Local delivery of a direct renin inhibitor into the kidney ameliorates progression of experimental glomerulonephritis.
Increasing evidence indicates that locally blocking renin-angiotensin system activity exerts a beneficial effect on glomerulonephritis (GN) progression leading to irreversible glomerulosclerosis. This is the first study on the pharmacological effect of the renal delivery of aliskiren, a direct renin inhibitor, in a progressive model of anti-Thy-1 GN. Local blockade of renin activity was accomplished by subrenal capsular implantation of a collagen sponge with aliskiren. The pharmacological effect was evaluated by semiquantitative and quantitative analysis of immunohistological findings and by analysis of glomerular microcirculation using an intravital microscope system. Quantitative mesangial matrix analysis showed that local treatment with aliskiren significantly suppressed mesangial matrix expansion and ameliorated the glomerular sclerotic index in the progressive model of ATS GN. Immunofluorescent studies revealed that renin expression at the juxtaglomerular region was enhanced in the ATS + aliskiren group, and pathological expressions of α-smooth muscle cell actin and type I collagen in ATS GN were remarkably decreased by local treatment with aliskiren. Furthermore, local delivery of aliskiren significantly improved glomerular blood flow levels. This study revealed that renally delivered aliskiren has a renoprotective effect on potentially progressive glomerulosclerosis.


Perceived Health Risks of Snus and Medicinal Nicotine Products.
Perceived health risk (PHR) of a tobacco product may influence both uptake and continued use. In this study, we examined PHRs of snus and medicinal nicotine using the PHR scale and the relationship of PHR responses to use of these products in smokers seeking an alternative to smoking. Smokers were randomly assigned to snus or to medicinal nicotine for a period of 12 weeks and asked to only use the assigned product. The PHR scale involves rating the extent of perceived risk of a product for different diseases and was given at baseline and weeks 4 and 12 during treatment. Relationships between PHR scale scores and study attrition, compliance with only using the product, and continued use of the product after treatment were determined. Response to the PHR scale showed no significant differences between the snus and medicinal nicotine for perceived risks for lung cancer, emphysema, and bronchitis. However, significant differences were observed for other cancers, heart disease, stroke and risk for addiction, particularly after product use, with higher scores among those assigned to snus. Scores on the PHR scale were not related to any of the trial outcome variables. Among smokers seeking an alternative to smoking in a clinic setting, PHR of a product changes after product use but may not be related to product use patterns. PHRs of snus or medicinal nicotine in smokers assigned to these products become more accurate after product use. PHR does not appear to be associated with patterns of product use; rather satisfaction with a product is a better indicator as to whether a smoker is compliant with only using the product or continues to use the product.


Cytotoxic flavaglines and bisamides from Aglaia edulis.
Two new cyclopenta[b]benzofurans, aglaroxin A 1-O-acetate (2) and 3'-methoxyaglaroxin A 1-O-acetate (3), a new benzo[b]oxepine, 19,20-dehydroedulisone A (4), and five new cyclopenta[bc]benzopyrans, edulirin A (5), edulirin A 10-O-acetate (6), 19,20-dehydroedulirin A (7), isoedulirin A (8), and edulirin B (9), were isolated from the bark of Aglaia edulis, along with one known cyclopenta[b]benzofuran, aglaroxin A (1). Additionally, four new amides, aglamides A-D (10-13), as well as three known compounds, aglalactone, scopoletin, and 5-hydroxy-3,6,7,4'-tetramethoxyflavone, were isolated from the leaves and/or twigs of this species. The structures of the new compounds (2-13) were elucidated by interpretation of their spectroscopic data. All isolates obtained in this study were evaluated for cytotoxicity against both several human cancer cell lines (Lu1, LNCaP, and MCF-7) and a nontumorigenic (HUVEC) cell line. Among these isolates, the cyclopenta[b]benzofurans (1-3) exhibited potent in vitro cytotoxic activity (ED50 range 0.001 to 0.8 microg/mL). Aglaroxin A 1-O-acetate (2) was further evaluated in the in vivo P388 lymphocytic leukemia model, by intraperitoneal injection, but found to be inactive in this model.


Lessons from Frankenstein: narrative myth as ethical model.
As Frankenstein's 200th anniversary nears, its use as a shorthand for ethical critique only increases. This article argues, though, that its lessons inhere in its unique structure, which enacts an interpretive process that models the multiplicity and uncertainty constitutive of ethical decision-making. Frankenstein deliberately functions as a modern myth, rewriting classical and Christian mythology to challenge the straightforward moral lessons often ascribed to the text. Complex portrayals of the creature and of Victor Frankenstein in the context of contemporary science make it impossible to read Victor as villain, victim or hero, or to take a consequentialist or nature-based stance in which the outcome of his research dictates its wrongness. The use of Paradise Lost insists on the creature's fundamental humanity. Indeed, the creature's voice frames the entire novel and serves as its structural centrepiece. His experience counters Victor's and vividly expresses the harm in a narrow focus on discovery and in the denial of responsibility for scientific work as it moves beyond the laboratory. Both the creature's and Captain Walton's stories stress the need to hear other voices and honour their distinct lived experiences. While Frankenstein-as-myth (re)produces science as the fundamental explanatory paradigm, it presents a vision of science as passionately personal and societally situated. Repeated disruptions of narrative cohesion question accuracy and causality, producing instead an acute awareness of perspective. Frankenstein argues for a reflective and dialogical narrative ethics: choices must be made and evaluated not according to a priori abstract rules, but within the attached stories.


Dithizone staining of intracellular zinc: an unexpected and versatile counterscreen for auxotrophic marker genes in Saccharomyces cerevisiae.
Auxotrophic marker genes such as URA3, LEU2, and HIS3 in Saccharomyces cerevisiae have long been used to select cells that have been successfully transformed with recombinant DNA. A longstanding challenge in working with these genes is that counterselection procedures are often lacking. This paper describes the unexpected discovery of a simple plate assay that imparts a bright red stain to cells experiencing nutritional stress from the lack of a marker gene. The procedure specifically stains a zinc-rich vesicular compartment analogous to the zinc-rich secretory vesicles found in insulin-secreting pancreatic islet cells and glutamate-secreting neurons. Staining was greatly diminished in zap1 mutants, which lack a homeostatic activator of zinc uptake, and in cot1 zrc1 double mutants, which lack the two yeast homologs of mammalian vesicle-specific zinc export proteins. Only one of 93 strains with temperature-sensitive alleles of essential genes exhibited an increase in dithizone staining at its non-permissive temperature, indicating that staining is not simply a sign of growth-arrested or dying cells. Remarkably, the procedure works with most commonly used marker genes, highlights subtle defects, uses no reporter constructs or expensive reagents, requires only a few hours of incubation, yields visually striking results without any instrumentation, and is not toxic to the cells. Many potential applications exist for dithizone staining, both as a versatile counterscreen for auxotrophic marker genes and as a powerful new tool for the genetic analysis of a biomedically important vesicular organelle.


Cheyne-Stokes respiration in congestive heart failure: continuous positive airway pressure of 5-8 cm H2O for 1 year in five cases.
Five adult patients with congestive heart failure (CHF) due to dilated cardiomyopathy complicated by Cheyne-Stokes respiration/central sleep apnea (CSR/CSA) were treated with continuous positive airway pressure (CPAP) with an initial pressure of 5 cm H2O. Four patients were followed up for 12 months with CPAP of 5 cm H2O. The rest, a 93-year-old patient, was followed up for 30 months, and the CPAP was reset at 8 cm H2O due to worsened cardiac function after 6 months and it was reset at 6 cm H2O due to dryness of the nose after 23 months. For all the patients with nightly CPAP use for 6.0+/-1.4 h per day for a year, frequency of CSR/CSA was significantly reduced after 3 and 12 months with CPAP (p<0.05). Moreover, their symptoms, cardiac function and sleep quality were significantly improved after 3 months (p<0.05), and were maintained above the pre-CPAP levels after 12 months, except for the oldest patient whose cardiac function tended to deteriorate. The results suggest that CSR/CSA in CHF can be treated with CPAP set at a lower pressure than the conventional method, and that CPAP at 5-8 cm H2O is often effective in eliminating CSR/CSA, improving sleep quality, and presumably maintaining cardiac function.


Calorimetric determination of surfactant/polyelectrolyte binding isotherms.
Mixing of oppositely charged surfactants and polyelectrolytes in aqueous solutions leads to cooperative surfactant adsorption onto the polyelectrolyte chains. Experimental determination of surfactant/polyelectrolyte binding isotherms is usually done using custom-built surfactant-ion-specific electrodes. As an alternative, we present an indirect isotherm approximation method that uses conventional isothermal titration calorimetry (ITC). The calorimetric data is fitted to the two-binding-state Satake-Yang adsorption model, which quantifies the extent of binding in terms of the binding constant (Ku) and the cooperativity parameter (u). This approach is investigated using two surfactant/polyelectrolyte mixtures: sodium perfluorooctanoate (FC7) and N,N,N-trimethylammonium derivatized hydroxyethyl cellulose (UCARE Polymer JR-400), whose binding behavior follows the Satake-Yang model, and dodecyltrimethylammonium bromide (DTAB) and poly(styrenesulfonate) (NaPSS), whose behavior deviates dramatically from the Satake-Yang model. These studies demonstrate that, in order to apply the indirect ITC method of binding isotherm determination, the surfactant/polyelectrolyte adsorption process must have no more than two dominant binding states. Thus, the technique works well for the FC7/JR-400 mixture. It fails in the case of the DTAB/NaPSS adsorption, but its mode of failure offers insight into the multiple-binding-state adsorption mechanism.


Severe Bilateral Mandibular Hyperplasia and Angle's Class III Malocclusion in Indonesia: A Case Report.
Malocclusion is an abnormal relationship between the teeth of the upper and lower jaws, with irregular tooth position, including crossbite and underbite. Malocclusion can occur in the form of crooked, protruding, or crowded teeth, affecting appearance, pronunciation, and mastication. Many factors lead to malocclusions, such as heredity, growth disturbance, and bad habits. Many Indonesians undergo orthodontic treatment to improve both function and appearance. The large demand for orthodontic treatment is due to increasing public knowledge about the impact of untreated malocclusion and the rising standard of living. We present a severe and rare case of malocclusion in Indonesia. A 20-year-old man presented with bilateral mandibular condylar hyperplasia and Angle's class III malocclusion. A multidisciplinary team, including plastic and oral surgeons, orthodontists, and psychologists, was created to address this problem. The first surgical procedure was chosen to achieve correction in the shortest possible time. Le Fort I osteotomy and mandibular bilateral sagittal split and anterior subapical osteotomies using Kole's procedure were performed. The patient underwent preoperative and postoperative examinations. After surgery, the occlusion was corrected and facial symmetry significantly improved.


Flaxseed oil rich in omega-3 protects aorta against inflammation and endoplasmic reticulum stress partially mediated by GPR120 receptor in obese, diabetic and dyslipidemic mice models.
The "first hit" to atherogenesis is driven by toll-like receptor 4, endoplasmic reticulum stress and ultimately metabolic dysfunction. In this study, we hypothesized that a flaxseed oil-enriched diet (FS) abolishes these inflammatory signaling pathway and restore metabolic homeostasis by activating the fatty acid receptor GPR120 in aorta of obese mice. Glucose homeostasis was assessed by GTT and ITT; lipidomics was performed using a Hybrid Ion Trap-Orbitrap Mass Spectrometer; serum lipids were measured using colorimetric assays; GPR120 and infiltrating macrophages were analyzed by immunofluorescence; protein immunoprecipitation and gene expression were evaluated by Western blot and RT-PCR, respectively. There were no differences in body weight and food intake between the groups from both strains (Swiss and LDLr-KO mice). GTT and cholesterol levels were improved by FS in both mice models. Lipidomics showed an increase in ω3 (C18:3) content, meanwhile stearic acid (C18:0) was not detected in endothelial tissue in response to FS. Moreover, FS markedly decreased pro-inflammatory (IL-1β, TNF-α, pIκBα, pIKKβ) and unfolded protein response markers (ATF6 and GRP78) in aorta. In Swiss mice, GPR120 was partially involved in the ω3-mediated anti-inflammatory actions, disrupting TLR4 pathway, but not in LDLr-KO mice. Partial replacement of dietary saturated by unsaturated ω3 fatty acids contributes to inhibition of cardiovascular risk markers, pro-inflammatory cytokines and ER stress sensors and effectors in the aorta. However, downregulation of inflammation is not mediated by arterial GPR120 activation.


Male involvement in PMTCT services in Mbeya Region, Tanzania.
Throughout all stages of programmes for the prevention of mother-to-child-transmission of HIV (PMTCT), high dropout rates are common. Increased male involvement and couples' joint HIV counselling/testing during antenatal care (ANC) seem crucial for improving PMTCT outcomes. Our study assessed male attitudes regarding partner involvement into ANC/PMTCT services in Mbeya Region, Tanzania, conducting 124 individual interviews and six focus group discussions. Almost all respondents generally supported PMTCT interventions. Mentioned barriers to ANC/PMTCT attendance included lacking information/knowledge, no time, neglected importance, the services representing a female responsibility, or fear of HIV-test results. Only few perceived couple HIV counselling/testing as disadvantageous. Among fathers who had refused previous ANC/PMTCT attendance, most had done so even though they were not perceiving a disadvantage about couple counselling/testing. The contradiction between men's beneficial attitudes towards their involvement and low participation rates suggests that external barriers play a large role in this decision-making process and that partner's needs should be more specifically addressed in ANC/PMTCT services.


The six-nucleotide deletion/insertion variant in the CASP8 promoter region is inversely associated with risk of squamous cell carcinoma of the head and neck.
Caspase 8 (CASP8) is an apoptosis-related cysteine peptidase involved in the death receptor pathway and likely in the mitochondrial pathway. A CASP8 promoter region six-nucleotide deletion/insertion (-652 6N ins/del) variant and a coding region D302H polymorphism are reportedly important in cancer development, but no reported study has assessed the associations of these genetic variations with risk of head and neck cancer. In a hospital-based study of non-Hispanic whites, we genotyped CASP8 -652 6N del and 302H variants in 1,023 patients with squamous cell carcinoma of the head and neck (SCCHN) and 1,052 cancer-free controls. Crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression models. The CASP8 -652 6N del variant genotypes or haplotypes were inversely associated with SCCHN risk (adjusted OR, 0.70; 95% CI, 0.57-0.85 for the ins/del + del/del genotypes compared with the ins/ins genotype; adjusted OR, 0.73; 95% CI, 0.55-0.97 for the del-D haplotype compared with the ins-D haplotype). Furthermore, the number of the CASP8 -652 6N del (but not 302H) variant allele tended to correlate with increased levels of camptothecin-induced p53-mediated apoptosis in T lymphocytes from 170 cancer-free controls. We concluded that the CASP8 -652 6N del variant allele may contribute to the risk of developing SCCHN in non-Hispanic white populations. Further validation by population-based case-control studies and rigorous mechanistic studies is warranted.


A framework and an algorithm to detect low-abundance DNA by a handy sequencer and a palm-sized computer.
Detection of DNA at low abundance with respect to the entire sample is an important problem in areas such as epidemiology and field research, as these samples are highly contaminated with non-target DNA. To solve this problem, many methods have been developed to date, but all require additional time-consuming and costly procedures. Meanwhile, the MinION sequencer developed by Oxford Nanopore Technology (ONT) is considered a powerful tool for tackling this problem, as it allows selective sequencing of target DNA. The main technology employed involves rejection of an undesirable read from a specific pore by inverting the voltage of that pore, which is referred to as 'Read Until'. Despite its usefulness, several issues remain to be solved in real situations. First, limited computational resources are available in field research and epidemiological applications. In addition, a high-speed online classification algorithm is required to make a prompt decision. Lastly, the lack of a theoretical approach for modeling of selective sequencing makes it difficult to analyze and justify a given algorithm. In this paper, we introduced a statistical model of selective sequencing, proposed an efficient constant-time classifier for any background DNA profile, and validated its optimal precision. To confirm the feasibility of the proposed method in practice, for a pre-recorded mock sample, we demonstrate that the method can selectively sequence a 100 kb region, consisting of 0.1% of the entire read pool, and achieve approximately 500-fold amplification. Furthermore, the algorithm is shown to process 26 queries per second with a $500 palm-sized next unit of computing box using an Intel® CoreTMi7 CPU without extended computer resources such as a GPU or high-performance computing. Next, we prepared a mixed DNA pool composed of Saccharomyces cerevisiae and lambda phage, in which any 200 kb region of S.cerevisiae consists of 0.1% of the whole sample. From this sample, a 30-230 kb region of S.cerevisiae chromosome 1 was amplified approximately 30-fold. In addition, this method allowed on-the-fly changing of the amplified region according to the uncovered characteristics of a given DNA sample. The source code is available at: https://bitbucket.org/ban-m/dyss.


Recent advances in activating surface reconstruction for the high-efficiency oxygen evolution reaction.
A climax in the development of cost-effective and high-efficiency transition metal-based electrocatalysts has been witnessed recently for sustainable energy and related conversion technologies. In this regard, structure-activity relationships based on several descriptors have already been proposed to rationally design electrocatalysts. However, the dynamic reconstruction of the surface structures and compositions of catalysts during electrocatalytic water oxidation, especially during the anodic oxygen evolution reaction (OER), complicate the streamlined prediction of the catalytic activity. With the achievements in operando and in situ techniques, it has been found that electrocatalysts undergo surface reconstruction to form the actual active species in situ accompanied with an increase in their oxidation state during OER in alkaline solution. Accordingly, a thorough understanding of the surface reconstruction process plays a critical role in establishing unambiguous structure-composition-property relationships in pursuit of high-efficiency electrocatalysts. However, several issues still need to be explored before high electrocatalytic activities can be realized, as follows: (1) the identification of initiators and pathways for surface reconstruction, (2) establishing the relationships between structure, composition, and electrocatalytic activity, and (3) the rational manipulation of in situ catalyst surface reconstruction. In this review, the recent progress in the surface reconstruction of transition metal-based OER catalysts including oxides, non-oxides, hydroxides and alloys is summarized, emphasizing the fundamental understanding of reconstruction behavior from the original precatalysts to the actual catalysts based on operando analysis and theoretical calculations. The state-of-the-art strategies to tailor the surface reconstruction such as substituting/doping with metals, introducing anions, incorporating oxygen vacancies, tuning morphologies and exploiting plasmonic/thermal/photothermal effects are then introduced. Notably, comprehensive operando/in situ characterization together with computational calculations are responsible for unveiling the improvement mechanism for OER. By delivering the progress, strategies, insights, techniques, and perspectives, this review will provide a comprehensive understanding of the surface reconstruction in transition metal-based OER catalysts and future guidelines for their rational development.


An alternative micrographic method for decreasing bleeding and recurrence in the treatment of rhinophyma.
Rhinophyma is a subtype of rosacea which develops at the advanced stage of rosacea and is characterized by an excessive enlargement of the sebaceous glands. Its etiology is not well-defined beyond the following usual suspects: vitamin deficiencies, stress, hormonal factors and the Demodex folliculorum mite. Carcinoma may develop in rhinophyma patients. The first surgical process for rhinophyma was applied by Daniel Sennert in 1629. The ideal surgical method for treatment of rhinophyma is still unclear and controversial. Massive bleeding makes a controlled excision of the mass impossible, which contributes to the recurrence of rhinophyma. In this case, we combined trichloroacetic acid (TCA 45%) with dermabrasion, a treatment which hasn't been reported previously. Our method was suggested by the Mohs micrographic surgery technique, which employs serial excisions.


[1940 to 1945: 5 years of practice in Lötschental].
The author who practised over 50 years ago in the Lötschental reviews his memories: the valley was endangered by avalanches cutting off all outside connections several times, the next colleague was not within reach but by a 2 hour walk, circumstances conditioning many isolated medical decisions (and their execution) as well as the work of a dentist or a veterinary doctor. Next to all these encumbrances the author remembers also many pleasant events and great satisfaction given by the special way of life and acting.


Racial and Ethnic Differences in End-of-Life Medicare Expenditures.
To determine to what extent demographic, social support, socioeconomic, geographic, medical, and End-of-Life (EOL) planning factors explain racial and ethnic variation in Medicare spending during the last 6 months of life. Retrospective cohort study. Health and Retirement Study (HRS). Decedents who participated in HRS between 1998 and 2012 and previously consented to survey linkage with Medicare claims (N = 7,105). Total Medicare expenditures in the last 180 days of life according to race and ethnicity, controlling for demographic factors, social supports, geography, illness burden, and EOL planning factors, including presence of advance directives, discussion of EOL treatment preferences, and whether death had been expected. The analysis included 5,548 (78.1%) non-Hispanic white, 1,030 (14.5%) non-Hispanic black, and 331 (4.7%) Hispanic adults and 196 (2.8%) adults of other race or ethnicity. Unadjusted results suggest that average EOL Medicare expenditures were $13,522 (35%, P < .001) more for black decedents and $16,341 (42%, P < .001) more for Hispanics than for whites. Controlling for demographic, socioeconomic, geographic, medical, and EOL-specific factors, the Medicare expenditure difference between groups fell to $8,047 (22%, P < .001) more for black and $6,855 (19%, P < .001) more for Hispanic decedents than expenditures for non-Hispanic whites. The expenditure differences between groups remained statistically significant in all models. Individuals-level factors, including EOL planning factors do not fully explain racial and ethnic differences in Medicare spending in the last 6 months of life. Future research should focus on broader systemic, organizational, and provider-level factors to explain these differences.


[Antihyperglycemic treatment guidelines for diabetes mellitus type 2 (Update 2023)].
Hyperglycemia significantly contributes to complications in patients with diabetes mellitus. While lifestyle interventions remain cornerstones of disease prevention and treatment, most patients with type 2 diabetes will eventually require pharmacotherapy for glycemic control. The definition of individual targets regarding optimal therapeutic efficacy and safety as well as cardiovascular effects is of great importance. In this guideline we present the most current evidence-based best clinical practice data for healthcare professionals.


Replication of human hepatitis delta virus in primary cultures of woodchuck hepatocytes.
We obtained two lines of evidence that monolayer cultures of primary woodchuck hepatocytes support replication of the genome of human hepatitis delta virus (HDV). (i) From a Northern (RNA blot) analysis of the HDV-related RNA in infected cultures, both genomic and antigenomic 1.7-kilobase RNA species were detected at 11 days after infection. The ratio of genomic RNA to antigenomic RNA was 2:1 to 10:1, comparable to that previously reported in studies of experimentally infected chimpanzees and woodchucks. (ii) Replication in culture was also demonstrated by in situ hybridization with a strand-specific probe. Such studies showed that only a small fraction of the cultured cells supported replication and that in such cells the relative and absolute levels of the HDV RNAs were comparable to those in liver cells infected in vivo. Furthermore, as with the in vivo studies, the HDV RNAs were predominantly localized to the nucleus. In summary, we demonstrated that cultured cells supported both the early events of HDV adsorption and penetration and the intermediate events of genome replication.


The voxel-wise analysis of false negative fMRI activation in regions of provoked impaired cerebrovascular reactivity.
Task-evoked Blood-oxygenation-level-dependent (BOLD-fMRI) signal activation is widely used to interrogate eloquence of brain areas. However, data interpretation can be improved, especially in regions with absent BOLD-fMRI signal activation. Absent BOLD-fMRI signal activation may actually represent false-negative activation due to impaired cerebrovascular reactivity (BOLD-CVR) of the vascular bed. The relationship between impaired BOLD-CVR and BOLD-fMRI signal activation may be better studied in healthy subjects where neurovascular coupling is known to be intact. Using a model-based prospective end-tidal carbon dioxide (CO2) targeting algorithm, we performed two controlled 3 tesla BOLD-CVR studies on 17 healthy subjects: 1: at the subjects' individual resting end-tidal CO2 baseline. 2: Around +6.0 mmHg CO2 above the subjects' individual resting baseline. Two BOLD-fMRI finger-tapping experiments were performed at similar normo- and hypercapnic levels. Relative BOLD fMRI signal activation and t-values were calculated for BOLD-CVR and BOLD-fMRI data. For each component of the cerebral motor-network (precentral gyrus, postcentral gyrus, supplementary motor area, cerebellum und fronto-operculum), the correlation between BOLD-CVR and BOLD-fMRI signal changes and t-values was investigated. Finally, a voxel-wise quantitative analysis of the impact of BOLD-CVR on BOLD-fMRI was performed. For the motor-network, the linear correlation coefficient between BOLD-CVR and BOLD-fMRI t-values were significant (p<0.01) and in the range 0.33-0.55, similar to the correlations between the CVR and fMRI Δ%signal (p<0.05; range 0.34-0.60). The linear relationship between CVR and fMRI is challenged by our voxel-wise analysis of Δ%signal and t-value change between normo- and hypercapnia. Our main finding is that BOLD fMRI signal activation maps are markedly dampened in the presence of impaired BOLD-CVR and highlights the importance of a complementary BOLD-CVR assessment in addition to a task-evoked BOLD fMRI to identify brain areas at risk for false-negative BOLD-fMRI signal activation.


[A cytogenetic study of the functions of the variable regions in human C heterochromatin. III. The relationship between the amount of C heterochromatin and the occurrence of the fetal alcohol syndrome].
It has been shown elsewhere that in children with growth retardation and gene syndromes (Russell-Silver, Dubowitz etc.), and in healthy children with inherited short stature the total amount of C heterochromatin in chromosomes 1, 9, and 16 was reduced as compared to the control. A correlation between the C heterochromatin reduction and the intrauterine growth retardation was suggested. A study of C heterochromatin in patients with fetal alcohol syndrome has shown that the chromosome sets of all the 11 children examined are identical to those of the above-mentioned patients. This fact may indicate that a small amount of C heterochromatin may play the leading role in realization of the alcohol effect, since this C heterochromatin deficiency makes the early embryogenesis open to injury to external effects. A possible functional role of C heterochromatin in disturbances of the developmental homeostasis are discussed. These disturbances concern the growth retardation and the lack of resistance to the effect of external and internal factors.


Neurocognitive and functional heterogeneity in depressed youth.
Depression is a common psychiatric illness that often begins in youth, and is sometimes associated with cognitive deficits. However, there is significant variability in cognitive dysfunction, likely reflecting biological heterogeneity. We sought to identify neurocognitive subtypes and their neurofunctional signatures in a large cross-sectional sample of depressed youth. Participants were drawn from the Philadelphia Neurodevelopmental Cohort, including 712 youth with a lifetime history of a major depressive episode and 712 typically developing (TD) youth matched on age and sex. A subset (MDD n = 368, TD n = 200) also completed neuroimaging. Cognition was assessed with the Penn Computerized Neurocognitive Battery. A recently developed semi-supervised machine learning algorithm was used to delineate neurocognitive subtypes. Subtypes were evaluated for differences in both clinical psychopathology and brain activation during an n-back working memory fMRI task. We identified three neurocognitive subtypes in the depressed group. Subtype 1 was high-performing (high accuracy, moderate speed), Subtype 2 was cognitively impaired (low accuracy, slow speed), and Subtype 3 was impulsive (low accuracy, fast speed). While subtypes did not differ in clinical psychopathology, they diverged in their activation profiles in regions critical for executive function, which mirrored differences in cognition. Taken together, these data suggest disparate mechanisms of cognitive vulnerability and resilience in depressed youth, which may inform the identification of biomarkers for prognosis and treatment response.


[Treatment of muscle-invasive and metastatic bladder cancer: update of the EAU guidelines].
New data regarding treatment of muscle-invasive and metastatic bladder cancer (MiM-BC) has emerged and led to an update of the European Association of Urology (EAU) guidelines for MiM-BC. To review the new EAU guidelines for MiM-BC with a specific focus on treatment. New literature published since the last update of the EAU guidelines in 2008 was obtained from Medline, the Cochrane Database of Systematic Reviews, and reference lists in publications and review articles and comprehensively screened by a group of urologists, oncologists, and a radiologist appointed by the EAU Guidelines Office. Previous recommendations based on the older literature on this subject were also taken into account. Levels of evidence (LEs) and grades of recommendations (GRs) were added based on a system modified from the Oxford Centre for Evidence-based Medicine Levels of Evidence. Current data demonstrate that neoadjuvant chemotherapy in conjunction with radical cystectomy (RC) is recommended in certain constellations of MiM-BC. RC remains the basic treatment of choice in localised invasive disease for both sexes. An attempt has been made to define the extent of surgery under standard conditions in both sexes. An orthotopic bladder substitute should be offered to both male and female patients lacking any contraindications, such as no tumour at the level of urethral dissection. In contrast to neoadjuvant chemotherapy, current advice recommends the use of adjuvant chemotherapy only within clinical trials. Multimodality bladder-preserving treatment in localised disease is currently regarded only as an alternative in selected, well-informed, and compliant patients for whom cystectomy is not considered for medical or personal reasons. In metastatic disease, the first-line treatment for patients fit enough to sustain cisplatin remains cisplatin-containing combination chemotherapy. With the advent of vinflunine, second-line chemotherapy has become available. In the treatment of localised invasive bladder cancer (BCa), the standard treatment remains radical surgical removal of the bladder within standard limits, including as-yet-unspecified regional lymph nodes. However, the addition of neoadjuvant chemotherapy must be considered for certain specific patient groups. A new drug for second-line chemotherapy (vinflunine) in metastatic disease has been approved and is recommended.


Do journals publishing in the field of urology endorse reporting guidelines? A survey of author instructions.
Reporting guidelines aim to ensure adequate and complete reporting of clinical studies and are an indispensable tool to translate scientific results into clinical practice. The extent to which reporting guidelines are incorporated into the author instructions of journals publishing in the field of urology remained unclear. We assessed the author instructions of uro-nephrological journals indexed in 'Journal Citation Reports 2009'. Two authors independently assessed the author guidelines. We evaluated additional information including whether a journal was published by or in association with a medical association. Discrepancies were resolved by re-checking the respective author instructions and by discussion with a third author. The recommendations of the International Committee of Journal Editors were endorsed by 32 journals (58.2%) but were mentioned in 12 (37.5%) only to give general advice about manuscript preparation. Fourteen journals (25.5%) mentioned at least one reporting guideline, with CONSORT the most frequently cited. Journals with high impact factors were more likely to endorse CONSORT (p < 0.009). Other reporting guidelines were mentioned by <6% of the journals. All key stakeholders involved in the publication process should more frequently promote the awareness and use of reporting guidelines.


Acute vasoreactivity testing during right heart catheterization in chronic thromboembolic pulmonary hypertension: Results from the pulmonary vascular disease phenomics study.
Chronic thromboembolic pulmonary hypertension (CTEPH) is believed to involve both vascular obstruction and vasoconstriction; hence, pulmonary vasodilators such as riociguat may be beneficial. Acute vasoreactivity testing (AVT) is seldom performed routinely in CTEPH patients, so there is limited understanding of the frequency and significance of an acute vasodilator response. Systematic vasodilator testing with oxygen (O2) and oxygen plus inhaled nitric oxide (O2 + iNO) was performed as part of the Pulmonary Vascular Disease Omics (PVDOMICS) NHLBI project, providing an opportunity to examine AVT responses in CTEPH. Patients with CTEPH enrolled in PVDOMICS (n = 49, 40 with prevalent CTEPH [82%]) underwent right heart catheterization including AVT with O2 and O2 + iNO. Hemodynamics were obtained at baseline and with each challenge. Fourteen of 49 patients (29%) had >20% drop in pulmonary vascular resistance (PVR) with O2. With O2 + iNO, 30/49 (61%) had >20% drop in PVR, 20% had >20% drop in mean pulmonary artery pressure (mPAP) and PVR, and 8% had >10 mmHg decline in mPAP to mPAP < 40 with normal cardiac output. Patients on riociguat had less response to O2 + iNO than patients on phosphodiesterase-5 inhibitors. Our findings shed light on the significant variability in vascular tone that is present in CTEPH, confirming that CTEPH represents a combination of mechanical obstruction and vasoconstriction that appears similar to that observed with Group 1 PAH. Additional study regarding whether results of acute vasodilator testing predict response to therapy and relate to prognosis is warranted.


Hemofiltration circuit use beyond 72 hours in pediatric continuous renal replacement therapy.
During continuous renal replacement therapy (CRRT), hemofiltration circuits ideally are changed after 72 h since tubing integrity and flow rates are not guaranteed after this time interval. This potential risk must be weighed against the risk of hypotension during elective circuit changes in the unstable patient. The aim of this study was to examine the safety of circuits used beyond 72 h in pediatric CRRT. A retrospective chart review of all patients who underwent CRRT at our institution from January 2003 to October 2005 was performed. Procedures were divided into standard (≤72 h) and extended (>72 h) circuit duration groups. Patients who had more than one CRRT procedure (n=13) were excluded from study. 71 CRRT procedures were performed for 71 patients. A total of 254 circuits were used, of which 64 (25%) were used for >72 h. For circuits >72 h, the mean duration of use was 5.5 days ± 1.8 (range 4-11). There were no differences between the groups in age (p=0.12), weight (p=0.48), diagnosis (p=0.21), CRRT indication (p=0.07), CRRT mode (p=0.37), anticoagulation (p=0.53), blood flow rate (p=0.06), replacement rate (p=0.50) or dialysate rate (p=0.89). There were no incidents of membrane or tubing rupture in either group. Use of hemofiltration circuits beyond 72 h may be safe in pediatric patients undergoing CRRT without increased risk of tubing rupture. Our data suggest a need to redefine the limits of prolonged circuit use in pediatric CRRT.


Trajectories of multimorbidity and impacts on successful aging.
Elderly people usually have multiple chronic diseases concurrently. However, studies of multimorbidity patterns over long time periods are scarce. The purpose of this study was to examine the joint trajectories of chronic multimorbidity among the Taiwanese elderly and to examine related factors and to predict later successful aging outcomes. The data used in this study were from a nation-representative panel survey conducted in Taiwan from 1993 to 2007. Those who participated in at least three waves of the survey were included in the analysis (in total 2584 persons and 57,012 observations). The chronic diseases included cardiovascular disease (CVD), chronic non-specific lung disease (CNSLD), arthritis, cancer, gastrointestinal disease (GI), and kidney disease. The multiple group-based trajectories analysis approach was applied to identify the trajectory groups. Four trajectory groups of multimorbidity were identified: low risk (55.51%), CVD risk only (15.55%), GI & CNSLD risk (20.20%), and multiple risks (8.74%). Related factors included age, level of education, physical functioning, depressive symptoms, and undergoing health examinations. The multimorbidity trajectories affected later physical functioning, depressive symptoms, cognitive function, and life satisfaction. Multiple trajectories of multimorbidity show the patterns of health burden and risks to successful aging among the elderly over time.


The efficacy of psychotherapy and pharmacotherapy in treating depressive and anxiety disorders: a meta-analysis of direct comparisons.
Although psychotherapy and antidepressant medication are efficacious in the treatment of depressive and anxiety disorders, it is not known whether they are equally efficacious for all types of disorders, and whether all types of psychotherapy and antidepressants are equally efficacious for each disorder. We conducted a meta-analysis of studies in which psychotherapy and antidepressant medication were directly compared in the treatment of depressive and anxiety disorders. Systematic searches in bibliographical databases resulted in 67 randomized trials, including 5,993 patients that met inclusion criteria, 40 studies focusing on depressive disorders and 27 focusing on anxiety disorders. The overall effect size indicating the difference between psychotherapy and pharmacotherapy after treatment in all disorders was g=0.02 (95% CI: -0.07 to 0.10), which was not statistically significant. Pharmacotherapy was significantly more efficacious than psychotherapy in dysthymia (g=0.30), and psychotherapy was significantly more efficacious than pharmacotherapy in obsessive-compulsive disorder (g=0.64). Furthermore, pharmacotherapy was significantly more efficacious than non-directive counseling (g=0.33), and psychotherapy was significantly more efficacious than pharmacotherapy with tricyclic antidepressants (g=0.21). These results remained significant when we controlled for other characteristics of the studies in multivariate meta-regression analysis, except for the differential effects in dysthymia, which were no longer statistically significant.


Trends of major, minor and rare earth elements in decomposing litter in a cool temperate ecosystem, South Korea.
The decomposition dynamics of 34 different elements in four different litter types (foliar and woody litter) from Pinus densiflora (Korean red pine) and Castanea crenata (Korean chestnut) was investigated in a cool temperate ecosystem using the litterbag method. Two contrasting trends were observed in the dynamics of elements with accumulated mass loss of litter and carbon. Leaf litter of Korean chestnut, which was richer in elements, showed a general decrease in concentrations of elements with accumulated mass loss of litter and carbon on a dry mass basis during decomposition in the field. Other litter types, with initially lower concentrations of elements, exhibited an increase in concentration on a dry mass basis during field incubation. Highest relative increase in the concentration was noticed for the minor elements, and for the woody litters. Concentrations of major and minor elements increased by factors ranging from 1.07 for antimony (Sb) to 853.7 for vanadium (V). Rare earth elements (REE) concentrations increased by factors ranging from 1.04 for scandium (Sc) to 83.5 for thorium (Th). Our results suggest that litter type plays an important role for nutrient dynamics. Results from principal component analysis for major, minor, and rare earth elements showed grouping of elements and high correlation among them (P < 0.05), which suggests a common source. At both sites, element concentrations were high in the soil, especially for REE. This suggests that increase in element concentrations during field incubation probably was due to transfer of elements from soil to the overlying decomposing litter.


Efficient metabolic pathway engineering in transgenic tobacco and tomato plastids with synthetic multigene operons.
The engineering of complex metabolic pathways requires the concerted expression of multiple genes. In plastids (chloroplasts) of plant cells, genes are organized in operons that are coexpressed as polycistronic transcripts and then often are processed further into monocistronic mRNAs. Here we have used the tocochromanol pathway (providing tocopherols and tocotrienols, collectively also referred to as "vitamin E") as an example to establish principles of successful multigene engineering by stable transformation of the chloroplast genome, a technology not afflicted with epigenetic variation and/or instability of transgene expression. Testing a series of single-gene constructs (encoding homogentisate phytyltransferase, tocopherol cyclase, and γ-tocopherol methyltransferase) and rationally designed synthetic operons in tobacco and tomato plants, we (i) confirmed previous results suggesting homogentisate phytyltransferase as the limiting enzymatic step in the pathway, (ii) comparatively characterized the bottlenecks in tocopherol biosynthesis in transplastomic leaves and tomato fruits, and (iii) achieved an up to tenfold increase in total tocochromanol accumulation. In addition, our results uncovered an unexpected light-dependent regulatory link between tocochromanol metabolism and the pathways of photosynthetic pigment biosynthesis. The synthetic operon design developed here will facilitate future synthetic biology applications in plastids, especially the design of artificial operons that introduce novel biochemical pathways into plants.


Soil chemical markers distinguishing human and pig decomposition islands: a preliminary study.
The decomposition of vertebrate cadavers on the soil surface produces nutrient-rich fluids that enter the soil profile, leaving clear evidence of the presence of a cadaver decomposition island. Few studies, however, have described soil physicochemistry under human cadavers, or compared the soil between human and non-human animal models. In this study, we sampled soil to 5 cm depth at distances of 0 cm and 30 cm from cadavers, as well as from control sites 90 cm distant, from five human and three pig cadavers at the Australian Facility for Taphonomic Experimental Research (AFTER). We found that soil moisture, electrical conductivity, nitrate, ammonium, and total phosphorus were higher in soil directly under cadavers (0 cm), with very limited lateral spread beyond 30 cm. These patterns lasted up to 700 days, indicating that key soil nutrients might be useful markers of the location of the decomposition island for up to 2 years. Soil phosphorus was always higher under pigs than humans, suggesting a possible difference in the decomposition and soil processes under these two cadaver types. Our preliminary study highlights the need for further experimental and replicated research to quantify variability in soil properties, and to identify when non-human animals are suitable analogues.


Remote substituent effects on the oxymercuration of 2-substituted norbornenes: an experimental and theoretical study.
The effect of a remote substituent on regioselectivity in the oxymercuration of 2-substituted norbornenes has been investigated experimentally and theoretically using density functional theory (DFT). Regioselectivities of 1:1 to 14:1 were observed with various 2-substituted norbornenes. Exo-2-substituted norbornenes always gave greater regioselectivities compared to the corresponding endo-2-substituted norbornenes. The effects of solvents on the regioselectivity have also been examined, and ethereal solvents were found to be the best choice giving the optimal yield and regioselectivity. The relative rate of oxymercuration was estimated by competition experiments. The least reactive substrate (X = OAc) gave the highest regioselectivity. According to DFT predictions, the increased difference between the reaction barriers that results in the greater regioselectivity is correlated directly with the larger polarity of the C=C double bond, which is attacked by the mercury and oxygen. A number of stable exo and endo conformers were predicted. All exo conformers show the same polarity of the double bond, while some endo conformers have a reversal of this polarity. All the conformers except those with the OAc substituent are very close in energy and thus should react. The existence of a mixture of endo conformers with the C=C double bond of opposite polarity clearly explains a decrease in regioselectivity for the endo species. The origin of the greatest regioselectivity for the OAc-2-norbornenes lies in the fact that the conformer with the largest polarity is notably lower in energy than others due to an internal C-H-O hydrogen bond.


Potential Benefits of Daytime Naps on Consecutive Days for Motor Adaptation Learning.
Daytime napping offers benefits for motor memory learning and is used as a habitual countermeasure to improve daytime functioning. A single nap has been shown to ameliorate motor memory learning, although the effect of consecutive napping on motor memory consolidation remains unclear. This study aimed to explore the effect of daytime napping over multiple days on motor memory learning. Twenty university students were divided into a napping group and no-nap (awake) group. The napping group performed motor adaption tasks before and after napping for three consecutive days, whereas the no-nap group performed the task on a similar time schedule as the napping group. A subsequent retest was conducted one week after the end of the intervention. Significant differences were observed only for speed at 30 degrees to complete the retention task, which was significantly faster in the napping group than in the awake group. No significant consolidation effects over the three consecutive nap intervention periods were confirmed. Due to the limitations of the different experimental environments of the napping and the control group, the current results warrant further investigation to assess whether consecutive napping may benefit motor memory learning, which is specific to speed.


Honokiol Alleviates Oxidative Stress-Induced Neurotoxicity via Activation of Nrf2.
Honokiol (Hon), a polyphenol and main active ingredient from the bark of Magnolia officinalis, has been documented as having multiple pharmacological functions, including neuroprotection. However, the mechanisms underlying its neuroprotective effects are not well-defined. In this study, we reported that Hon attenuates the H2O2- or 6-hydroxydopamine (6-OHDA)-induced apoptosis of PC12 cells by increasing the glutathione level and upregulating a multitude of cytoprotective proteins, including heme oxygenase 1, NAD(P)H:quinone oxidoreductase 1, thioredoxin 1, and thioredoxin reductase 1. Further studies reveal that Hon promotes transcription factor Nrf2 nuclear translocation and activation. Moreover, the cytoprotection of Hon was antagonized by silence of Nrf2 expression, highlighting the fact that Nrf2 is critically engaged in the cellular functions of Hon. Taken together, our study identified that Hon is an effective agonist of Nrf2 in the neuronal system and displays potent neuroprotection against oxidative stress-mediated PC12 cell damage. These findings indicate that Hon is promising for further development as a therapeutic drug against oxidative stress-related neurodegenerative disorders.


Developing a STEM+M Identity in Underrepresented Minority Youth Through Biomechanics and Sports-Based Education.
A Science, Technology, Engineering, Math, and Medicine (STEM+M) identity, a form of social identity, is the extent to which an individual feels accepted in the STEM+M career fields. The development of a strong STEM+M identity hinges largely on one's perceived self-efficacy in STEM+M and can be bolstered by associating STEM+M with other areas in which an individual already exhibits self-efficacy. In this study, a basketball camp served as a platform for STEM+M education in an effort to link participants' self-efficacy in basketball to STEM+M concepts where they may feel less self-efficacious. Over the first 2 years of the program, known as the Youth Sports Lab (YSL), two cohorts of underrepresented minority (URM) middle school students attended a 4-day long basketball camp hosted at Columbia University in partnership with Harlem- and Albany-based afterschool programs. The camp consisted of basketball training, jump plate fabrication, data collection, invited speakers, and group-based research projects. Our hypotheses were that participation in the program would lead to improved (1) familiarity, (2) perceived importance, and (3) interest in STEM+M. Participant responses, gathered from a 17-question Likert-scale survey administered before and after the camp, demonstrated 10 questions with significantly increased responses due to the program. The results support the conclusion that the sports-based engineering program increased STEM+M identity in the URM cohort. Future improvements to the program will include midyear student engagement and long-term follow-up.


A droplet energy harvesting and actuation system for self-powered digital microfluidics.
When a water droplet slides down a hydrophobic surface, a major energy it possesses is kinetic energy. However, people may ignore another important energy source: triboelectrification. To quantify and utilize triboelectrification energy, a phenomenon is presented in this study: one droplet slides down a tilted chip with a hydrophobic coating and patterned electrodes, triboelectrification happens and the induced charges are transferred to another horizontally placed chip with copper wires, on which another droplet is actuated by the transferred charges. The mechanism of this phenomenon is triboelectrification, electrostatic induction and EWOD (electrowetting on dielectrics). When an 80 μL droplet slides down the chip, the induced charges build up a potential difference between the electrodes of 46 V. With this potential difference, the droplet actuation is achieved not only on the horizontal chip, but also on the vertical chip. By patterning a comb-shaped electrode, functions for droplet manipulations are achieved. Theoretical analysis is conducted to quantify the frictional force, gravitational force and driving force (EWOD force). The presented concept and device could be employed for a self-powered digital microfluidics (DMF) system, replacing the bulky and energy consuming voltage sources which are commonly used in DMF devices.


The Effects of Vibration Exposure on Lower-Limb Extensor Muscles' Stiffness, Elasticity, and Strength Responses in Untrained Young Individuals: A Randomized Controlled Trial.
The whole-body vibration (WBV) effects on muscle strength show inconsistent results. Moreover, there is no study about the WBV effect on stiffness, elasticity, and muscle strength. Therefore, the study aimed to examine the effect of WBV exposure with static squat posture on the stiffness, elasticity, and strength of the lower-limb extensor muscles. Forty healthy untrained young adults were divided into WBV and control groups. The experimental group received WBV exposure on 2 nonconsecutive days of the week, for 6 weeks. The MyotonPRO device was used for the assessment of the knee extensor and the ankle dorsiflexors' stiffness and elasticity. Isometric muscle strength was evaluated with a hand-held dynamometer. All measurements were done by the same assessor at baseline, and the following 6 weeks. Significant group-by-time interactions were found for the elasticity scores of the right (d = 0.84, P = .01) and left (d = 0.77, P = .02) ankle dorsiflexors. Similar to the elasticity measurements, significant group-by-time interactions were observed in the muscle strength scores of the right (d = 0.45, P = .046) and left (d = 1.25, P < .001) ankle dorsiflexors. No significant effects were observed in any of the evaluated muscle stiffness measurements (P > .05), and there was no significant group-by-time interaction in knee-extensor muscle strength and elasticity scores (P > .05). The study results indicate that if the ankle dorsiflexor strength and elasticity are desired to be increased, the 6-week WBV exposure in a static squat posture can be used in healthy individuals.


Work Schedule Patching in Health Care: Exploring Implementation Approaches.
The authors propose a typology of "work schedule patching," the ongoing adjustments made to plug scheduling holes after employers post schedules. Patching occurs due to changes in employer work demands, or employee nonwork demands necessitating scheduling adjustments, which are reactive or proactive. Using qualitative data from eight health-care facilities, the authors identified three narratives justifying schedule patching implementation approaches (share-the-pain, work-life-needs, and reverse-status-rotation) with variation in formalization and improvisation. Exploratory analysis showed a suggestive link between improvised work-life scheduling and lower pressure ulcers. This article advances theory on balancing the "service triangle" of scheduling in-service economies including health care.


Hyperoxia does not affect oxygen delivery in healthy volunteers while causing a decrease in sublingual perfusion.
To determine the human dose-response relationship between a stepwise increase in arterial oxygen tension and its associated changes in DO2 and sublingual microcirculatory perfusion. Fifteen healthy volunteers breathed increasing oxygen fractions for 10 minutes to reach arterial oxygen tensions of baseline (breathing air), 20, 40, 60 kPa, and max kPa (breathing oxygen). Systemic hemodynamics were measured continuously by the volume-clamp method. At the end of each period, the sublingual microcirculation was assessed by SDF. Systemic DO2 was unchanged throughout the study (Pslope = .8). PVD decreased in a sigmoidal fashion (max -15% while breathing oxygen, SD18, Pslope = .001). CI decreased linearly (max -10%, SD10, Pslope < .001) due to a reduction in HR (max -10%, SD7, Pslope = .009). There were no changes in stroke volume or MAP. Most changes became apparent above an arterial oxygen tension of 20 kPa. In healthy volunteers, supraphysiological arterial oxygen tensions have no effect on systemic DO2 . Sublingual microcirculatory PVD decreased in a dose-dependent fashion. All hemodynamic changes appear negligible up to an arterial oxygen tension of 20 kPa.


Modeling the autoinhibition of clarithromycin metabolism during repeated oral administration.
Clarithromycin decreases CYP3A4 activity and thus gradually inhibits its own metabolism as well as that of coadministered drugs. The aim of this study was to obtain an understanding of the time course of these changes. The plasma concentration-time profiles of clarithromycin and its active metabolite, 14(R)-hydroxy-clarithromycin, in 12 young healthy volunteers after oral administration of a clarithromycin suspension (500 mg twice a day [b.i.d.] for seven doses) were modeled by population pharmacokinetic analysis in the NONMEM program. The nonlinearity of clarithromycin metabolism was considered during model development, and the metabolite disposition kinetics were assumed to be linear. The absorption kinetics of clarithromycin were best described by a Weibull function model. The pharmacokinetics of clarithromycin and its 14(R)-hydroxyl metabolite were adequately described by a one-compartment model each for clarithromycin and its metabolite as well as an inhibition compartment that reflects the autoinhibition of clarithromycin metabolism. Up to 90% of the apparent total clarithromycin clearance (60 liters/h) was susceptible to reversible autoinhibition, depending on the concentration in the inhibition compartment. The proposed semimechanistic population pharmacokinetic model successfully described the autoinhibition of clarithromycin metabolism and may be used to adjust the doses of other drugs that are metabolized by CYP3A4 and that are coadministered with clarithromycin. Simulations showed that for the standard dose of 500 mg b.i.d., no further increase in the level of exposure occurs after approximately 48 h of treatment. For a 1,000-mg b.i.d. dose, the achievement of steady state is expected to take several days and to achieve a 3.6-fold higher level of clarithromycin exposure than the 500-mg b.i.d. dose. This evaluation provides a rationale for safer and more effective therapy with clarithromycin.


Toxic, cytotoxic, and genotoxic effects of a glyphosate formulation (Roundup®SL-Cosmoflux®411F) in the direct-developing frog Eleutherodactylus johnstonei.
The aerial spraying of glyphosate formulations in Colombia to eradicate illegal crops has generated great concern about its possible impact on nontarget organisms, particularly amphibians. This study evaluated the toxic, cytotoxic, and genotoxic effects of a glyphosate formulation (Roundup®SL-Cosmoflux®411F) in the direct-developing frog Eleutherodactylus johnstonei by estimating the median lethal application rate (LC50 ), median hemolytic application rate (HD50 ), and extent of DNA damage using the in vitro and in vivo Comet assays. Toxicity results indicated that the application rate [37.4 µg acid equivalent (a.e.)/cm(2) ] equivalent to that used in aerial spraying (3.74 kg a.e./ha) is not lethal in male and female adult frogs, whereas neonates are highly sensitive. Glyphosate formulation at application rates above 5.4 µg a.e./cm(2) (in vivo) and concentrations above 95 µg a.e./mL (in vitro) showed clear evidence of cytotoxicity. In vivo and in vitro exposure of E. johnstonei erythrocytes to the glyphosate formulation induced DNA breaks in a dose-dependent manner with statistically significant values (P < 0.05) at all doses tested. DNA damage initially increased with the duration of exposure and then decreased, suggesting that DNA repair events were occurring during in vivo and in vitro exposures. These results are discussed from the perspective of possible ecotoxicological risks to anuran species from exposure to glyphosate formulation.


Effect of levamisole on E rosette inhibition by serum of malnourished children.
E rosette forming lymphocyte levels were measured in 5 normal children (in the presence or absence of levamisole) after in vitro gamma globulin (AGG) or sera containing E rosette inhibitory substance obtained from kwashiorkor children. The experiments were repeated using lymphocytes from 5 kwashiorkor children who showed detectable levels of serum E rosette inhibitory substance. There was a diminution in the E rosette formation of normal lymphocytes treated with AGG or with serum of kwashiorkor children having E rosette inhibitory substance. Addition of levamisole in vitro significantly increased the levels of E rosettes. Similarly low levels of E rosettes were demonstrated when lymphocytes of kwashiorkor children were incubated with autologous sera. Treatment with levamisole in vitro also improved the levels of E rosettes.


A SARS-CoV-2 neutralizing antibody selected from COVID-19 patients binds to the ACE2-RBD interface and is tolerant to most known RBD mutations.
The novel betacoronavirus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) causes a form of severe pneumonia disease called coronavirus disease 2019 (COVID-19). To develop human neutralizing anti-SARS-CoV-2 antibodies, antibody gene libraries from convalescent COVID-19 patients were constructed and recombinant antibody fragments (scFv) against the receptor-binding domain (RBD) of the spike protein were selected by phage display. The antibody STE90-C11 shows a subnanometer IC50 in a plaque-based live SARS-CoV-2 neutralization assay. The in vivo efficacy of the antibody is demonstrated in the Syrian hamster and in the human angiotensin-converting enzyme 2 (hACE2) mice model. The crystal structure of STE90-C11 Fab in complex with SARS-CoV-2-RBD is solved at 2.0 Å resolution showing that the antibody binds at the same region as ACE2 to RBD. The binding and inhibition of STE90-C11 is not blocked by many known emerging RBD mutations. STE90-C11-derived human IgG1 with FcγR-silenced Fc (COR-101) is undergoing Phase Ib/II clinical trials for the treatment of moderate to severe COVID-19.


Silencing of STAT3 via Peptidomimetic LNP-Mediated Systemic Delivery of RNAi Downregulates PD-L1 and Inhibits Melanoma Growth.
Cutaneous melanoma is the most aggressive skin cancer with notorious drug resistance. Inhibition of immune checkpoint molecules is one of the most promising approaches for cancer therapy. Herein, we show that RNAi mediated silencing of STAT3 expression in the tumor tissue robustly inhibit tumor growth in B16F10 mouse model of melanoma. We designed a peptidomimetic-based lipid nanoparticles (LNPs) for the delivery of siRNA in mouse model of melanoma. When systemically administered, the novel formulation (denote DoCh) preferentially delivered siRNA to the tumor tissue. Remarkably, sequential intravenous injections of siRNA against STAT3 induced profound silencing of STAT3 expression in tumor tissue, which resulted in significant downregulation of PD-L1, leading to significant inhibition of tumor growth through inhibition of tumor immune checkpoint. Moreover, DoCh-mediated siRNA delivery did not show noticeable damage to the major organs. Collectively, our data demonstrated that DoCh LNP is a promising tumor-targeted siRNA delivery system.


A novel p-LaFeO3/n-Ag3PO4 heterojunction photocatalyst for phenol degradation under visible light irradiation.
A novel heterojunction photocatalyst p-LaFeO3/n-Ag3PO4 has been prepared via a facile in situ precipitation method. It exhibits higher activity than individual Ag3PO4 and LaFeO3 in the degradation of phenol. The excellent activity is mainly attributed to its more effective separation of electron-hole pairs.


The problematisation of existence: towards a philosophy of complexity.
By assuming that the Universe is best described as a cellular automaton, and by making use of results from the field of computational mechanics, this paper discusses an extension of the notion of existence from a simple binary opposition to that of a continuum. It is argued that none of the traditional objects of science, or any objects from any discipline, formal or not, can be said to be real in any absolute sense though a substantial realism may be associated with them. By problematising existence it is proposed that an evolutionary philosophy referred to as critical pluralism is more sensitive to the demands of complexity than contemporary scientific approaches. Though many of the conclusions reported herein are not original, the fact that they can be 'proved' in a scientific sense, and explored scientifically, is certainly of interest and is an interpretation of complexity theory that has received little attention.


Gene-gene and gene-environmental interactions of childhood asthma: a multifactor dimension reduction approach.
The importance of gene-gene and gene-environment interactions on asthma is well documented in literature, but a systematic analysis on the interaction between various genetic and environmental factors is still lacking. We conducted a population-based, case-control study comprised of seventh-grade children from 14 Taiwanese communities. A total of 235 asthmatic cases and 1,310 non-asthmatic controls were selected for DNA collection and genotyping. We examined the gene-gene and gene-environment interactions between 17 single-nucleotide polymorphisms in antioxidative, inflammatory and obesity-related genes, and childhood asthma. Environmental exposures and disease status were obtained from parental questionnaires. The model-free and non-parametrical multifactor dimensionality reduction (MDR) method was used for the analysis. A three-way gene-gene interaction was elucidated between the gene coding glutathione S-transferase P (GSTP1), the gene coding interleukin-4 receptor alpha chain (IL4Ra) and the gene coding insulin induced gene 2 (INSIG2) on the risk of lifetime asthma. The testing-balanced accuracy on asthma was 57.83% with a cross-validation consistency of 10 out of 10. The interaction of preterm birth and indoor dampness had the highest training-balanced accuracy at 59.09%. Indoor dampness also interacted with many genes, including IL13, beta-2 adrenergic receptor (ADRB2), signal transducer and activator of transcription 6 (STAT6). We also used likelihood ratio tests for interaction and chi-square tests to validate our results and all tests showed statistical significance. The results of this study suggest that GSTP1, INSIG2 and IL4Ra may influence the lifetime asthma susceptibility through gene-gene interactions in schoolchildren. Home dampness combined with each one of the genes STAT6, IL13 and ADRB2 could raise the asthma risk.


Cognitive epidemiology.
This glossary provides a guide to some concepts, findings and issues of discussion in the new field of research in which intelligence test scores are associated with mortality and morbidity. Intelligence tests are devised and studied by differential psychologists. Some of the major concepts in differential psychology are explained, especially those regarding cognitive ability testing. Some aspects of IQ (intelligence) tests are described and some of the major tests are outlined. A short guide is given to the main statistical techniques used by differential psychologists in the study of human mental abilities. There is a discussion of common epidemiological concepts in the context of cognitive epidemiology.


Therapeutic Targets and Prognostic Biomarkers Among CXC Chemokines in Pancreatic Ductal Adenocarcinoma Microenvironment.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by occult onset, rapid progression, and poor prognosis. CXC chemokines play an important role in tumor microenvironment and development. However, the potential mechanistic values of CXC chemokines as clinical biomarkers and therapeutic targets in PDAC have not been fully clarified. The altered expression, interaction network, and clinical data of CXC chemokines in patients with PDAC were analyzed by the data from the Gene Expression Omnibus and the Tumor Cancer Genome Atlas. CXCL5 transcriptional level was significantly elevated in PDAC tissues. A significant correlation was found between the expression of CXC1/3/5/8 and the pathological stage of PDAC patients. The PDAC patients with low transcriptional levels of CXCL5/9/10/11/17 were associated with a significantly better prognosis. The functions of differentially expressed CXC chemokines are primarily related to the chemokine signaling pathway, cytokine-cytokine receptor interaction, and viral protein interaction with cytokine and cytokine receptor. RELA, NFKB1, and SP1 are key transcription factors for CXC chemokines, and the SRC family of tyrosine kinases, mitogen-activated protein kinases, CDK5, PRKCQ, ROCK1, ITK, IKBKE, JAK3, and NTRK2 are CXC chemokine targets. The results indicated that CXC chemokines might serve as therapeutic targets and prognostic biomarkers in PDAC.


On the ability of molecular dynamics force fields to recapitulate NMR derived protein side chain order parameters.
Molecular dynamics (MD) simulations have become a central tool for investigating various biophysical questions with atomistic detail. While many different proxies are used to qualify MD force fields, most are based on largely structural parameters such as the root mean square deviation from experimental coordinates or nuclear magnetic resonance (NMR) chemical shifts and residual dipolar couplings. NMR derived Lipari-Szabo squared generalized order parameter (O(2) ) values of amide NH bond vectors of the polypeptide chain were also often employed for refinement and validation. However, with a few exceptions, side chain methyl symmetry axis order parameters have not been incorporated into experimental reference sets. Using a test set of five diverse proteins, the performance of several force fields implemented in the NAMDD simulation package was examined. It was found that simulations employing explicit water implemented using the TIP3 model generally performed significantly better than those using implicit water in reproducing experimental methyl symmetry axis O(2) values. Overall the CHARMM27 force field performs nominally better than two implementations of the Amber force field. It appeared that recent quantum mechanics modifications to side chain torsional angles of leucine and isoleucine in the Amber force field have significantly hindered proper motional modeling for these residues. There remained significant room for improvement as even the best correlations of experimental and simulated methyl group Lipari-Szabo generalized order parameters fall below an R(2) of 0.8.


Morphological integration in mammalian limb proportions: dissociation between function and development.
During mammalian evolution, fore- and hindlimbs underwent a fundamental reorganization in the transformation from the sprawled to the parasagittal condition. This caused a dissociation between serial and functional homologues. The mobilized scapula functions as the new proximal forelimb element and is functionally analogous to the femur of the hindlimb. Tarsus and metatarsus built a new functional hindlimb element that is functionally analogous to the forearm of the forelimb. Morphological covariation between serially homologous fore- and hindlimb elements can conflict with biomechanical demands when certain intralimb proportions are required for the postural stability of motion. The limb proportions of 189 mammalian species were examined to test whether intralimb proportions are governed by a general principle that corresponds to biomechanical predictions. Morphological covariation between functionally analogous and serially homologous fore- and hindlimb elements was tested by a correlation analysis. A clear relationship exists between the proportions of the first and the third elements of each limb, while the middle element is less involved in alterations of intralimb proportions. Hindlimb proportions are largely uniform across mammals and correspond to biomechanical predictions regarding postural stability. The greater variability in forelimb proportion is likely be the expression of various adaptations but might results also from constraints due to the shared developmental programs with the hindlimb.


The C-terminal HDEL sequence is sufficient for retention of secretory proteins in the endoplasmic reticulum (ER) but promotes vacuolar targeting of proteins that escape the ER.
Proteins are co-translationally transferred into the endoplasmic reticulum (ER) and then either retained or transported to different intracellular compartments or to the extracellular space. Various molecular signals necessary for retention in the ER or targeting to different compartments have been identified. In particular, the HDEL and KDEL signals used for retention of proteins in yeast and animal ER have also been described at the C-terminal end of soluble ER processing enzymes in plants. The fusion of a KDEL extension to vacuolar proteins is sufficient for their retention in the ER of transgenic plant cells. However, recent results obtained using the same strategy indicate that HDEL does not contain sufficient information for full retention of phaseolin expressed in tobacco. In the present study, an HDEL C-terminal extension was fused to the vacuolar or extracellular (delta pro) forms of sporamin. The resulting SpoHDEL or delta proHDEL, as well as Spo and delta pro, were expressed at high levels in transgenic tobacco cells (Nicotiana tabacum cv BY2). The intracellular location of these different forms of recombinant sporamin was studied by subcellular fractionation. The results clearly indicate that addition of an HDEL extension to either Spo or delta pro induces accumulation of these sporamin forms in a compartment that co-purifies with the ER markers NADH cytochrome C reductase, binding protein (BiP) and calnexin. In addition, a significant SpoHDEL or delta proHDEL fraction that escapes the ER retention machinery is transported to the vacuole. From these results, it may be proposed that, in addition to its function as an ER retention signal, HDEL could also act in quality control by targeting chaperones or chaperone-bound proteins that escape the ER to the plant lysosomal compartment for degradation.


Social determinants and heat shock protein-70 among African American and non-Hispanic white women with atherosclerosis: a pilot study.
African American (AA) women are nearly twice as likely as non-Hispanic White (NHW) women to develop atherosclerosis associated with cardiovascular disease. Compelling evidence demonstrates that stress-related biomarkers, such as heat shock protein-70 (HSP70), are associated with increased atherosclerosis risk. Yet little is known about how social factors such as perceived discrimination, subjective social status, and socioeconomic status contribute to the levels of these biomarkers in women with atherosclerosis. The aims of this pilot study were to (1) describe perceived everyday discrimination, subjective social status, perceived stress, and HSP70 level in AA and NHW women diagnosed with coronary or carotid artery disease requiring intervention and (2) determine the extent to which perceived discrimination, subjective social status, and perceived stress are associated with HSP70 level, controlling for age, education, and race. The sample for this cross-sectional, descriptive pilot study consisted of 10 AA and 21 NHW women admitted to the hospital for elective percutaneous cardiac intervention or carotid endarterectomy. Participants completed questionnaires measuring psychosocial variables and provided blood samples for analysis of HSP70. Race, age, education, perceived stress, perceived discrimination, and subjective social status significantly (p = .022) explained 34% of the variance in HSP70 levels. However, only subjective social status (p = .031) and AA race (p = .031) were significant independent predictors of HSP70 levels, with lower subjective social status and AA race associated with higher HSP70. Although larger studies are needed to confirm these results, findings imply that race and subjective social status may play an important role in predicting stress biomarker levels.


The serotonin syndrome scale: first results on validity.
As a modification of the diagnostic criteria of the serotonin syndrome proposed by Sternbach, we developed the Serotonin syndrome scale for the operationalized assessment of both the presence and the severity of the core symptoms of the serotonin syndrome. In a first study on the validity of this scale, the relationships between the serotonin syndrome score (SSS) and both the paroxetine plasma levels (n = 42) and the loudness dependence of the auditory evoked potentials (LDAEP; n = 24) were investigated in depressed patients treated with paroxetine. A strong LDAEP is supposed to indicate low central serotonergic neurotransmission, and vice versa. The SSS was positively related to paroxetine plasma levels and negatively to the LDAEP. Both results support the validity of the serotonin syndrome scale. Using a SSS > 6 as diagnostic criterion, mild serotonin syndromes were diagnosed in 5 of our 42 patients. The Serotonin syndrome scale may become a useful tool for clinicians and scientists dealing with the serotonin syndrome.


Phenotypic and cytogenetic characterization of human bladder urothelia expanded in vitro.
A simple method for the harvest of bladder cell types from surgical specimens was used to generate strains of normal human urothelial cells that could be reproducibly cultivated, passaged and extensively expanded in serum-free medium. Immunostaining of the bladder epithelial cells with broadly reacting anti-cytokeratin antibodies and with an anti-cytokeratin antibody specific to cytokeratin 7, a transitional cell marker, indicated that they expressed a stable epithelial phenotype with serial passage. Low levels of immunostaining for E-cadherin and low levels of E-cadherin messenger ribonucleic acid, as determined by Northern blot analysis, and strongly positive immunostaining with an anti-vimentin antibody indicated collectively that the uroepithelial cells express a nonbarrier-forming phenotype under these culture conditions. However, when the urothelial cells were implanted subcutaneously into athymic mice on biodegradable synthetic polymers, they formed multilayered structures, suggesting that they retain the capability to differentiate in a living host. The urothelial cells proliferated in an epidermal growth factor independent manner and expressed high levels of transforming growth factor-alpha and amphiregulin messanger ribonucleic acids, suggesting the possibility of autocrine regulation of growth by epidermal growth factor-like factors. Cytogenetic analysis indicated that urothelial cells cultured for 6 passages possessed a normal chromosomal complement. These results demonstrate that primary cultures of autologous human bladder epithelial cells can be extensively expanded in vitro and, consequently, might be used in cell transplantation strategies for genitourinary reconstruction.


Efficacy of a paper-based interleukin-6 test strip combined with a spectrum-based optical reader for sequential monitoring and early recognition of respiratory failure in elderly pneumonia-a pilot study.
Introduction: Community-acquired pneumonia (CAP) is lethal in elderly individuals who are more vulnerable to respiratory failure and require more emergency ventilation support than younger individuals. Interleukin-6 (IL-6) plays a crucial role and has predictive value in CAP; high serum IL-6 concentrations in adults are associated with high respiratory failure and mortality rates. Early detection of IL-6 concentrations can facilitate the timely stratification of patients at risk of acute respiratory failure. However, conventional enzyme-linked immunosorbent assay (ELISA) IL-6 measurement is laborious and time-consuming. Methods: The IL-6 rapid diagnostic system combined with a lateral flow immunoassay-based (LFA-based) IL-6 test strip and a spectrum-based optical reader is a novel tool developed for rapid and sequential bedside measurements of serum IL-6 concentrations. Here, we evaluated the correlation between the IL-6 rapid diagnostic system and the ELISA and the efficacy of the system in stratifying high-risk elderly patients with CAP. Thirty-six elderly patients (median age: 86.5 years; range: 65-97 years) with CAP were enrolled. CAP diagnosis was established based on the Infectious Diseases Society of America (IDSA) criteria. The severity of pneumonia was assessed using the CURB-65 score and Pneumonia Severity Index (PSI). IL-6 concentration was measured twice within 24 h of admission. Results: The primary endpoint variable was respiratory failure requiring invasive mechanical or non-invasive ventilation support after admission. IL-6 rapid diagnostic readouts correlated with ELISA results (p < 0.0001) for 30 samples. Patients were predominantly male and bedridden (69.4%). Ten patients (27.7%) experienced respiratory failure during admission, and five (13.9%) died of pneumonia. Respiratory failure was associated with a higher mortality rate (p = 0.015). Decreased serum IL-6 concentration within 24 h after admission indicated a lower risk of developing respiratory failure in the later admission course (Receiver Operating Characteristic [ROC] curve = 0.696). Conclusion: Sequential IL-6 measurements with the IL-6 rapid diagnostic system might be useful in early clinical risk assessment and severity stratification of elderly patients with pneumonia. This system is a potential point-of-care diagnostic device for sequential serum IL-6 measurements that can be applied in variable healthcare systems.


Childhood-Onset Systemic Lupus Erythematosus: A Cohort Study.
To determine the clinical and immunological characteristics and short-term outcome of children with systemic lupus erythematosus (SLE). A descriptive cohort study. Paediatric Rheumatology Clinic, The Aga Khan University Hospital, Karachi, from January 2011 to December 2015. Clinical and immunological profile and short-term outcome of children less than 16 years of age admitted in the paediatric ward, with the diagnosis of SLE was studied. Demographic data, clinical presentation, laboratory findings, immunological profile and treatment regimens of these children were evaluated. Thirty-two children, satisfying the criteria of American College of Rheumatology (ACR) for SLE, were enrolled during the study period of five consecutive years. A female predominance was observed with 28 (87.5%) patients being female (F:M 7:1). Mean age at symptom onset was 10.5 +2.7 years; and 8.8 +2.1 years in females and males, respectively. The mean age at diagnosis was 11.3 +2.8 years in females and 9.4 +1.9 years in males. Prolonged fever was the most common non-specific symptom found in 27 (84%), followed by pallor in 13 (41%) patients. Twenty-two (69%) children were found to be anemic and 18 patients (56%) having signs of arthritis at presentation. Renal involvement was observed in 15 (47%) patients. The most common laboratory finding was anemia, found in 22 (69%) of cases. The most common immunological markers were serum anti-neutrophil antibodies (ANA), positive in 28 (88%) patients, followed by anti double-stranded DNA antibodies, raised in 26 (81%) of cases. Out of 32, 12 patients were lost to follow-up. Of the remaining 20 children who were followed for four years, ten (50%) went into remission. Childhood-onset SLE encompasses a wide variety of manifestations with a female preponderance. Fever, arthralgia and pallor are the most frequent clinical manifestations among the children. Hemolytic anemia (HA) is the most common laboratory abnormality, with ANA and anti ds-DNA antibodies positivity in the majority of padiatric patients.


Coagulation Factor Xa and Protease-Activated Receptor 2 as Novel Therapeutic Targets for Diabetic Nephropathy.
The role of hypercoagulability in the pathogenesis of diabetic nephropathy (DN) remains elusive. We recently reported the increased infiltration of macrophages expressing tissue factor in diabetic kidney glomeruli; tissue factor activates coagulation factor X (FX) to FXa, which in turn stimulates protease-activated receptor 2 (PAR2) and causes inflammation. Here, we demonstrated that diabetes mellitus increased renal FX mRNA, urinary FXa activity, and FX expression in glomerular macrophages. Administration of an oral FXa inhibitor, edoxaban, ameliorated DN with concomitant reductions in the expression of PARs (Par1 and Par2) and of proinflammatory and profibrotic genes. Diabetes mellitus induced PAR2, and lack of Par2 ameliorated DN. FXa or PAR2 agonist increased inflammatory cytokines in endothelial cells and podocytes in vitro. We conclude that enhanced FXa and PAR2 exacerbate DN and that both are promising targets for preventing DN. Alleviating inflammation is probably more important than inhibiting coagulation per se when treating kidney diseases using anticoagulants.


Anodal Transcutaneous Spinal Direct Current Stimulation (tsDCS) Selectively Inhibits the Synaptic Efficacy of Nociceptive Transmission at Spinal Cord Level.
Recently studies have aimed at developing transcutaneous spinal direct current stimulation (tsDCS) as a non-invasive technique to modulate spinal function in humans. Independent studies evaluating its after-effects on nociceptive or non-nociceptive somatosensory responses have reported comparable effects suggesting that tsDCS impairs axonal conduction of both the spino-thalamic and the medial lemniscus tracts. The present study aimed to better understand how tsDCS affects, in humans, the spinal transmission of nociceptive and non-nociceptive somatosensory inputs. We compared the after-effects of anodal low-thoracic, anodal cervical and sham tsDCS on the perception and brain responses elicited by laser stimuli selectively activating Aδ-thermonociceptors of the spinothalamic system and vibrotactile stimuli selectively activating low-threshold Aβ-mechanoreceptors of the lemniscal system, delivered to the hands and feet. Low-thoracic tsDCS selectively and significantly affected the LEP-N2 wave elicited by nociceptive stimulation of the lower limbs, without affecting the LEP-N2 wave elicited by nociceptive stimulation of the upper limbs, and without affecting the SEP-N2 wave elicited by vibrotactile stimulation of either limb. This selective and segmental effect indicates that the neuromodulatory after-effects of tsDCS cannot be explained by anodal blockade of axonal conduction and, instead, are most probably due to a segmental effect on the synaptic efficacy of the local processing and/or transmission of nociceptive inputs in the dorsal horn.


Enhanced energy recovery using a cascaded reverse electrodialysis stack for salinity gradient power generation.
Despite significant advances in the field applications of reserve electrodialysis (RED) to produce salinity gradient power, net energy production remains an issue owing to limitations such as high energy requirement for high flow rates of feed solutions, and severe fouling and pressure build up when thin spacers are used. Therefore, to maximize the performance and efficiency of energy harvesting in the RED, a cascaded RED stack, with multiple stages between the anode and cathode electrodes, was investigated. In cascaded stacks, 100-cell paired stacks were divided into several stages, so the feed water flowed into the first stage, and the effluent from the first stage was then reused in the next stages. This cascaded stack could overcome the typical drawbacks of RED (large amount of feed water required, intensive pumping energy, and low net energy production). Although 25% of the feed water volume was used in the 4-stage cascaded stack (100-cell-pairs) compared to the conventional stack (100-cell-pairs with a parallel flow operation), much more energy was produced with the 4-stage cascaded stack. The net power density and net specific energy with the 4-stage cascaded stack were the highest at 0.5 cm/s (0.48 W/m2) and 0.25 cm/s (0.06 kWh/m3), respectively. This is very promising for the practical application of RED since feed water volumes can be greatly reduced, which could reduce the burden on the feed water pretreatment step. Consequently, we can build a compact RED plant with smaller pretreatment processes and fewer RED unit stacks.


The Clinical Picture of Psychosis in Manifest Huntington's Disease: A Comprehensive Analysis of the Enroll-HD Database.
Background: Psychotic symptoms have been under-investigated in Huntington's disease (HD) and research is needed in order to elucidate the characteristics linked to the unique phenotype of HD patients presenting with psychosis. Objective: To evaluate the frequency and factors associated with psychosis in HD. Methods: Cross-sectional study including manifest individuals with HD from the Enroll-HD database. Both conventional statistical analysis (Stepwise Binary Logistic Regression) and five machine learning algorithms [Least Absolute Shrinkage and Selection Operator (LASSO); Elastic Net; Support Vector Machines (SVM); Random Forest; and class-weighted SVM] were used to describe factors associated with psychosis in manifest HD patients. Results: Approximately 11% of patients with HD presented history of psychosis. Logistic regression analysis indicated that younger age at HD clinical diagnosis, lower number of CAG repeats, history of [alcohol use disorders, depression, violent/aggressive behavior and perseverative/obsessive behavior], lower total functional capacity score, and longer time to complete trail making test-B were associated with psychosis. All machine learning algorithms were significant (chi-square p < 0.05) and capable of distinguishing individual HD patients with history of psychosis from those without a history of psychosis with prediction accuracy around 71-73%. The most relevant variables were similar to those found in the conventional analyses. Conclusions: Psychiatric and behavioral symptoms as well as poorer cognitive performance were related to psychosis in HD. In addition, psychosis was associated with lower number of CAG repeats and younger age at clinical diagnosis of HD, suggesting that these patients may represent a unique phenotype in the HD spectrum.


Influence of polymorphic OATP1B-type carriers on the disposition of docetaxel.
Docetaxel is extensively metabolized by CYP3A4 in the liver but mechanisms by which the drug is taken up into hepatocytes remain poorly understood. We hypothesized that (i) liver uptake of docetaxel is mediated by the polymorphic solute carriers OATP1B1 and OATP1B3 and (ii) inherited genetic defects in this process may impair systemic drug elimination. Transport of docetaxel was studied in vitro using various cell lines stably transfected with OATP1B1*1A (wild-type), OATP1B1*5 [c.521T>C (V174A); rs4149056], OATP1B3, or the mouse transporter Oatp1b2. Docetaxel clearance was evaluated in wild-type and Oatp1b2-knockout mice as well as in two cohorts of patients with multiple variant transporter genotypes (n = 213). Docetaxel was found to be a substrate for OATP1B1, OATP1B3, and Oatp1b2 but was not transported by OATP1B1*5. Deficiency of Oatp1b2 in mice was associated with an 18-fold decrease in docetaxel clearance (P = 0.0099), which was unrelated to changes in intrinsic metabolic capacity in mouse liver microsomes. In patients, however, none of the studied common reduced function variants in OATP1B1 or OATP1B3 were associated with docetaxel clearance (P > 0.05). The existence of at least two potentially redundant uptake transporters in the human liver with similar affinity for docetaxel supports the possibility that functional defects in both of these proteins may be required to confer substantially altered disposition phenotypes. In view of the established exposure-toxicity relationships for docetaxel, we suggest that caution is warranted if docetaxel has to be administered together with agents that potently inhibit both OATP1B1 and OATP1B3.


Delta-opioid receptors as targets for migraine therapy.
The purpose of this review is to contrast the properties of the δ-opioid receptor with those of the μ-opioid receptor, which is the primary target of most currently available opioid analgesics. We also discuss preclinical evidence that indicates the potential efficacy of δ-opioid receptor agonists as migraine therapy. The use of currently available opioid analgesics is highly problematic for patients with migraine. Delta-opioid receptors have key differences from μ receptors; these differences make the δ receptor an attractive therapeutic target for migraine. Delta-opioid receptors are expressed in both the peripheral and central nervous system in anatomical regions and cell types that are believed to play a role in migraine. Delta-receptor agonists have also shown promising effects in multiple migraine models, including nitroglycerin evoked hyperalgesia and conditioned place aversion, and cortical spreading depression. Evidence from animal models indicates that activation of δ receptors is less likely to cause tolerance and dependence, and less likely to cause hyperalgesia. In addition, δ receptors may have antidepressant and anxiolytic properties that are distinct from those of μ receptors. In human studies investigating other conditions, δ-receptor agonists have been generally safe and well tolerated. Delta-opioid receptor agonists have promising potential as acute and/or preventive migraine therapies, without the problems associated with currently used opioid analgesics.


Resonance promoted ring-opening metathesis polymerization of twisted amides.
The living ring-opening metathesis polymerization (ROMP) of an unsaturated twisted amide using the third-generation Grubbs initiator is described. Unlike prior examples of ROMP monomers that rely on angular or steric strain for propagation, this system is driven by resonance destabilization of the amide that arises from geometric constraints of the bicyclic framework. Upon ring-opening, the amide can rotate and rehybridize to give a stabilized and planar conjugated system that promotes living propagation. The absence of other strain elements in the twisted amide is supported by the inability of a carbon analogue of the monomer to polymerize and computational studies that find resonance destabilization accounts for 11.3 kcal mol-1 of the overall 12.0 kcal mol-1 ring strain. The twisted amide polymerization is capable of preparing high molecular weight polymers rapidly at room temperature, and post-polymerization modification combined with 2D NMR spectroscopy confirms a regioirregular polymer microstructure.