in African Americans. Oxidative stress results from an imbalance of prooxidants and antioxidants and leads to endothelial dysfunction that promotes vascular inflammation and atherosclerosis. Aminothiol markers of oxidative stress are associated with CVD risk factors and metabolic syndrome; however, little is known about racial differences in levels of oxidative stress. We sought to investigate whether oxidative stress would be higher in African Americans compared to whites independently of traditional risk factor burden. We assessed oxidative stress in a biracial, community-based cohort. In 620 subjects (59% female, 52% African American) in the Morehouse and Emory Team up to Eliminate Health Disparities (META-Health) study, we measured plasma levels of glutathione, an intracellular antioxidant, and its redox potential as a ratio of reduced and oxidized glutathione (E(h) glutathione). African Americans had lower glutathione levels (P<0.001) compared to whites. There was a trend toward more oxidized E(h) glutathione (P = 0.07) in African Americans; however, this did not reach statistical significance. After adjustment for demographics and CVD risk factors, African-American race remained a significant correlate of lower glutathione levels (P<0.001) and a more oxidized E(h) glutathione (P = 0.04). After further adjustment for high-sensitivity C-reactive protein (hsCRP), glutathione remained significantly lower in African Americans (P = 0.001). African Americans with or without metabolic syndrome had lower glutathione levels compared to whites with or without metabolic syndrome, respectively (both P ≤ 0.001), and African Americans without metabolic syndrome had a more oxidized E(h) glutathione compared to whites without metabolic syndrome (P = 0.003). African Americans have higher levels of oxidative stress than whites, even after adjustment for differences in CVD risk factors and inflammation. Racial differences in oxidative stress may play a key role in understanding observed racial disparities in CVD.


Implementing practice change in chronic cancer pain management: clinician response to a phase III study of ketamine.
An adequately powered, double-blind, multisite, randomised controlled trial has shown no net clinical benefit for subcutaneous ketamine over placebo in the management of cancer pain refractory to combination opioid and co-analgesic therapy. The results of the trial were disseminated widely both nationally and internationally. To determine whether the trial had impacted on clinical practice in Australasia. Members of the Australia and New Zealand Society of Palliative Medicine were sent an online ketamine utilisation survey. A total of 123/392 clinicians responded (31% response rate). The majority of respondents had practised for more than 10 years in a metropolitan hospital setting. Ketamine had been prescribed by 91% of respondents, and 92% were aware of the trial. As a result, 65% of respondents had changed practice (17% no longer prescribed ketamine, 46% used less and 2% more). Thirty-five per cent had not changed practice. Reasons for change included belief in the results of the study, concerns over the toxicity reported or because there were alternatives for pain control. Of those who prescribed less, over 80% were more selective and would now only use the drug in certain clinical situations or pain types, or when all other medications had failed. Although two-thirds of respondents reported practice change as a result of the randomised controlled trial, a minority remained convinced of the benefit of the drug from their own observations and would require additional evidence.


CAR T-Cell Therapy Is Effective but Not Long-Lasting in B-Cell Lymphoma of the Brain.
Advanced central nervous system (CNS) lymphoma is an exclusion criterion for most chimeric antigen receptor (CAR) T-cell studies due to the associated levels of neurotoxicity. In this study, we described five patients with chemorefractory B-cell CNS lymphoma who received CAR19 and CAR22 T-cell "Cocktail" therapy and follow-up for 6-16 months. All patients experienced cytokine release syndrome (CRS). Two patients experienced CAR T-cell-related encephalopathy syndrome (CRES), which was controllable. The best response was observed in two patients, who successfully achieved complete remissions (CR), and the other three patients achieved partial remissions (PR). Four patients had progressive disease (PD) after remission. In addition, one CR patient and one PD patient accepted CAR T-cell infusion following hematopoietic stem cell transplantation therapy in the 3rd month and were in ongoing remission for 14 and 6 months of follow-up, respectively. The targeted antigens in two patients were still positive, and CAR T-cells were reboosted in the cerebrospinal fluid (CSF) after PD, but a small number of CD3-positive T-cells were observed to infiltrate into the tumor. Our study indicates the efficacy of CAR T-cell therapy for CNS lymphoma with an acceptable safety profile; however, the remission did not last long, perhaps due to the tumor immunosuppressive microenvironment (TME) of the CNS. CAR T-cell therapy should be combined with other treatments to help improve the TME of cerebral lymphoma.


Mallory body formation is associated with epigenetic phenotypic change in hepatocytes in vivo.
Microarrays were done on the livers of mice fed DDC for 10 weeks, withdrawn 1 month (DDC primed livers) and refed 6 days, and compared with mice fed the control diet. The expression of a large number of genes changed when DDC was fed or refed. A Venn diagram analysis identified 649 genes where gene expression was changed in the same direction. The epigenetic memory of the DDC primed liver involved an increase in the expression of ubiquitin D, alpha fetoprotein, connective tissue growth factor, integrin beta 2, DNA methyl transferase 3a and DNA damage-inducible 45 gamma. DNA methyl transferase 3b was down-regulated as was Cbp/p300. When DDC was refed, DNA methyltransferase and histone deacetylase were up-regulated as shown by microarray analysis. Histone3 lysine9 acetylation was increased by DDC and DDC refeeding and DNA methyltransferases were not changed as shown by Western blot analysis. The data suggest the concept that the epigenetic memory that explains why DDC primed hepatocytes form MBs in 7 days of DDC refeeding is primarily the result of epigenetic modifications of gene expression through changes in histone acetylation and methylation, as well as DNA methylation.


Is marijuana a foe of male sexuality?: Data from a large cohort of men with sexual dysfunction.
Although it has been assumed that chronic cannabis use may have an unfavorable impact on male sexual function and its metabolic correlates, evidence from clinical studies remains inconclusive. To investigate the relationship between cannabis use and sexual behavior, anthropometrics and metabolic/vascular profiles in a large series of men evaluated for sexual dysfunction. A total of 4800 men (mean age 50.8 years) attending an andrology outpatient clinic for sexual dysfunction were studied. Sexual symptoms, hormonal, metabolic, and instrumental (penile color Doppler ultrasound, PCDU) parameters were evaluated according to the reported habitual use of recreational substances (no use, 1-2 joints/week, >2 joints/week, and use of illicit drugs other than cannabis). When compared with non-users, cannabis users were younger and exhibited a lower prevalence of comorbidities as well as better PCDU parameters, despite reporting higher alcohol and tobacco consumption. After adjustment for confounders, cannabis use was associated with a greater instability in the couple's relationship and a higher frequency of masturbation. In addition, the group smoking >2 joints/week showed a significantly lower body mass index than both controls and users of substances other than cannabis. Men who reported using recreational drugs (either cannabis or other) exhibited significantly lower levels of both total and low-density lipoprotein cholesterol than non-users. At the PCDU, smoking 1-2 joints/week was associated with significantly higher dynamic peak systolic velocity than both non-drug use and use of >2 joints/week. Prolactin levels were significantly higher in individuals smoking 1-2 joints/week and in those who used substances other than cannabis when compared with controls, whereas no difference in total testosterone levels was observed. In men with sexual dysfunction, mild cannabis consumption may be associated with a more favorable anthropometric and lipid profile and with a better penile arterial vascular response to intracavernous prostaglandin injection.


Effects of aminoglycoside antibiotics on polymorphonuclear leukocyte function in vivo.
In vitro incubation of aminoglycoside antibiotics with human polymorphonuclear leukocytes (PMNs) has been shown to induce abnormalities in cell function. This study was designed to determine whether there are similar abnormalities in leukocyte function after exposure to the action of these agents in vivo. Four aminoglycosides (gentamicin, tobramycin, netilmicin, and amikacin) were tested. In vitro incubation did not induce a chemotactic defect when measured by an under-agarose method. However, inhibition of candidacidal activity was reproducible after in vitro incubation of all aminoglycosides tested. Nevertheless, when the aminoglycosides were administered intravenously to normal volunteers, PMN function, including adherence to nylon wool columns, chemotaxis, phagocytosis, and killing of Candida albicans, was unimpaired at 1, 3, and 24 h postinfusion. Therefore, we conclude that aminoglycoside antibiotic administration does not induce PMN dysfunction in vivo.


Different genetic requirements for anterior RNA localization revealed by the distribution of Adducin-like transcripts during Drosophila oogenesis.
The proteins encoded by polar-localized mRNAs play an important role in cell fate specification along the anteroposterior axis of the Drosophila embryo. The only maternally synthesized mRNA known previously to be localized to the anterior cortex of both the oocyte and the early embryo is the bicoid mRNA whose localization is required to generate a homeodomain protein gradient that specifies position along the anteroposterior embryonic axis. We have identified and characterized a second mRNA that is localized to the anterior pole of the oocyte and early embryo. This mRNA encodes a Drosophila homolog of mammalian adducin, a membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network. A comparison of the spatial distribution of bicoid and Adducin-like transcripts in the maternal-effect RNA-localization mutants exuperantia, swallow, and staufen indicates different genetic requirements for proper localization of these two mRNAs to the anterior pole of the oocyte and early embryo.


miR-21-3p/IL-22 Axes Are Major Drivers of Psoriasis Pathogenesis by Modulating Keratinocytes Proliferation-Survival Balance and Inflammatory Response.
Psoriasis is a chronic inflammatory skin disease that is mediated by complex crosstalk between immune cells and keratinocytes (KCs). Emerging studies have showed a specific psoriatic microRNAs signature, in which miR-21 is one of the most upregulated and dynamic miRNAs. In this study, we focused our investigations on the passenger miR-21-3p strand, which is poorly studied in skin and in psoriasis pathogenesis. Here, we showed the upregulation of miR-21-3p in an IMQ-induced psoriasiform mouse model. This upregulation was correlated with IL-22 expression and functionality, both in vitro and in vivo, and it occurred via STAT3 and NF-κB signaling. We identified a network of differentially expressed genes involved in abnormal proliferation control and immune regulatory genes implicated in the molecular pathogenesis of psoriasis in response to miR-21-3p overexpression in KCs. These results were confirmed by functional assays that validated the proliferative potential of miR-21-3p. All these findings highlight the importance of miR-21-3p, an underestimated miRNA, in psoriasis and provide novel molecular targets for therapeutic purposes.


Retinitis pigmentosa-associated cystoid macular oedema: pathogenesis and avenues of intervention.
Hereditary retinal diseases are now the leading cause of blindness certification in the working age population (age 16-64 years) in England and Wales, of which retinitis pigmentosa (RP) is the most common disorder. RP may be complicated by cystoid macular oedema (CMO), causing a reduction of central vision. The underlying pathogenesis of RP-associated CMO (RP-CMO) remains uncertain, however, several mechanisms have been proposed, including: (1) breakdown of the blood-retinal barrier, (2) failure (or dysfunction) of the pumping mechanism in the retinal pigment epithelial, (3) Müller cell oedema and dysfunction, (4) antiretinal antibodies and (5) vitreous traction. There are limited data on efficacy of treatments for RP-CMO. Treatments attempted to date include oral and topical carbonic anhydrase inhibitors, oral, topical, intravitreal and periocular steroids, topical non-steroidal anti-inflammatory medications, photocoagulation, vitrectomy with internal limiting membrane peel, oral lutein and intravitreal antivascular endothelial growth factor injections. This review summarises the evidence supporting these treatment modalities. Successful management of RP-CMO should aim to improve both quality and quantity of vision in the short term and may also slow central vision loss over time.


-Factors of dissatisfaction with health care. A Delphi study-.
To study the causes of the disagreement between the general atmosphere of insatisfaction inherent in the assistance offered by the health care system and the favourable evaluation that the public shows in the questionnaires carried out in the field of primary health care. The less satisfactory issues of the health service offert are also identified. A Delphi thecnique has been used as consensus method. Community setting: Salamanca urban area. The Delphi group is made up of people working in jobs with a pronounced social character: members of neighbour associations, educators, social workers, etc. Three consecutive questionnaires were distributed among fifty people. Twenty-seven of them completed the three rounds. The score of the reasons of disagreement perceived as the most important were: the difficulties of access at a specialised level, 8.3 points; the inequality of the services offered by the two organizative models that coexist in the primary health care, 7.1; the lack of discrimination between the primary and the specialized level, 6.8. The highest scores were for the following complaints: excessive waiting lists at the second care level (8.5), delay in solving the problems (7.8) and masification at the consultancy (7.1). The most satisfactory aspects are the possibility of free choice of doctor, 7.9 points; the previous appointement system, 7.6; and a reliable relationship with the doctor, 7.3. To take into account these factors in the future design and interpretation of inquiries will increase their information validity and usefulness.


Noncanonical Form of ERAD Regulates Cardiac Hypertrophy.
Cardiac hypertrophy increases demands on protein folding, which causes an accumulation of misfolded proteins in the endoplasmic reticulum (ER). These misfolded proteins can be removed by the adaptive retrotranslocation, polyubiquitylation, and a proteasome-mediated degradation process, ER-associated degradation (ERAD), which, as a biological process and rate, has not been studied in vivo. To investigate a role for ERAD in a pathophysiological model, we examined the function of the functional initiator of ERAD, valosin-containing protein-interacting membrane protein (VIMP), positing that VIMP would be adaptive in pathological cardiac hypertrophy in mice. We developed a new method involving cardiac myocyte-specific adeno-associated virus serovar 9-mediated expression of the canonical ERAD substrate, TCRα, to measure the rate of ERAD, ie, ERAD flux, in the heart in vivo. Adeno-associated virus serovar 9 was also used to either knock down or overexpress VIMP in the heart. Then mice were subjected to transverse aortic constriction to induce pressure overload-induced cardiac hypertrophy. ERAD flux was slowed in both human heart failure and mice after transverse aortic constriction. Surprisingly, although VIMP adaptively contributes to ERAD in model cell lines, in the heart, VIMP knockdown increased ERAD and ameliorated transverse aortic constriction-induced cardiac hypertrophy. Coordinately, VIMP overexpression exacerbated cardiac hypertrophy, which was dependent on VIMP engaging in ERAD. Mechanistically, we found that the cytosolic protein kinase SGK1 (serum/glucocorticoid regulated kinase 1) is a major driver of pathological cardiac hypertrophy in mice subjected to transverse aortic constriction, and that VIMP knockdown decreased the levels of SGK1, which subsequently decreased cardiac pathology. We went on to show that although it is not an ER protein, and resides outside of the ER, SGK1 is degraded by ERAD in a noncanonical process we call ERAD-Out. Despite never having been in the ER, SGK1 is recognized as an ERAD substrate by the ERAD component DERLIN1, and uniquely in cardiac myocytes, VIMP displaces DERLIN1 from initiating ERAD, which decreased SGK1 degradation and promoted cardiac hypertrophy. ERAD-Out is a new preferentially favored noncanonical form of ERAD that mediates the degradation of SGK1 in cardiac myocytes, and in so doing is therefore an important determinant of how the heart responds to pathological stimuli, such as pressure overload.


Agroforestry diversity, indigenous food consumption and nutritional outcomes in Sauria Paharia tribal women of Jharkhand, India.
Like several indigenous populations, Sauria Paharias, a vulnerable indigenous tribal group residing in a biodiverse environment of Jharkhand, India, have high levels of undernutrition. We assessed agroforestry and dietary diversity, food consumption especially indigenous food (IF) intake and nutritional status of Sauria Paharia women through a cross-sectional study conducted in 18 villages of Godda district, Jharkhand. Household level information was elicited through household surveys including a dietary survey and a food frequency questionnaire. Twenty-four-hour dietary recalls (24 HDR) and anthropometric assessments were taken on one randomly selected woman per household. An index, Food Accessed Diversity Index (FADI) created to measure agroforestry diversity, showed a low mean score of 0.21 ± 0.15 and range: 0, 0.85. Fifty-nine percent of women consumed any IF during 24 HDR. Median minimum dietary diversity score for women (MDD-W) was 3 (acceptable score ≥5). More than 96% of women had intakes below estimated average requirements for all nutrients studied (energy; vitamins A, C, thiamine, riboflavin, niacin, pyridoxine; folate; iron; calcium and zinc) except protein; 41% women were underweight. IF consumption was independently associated with calcium and vitamin A intake. Decision trees developed for micronutrient consumption at different levels of MDD-W score and IF consumption scenarios revealed 1.3 to 2.9 times higher consumption of micronutrients among women with MDD-W ≥ 3 or 4. Strategies like agricultural extension programmes promoting indigenous varieties and nutrition education for increasing dietary diversity with IFs have potential to address undernutrition in Sauria Paharia women.


The HB22.7 Anti-CD22 monoclonal antibody enhances bortezomib-mediated lymphomacidal activity in a sequence dependent manner.
Most non-Hodgkin's lymphomas (NHL) initially respond to chemotherapy, but relapse is common and treatment is often limited by chemotherapy-related toxicity. Bortezomib, is a highly selective proteasome inhibitor with anti-NHL activity; it is currently FDA approved for second-line treatment of mantle cell lymphoma (MCL). Bortezomib exerts its activity in part through the generation of reactive oxygen species (ROS) and also by the induction of apoptosis.We previously validated CD22 as a potential target in treating NHL and have shown that the anti-CD22 ligand blocking antibody, HB22.7, has significant independent lymphomacidal properties in NHL xenograft models. We sought to determine whether or not these agents would work synergistically to enhance cytotoxicity. Our results indicate that treatment of NHL cell lines with HB22.7 six hours prior to bortezomib significantly diminished cell viability. These effects were not seen when the agents were administered alone or when bortezomib was administered prior to HB22.7. Additionally, HB22.7 treatment prior to bortezomib increased apoptosis in part through enhanced ROS generation. Finally, in a mouse xenograft model, administration of HB22.7 followed 24 hours later by bortezomib resulted in 23% smaller tumor volumes and 20% enhanced survival compared to treatment with the reverse sequence. Despite the increased efficacy of HB22.7 treatment followed by bortezomib, there was no corresponding decrease in peripheral blood cell counts, indicating no increase in toxicity. Our results suggest that pre-treatment with HB22.7 increases bortezomib cytotoxicity, in part through increased reactive oxygen species and apoptosis, and that this sequential treatment combination has robust efficacy in vivo.


Clinical scenarios for neoadjuvant chemotherapy of squamous penile cancer that is clinically node positive.
Squamous penile cancer may be localized to the phallus, metastatic to regional lymph nodes, or metastatic to distant lymph nodes or other organs. In the clinical situation of regional lymph node metastasis, a multimodality approach can have a big impact on outcomes. In particular, use of systemic chemotherapy as a neoadjuvant treatment is discussed, with several examples illustrating instances of regression and of resistance, and contrasting with adjuvant timing for use of chemotherapy. Radiation with coordinated combined chemotherapy is another complementary, locally directed approach that can be considered for men with squamous penile cancer with regional lymph node spread. The randomized trial InPACT (International Penile Cancer Adjuvant Chemotherapy Trial, NCT02305654) will enroll some of the squamous penile cancer patients with clinically node positive disease.


Changes in stiffness of resin-infiltrated demineralized dentin after remineralization by a bottom-up biomimetic approach.
This study examined changes in elastic modulus, mineral density and ultrastructure of resin-infiltrated dentin after biomimetic remineralization. Sixty demineralized dentin beams were infiltrated with Clearfil Tri-S Bond, One-Step or Prime&Bond NT. They were immersed in simulated body fluid (SBF) for 1 week to maximize water sorption before determining the baseline elastic moduli. For each adhesive (N = 20) half of the beams remained immersed in SBF (control). The rest were immersed in a biomimetic remineralization medium. The elastic moduli were measured weekly for 15 additional weeks. Representative remineralized specimens were evaluated by X-ray microtomography and transmission electron microscopy (TEM). The elastic moduli of control resin-infiltrated dentin remained consistently low, while those immersed in the biomimetic remineralization medium increased by 55-118% after 4 months. X-ray microtomography of the remineralized specimens revealed decreases in mineral density from the beam surface to the beam core that were indicative of external mineral aggregation and internal mineral deposition. Interfibrillar and intrafibrillar remineralization of resin-sparse intertubular dentin were seen under TEM, together with remineralized peritubular dentin. Biomimetic remineralization occurs by diffusion of nanoprecursors and biomimetic analogs in completely demineralized resin-infiltrated dentin and proceeds without the contribution of materials released from a mineralized dentin base.