A Prospective, Population-Based Study of Trends in Operative Vaginal Delivery Compared to Cesarean Delivery Rates in Low- and Middle-Income Countries, 2010-2016.
Few data are available on cesarean delivery and operative vaginal delivery trends in low- and middle-income countries. Our objective was to analyze a prospective population-based registry including eight sites in seven low- and middle-income countries to observe trends in operative vaginal delivery versus cesarean delivery rates over time, across sites. A prospective population-based study, including home and facility births among women enrolled from 2010 to 2016, was performed in communities in Argentina, Democratic Republic of Congo, Guatemala, India, Kenya, Pakistan, and Zambia. Women were enrolled during pregnancy and delivery outcome data were collected. We analyzed 354,287 women; 4,119 (1.2%) underwent an operative vaginal delivery and 45,032 (11.2%) delivered by cesarean. Across all sites with data for 7 years, rates of operative vaginal delivery decreased from 1.6 to 0.3%, while cesarean delivery increased from 6.4 to 14.4%. Similar trends were seen when individual country data were analyzed. Operative vaginal delivery rates decreased in both hospitals and clinics, except in the hospital setting at one of the Indian sites. In low- and middle-income countries, operative vaginal delivery is becoming less utilized while cesarean delivery is becoming an increasingly common mode of delivery.


Modular core-shell polymeric nanoparticles mimicking viral structures for vaccination.
Recent advances in the development of protein-based vaccines have expanded the opportunities for preventing and treating both infectious diseases as well as cancer. However, the development of readily and efficient antigen delivery systems capable of stimulating strong cytotoxic T-lymphocyte (CTL) responses remains a challenge. With the attempt to closely mimic the properties of viruses in terms of their size and molecular organization, we constructed RNA (which is a ligand for Toll-like receptor 7 (TLR7) and TLR8) and antigen-loaded nanoparticles resembling the structural organization of viruses. Cationic polymers containing either azide or bicyclo[6.1.0]nonyne (BCN) groups were synthesized as electrostatic glue that binds negatively charged single stranded RNA (PolyU) to form a self-crosslinked polyplex core. An azide-modified model antigen (ovalbumin, OVA) and a BCN-modified mannosylated or galactosylated polymer were sequentially conjugated to the RNA core via disulfide bonds using copper free click chemistry to form the shell of the polyplexes. The generated reducible virus mimicking particles (VMPs) with a diameter of 200 nm and negatively surface charge (-14 mV) were colloidally stable in physiological conditions. The immunogenicity of these VMP vaccines was evaluated both in vitro and in vivo. The surface mannosylated VMPs (VMP-Man) showed 5 times higher cellular uptake by bone marrow derived DCs (BMDCs) compared to galactosylated VMP (VMP-Gal) counterpart. Moreover, VMP-Man efficiently activated DCs and greatly facilitated MHC I Ag presentation in vitro. Vaccination of mice with VMP-Man elicited strong OVA-specific CTL responses as well as humoral immune responses. These results demonstrate that the modular core-shell polymeric nanoparticles described in this paper are superior in inducing strong and durable immune responses compared to adjuvanted protein subunit vaccines and offer therefore a flexible platform for personalized vaccines.


Diverse Plant-Associated Pleosporalean Fungi from Saline Areas: Ecological Tolerance and Nitrogen-Status Dependent Effects on Plant Growth.
Similar to mycorrhizal mutualists, the rhizospheric and endophytic fungi are also considered to act as active regulators of host fitness (e.g., nutrition and stress tolerance). Despite considerable work in selected model systems, it is generally poorly understood how plant-associated fungi are structured in habitats with extreme conditions and to what extent they contribute to improved plant performance. Here, we investigate the community composition of root and seed-associated fungi from six halophytes growing in saline areas of China, and found that the pleosporalean taxa (Ascomycota) were most frequently isolated across samples. A total of twenty-seven representative isolates were selected for construction of the phylogeny based on the multi-locus data (partial 18S rDNA, 28S rDNA, and transcription elongation factor 1-α), which classified them into seven families, one clade potentially representing a novel lineage. Fungal isolates were subjected to growth response assays by imposing temperature, pH, ionic and osmotic conditions. The fungi had a wide pH tolerance, while most isolates showed a variable degree of sensitivity to increasing concentration of either salt or sorbitol. Subsequent plant-fungal co-culture assays indicated that most isolates had only neutral or even adverse effects on plant growth in the presence of inorganic nitrogen. Interestingly, when provided with organic nitrogen sources the majority of the isolates enhanced plant growth especially aboveground biomass. Most of the fungi preferred organic nitrogen over its inorganic counterpart, suggesting that these fungi can readily mineralize organic nitrogen into inorganic nitrogen. Microscopy revealed that several isolates can successfully colonize roots and form melanized hyphae and/or microsclerotia-like structures within cortical cells suggesting a phylogenetic assignment as dark septate endophytes. This work provides a better understanding of the symbiotic relationship between plants and pleosporalean fungi, and initial evidence for the use of this fungal group in benefiting plant production.


COVID-19-The Potential Beneficial Therapeutic Effects of Spironolactone during SARS-CoV-2 Infection.
In March 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 was declared a global pandemic by the World Health Organization (WHO). The clinical course of the disease is unpredictable but may lead to severe acute respiratory infection (SARI) and pneumonia leading to acute respiratory distress syndrome (ARDS). It has been shown that pulmonary fibrosis may be one of the major long-term complications of COVID-19. In animal models, the use of spironolactone was proven to be an important drug in the prevention of pulmonary fibrosis. Through its dual action as a mineralocorticoid receptor (MR) antagonist and an androgenic inhibitor, spironolactone can provide significant benefits concerning COVID-19 infection. The primary effect of spironolactone in reducing pulmonary edema may also be beneficial in COVID-19 ARDS. Spironolactone is a well-known, widely used and safe anti-hypertensive and antiandrogenic medication. It has potassium-sparing diuretic action by antagonizing mineralocorticoid receptors (MRs). Spironolactone and potassium canrenoate, exerting combined pleiotropic action, may provide a therapeutic benefit to patients with COVID-19 pneumonia through antiandrogen, MR blocking, antifibrotic and anti-hyperinflammatory action. It has been proposed that spironolactone may prevent acute lung injury in COVID-19 infection due to its pleiotropic effects with favorable renin-angiotensin-aldosterone system (RAAS) and ACE2 expression, reduction in transmembrane serine protease 2 (TMPRSS2) activity and antiandrogenic action, and therefore it may prove to act as additional protection for patients at highest risk of severe pneumonia. Future prospective clinical trials are warranted to evaluate its therapeutic potential.


Full-length sequence analysis of subacute sclerosing panencephalitis (SSPE) virus, a mutant of measles virus, isolated from brain tissues of a patient shortly after onset of SSPE.
Subacute sclerosing panencephalitis (SSPE) virus, a measles virus (MeV) mutant, was isolated from brain tissues of a patient shortly after the clinical onset, and the entire viral genome was sequenced. The virus, named SSPE-Kobe-1, formed syncytia on B95a and Vero/SLAM cells without producing cell-free infectious virus particles, which is characteristic of SSPE virus. Phylogenetic analysis classified SSPE-Kobe-1 into genotype D3. When compared with an MeV field isolate of the same genotype (Ich-B strain), SSPE-Kobe-1 exhibited mutation rates of 0.8-1.6% at the nucleotide level in each of the proteincoding regions of the viral genome. It is noteworthy that the mutation rate of the M gene (1.2%) of SSPE-Kobe-1 was considerably lower than for other SSPE virus strains reported so far, but that the majority of the mutations (75%) were the uridine-to-cytidine biased hypermutation characteristic of the SSPE virus M gene. At the amino acid level, the viral proteins, such as N, P, C, V, M, F, H and L proteins, had point-mutations on 3, 7, 1, 4, 3, 9, 8 and 14 residues, respectively, compared with the Ich-B strain. In addition, the F and H proteins had mutated C-termini due to single-point mutations near or at the stop codons. Two of the three mutations in the M protein were Leu-to-Pro mutations, which are likely to affect the conformation and, therefore, the function of the protein. Because of the relatively small number of mutations, SSPE-Kobe-1 would be a useful tool to study genetic evolution of SSPE virus.


Nitric oxide degradation of heparin and heparan sulphate.
NO is a bioactive free radical produced by NO synthase in various tissues including vascular endothelium. One of the degradation products of NO is HNO2, an agent known to degrade heparin and heparan sulphate. This report documents degradation of heparin by cultured endothelial-cell-derived as well as exogenous NO. An exogenous narrow molecular-mass preparation of heparin was recovered from the medium of cultured endothelial cells using strong-anion exchange. In addition, another narrow molecular-mass preparation of heparin was gassed with exogenous NO under argon. Degradation was evaluated by gel-filtration chromatography. Since HNO2 degrades heparin under acidic conditions, the reaction with NO gas was studied under various pH conditions. The results show that the degradation of exogenous heparin by endothelial cells is inhibited by NO synthase inhibitors. Exogenous NO gas at concentrations as low as 400 p.p.m. degrades heparin and heparan sulphate. Exogenous NO degrades heparin at neutral as well as acidic pH. Endothelial-cell-derived NO, as well as exogenous NO gas, did not degrade hyaluronan, an unrelated glycosaminoglycan that resists HNO2 degradation. Peroxynitrite, a metabolic product of the reaction of NO with superoxide, is an agent that degrades hyaluronan; however, peroxynitrite did not degrade heparin. Thus endothelial-cell-derived NO is capable of degrading heparin and heparan sulphate via HNO2 rather than peroxynitrite. These observations may be relevant to various pathophysiological processes in which extracellular matrix is degraded, such as bone development, apoptosis, tissue damage from inflammatory responses and possible release of growth factors and cytokines.


Mortality risk factors associated with familial Mediterranean fever among a cohort of 1.25 million adolescents.
There are limited data on long-term comorbidities and mortality among patients with familial Mediterranean fever (FMF). Our objective was to evaluate comorbidities and death rates among individuals with FMF. We studied a nationwide, population-based, retrospective cohort of 1225 individuals with FMF (59% men) in a database of 1 244 350 adolescents (16-20 years of age) medically evaluated for military service between 1973 and 1997. This cohort was linked with the national mortality, cancer and end-stage renal disease (ESRD) registries in Israel. Study outcomes were all-cause mortality, occurrence of ESRD and malignancy by the age of 50 years. During 30 years of follow-up, death rates were 8.73/10(4) versus 4.32/10(4) person-years in the FMF and control groups, respectively (p=0.002). In a multivariable analysis adjusted for age, birth year, socio-economic status, education, ethnicity and body mass index, FMF was associated with increased mortality in men (HR=1.705 (95% CI 1.059 to 2.745), p=0.028) and women (HR=2.48 (1.032 to 5.992), p=0.042). Renal amyloidosis accounted for 35% and 60% of deaths in men and women, respectively. FMF was not associated with an increased incidence of cancer. FMF is associated with increased all-cause mortality that is likely attributed to reduced colchicine compliance or responsiveness. Individuals with FMF do not have an increased incidence of cancer. These results support the awareness among medical community to decrease the higher than average mortality rate among participants with FMF.


Tuberculosis Vaccine Development: Progress in Clinical Evaluation.
Tuberculosis (TB) is the leading killer among all infectious diseases worldwide despite extensive use of the Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccine. A safer and more effective vaccine than BCG is urgently required. More than a dozen TB vaccine candidates are under active evaluation in clinical trials aimed to prevent infection, disease, and recurrence. After decades of extensive research, renewed promise of an effective vaccine against this ancient airborne disease has recently emerged. In two innovative phase 2b vaccine clinical trials, one for the prevention of Mycobacterium tuberculosis infection in healthy adolescents and another for the prevention of TB disease in M. tuberculosis-infected adults, efficacy signals were observed. These breakthroughs, based on the greatly expanded knowledge of the M. tuberculosis infection spectrum, immunology of TB, and vaccine platforms, have reinvigorated the TB vaccine field. Here, we review our current understanding of natural immunity to TB, limitations in BCG immunity that are guiding vaccinologists to design novel TB vaccine candidates and concepts, and the desired attributes of a modern TB vaccine. We provide an overview of the progress of TB vaccine candidates in clinical evaluation, perspectives on the challenges faced by current vaccine concepts, and potential avenues to build on recent successes and accelerate the TB vaccine research-and-development trajectory.


Rice bran oil, not fiber, lowers cholesterol in humans.
The cholesterol-lowering abilities of rice bran's fiber and oil apart from its fatty acid composition remain unclear. The objective of the study was to assess the effects of defatted rice bran and rice bran oil in an average American diet on blood lipids in moderately hypercholesterolemic persons. Study 1 used a parallel-arm design. Twenty-six healthy volunteers consumed a diet with 13-22 g dietary fiber/d for 3 wk, and then 13 of the volunteers were switched to a diet with defatted rice bran to double the fiber intake for 5 wk. Study 2 was a randomized, crossover, 10-wk feeding study performed in 14 volunteers who consumed a diet with rice bran oil (1/3 of the total dietary fat) substituted for an oil blend that had a fatty acid composition similar to that of the rice bran oil. Serum lipids and factor VII were measured in both studies. Defatted rice bran did not lower lipid concentrations. In study 2, total cholesterol was significantly lower with consumption of the diet containing rice bran oil than with consumption of the control diet. Moreover, with consumption of the rice bran oil diet, LDL cholesterol decreased by 7% (P < 0.0004), whereas HDL cholesterol was unchanged. Rice bran oil, not fiber, lowers cholesterol in healthy, moderately hypercholesterolemic adults. There were no substantial differences in the fatty acid composition of the diets; therefore, the reduction of cholesterol was due to other components present in the rice bran oil, such as unsaponifiable compounds.


Phylodynamic analysis of the dissemination of HIV-1 CRF01_AE in Vietnam.
To estimate the epidemic history of HIV-1 CRF01_AE in Vietnam and adjacent Guangxi, China, we determined near full-length nucleotide sequences of CRF01_AE from a total of 33 specimens collected in 1997-1998 from different geographic regions and risk populations in Vietnam. Phylogenetic and Bayesian molecular clock analyses were performed to estimate the date of origin of CRF01_AE lineages. Our study reconstructs the timescale of CRF01_AE expansion in Vietnam and neighboring regions and suggests that the series of CRF01_AE epidemics in Vietnam arose by the sequential introduction of founder strains into new locations and risk groups. CRF01_AE appears to have been present among heterosexuals in South-Vietnam for more than a decade prior to its epidemic spread in the early 1990s. In the late 1980s, the virus spread to IDUs in Southern Vietnam and subsequently in the mid-1990s to IDUs further north. Our results indicate the northward dissemination of CRF01_AE during this time.


Midkine (MK), the product of a retinoic acid responsive gene, and pleiotrophin constitute a new protein family regulating growth and differentiation.
Using mouse teratocarcinoma system, we found a novel retinoic acid responsive gene. Midkine (MK), the product of the gene is a secreted, heparin-binding protein of molecular weight 14,000. MK gene is intensely expressed in the midgestation period, and in the adult mouse, the kidney is the principal site of its expression. MK and pleiotrophin have 50% sequence identity and constitute a new protein family regulating growth and differentiation. They share neurite outgrowth activity; other activities, either specific for one or common to both, have been reported. Furthermore, MK is of significant interest in cancer biology.


Circadian gene variants and susceptibility to type 2 diabetes: a pilot study.
Disruption of endogenous circadian rhythms has been shown to increase the risk of developing type 2 diabetes, suggesting that circadian genes might play a role in determining disease susceptibility. We present the results of a pilot study investigating the association between type 2 diabetes and selected single nucleotide polymorphisms (SNPs) in/near nine circadian genes. The variants were chosen based on their previously reported association with prostate cancer, a disease that has been suggested to have a genetic link with type 2 diabetes through a number of shared inherited risk determinants. The pilot study was performed using two genetically homogeneous Punjabi cohorts, one resident in the United Kingdom and one indigenous to Pakistan. Subjects with (N = 1732) and without (N = 1780) type 2 diabetes were genotyped for thirteen circadian variants using a competitive allele-specific polymerase chain reaction method. Associations between the SNPs and type 2 diabetes were investigated using logistic regression. The results were also combined with in silico data from other South Asian datasets (SAT2D consortium) and white European cohorts (DIAGRAM+) using meta-analysis. The rs7602358G allele near PER2 was negatively associated with type 2 diabetes in our Punjabi cohorts (combined odds ratio [OR] = 0.75 [0.66-0.86], p = 3.18 × 10(-5)), while the BMAL1 rs11022775T allele was associated with an increased risk of the disease (combined OR = 1.22 [1.07-1.39], p = 0.003). Neither of these associations was replicated in the SAT2D or DIAGRAM+ datasets, however. Meta-analysis of all the cohorts identified disease associations with two variants, rs2292912 in CRY2 and rs12315175 near CRY1, although statistical significance was nominal (combined OR = 1.05 [1.01-1.08], p = 0.008 and OR = 0.95 [0.91-0.99], p = 0.015 respectively). None of the selected circadian gene variants was associated with type 2 diabetes with study-wide significance after meta-analysis. The nominal association observed with the CRY2 SNP, however, complements previous findings and confirms a role for this locus in disease susceptibility.


Graft-versus-host disease and graft-versus-tumor effects after allogeneic hematopoietic cell transplantation.
We designed a minimal-intensity conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) in patients with advanced hematologic malignancies unable to tolerate high-intensity regimens because of age, serious comorbidities, or previous high-dose HCT. The regimen allows the purest assessment of graft-versus-tumor (GVT) effects apart from conditioning and graft-versus-host disease (GVHD) not augmented by regimen-related toxicities. Patients received low-dose total-body irradiation ± fludarabine before HCT from HLA-matched related (n = 611) or unrelated (n = 481) donors, followed by mycophenolate mofetil and a calcineurin inhibitor to aid engraftment and control GVHD. Median patient age was 56 years (range, 7 to 75 years). Forty-five percent of patients had comorbidity scores of ≥ 3. Median follow-up time was 5 years (range, 0.6 to 12.7 years). Depending on disease risk, comorbidities, and GVHD, lasting remissions were seen in 45% to 75% of patients, and 5-year survival ranged from 25% to 60%. At 5 years, the nonrelapse mortality (NRM) rate was 24%, and the relapse mortality rate was 34.5%. Most NRM was a result of GVHD. The most significant factors associated with GVHD-associated NRM were serious comorbidities and grafts from unrelated donors. Most relapses occurred early while the immune system was compromised. GVT effects were comparable after unrelated and related grafts. Chronic GVHD, but not acute GVHD, further increased GVT effects. The potential benefit associated with chronic GVHD was outweighed by increased NRM. Allogeneic HCT relying on GVT effects is feasible and results in cures of an appreciable number of malignancies. Improved results could come from methods that control progression of malignancy early after HCT and effectively prevent GVHD.


The burden of childhood injuries and evidence based strategies developed using the injury surveillance system in Pasto, Colombia.
This article characterises the burden of childhood injuries and provides examples of evidence-based injury prevention strategies developed using a citywide injury surveillance system in Pasto, Colombia. Fatal (2003-2007) and non-fatal (2006-2007) childhood injury data were analysed by age, sex, cause, intent, place of occurrence, and disposition. Boys accounted for 71.5% of fatal and 64.9% of non-fatal injuries. The overall fatality rate for all injuries was 170.8 per 100,000 and the non-fatal injury rate was 4,053 per 100,000. Unintentional injuries were the leading causes of fatal injuries for all age groups, except for those 15-19 years whose top four leading causes were violence-related. Among non-fatal injuries, falls was the leading mechanism in the group 0-14 years. Interpersonal violence with a sharp object was the most important cause for boys aged 15-19 years. Home was the most frequent place of occurrence for both fatal and non-fatal injuries for young children 0-4 years old. Home, school and public places became an important place for injuries for boys in the age group 5-15 years. The highest case-fatality rate was for self-inflicted injuries (8.9%). Although some interventions have been implemented in Pasto to reduce injuries, it is necessary to further explore risk factors to better focus prevention strategies and their evaluation. We discuss three evidence-based strategies developed to prevent firework-related injuries during festival, self-inflicted injuries, and road traffic-related injuries, designed and implemented based on the injury surveillance data.


The Overlap between Irritable Bowel Syndrome and Non-Celiac Gluten Sensitivity: A Clinical Dilemma.
The spectrum of gluten-related disorders has widened in recent times and includes celiac disease, non-celiac gluten sensitivity, and wheat allergy. The complex of symptoms associated with these diseases, such as diarrhea, constipation or abdominal pain may overlap for the gluten related diseases, and furthermore they can be similar to those caused by various other intestinal diseases, such as irritable bowel syndrome (IBS). The mechanisms underlying symptom generation are diverse for all these diseases. Some patients with celiac disease may remain asymptomatic or have only mild gastrointestinal symptoms and thus may qualify for the diagnosis of IBS in the general clinical practice. Similarly, the overlap of symptoms between IBS and non-celiac gluten sensitivity (NCGS) often creates a dilemma for clinicians. While the treatment of NCGS is exclusion of gluten from the diet, some, but not all, of the patients with IBS also improve on a gluten-free diet. Both IBS and NCGS are common in the general population and both can coexist with each other independently without necessarily sharing a common pathophysiological basis. Although the pathogenesis of NCGS is not well understood, it is likely to be heterogeneous with possible contributing factors such as low-grade intestinal inflammation, increased intestinal barrier function and changes in the intestinal microbiota. Innate immunity may also play a pivotal role. One possible inducer of innate immune response has recently been reported to be amylase-trypsin inhibitor, a protein present in wheat endosperm and the source of flour, along with the gluten proteins.


The NLP toxin family in Phytophthora sojae includes rapidly evolving groups that lack necrosis-inducing activity.
Necrosis- and ethylene-inducing-like proteins (NLP) are widely distributed in eukaryotic and prokaryotic plant pathogens and are considered to be important virulence factors. We identified, in total, 70 potential Phytophthora sojae NLP genes but 37 were designated as pseudogenes. Sequence alignment of the remaining 33 NLP delineated six groups. Three of these groups include proteins with an intact heptapeptide (Gly-His-Arg-His-Asp-Trp-Glu) motif, which is important for necrosis-inducing activity, whereas the motif is not conserved in the other groups. In total, 19 representative NLP genes were assessed for necrosis-inducing activity by heterologous expression in Nicotiana benthamiana. Surprisingly, only eight genes triggered cell death. The expression of the NLP genes in P. sojae was examined, distinguishing 20 expressed and 13 nonexpressed NLP genes. Real-time reverse-transcriptase polymerase chain reaction results indicate that most NLP are highly expressed during cyst germination and infection stages. Amino acid substitution ratios (Ka/Ks) of 33 NLP sequences from four different P. sojae strains resulted in identification of positive selection sites in a distinct NLP group. Overall, our study indicates that expansion and pseudogenization of the P. sojae NLP family results from an ongoing birth-and-death process, and that varying patterns of expression, necrosis-inducing activity, and positive selection suggest that NLP have diversified in function.


The epidemiology of depersonalisation and derealisation. A systematic review.
Symptoms of depersonalisation (DP) and derealisation (DR) are increasingly recognised in both clinical and non-clinical settings, but their importance and underlying pathophysiology is only now being addressed. This paper is a systematic review of the current state of knowledge about the prevalence of depersonalisation and derealisation using computerised databases and citation searches. All potential studies were examined and numerical data included. Three categories of study are reviewed: questionnaire and interview surveys of selected student and non-clinical samples; population-based community surveys using standardised diagnostic interviews; and clinical surveys of depersonalisation/derealisation symptoms occurring within inpatients with psychiatric disorders. In addition, we present newly analysed data of the prevalence of depersonalisation/derealisation from five large population-based studies. Epidemiological surveys demonstrate that transient symptoms of depersonalisation/derealisation in the general population are common, with a lifetime prevalence rate of between 26 and 74% and between 31 and 66% at the time of a traumatic event. Community surveys employing standardised diagnostic interviews reveal rates of between 1.2 and 1.7 % for one month prevalence in a UK sample and a 2.4% current prevalence rate in a Canadian sample. Current prevalence rates in samples of consecutive inpatient admissions are reported between 1 and 16%, although screening measures employed may have resulted in these being an underestimate. Prevalence rates in clinical samples of specific psychiatric disorders vary between 30% of war veterans with PTSD and 60% of those with unipolar depression. There is a high prevalence within panic disorder with rates varying from 7.8 to 82.6%. DP and DR symptoms are common in normal and psychiatric populations, but prevalence estimates are hampered by inconsistent definitions and the use of variable time-frames. Population-based surveys using diagnostic interviews yield prevalence rates of clinically significant DP/DR in the region of 1-2%. Surveys of clinical populations in which common screening and assessment instruments were used also yield consistently high prevalence rates. The use of reliable diagnostic assessments and rating scales is needed. The relationship between DP/DR and certain other psychiatric disorders (e. g. panic) suggests possible common pathophysiological or aetiological factors.


Mapping of the inducible IkappaB phosphorylation sites that signal its ubiquitination and degradation.
Extracellular stimuli that activate the transcription factor NF-kappaB cause rapid phosphorylation of the IkappaBalpha inhibitor, which retains NF-kappaB in the cytoplasm of nonstimulated cells. Phosphorylation of IkappaBalpha is followed by its rapid degradation, the inhibition of which prevents NF-kappaB activation. To determine the relationship between these events, we mapped the inducible phosphorylation sites of IkappaBalpha. We found that two residues, serines 32 and 36, were phosphorylated in response to either tumor necrosis factor, interleukin-1, or phorbol ester. Substitution of either serine blocks or slows down induction of IkappaBalpha degradation. Substitutions of the homologous sites in IkappaBbeta, serines 19 and 23, also prevent inducible IkappaBbeta degradation. We suggest that activation of a single IkappaB kinas e or closely related IkappaB kinases is the first cr itical step in NF-kappaB activation. Once phosphorylated, IkappaB is ubiquitinated. Unlike wild-type IkappaBalpha, the phosphorylation-defective mutants do not undergo inducible polyubiquitination. As substitution of a conserved lysine residue slows down the ubiquitination and degradation of IkappaBalpha without affecting its phosphorylation, polyubiquitination is required for inducible IkappaB degradation.


Greenshell™ Mussels: A Review of Veterinary Trials and Future Research Directions.
The therapeutic benefits of Greenshell™ mussel (GSM; Perna canaliculus) preparations have been studied using in vitro test systems, animal models, and human clinical trials focusing mainly on anti-inflammatory and anti-arthritic effects. Activity is thought to be linked to key active ingredients that include omega-3 polyunsaturated fatty acids, a variety of carotenoids and other bioactive compounds. In this paper, we review the studies that have been undertaken in dogs, cats, and horses, and outline new research directions in shellfish breeding and high-value nutrition research programmes targeted at enhancing the efficacy of mussel and algal extracts. The addition of GSM to animal diets has alleviated feline degenerative joint disease and arthritis symptoms, and chronic orthopaedic pain in dogs. In horses, GSM extracts decreased the severity of lameness and joint pain and provided improved joint flexion in limbs with lameness attributed to osteoarthritis. Future research in this area should focus on elucidating the key active ingredients in order to link concentrations of these active ingredients with their pharmacokinetics and therapeutic effects. This would enable consistent and improved efficacy from GSM-based products for the purpose of improved animal health.


Does routine follow up after head injury help? A randomised controlled trial.
To evaluate the Medical Disability Society's 1988 recommendation that "every patient attending hospital after a head injury should be registered and offered an outpatient follow up appointment" by determining whether offering a routine follow up service to patients presenting to hospital with a head injury of any severity affects outcome six months later. A randomised controlled trial design with masked assessment of outcome. A mixed rural and urban health district with a population of about 560000. 1156 consecutive patients resident in Oxfordshire aged between 16 and 65 years presenting over 13 months to accident and emergency departments or admitted to hospital and diagnosed as having a head injury of any severity, including those with other injuries. Patients were registered and randomised to one of two groups. Both groups continued to receive the standard service offered by the hospitals. The early follow up group were approached at 7-10 days after injury and offered additional information, advice, support, and further intervention as needed. All randomised patients were approached for follow up assessment six months after injury by independent clinicians blind to their group. Validated questionnaires were used to elicit ratings of post-concussion symptoms (the Rivermead postconcussion symptoms questionnaire), and changes in work, relationships, leisure, social, and domestic activities (the Rivermead head injury follow up questionnaire). The two groups were comparable at randomisation. Data was obtained at six months on 226 of 577 "control" patients and 252 of 579 "trial" patients (59% were lost to follow up). There were no significant differences overall between the trial and control groups at follow up, but subgroup analysis of the patients with moderate or severe head injuries (posttraumatic amnesia > or = one hour, or admitted to hospital), showed that those in the early intervention group had significantly fewer difficulties with everyday activities (P = 0.03). The results from the 41% of patients followed up do not support the recommendation of offering a routine follow up to all patients with head injury, but they do suggest that routine follow up is most likely to be beneficial to patients with moderate or severe head injuries. Some of those with less severe injuries do continue to experience difficulties and need access to services. A further trial is under way to test these conclusions.


[Budget impact of the incorporation of GeneXpert MTB/RIF for diagnosis of pulmonary tuberculosis from the perspective of the Brazilian Unified National Health System, Brazil, 2013-2017].
The study aimed to estimate the budget impact of GeneXpert MTB/RIF for diagnosis of tuberculosis from the perspective of the Brazilian National Program for Tuberculosis Control, drawing on a static model using the epidemiological method, from 2013 to 2017. GeneXpert MTB/RIF was compared with two diagnostic sputum smear tests. The study used epidemiological, population, and cost data, exchange rates, and databases from the Brazilian Unified National Health System. Sensitivity analysis of scenarios was performed. Incorporation of GeneXpert MTB/RIF would cost BRL 147 million (roughly USD 45 million) in five years and would have an impact of 23 to 26% in the first two years and some 11% between 2015 and 2017. The results can support Brazilian and other Latin American health administrators in planning and managing the decision on incorporating the technology.


Oleanolic acid inhibits colorectal cancer angiogenesis in vivo and in vitro via suppression of STAT3 and Hedgehog pathways.
Angiogenesis is an essential process of cancer progression and is regulated by multiple intracellular signaling pathways, including signal transducer and activator of transcription 3 (STAT3) and sonic hedgehog (SHH). Thus, these pathways have become a promising target for anti‑cancer therapeutic strategies. Oleanolic acid (OA) is an active compound present in various herbal medicines, which have been used historically for the clinical treatment of various types of human malignancies, including colorectal cancer (CRC). The present study used a CRC mouse xenograft model and human umbilical vein endothelial cells (HUVECs) to evaluate the effect of OA on tumor angiogenesis and on the activation of the STAT3 and SHH signaling pathways. It was determined that OA treatment significantly inhibited tumor growth and reduced intratumoral microvessel density (MVD) in CRC mice. In addition, OA treatment inhibited the proliferation, migration and tube formation in HUVECs, in a dose and time-dependent manner. Furthermore, OA markedly suppressed the activation of the STAT3 and SHH signaling pathways and inhibited the expression of the pro‑angiogenic vascular endothelial growth factor A and basic fibroblast growth factor, two important target genes of the aforementioned signaling pathways. Therefore it is suggested that inhibition of tumor angiogenesis via the suppression of multiple signaling pathways may be one of the underlying mechanisms by which OA exerts its anti-cancer effect.


Total synthesis and absolute stereochemistry of the proteasome inhibitors cystargolides A and B.
The absolute stereochemistry of the cystargolides was determined by total synthesis. Evaluation of synthetic cystargolides and derivatives showed that the natural (2S,3R) stereochemistry is essential for activity. Moreover, benzyl esters (-)-10 and (-)-15 were found to be about 100 times more potent, and to selectively kill MCF-7 cancerous cells.


ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis.
Multiple sclerosis (MS) is a complex disease with new drugs becoming available in the past years. There is a need for a reference tool compiling current data to aid professionals in treatment decisions. To develop an evidence-based clinical practice guideline for the pharmacological treatment of people with MS. This guideline has been developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology and following the updated EAN recommendations. Clinical questions were formulated in Patients-Intervention-Comparator-Outcome (PICO) format and outcomes were prioritized. The quality of evidence was rated into four categories according to the risk of bias. The recommendations with assigned strength (strong and weak) were formulated based on the quality of evidence and the risk-benefit balance. Consensus between the panelists was reached by use of the modified nominal group technique. A total of 10 questions were agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease-modifying drugs approved by the European Medicine Agency (EMA) at the time of publication. A total of 21 recommendations were agreed by the guideline working group after three rounds of consensus. The present guideline will enable homogeneity of treatment decisions across Europe.


Tactile-Foot Stimulation Can Assist the Navigation of People with Visual Impairment.
Background. Tactile interfaces that stimulate the plantar surface with vibrations could represent a step forward toward the development of wearable, inconspicuous, unobtrusive, and inexpensive assistive devices for people with visual impairments. Objective. To study how people understand information through their feet and to maximize the capabilities of tactile-foot perception for assisting human navigation. Methods. Based on the physiology of the plantar surface, three prototypes of electronic tactile interfaces for the foot have been developed. With important technological improvements between them, all three prototypes essentially consist of a set of vibrating actuators embedded in a foam shoe-insole. Perceptual experiments involving direction recognition and real-time navigation in space were conducted with a total of 60 voluntary subjects. Results. The developed prototypes demonstrated that they are capable of transmitting tactile information that is easy and fast to understand. Average direction recognition rates were 76%, 88.3%, and 94.2% for subjects wearing the first, second, and third prototype, respectively. Exhibiting significant advances in tactile-foot stimulation, the third prototype was evaluated in navigation tasks. Results show that subjects were capable of following directional instructions useful for navigating spaces. Conclusion. Footwear providing tactile stimulation can be considered for assisting the navigation of people with visual impairments.


Lymphocyte subsets and inflammatory factors as predictors of immunotherapy efficacy in patients with hepatocellular carcinoma.
We aimed to investigate the correlation between lymphocyte subpopulations expressing inhibitor receptors, IL-6 levels, and the efficacy of immunotherapy in patients with hepatocellular carcinoma. Blood samples were prospectively collected before and after immunotherapy from patients with intermediate and advanced hepatocellular carcinoma who were treated with immunotherapy at the Fifth Medical Center of the PLA General Hospital from August 2022 to October 2023. According to the efficacy of the patients, patients were divided into effective and ineffective groups, with 40 in the effective group and 44 in the ineffective group. We compared changes in lymphocyte subsets and IL-6 levels between the two groups. Optimal cut-off value was determined using ROC curves. Then, patients were categorized into high and low groups based on cut-off value, and the disease control rates and progression free survival were compared. Before immunotherapy, there were no significant differences in the baseline levels of lymphocyte subsets (PD1 + TIM3 + T/T, TIGIT + T/T, TIM3 + T/T, CTLA4 + T/T, LAG3 + T/T, PD1 + T/T) and IL-6 between the two groups (P > 0.05). After immunotherapy, the levels of PD1 + TIM3 + T/T, TIGIT + T/T, and IL-6 in the effective group were lower than those in the ineffective group and these differences were statistically significant (P = 0.001, P = 0.008, P = 0.000). However, the levels of other lymphocyte subsets showed no significant difference. Using the ROC curve to assess efficacy prediction, PD1 + TIM3 + T/T, TIGIT + T/T and IL-6 demonstrated high predictive ability (AUC = 0.79, AUC = 0.81, AUC = 0.78). The predictive value of efficacy was further improved when all three factors were combined (AUC = 0.92, P = 0.000). Based on the ROC curve, we identified optimal cut-off value for three factors. Notably, patients with values below the optimal cut-off value had higher disease control rate and progression free survival. The levels of PD1 + TIM3 + T/T, TIGIT + T/T, and IL-6 after 2 cycles of immunotherapy may serve as predictors of treatment efficacy in patients with hepatocellular carcinoma.


Regulation of primary metabolic pathways in oyster mushroom mycelia induced by blue light stimulation: accumulation of shikimic acid.
Shikimic acid is a key intermediate in the aromatic amino acid pathway as well as an important starting material for the synthesis of Tamiflu, a potent and selective inhibitor of the neuraminidase enzyme of influenza viruses A and B. Here we report that in oyster mushroom (Pleurotus ostreatus) mycelia cultivated in the dark, stimulation with blue light-emitting diodes induces the accumulation of shikimic acid. An integrated analysis of primary metabolites, gene expression and protein expression suggests that the accumulation of shikimic acid caused by blue light stimulation is due to an increase in 3-deoxy-D-arabinoheptulosonate 7-phosphate synthase (DAHPS, EC220.127.116.11), the rate-determining enzyme in the shikimic acid pathway, as well as phosphofructokinase (PFK, EC188.8.131.52) and glucose-6-phosphate dehydrogenase (G6PD, EC126.96.36.199), the rate-determining enzymes in the glycolysis and pentose phosphate pathways, respectively. This stimulation results in increased levels of phosphoenolpyruvic acid (PEP) and erythrose-4-phosphate (E4P), the starting materials of shikimic acid biosynthesis.


Automaticity and multiple memory systems.
A large number of criteria have been proposed for determining when a behavior has become automatic. Almost all of these were developed before the widespread acceptance of multiple memory systems. Consequently, popular frameworks for studying automaticity often neglect qualitative differences in how different memory systems guide initial learning. Unfortunately, evidence suggests that automaticity criteria derived from these frameworks consistently misclassify certain sets of initial behaviors as automatic. Specifically, criteria derived from cognitive science mislabel much behavior still under the control of procedural memory as automatic, and criteria derived from animal learning mislabel some behaviors under the control of declarative memory as automatic. Even so, neither set of criteria make the opposite error-that is, both sets correctly identify any automatic behavior as automatic. In fact, evidence suggests that although there are multiple memory systems and therefore multiple routes to automaticity, there might nevertheless be only one common representation for automatic behaviors. A number of possible cognitive and cognitive neuroscience models of this single automaticity system are reviewed. WIREs Cogn Sci 2012, 3:363-376. doi: 10.1002/wcs.1172 For further resources related to this article, please visit the WIREs website.


Barriers and facilitators experienced in collaborative prospective research in orthopaedic oncology: A qualitative study.
As tumours of bone and soft tissue are rare, multicentre prospective collaboration is essential for meaningful research and evidence-based advances in patient care. The aim of this study was to identify barriers and facilitators encountered in large-scale collaborative research by orthopaedic oncological surgeons involved or interested in prospective multicentre collaboration. All surgeons who were involved, or had expressed an interest, in the ongoing Prophylactic Antibiotic Regimens in Tumour Surgery (PARITY) trial were invited to participate in a focus group to discuss their experiences with collaborative research in this area. The discussion was digitally recorded, transcribed and anonymised. The transcript was analysed qualitatively, using an analytic approach which aims to organise the data in the language of the participants with little theoretical interpretation. The 13 surgeons who participated in the discussion represented orthopaedic oncology practices from seven countries (Argentina, Brazil, Italy, Spain, Denmark, United States and Canada). Four categories and associated themes emerged from the discussion: the need for collaboration in the field of orthopaedic oncology due to the rarity of the tumours and the need for high level evidence to guide treatment; motivational factors for participating in collaborative research including establishing proof of principle, learning opportunity, answering a relevant research question and being part of a collaborative research community; barriers to participation including funding, personal barriers, institutional barriers, trial barriers, and administrative barriers and facilitators for participation including institutional facilitators, leadership, authorship, trial set-up, and the support of centralised study coordination. Orthopaedic surgeons involved in an ongoing international randomised controlled trial (RCT) were motivated by many factors to participate. There were a number of barriers to and facilitators for their participation. There was a collective sense of fatigue experienced in overcoming these barriers, which was mirrored by a strong collective sense of the importance of, and need for, collaborative research in this field. The experiences were described as essential educational first steps to advance collaborative studies in this area. Knowledge gained from this study will inform the development of future large-scale collaborative research projects in orthopaedic oncology.Cite this article: J. S. Rendon, M. Swinton, N. Bernthal, M. Boffano, T. Damron, N. Evaniew, P. Ferguson, M. Galli Serra, W. Hettwer, P. McKay, B. Miller, L. Nystrom, W. Parizzia, P. Schneider, A. Spiguel, R. Vélez, K. Weiss, J. P. Zumárraga, M. Ghert. Barriers and facilitators experienced in collaborative prospective research in orthopaedic oncology: A qualitative study. Bone Joint Res 2017;6:-314. DOI: 10.1302/2046-3758.65.BJR-2016-0192.R1.


Distinct roles of dorsal and ventral subthalamic neurons in action selection and cancellation.
The subthalamic nucleus (STN) supports action selection by inhibiting all motor programs except the desired one. Recent evidence suggests that STN can also cancel an already selected action when goals change, a key aspect of cognitive control. However, there is little neurophysiological evidence for dissociation between selecting and cancelling actions in the human STN. We recorded single neurons in the STN of humans performing a stop-signal task. Movement-related neurons suppressed their activity during successful stopping, whereas stop-signal neurons activated at low-latencies near the stop-signal reaction time. In contrast, STN and motor-cortical beta-bursting occurred only later in the stopping process. Task-related neuronal properties varied by recording location from dorsolateral movement to ventromedial stop-signal tuning. Therefore, action selection and cancellation coexist in STN but are anatomically segregated. These results show that human ventromedial STN neurons carry fast stop-related signals suitable for implementing cognitive control.


Proteomic response of human neuroblastoma cells to azaspiracid-1.
Azaspiracid-1 is a novel algal toxin, which causes an instantaneous rise of intracellular messengers, and an irreversible disarrangement of the actin cytoskeleton. Little is known regarding the molecular mechanisms that are involved in azaspiracid-1 toxicity. This study investigated global changes in protein expression by stable-isotope labelling with amino acids in culture and mass spectrometry, following exposure of human neuroblastoma cells to azaspiracid-1. The most highly upregulated proteins were involved in cellular energy metabolism, followed by cytoskeleton regulating proteins. The majority of downregulated proteins were involved in transcription, translation and protein modification. In addition, two proteins, component of oligomeric Golgi complex 5 and ras-related protein RAB1, which are involved in the maintenance of the Golgi complex and vesicle transport, respectively, were downregulated. Electron microscopy revealed a disruption of the Golgi complex by azaspiracid-1, and an accumulation of vesicles. In this study, the differential protein expression was examined prior to changes of the cytoskeleton structure in order to capture the primary effects of azaspiracid-1, however the observed changes were of unexpected complexity. Azaspiracid-1 caused a pronounced, but temporary depletion of ATP, which may be the reason for the observed complexity of cellular changes.


Patient and carer experience of blended diet via gastrostomy: a qualitative study.
Home enteral feeding is becoming increasingly prevalent within the UK. The use of commercial prescription formula is considered best practice; however, increasingly, patients are choosing to use blended diet via gastrostomy. There is anecdotal evidence suggesting both physical and social benefits, although there are concerns regarding the safety and efficacy of this method of feeding. The present study explores the experiences of patients who are currently using or have used this method of feeding in the past. Patients currently using or having previously used blended diet via gastrostomy were identified. Patients and their carers, where applicable, were invited to participate in a semi-structured interview. The data were transcribed and themes were identified. Thematic analysis of the data collected showed that patients had an overall positive experience of blended diet with few or no identified disadvantages. Participants reported improvements in gastrointestinal symptoms, as well as general wellbeing, in addition to the social benefits of their family member being included in family mealtimes. Reference was made to the lack of support for this method of feeding and the desire for blended diet to be offered as an alternative to commercial enteral feed. This research highlights the benefits of blended diet via gastrostomy as an alternative to commercial formula. More research is needed to develop evidence-based guidelines for patients and the healthcare professionals supporting them.


Sequence tag scanning: a new explorative strategy for recognition of unexpected protein alterations by nanoelectrospray ionization-tandem mass spectrometry.
Protein analysis by database search engines using tandem mass spectra is limited by the presence of unexpected protein modifications, sequence isoforms which may not be in the protein databases, and poor quality tandem mass spectrometry (MS/MS) of low abundance proteins. The analysis of expected protein modifications can be efficiently addressed by precursor ion scanning. However, it is limited to modifications that show such a characteristic loss in a peptide independent manner. We observed that proline and aspartic acid induced backbone fragmentation is accompanied by a low intensity signal for loss of H3PO4 for several pSer- or pThr-phosphopeptides. We describe here the use of peptide-specific fragments that can be used after a protein was identified to allow in-depth characterization of modifications and isoforms. We consider high abundance fragments formed by cleavage at the C-terminal side of aspartic acid, at the N-terminal side of proline and low mass ions such as a2, b2, b3, y1, y2, and y3. The MS/MS dataset is filtered for each sequence tag of interest by an in silico precursor ion scan. The resulting extracted ion traces are then combined by multiplication to increase specificity. Since the strategy is based on common peptide segments which are shared by different isoforms of peptides it can be applied to the analysis of any post-translational modification or sequence variants of a protein. This is demonstrated for the cases of serine and threonine phosphorylation, histone H1 acetylation and the spotting of multiple H1 isoforms.


A morphometric study of the lungs of different sized bats: correlations between structure and function of the chiropteran lung.
1. The lungs of four species of bats, Phyllostomus hastatus (PH, mean body mass, 98 g), Pteropus lylei (PL, 456 g), Pteropus alecto (PA, 667 g), and Pteropus poliocephalus (PP, 928 g) were analysed by morphometric methods. These data increase fivefold the range of body masses for which bat lung data are available, and allow more representative allometric equations to be formulated for bats. 2. Lung volume ranged from 4.9 cm3 for PH to 39 cm3 for PP. The volume density of the lung parenchyma (i.e. the volume proportion of the parenchyma in the lung) ranged from 94% in PP to 89% in PH. Of the components of the parenchyma, the alveoli composed 89% and the blood capillaries about 5%. 3. The surface area of the alveoli exceeded that of the blood-gas (tissue) barrier and that of the capillary endothelium whereas the surface area of the red blood cells as well as that of the capillary endothelium was greater than that of the tissue barrier. PH had the thinnest tissue barrier (0.1204 microns) and PP had the thickest (0.3033 microns). 4. The body mass specific volume of the lung, that of the volume of pulmonary capillary blood, the surface area of the blood-gas (tissue) barrier, the diffusing capacity of the tissue barrier, and the total morphometric pulmonary diffusing capacity in PH all substantially exceeded the corresponding values of the pteropid species (i.e. PL, PA and PP). This conforms with the smaller body mass and hence higher unit mass oxygen consumption of PH, a feature reflected in the functionally superior gas exchange performance of its lungs. 5. Morphometrically, the lungs of different species of bats exhibit remarkable differences which cannot always be correlated with body mass, mode of flight and phylogeny. Conclusive explanations of these pulmonary structural disparities in different species of bats must await additional physiological and flight biomechanical studies. 6. While the slope, the scaling factor (b), of the allometric equation fitted to bat lung volume data (b = 0.82) exceeds the value for flight VO2max (b = 0.70), those for the surface area of the blood-gas (tissue) barrier (b = 0.74), the pulmonary capillary blood volume (b = 0.74), and the total morphometric lung diffusing capacity for oxygen (b = 0.69) all correspond closely to the VO2max value. 7. Allometric comparisons of the morphometric pulmonary parameters of bats, birds and non-flying mammals reveal that superiority of the bat lung over that of the non-flying mammal.(ABSTRACT TRUNCATED AT 400 WORDS)


White muscle strain in the common carp and red to white muscle gearing ratios in fish
White muscle strains were recorded using sonomicrometry techniques for 70 fast-starts in the common carp Cyprinus carpio L. High-speed cine images were recorded simultaneously for 54 of these starts, and muscle strain was calculated independently from the digitized outlines of the fish. Sonomicrometry measurements of superficial muscle strain were not significantly different from the strain as calculated from the theory of simple bending of a homogeneous material: superficial muscle strain thus varied with chordwise distance from the spine. However, white muscle strain across a transverse section of the myotome shows less variation with chordwise position than would be expected from simple bending theory. Muscle strains measured using sonomicrometry thus do not necessarily represent the more uniform strain predicted for the whole section of the fish. White muscle strain can be accurately predicted from the spine curvatures as measured from the cine images if the gearing ratio between the red and white muscle fibres is known. A model for calculating the gearing ratio from the helical muscle fibre geometry was re-evaluated using current data for the kinematics of fast-starting C. carpio. This model predicted a mean gearing ratio of 2.8 for these fast-starts. A quicker, alternative approach to estimating gearing ratio from the position of the centroid of white fibre area is proposed and results in ratios similar to those calculated from the model of helical geometry. White muscle strains in fish can thus be estimated from measurements of spine curvature and muscle distribution alone.


Fluoxetine epigenetically alters the CaMKIIα promoter in nucleus accumbens to regulate ΔFosB binding and antidepressant effects.
Chronic social defeat stress in mice produces a susceptible phenotype characterized by several behavioral abnormalities consistent with human depression that are reversed by chronic but not acute exposure to antidepressant medications. Recent work in addiction models demonstrates that the transcription factor ΔFosB and protein kinase calmodulin-dependent protein kinase II (CaMKII) are co-regulated in nucleus accumbens (NAc), a brain reward region implicated in both addiction and depression models including social defeat. Previous work has also demonstrated that ΔFosB is induced in NAc after chronic social defeat stress or after chronic antidepressant treatment, wherein it mediates a pro-resilience or antidepressant-like phenotype. Here, using chromatin immunoprecipitation assays, we found that ΔFosB binds the CaMKIIα gene promoter in NAc and that this binding increases after mice are exposed to chronic social defeat stress. Paradoxically, chronic exposure to the antidepressant fluoxetine reduces binding of ΔFosB to the CaMKIIα promoter and reduces CaMKII expression in NAc, despite the fact that ΔFosB is induced under these conditions. These data suggest a novel epigenetic mechanism of antidepressant action, whereby fluoxetine induces some chromatin change at the CaMKIIα promoter, which blocks the ΔFosB binding. Indeed, chronic fluoxetine reduces acetylation and increases lysine-9 dimethylation of histone H3 at the CaMKIIα promoter in NAc, effects also seen in depressed humans exposed to antidepressants. Overexpression of CaMKII in NAc blocks fluoxetine's antidepressant effects in the chronic social defeat paradigm, whereas inhibition of CaMKII activity in NAc mimics fluoxetine exposure. These findings suggest that epigenetic suppression of CaMKIIα expression in NAc is behaviorally relevant and offer a novel pathway for possible therapeutic intervention in depression and related syndromes.


Changes in hepatic RNA, poly(A)+RNA, and poly(A)-RNA during the acute phase response to inflammation.
The steady state changes in total rat hepatic cytoplasmic RNA, poly(A)+ RNA and poly(A)-RNA were assessed in response to turpentine induced inflammation. From 18 to 24 h after injury, cytoplasmic RNA doubled, while poly(A)+ RNA peaked at 24 h, 3.5 times over control animals. Cell-free translation showed significant increases in messenger RNA levels beginning at 18 h. Gel electrophoresis of translation products revealed significant increases in several polypeptides and a decrease in others. Poly(A)-RNA from control and injured rats translated to an insignificant level and the electrophoretic gel patterns of their proteins were similar. Furthermore, no change had occurred in the 3' poly(A)-sequences during the course of inflammation.


Propofol versus Ketofol for Sedation of Pediatric Patients Undergoing Transcatheter Pulmonary Valve Implantation: A Double-blind Randomized Study.
The study was done to compare propofol and ketofol for sedation of pediatric patients scheduled for elective pulmonary valve implantation in a catheterization laboratory. This was a double-blind randomized study. This study was conducted in Prince Sultan Cardiac Centre, Saudi Arabia. The study included 60 pediatric patients with pulmonary regurge undergoing pulmonary valve implantation. The study included sixty patients, classified into two groups (n = 30). Group A: Propofol was administered as a bolus dose (1-2 mg/kg) and then a continuous infusion of 50-100 μg/kg/min titrated as needed. Group B: Ketofol was administered 1-2 mg/kg and then infusion of 20-60 μg/kg/min. The medication was prepared by the nursing staff and given to anesthetist blindly. The monitors included heart rate, mean arterial blood pressure, respiratory rate, temperature, SPO2and PaCO2, Michigan Sedation Score, fentanyl dose, antiemetic medications, and Aldrete score. The comparison of heart rate, mean arterial pressure, respiratory rate, temperature, SPO2and PaCO2, Michigan Sedation Score, and Aldrete score were insignificant (P > 0.05). The total fentanyl increased in Group A more than Group B (P = 0.045). The required antiemetic drugs increased in Group A patients more than Group B (P = 0.020). The durations of full recovery and in the postanesthesia care unit were longer in Group A than Group B (P = 0.013, P < 0.001, respectively). The use of propofol and ketofol is safe and effective for sedation of pediatric patients undergoing pulmonary valve implantation in a catheterization laboratory. However, ketofol has many advantages more than the propofol. Ketofol has a rapid onset of sedation, a rapid recovery time, decreased incidence of nausea and vomiting and leads to rapid discharge of patients from the postanesthesia care unit.


18F-FDG PET-CT Findings Before and After Laparoscopic Cryoablation of Small Renal Mass: An Initial Report.
The aim of this study was to describe the characteristics of positron emission tomography (PET) molecular imaging combined with low-dose computed tomography (CT) in small renal mass (SRM) treated with cryoablation (CA). Currently, treatment success is defined by the absence of contrast enhancement at CT. However, the use of contrast is relatively contraindicated in patients with renal function impairment, mandating alternative follow-up strategies. Several reasons were identified as criteria for performing PET-CT before and/or after SRM-CA in 9 patients, and the results were retrospectively studied. The histology revealed renal cell carcinoma in 7 patients and oncocytoma in 2 patients. In 6 patients, a PET-CT was performed before and after CA. In one patient, the PET-CT was performed only before CA and in 2 patients only after CA. Before CA, clearly there was metabolic uptake of fluorine-18 fluorodeoxyglucose (18F-FDG) in the SRM in all patients. Following CA, the absence of 18F-FDG uptakes in the SRM could clearly be noticed. However, the tracer cannot always be distinguished from focal recurrence or reactive inflammatory tissue. In one patient, asymptomatic metastatic bone lesions were noticed when performing PET-CT at follow-up. This pilot study with 18F-FDG PET-CT for the follow-up of SRM cryosurgery showed that 18F-FDG PET-CT imaging could be used to characterize cryoablative tissue injury at different times after CA.


The effects of tai chi chuan exercise training on countermovement jump performance in the elderly.
This study sought to compare the biomechanical parameters of the lower extremities during a countermovement jump in elderly people who are engaged in frequent practice of tai chi chuan (TCG) and in the general population of healthy elderly people (HG). Each group included 12 participants. Ten Vicon Motion System infrared cameras and two Kistler force plates were employed for measurement. The jump height, duration, centre of mass (COM) displacement, joint ROM, and upward velocity were analysed in this study. Motion analysis and force platform data were combined to calculate joint moments and powers during the takeoff phase. The data were analysed using independent sample t-tests. The results showed that the tai chi chuan practitioner group (0.13 m) achieved 44% higher jump heights (p < 0.05). The COM displacement during squatting was lower in the TCG (0.25 m) than in the HG (0.19 m) (p < 0.05). The knee and ankle ROMs of the TCG were higher than those of the HG (p < 0.05). Peak knee moment 23% and peak knee power 32% higher in TCG compared to the HG (p < 0.05), suggesting that frequent practice of tai chi chuan may slow the rate of knee degeneration.


Intraluminal laser speckle rheology using an omni-directional viewing catheter.
A number of disease conditions in luminal organs are associated with alterations in tissue mechanical properties. Here, we report a new omni-directional viewing Laser Speckle Rheology (LSR) catheter for mapping the mechanical properties of luminal organs without the need for rotational motion. The LSR catheter incorporates multiple illumination fibers, an optical fiber bundle and a multi-faceted mirror to permit omni-directional viewing of the luminal wall. By retracting the catheter using a motor-drive assembly, cylindrical maps of tissue mechanical properties are reconstructed. Evaluation conducted in a test phantom with circumferentially-varying mechanical properties demonstrates the capability of the LSR catheter for the accurate mechanical assessment of luminal organs.


Evaluation of Anti-Wrinkle Effects of DuOligo, Composed of Lactulose and Galactooligosaccharides.
Currently, alternatives to prebiotics for skin treatment are receiving much interest. However, little is known about the efficacy of topically applied prebiotics in skin anti-aging. This study was conducted to observe the anti-aging effects of DuOligo, which is composed of lactulose and galactooligosaccharides (GOS). We investigated wrinkle-related parameters by quantitative and qualitative skin evaluation in healthy women who consumed DuOligo for 8 weeks. The double-blind, randomized, and placebo-controlled study included subjects who were divided into two groups (Placebo: dextrin 4.5 g/d, n=14, 51.50 y vs. DuOligo: DuOligo 4.5 g/d, n=14, 52.65 y). The DuOligo group showed a reduction in mean wrinkle length and depth measured via quantitative skin evaluation after 8 weeks, whereas the Placebo group showed slight increases in these parameters (P<0.001). The wrinkle severity rating scale in the DuOligo group was decreased after 8 weeks, but it increased in the Placebo group (Placebo group: 0.14 vs. DuOligo group: -0.86, P<0.001). The global aesthetic improvement scale for the DuOligo group was significantly higher than that for the Placebo group at week 8 (P<0.001). In conclusion, our findings suggest that oral consumption of DuOligo is beneficial to the skin, and present the possibility of new nutritional strategies for wrinkle care.


Time dependent processing in a parallel pipeline architecture.
Pipeline architectures provide a versatile and efficient mechanism for constructing visualizations, and they have been implemented in numerous libraries and applications over the past two decades. In addition to allowing developers and users to freely combine algorithms, visualization pipelines have proven to work well when streaming data and scale well on parallel distributed-memory computers. However, current pipeline visualization frameworks have a critical flaw: they are unable to manage time varying data. As data flows through the pipeline, each algorithm has access to only a single snapshot in time of the data. This prevents the implementation of algorithms that do any temporal processing such as particle tracing; plotting over time; or interpolation, fitting, or smoothing of time series data. As data acquisition technology improves, as simulation time-integration techniques become more complex, and as simulations save less frequently and regularly, the ability to analyze the time-behavior of data becomes more important. This paper describes a modification to the traditional pipeline architecture that allows it to accommodate temporal algorithms. Furthermore, the architecture allows temporal algorithms to be used in conjunction with algorithms expecting a single time snapshot, thus simplifying software design and allowing adoption into existing pipeline frameworks. Our architecture also continues to work well in parallel distributed-memory environments. We demonstrate our architecture by modifying the popular VTK framework and exposing the functionality to the ParaView application. We use this framework to apply time-dependent algorithms on large data with a parallel cluster computer and thereby exercise a functionality that previously did not exist.


Effects of Cocoa Polyphenols and Dark Chocolate on Obese Adults: A Scoping Review.
Obesity remains a major public health problem due to its increasing prevalence. Natural products have become common as adjunct therapeutic agents for treating obesity and preventing metabolic diseases. Cocoa and its products are commonly consumed worldwide. Dark chocolate, a rich source of polyphenols, has received attention lately for its beneficial role in the management of obesity; however, conflicting results are still being reported. This scoping review aims to provide a comprehensive understanding of the existing literature on the relationship and effects of cocoa and dark chocolate intake among obese adults. We searched multiple databases for research investigating the consumption of cocoa and/or dark chocolate in managing obesity among adults. This review includes epidemiological and human studies that were published in English over the last 10 years. Our review of the current literature indicates that epidemiological and human trials with obese adults have shown inconsistent results, which may be due to the different populations of subjects, and different types of cocoa products and doses used for intervention. Studies among obese adults are mainly focusing on obese individuals with comorbidities, as such more studies are needed to elucidate the role of cocoa polyphenols in weight control and preventing the risk of chronic diseases among obese individuals without comorbidities as well as healthy individuals. Careful adjustment of confounding factors would be required. The effects of cocoa and dark chocolate intake on obese adults were discussed, and further research is warranted to identify the gaps.


Cytoprotective effects of polyenoylphosphatidylcholine (PPC) on beta-cells during diabetic induction by streptozotocin.
Polyenoylphosphatidylcholine (PPC), a phosphatidylcholine-rich phospholipid extracted from soybean, has been reported to protect liver cells from alloxan-induced cytotoxicity. The present study aimed to investigate whether PPC protects pancreatic beta-cells from the cytotoxic injury induced by streptozotocin, thus preserving insulin synthesis and secretion. beta-Cells of the PPC-treated rats showed a significant reduction of cell death with lesser destruction of plasma membrane on streptozotocin insult. They demonstrated a rapid recovery of GLUT-2 expression, whereas almost irreversible depletion of membrane-bound GLUT-2 was seen in beta-cells of the rats treated with only streptozotocin. A similar cytoprotective effect of PPC was also monitored in the PPC-pretreated MIN6 cells. These beta-cells retained their ability to synthesize and secrete insulin and no alteration of glucose metabolism was detected. These results strongly suggest that PPC plays important roles not only in protecting beta-cells against cytotoxicity but also in maintaining their insulin synthesis and secretion for normal glucose homeostasis.


Switchable aerobic/anaerobic multi-substrate biofuel cell operating on anodic and cathodic enzymatic cascade assemblies.
Enzymatic fuel cells may become more accessible for applications powering portable electronic devices by broadening the range of potentially usable fuels and oxidizers. In this work we demonstrate the operation of an integrated, yet versatile multi-substrate biofuel cell utilizing either glucose, fructose, sucrose or combinations of thereof as biofuels, and molecular oxygen originating from solution phase and/or an internal chemical source, as the oxidizer. In order to achieve this goal we designed an enzymatic cascade-functionalized anode consisting of invertase (INV), mutarotase (MUT), glucose oxidase (GOX), and fructose dehydrogenase (FDH), deposited on top of a mesoporous carbon nanoparticle matrix, in which electron relay molecules had been entrapped. The anode was then conjugated to a compatible enzymatic cathode that employs a cascade of catalase (CAT) and bilirubin oxidase (BOD), allowing the cell to operate in an aerobic environment and/or to utilize, under anaerobic conditions for instance, hydrogen peroxide as a source for the oxygen oxidizer. While operated in the presence of the sugar mixture and hydrogen peroxide, the power output of the dually cascaded biofuel cell reaches a peak power density of 0.25 mW cm-2 and demonstrates an open circuit potential of 0.65 V. To our knowledge this is the first reported biofuel cell that discharges with both anodic and cathodic enzymatic cascade architectures and the first biofuel cell that is repeatedly switched between aerobic and anaerobic conditions without any significant decrease in the discharge performance.


Osteoporosis in rheumatoid arthritis: safety of low dose corticosteroids.
Fear of inducing generalised osteoporosis is one reason why corticosteroids are withheld in patients with rheumatoid arthritis (RA). No studies, however, have directly measured bone density in such patients at clinically relevant sites. To assess this risk we measured bone mineral density in the lumbar spine and femoral neck by dual photon absorptiometry in 84 patients with RA, 44 of whom had been treated with low dose prednis(ol)one (mean dose +/- SE 8.0 +/- 0.5 mg/day; mean duration of treatment 89.6 +/- 12.0 months). There were significant reductions in bone mineral density in patients treated with corticosteroids (lumbar 9.6%, p less than 0.001; femoral 12.2%, p less than 0.001) and in those who had not received corticosteroids (lumbar 6.9%, p less than 0.01; femoral 8.9%, p less than 0.001), but the differences between the two groups were not significant. We conclude on the basis of these studies that low dose oral corticosteroids do not increase the risk of generalised osteoporosis in patients with rheumatoid arthritis.


Willingness to Participate in Longitudinal Research Among People with Chronic Pain Who Take Medical Cannabis: A Cross-Sectional Survey.
Background: Regulatory barriers limit clinical trials of medical cannabis in the United States. Longitudinal cohort studies may be one feasible alternative that could yield clinically relevant information. Willingness to participate in such studies is not known. Materials and Methods: In October 2016, we surveyed a convenience sample of patients with chronic pain from two New York registered organizations (responsible for growing, processing, distributing, and retailing medical cannabis products). After a vignette describing a longitudinal cohort study involving weekly patient-reported outcomes and quarterly assessments of physical functioning and urine and blood tests, we asked about respondents' willingness to participate. We examined willingness to participate, duration of participation, and frequency of data collections overall and by subgroups, using multivariable logistic regression models. Results: Of 405 respondents (estimated response rate: 30%), 54% were women and 81% were white non-Hispanic. Neuropathy was the most common pain condition (67%) followed by inflammatory bowel disease (19%). Of respondents, 94% (95% CI 92-97%) thought that the study should be done, 85% (95% CI 81-88%) would definitely or probably enroll if asked, 76% (95% CI 72-81%) would participate for ≥1 year, and 59% (95% CI 54-64%) would respond to questions at least daily. Older age was the only factor associated with lower willingness to participate, lower willingness to participate for ≥1 year, and lower willingness to respond to questions at least daily. Conclusions: Nearly all respondents were supportive of the proposed study and most reported that they would enroll if asked. Enhanced engagement with older individuals may be needed to promote equal enrollment. Recruitment for longitudinal cohort studies with frequent data collection appears feasible in this patient population.


Nucleotide excision repair of DNA with recombinant human proteins: definition of the minimal set of factors, active forms of TFIIH, and modulation by CAK.
During human nucleotide excision repair, damage is recognized, two incisions are made flanking a DNA lesion, and residues are replaced by repair synthesis. A set of proteins required for repair of most lesions is RPA, XPA, TFIIH, XPC-hHR23B, XPG, and ERCC1-XPF, but additional components have not been excluded. The most complex and difficult to analyze factor is TFIIH, which has a 6-subunit core (XPB, XPD, p44, p34, p52, p62) and a 3-subunit kinase (CAK). TFIIH has roles both in basal transcription initiation and in DNA repair, and several inherited human disorders are associated with mutations in TFIIH subunits. To identify the forms of TFIIH that can function in repair, recombinant XPA, RPA, XPC-hHR23B, XPG, and ERCC1-XPF were combined with TFIIH fractions purified from HeLa cells. Repair activity coeluted with the peak of TFIIH and with transcription activity. TFIIH from cells with XPB or XPD mutations was defective in supporting repair, whereas TFIIH from spinal muscular atrophy cells with a deletion of one p44 gene was active. Recombinant TFIIH also functioned in repair, both a 6- and a 9-subunit form containing CAK. The CAK kinase inhibitor H-8 improved repair efficiency, indicating that CAK can negatively regulate NER by phosphorylation. The 15 recombinant polypeptides define the minimal set of proteins required for dual incision of DNA containing a cisplatin adduct. Complete repair was achieved by including highly purified human DNA polymerase delta or epsilon, PCNA, RFC, and DNA ligase I in reaction mixtures, reconstituting adduct repair for the first time with recombinant incision factors and human replication proteins.


Results of islet isolation and their relationship to the clinical outcome of kidney transplantation in cases where both grafts are harvested from the same non-heart-beating donor.
Grafts from non-heart-beating donors (NHBDs) are used because of the limited availability of heart-beating brain-dead donors. These grafts sustain ischemic damage, and the severity of this damage varies among different areas of an organ. This study determined whether the results of islet isolation were correlated with the clinical outcomes of kidney transplantations in cases where both grafts were harvested from the same NHBD. Islets we isolated from the pancreata of 23 NHBDs between February 2004 and March 2007. Forty-six kidneys were also harvested from these NHBDs. The recipients of kidney transplants were divided into the successful isolation (n = 14) and failed isolation (n = 32) groups depending on the results of islet isolation. The clinical outcomes of kidney transplantation were compared between the recipients in these two groups. The immediate graft function rate and the 1-year graft survival rate after kidney transplantation in both groups were similar. Hemodialysis after transplantation was required for 6.0 days (SD, 5.2 days) in the successful isolation group and for 12.7 days (13.1 days) in the failed isolation group (p < 0.05). The serum creatinine concentrations at 1, 3, 6, and 12 months after transplantation were elevated in the failed isolation group (p < 0.05). The islet yield was inversely correlated with the requirement of hemodialysis (days) and the serum creatinine level at 1 month after transplantation. However, hemodialysis was required for only 7 days in the recipients of six kidneys that were obtained from NHBDs from whom <40,000 IEQ were obtained (extreme failure of islet isolation). The results of islet isolation were found to correlate with the kidney function after transplantation when both grafts are harvested from the same NHBD. However, the marginal conditions of NHBDs affect the results of islet isolation more than they do the posttransplantation kidney function.


Head-Mounted Virtual Reality and Mental Health: Critical Review of Current Research.
eHealth interventions are becoming increasingly used in public health, with virtual reality (VR) being one of the most exciting recent developments. VR consists of a three-dimensional, computer-generated environment viewed through a head-mounted display. This medium has provided new possibilities to adapt problematic behaviors that affect mental health. VR is no longer unaffordable for individuals, and with mobile phone technology being able to track movements and project images through mobile head-mounted devices, VR is now a mobile tool that can be used at work, home, or on the move. In line with recent advances in technology, in this review, we aimed to critically assess the current state of research surrounding mental health. We compiled a table of 82 studies that made use of head-mounted devices in their interventions. Our review demonstrated that VR is effective in provoking realistic reactions to feared stimuli, particularly for anxiety; moreover, it proved that the immersive nature of VR is an ideal fit for the management of pain. However, the lack of studies surrounding depression and stress highlight the literature gaps that still exist. Virtual environments that promote positive stimuli combined with health knowledge could prove to be a valuable tool for public health and mental health. The current state of research highlights the importance of the nature and content of VR interventions for improved mental health. While future research should look to incorporate more mobile forms of VR, a more rigorous reporting of VR and computer hardware and software may help us understand the relationship (if any) between increased specifications and the efficacy of treatment.


Transformation of Triclosan by Fe(III)-saturated montmorillonite.
Abiotic transformation of triclosan (TCS) was investigated by incubating TCS with Fe(III)- and Na-montmorillonite at 40% relative humidity and room temperature for up to 100 days. The TCS transformation products were characterized using LC/MS, GC/MS, and computational modeling and quantified using HPLC/UV and GC/MS. Within 1-5 days, depending on the initial TCS concentrations, about 55% of the TCS was rapidly transformed in the presence of Fe(III)-montmorillonite, producing 2,4-dichlorophenol, 3-chlorophenol, 2,4-dichlorophenol dimer, chlorophenoxy phenols, and TCS dimers and trimers. Computational modeling based on density functional theory confirmed the formation of four TCS dimer conformers and six TCS trimer conformers. The TCS phenoxy radicals, produced by Fe(III) oxidation of TCS, react with other TCS molecules to form TCS dimers. The TCS trimers were formed by attachment of TCS dimer phenoxy radicals, produced by Fe(III) oxidation of TCS dimers, with TCS molecules. Significantly smaller quantities of TCS transformation products were detected in the reactions with Na-montmorillonite compared to the reactions with Fe(III)-montmorillonite. Formation of a significant amount of 2,4-dichlorophenol, especially in reaction with Fe(III)-montmorillonite, may have negative impact on the environment because of its toxicity. However, mineral-facilitated TCS polymerization may reduce its mobility and bioavailability in soils.


Sacrohysteropexy performed as uterus conserving surgery for pelvic organ prolapse: Review of case files.
To assess the outcome and safety of sacrohysteropexy as uterus conserving surgery for pelvic organ prolapse in young women and to assess patients' satisfaction with the procedure. This is a case series of patients operated at Sind Government Lyari General Hospital and Civil Hospital Karachi, between January, 2007 to October, 2015. Data of the patients who had sacrohysteropexy were reviewed. Complications during surgery and post-operative period including haemorrhage, visceral injury, paralytic ileus and peritonitis were studied. Success of procedure, need of blood transfusion, hospital stay and condition on discharge and six weeks follow-up were noted. Data were analyzed using SPSS version 16. Mean ± SD was calculated for numerical, while frequencies were computed for categorical variables. Data of 60 patients were reviewed. Early post-operative success was 100%. Duration of surgery was less than two hours in 57 (95%) patients. Blood loss was negligible in majority of cases. Out of all 60 cases, 52 (86.7%) did not suffer any complication. One patient had ureteric injury, while one patient sustained bowel injury. Two patients had paralytic ileus. Four patients suffered from abdominal wound infection. All patients were managed satisfactorily. Mean duration of stay in hospital was four days. Upon follow up 96.7% patients were satisfied with results of operative procedure. Sixteen (26.7%) patients complained of backache on follow-up visit. This review concludes that sacrohysteropexy was successful in all cases in early post-operative period. It is a safe procedure and should be considered as an option for the treatment of pelvic organ prolapse in young women, in whom uterine conservation is required.


Adenylyl Cyclase 6 Mediates Inhibition of TNF in the Inflammatory Reflex.
Macrophage cytokine production is regulated by neural signals, for example in the inflammatory reflex. Signals in the vagus and splenic nerves are relayed by choline acetyltransferase+ T cells that release acetylcholine, the cognate ligand for alpha7 nicotinic acetylcholine subunit-containing receptors (α7nAChR), and suppress TNF release in macrophages. Here, we observed that electrical vagus nerve stimulation with a duration of 0.1-60 s significantly reduced systemic TNF release in experimental endotoxemia. This suppression of TNF was sustained for more than 24 h, but abolished in mice deficient in the α7nAChR subunit. Exposure of primary human macrophages and murine RAW 264.7 macrophage-like cells to selective ligands for α7nAChR for 1 h in vitro attenuated TNF production for up to 24 h in response to endotoxin. Pharmacological inhibition of adenylyl cyclase (AC) and knockdown of adenylyl cyclase 6 (AC6) or c-FOS abolished cholinergic suppression of endotoxin-induced TNF release. These findings indicate that action potentials in the inflammatory reflex trigger a change in macrophage behavior that requires AC and phosphorylation of the cAMP response element binding protein (CREB). These observations further our mechanistic understanding of neural regulation of inflammation and may have implications for development of bioelectronic medicine treatment of inflammatory diseases.


Music, heart rate variability, and symptom clusters: a comparative study.
This study aimed to explore the possible range of change of a single-session music intervention (SMI) on symptom clusters and neurological reactivity for women with breast cancer undergoing chemotherapy. A parallel and randomized, controlled study with repeated measures design was used. A total of 100 women with breast cancer were randomly assigned to the SMI or a control group. The outcome measurements of symptom cluster were collected using the Multidimensional Fatigue Symptom Inventory, Pittsburgh Sleep Quality Index, the Hospital Anxiety and Depression Scale, and the neurological reactivity with heart rate variability at four time points: before commencement of the intervention (T0), immediately afterward (T1), 1 week later (T2), and 3 weeks after the intervention (T3). Of the 50 women in each group, 46 in the SMI and 48 in the control group completed the post-test at T3. Multivariate analysis of variance indicated that the SMI group had a medium effect in change of symptom clusters compared to the control group at T2. Moreover, after adjusting for baseline between normal and higher levels of sympathetic tone activity, significant differences existed in fatigue and depression at T2 and sleep disturbance at T3. A single-session music intervention can be effectively used to reduce symptom clusters for women with breast cancer. Targeting those who have a higher level of sympathetic tone activity is recommended.


Coronary vascular hemodynamic and permeability changes during reperfusion after no-flow ischemia in isolated, diltiazem-treated rabbit hearts.
Effects of diltiazem on coronary vascular functional integrity were assessed in isolated rabbit hearts during reperfusion after 30 min of global, no-flow ischemia. External detection of radiolabeled albumin, [125I]bovine serum albumin ([125I]BSA), and compartmental-model analysis were used to estimate the mean transit time of [125I]BSA (tBSA), vascular volume (V1), and vascular into extravascular space clearance (F21) for [125I]BSA. Perfusion pressure, left ventricular (LV) end-diastolic pressure, LV developed pressure, maximum +dP/dt, and V1 remained constant during 5 h of continuous perfusion, while tBSA and F21 gradually increased (1.5 and 2.4 times baseline, respectively). Diltiazem, 4 microM, increased total water content (8.5%) and decreased perfusion pressure (11%), LV developed pressure (22%), and +dP/dt (24%) in nonischemic control experiments, but did not significantly affect estimates of V1, extracellular space, tBSA, or albumin permeation. During reperfusion after 30 min of ischemia, V1 increased 40% and perfusion pressure increased 60%, while tBSA and F21 increased three and eight times baseline, respectively. LV developed pressure and +dP/dt returned to control levels, even though the water content and extracellular space of ischemic hearts were increased significantly. Diltiazem, 4 microM, blocked ischemia-reperfusion-induced increases in water content, extracellular space, vascular resistance, V1, and vascular permeability to [125I]BSA, without reducing LV developed pressure or +dP/dt relative to nonischemic diltiazem controls. These results suggest that protection of ischemic myocardium by diltiazem is mediated, at least in part, by preservation of vascular functional integrity.


Effects of differential rates of alternative reinforcement on resurgence of human behavior.
Despite the success of exposure-based psychotherapies in anxiety treatment, relapse remains problematic. Resurgence, the return of previously eliminated behavior following the elimination of an alternative source of reinforcement, is a promising model of operant relapse. Nonhuman resurgence research has shown that higher rates of alternative reinforcement result in faster, more comprehensive suppression of target behavior, but also in greater resurgence when alternative reinforcement is eliminated. This study investigated rich and lean rates of alternative reinforcement on response suppression and resurgence in typically developing humans. In Phase 1, three groups (Rich, n = 18; Lean, n = 18; Control, n = 10) acquired the target response. In Phase 2, target responding was extinguished and alternative reinforcement delivered on RI 1 s, RI 3 s, and extinction schedules, respectively. Resurgence was assessed during Phase 3 under extinction conditions for all groups. Target responding was suppressed most thoroughly in Rich and partially in Lean. Target responding resurged in the Rich and Lean groups, but not in the Control group. Between groups, resurgence was more pronounced in the Rich group than the Lean and Control groups. Clinical implications of these findings, including care on the part of clinicians when identifying alternative sources of reinforcement, are discussed.


Crop climate suitability mapping on the cloud: a geovisualization application for sustainable agriculture.
Climate change, food security, and environmental sustainability are pressing issues faced by today's global population. As production demands increase and climate threatens crop productivity, agricultural research develops innovative technologies to meet these challenges. Strategies include biodiverse cropping arrangements, new crop introductions, and genetic modification of crop varieties that are resilient to climatic and environmental stressors. Geography in particular is equipped to address a critical question in this pursuit-when and where can crop system innovations be introduced? This manuscript presents a case study of the geographic scaling potential utilizing common bean, delivers an open access Google Earth Engine geovisualization application for mapping the fundamental climate niche of any crop, and discusses food security and legume biodiversity in Sub-Saharan Africa. The application is temporally agile, allowing variable growing season selections and the production of 'living maps' that are continually producible as new data become available. This is an essential communication tool for the future, as practitioners can evaluate the potential geographic range for newly-developed, experimental, and underrepresented crop varieties for facilitating sustainable and innovative agroecological solutions.


Glucocorticoids counteract hypertrophic effects of myostatin inhibition in dystrophic muscle.
Duchenne muscular dystrophy (DMD) is a devastating genetic muscle disease resulting in progressive muscle degeneration and wasting. Glucocorticoids, specifically prednisone/prednisolone and deflazacort, are commonly used by DMD patients. Emerging DMD therapeutics include those targeting the muscle-wasting factor, myostatin (Mstn). The aim of this study was to investigate how chronic glucocorticoid treatment impacts the efficacy of Mstn inhibition in the D2.mdx mouse model of DMD. We report that chronic treatment of dystrophic mice with prednisolone (Pred) causes significant muscle wasting, entailing both activation of the ubiquitin-proteasome degradation pathway and inhibition of muscle protein synthesis. Combining Pred with Mstn inhibition, using a modified Mstn propeptide (dnMstn), completely abrogates the muscle hypertrophic effects of Mstn inhibition independently of Mstn expression or SMAD3 activation. Transcriptomic analysis identified that combining Pred with dnMstn treatment affects gene expression profiles associated with inflammation, metabolism, and fibrosis. Additionally, we demonstrate that Pred-induced muscle atrophy is not prevented by Mstn ablation. Therefore, glucocorticoids interfere with potential muscle mass benefits associated with targeting Mstn, and the ramifications of glucocorticoid use should be a consideration during clinical trial design for DMD therapeutics. These results have significant implications for past and future Mstn inhibition trials in DMD.


Integrating evolutionary and functional tests of adaptive hypotheses: a case study of altitudinal differentiation in hemoglobin function in an Andean Sparrow, Zonotrichia capensis.
In air-breathing vertebrates, the physiologically optimal blood-O2 affinity is jointly determined by the prevailing partial pressure of atmospheric O2, the efficacy of pulmonary O2 transfer, and internal metabolic demands. Consequently, genetic variation in the oxygenation properties of hemoglobin (Hb) may be subject to spatially varying selection in species with broad elevational distributions. Here we report the results of a combined functional and evolutionary analysis of Hb polymorphism in the rufous-collared sparrow (Zonotrichia capensis), a species that is continuously distributed across a steep elevational gradient on the Pacific slope of the Peruvian Andes. We integrated a population genomic analysis that included all postnatally expressed Hb genes with functional studies of naturally occurring Hb variants, as well as recombinant Hb (rHb) mutants that were engineered through site-directed mutagenesis. We identified three clinally varying amino acid polymorphisms: Two in the α(A)-globin gene, which encodes the α-chain subunits of the major HbA isoform, and one in the α(D)-globin gene, which encodes the α-chain subunits of the minor HbD isoform. We then constructed and experimentally tested single- and double-mutant rHbs representing each of the alternative α(A)-globin genotypes that predominate at different elevations. Although the locus-specific patterns of altitudinal differentiation suggested a history of spatially varying selection acting on Hb polymorphism, the experimental tests demonstrated that the observed amino acid mutations have no discernible effect on respiratory properties of the HbA or HbD isoforms. These results highlight the importance of experimentally validating the hypothesized effects of genetic changes in protein function to avoid the pitfalls of adaptive storytelling.