Biomechanical Study Comparing Cut-out Resistance of the X-Bolt® and Dynamic Hip Screw at Various Tip-Apex Distances.
Bone quality in hip fractures is poor and there is a need to not only correctly position metalwork within the femoral head, but also for implants to resist cut-out. New implant designs may help to reduce metalwork cut-out, leading to fewer failures of fixation. This study compared the cut-out strength of a Dynamic Hip Screw (DHS) to that of an X-Bolt® (X-Bolt Orthopaedics, Dublin, Ireland) implant in an osteoporotic Sawbones® (Sawbones, Vashon Island, WA) model. An unstable fracture model (AO 31-A2) was created using low-density 5 pound per cubic foot (pcf) Sawbones®. The DHS and X-Bolts® were inserted into the Sawbones® femoral head at Tip-Apex Distances (TAD) of 10mm, 15mm, 20mm, 25mm, 30mm and 40mm. A cyclic-loading Instron® machine (Instron Corp., Norwood, MA) pushed the bone at a compression rate of 5mm per minute at a 20-degree angle to the axis of the implant with an upper force limit of 4000N. Maximum force reached and load to failure, defined as movement of the implant by 5mm, were recorded. Four implants were used per group to give a total of 48 tests between the two groups. The X-Bolt® demonstrated a superior average maximum total load push-out force compared to the DHS group for all of the TAD configurations tested. The maximum force reached in the X-Bolt® group was significantly higher than that in the DHS group at a TAD of 10mm (X-Bolt® 3299.25N vs. DHS 2843.75N, P<0.029) and 30mm (X-Bolt® 2908.25N vs. DHS 2030N, P<0.029). The X-Bolt® also had a higher load to failure than the DHS group at all of the TAD values tested. The X-Bolt® implant gave superior performance compared to the standard DHS, as reflected by a greater push-out force in an osteoporotic Sawbones® model.


Association of Serum Levels of Adipokines and Insulin With Risk of Barrett's Esophagus: A Systematic Review and Meta-Analysis.
Metabolically active visceral fat may be associated with esophageal inflammation, metaplasia, and neoplasia. We performed a meta-analysis to evaluate the association of serum adipokines and insulin with Barrett's esophagus (BE). We performed a systematic search of multiple electronic databases, through April 2015, to identify all studies reporting associations between leptin, adiponectin, insulin, insulin resistance, and risk of BE in adults. Comparing the highest study-specific category with the reference category for each hormone, we estimated the summary adjusted odds ratio (aOR) and 95% confidence intervals (CI), using a random effects model. We identified 9 observational studies (10 independent cohorts; 1432 patients with BE total, and 3550 control subjects). Meta-analysis revealed that high serum level of leptin was associated with 2-fold higher risk of BE (BE cases vs population control subjects in 5 studies: aOR, 2.23; 95% CI, 1.31-3.78; I(2), 59%). Total serum level of adiponectin was not associated with BE (BE cases vs population control subjects in 5 studies: aOR, 0.79; 95% CI, 0.46-1.34; I(2), 65%), although 1 study observed decreased risk of BE with increased level of low-molecular-weight adiponectin. High serum level of insulin was associated with increased risk of BE (BE cases vs population control subjects in 3 studies: aOR, 1.74; 95% CI, 1.14-2.65; I(2), 0), whereas insulin resistance was not associated with increased risk of BE (BE cases vs gastroesophageal reflux disease control subjects in 2 studies: aOR, 0.98; 95% CI, 0.42-2.30; I(2), 64%). Increased serum levels of leptin and insulin are associated with increased risk of BE, compared with population control subjects. In contrast, increased total serum levels of adiponectin and insulin do not seem to modify BE risk. Well-designed longitudinal studies of incident BE are needed to clarify existing associations of serum adipokines and insulin with BE.


Swimming training potentiates the recovery of femoral neck strength in young diabetic rats under insulin therapy.
To test whether swimming training benefits femoral neck strength in young diabetic rats under insulin therapy. A total of 60 male Wistar rats (age: 40 days) were divided equally into the following six groups: control sedentary, control exercise, diabetic sedentary, diabetic exercise, diabetic sedentary plus insulin and diabetic exercise plus insulin. Diabetes was induced with a unique intraperitoneal injection (60 mg/kg body weight) of streptozotocin. Seven days after the injection and after 12 hours of fasting, the animals with blood glucose levels ≥300 mg/dL were considered diabetic. Seven days after the induction of diabetes, the animals in the exercise groups were subjected to progressive swimming training (final week: 90 min/day; 5 days/week; 5% load) for eight weeks. The animals in the insulin groups received a daily dose of insulin (2-4 U/day) for the same period. Severe streptozotocin-induced diabetes reduced the structural properties of the femoral neck (trabecular bone volume, trabecular thickness and collagen fiber content). The femoral neck mechanical properties (maximum load and tenacity) were also impaired in the diabetic rats. Insulin therapy partially reversed the damage induced by diabetes on the structural properties of the bone and mitigated the reductions in the mechanical properties of the bone. The combination of therapies further increased the femoral neck trabecular bone volume (∼30%), trabecular thickness (∼24%), collagen type I (∼19%) and type III (∼13%) fiber contents, maximum load (∼25%) and tenacity (∼14%). Eight weeks of swimming training potentiates the recovery of femoral neck strength in young rats with severe streptozotocin-induced diabetes under insulin therapy.


Detection of Modified Forms of Cytosine Using Sensitive Immunohistochemistry.
Methylation of cytosine bases (5-methylcytosine, 5mC) occurring in vertebrate genomes is usually associated with transcriptional silencing. 5-hydroxylmethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) are the recently discovered modified cytosine bases produced by enzymatic oxidation of 5mC, whose biological functions remain relatively obscure. A number of approaches ranging from biochemical to antibody based techniques have been employed to study the genomic distribution and global content of these modifications in various biological systems. Although some of these approaches can be useful for quantitative assessment of these modified forms of 5mC, most of these methods do not provide any spatial information regarding the distribution of these DNA modifications in different cell types, required for correct understanding of their functional roles. Here we present a highly sensitive method for immunochemical detection of the modified forms of cytosine. This method permits co-detection of these epigenetic marks with protein lineage markers and can be employed to study their nuclear localization, thus, contributing to deciphering their potential biological roles in different experimental contexts.


Homocysteine and cardiovascular disease.
An elevated level of total homocysteine (tHcy) in blood, denoted hyperhomocysteinemia, is emerging as a prevalent and strong risk factor for atherosclerotic vascular disease in the coronary, cerebral, and peripheral vessels, and for arterial and venous thromboembolism. The basis for these conclusions is data from about 80 clinical and epidemiological studies including more than 10,000 patients. Elevated tHcy confers a graded risk with no threshold, is independent of but may enhance the effect of the conventional risk factors, and seems to be a particularly strong predictor of cardiovascular mortality. Hyperhomocysteinemia is attributed to commonly occurring genetic and acquired factors including deficiencies of folate and vitamin B12. Supplementation with B-vitamins, in particular with folic acid, is an efficient, safe, and inexpensive means to reduce an elevated tHcy level. Studies are now in progress to establish whether such therapy will reduce cardiovascular risk.


Work in dry cleaning and the incidence of cancer of the oral cavity, larynx, and oesophagus.
To investigate whether employment in dry cleaning, and potential exposure to perchloroethylene (PCE), were associated with increased risk of carcinoma of the oral cavity and pharynx, larynx, oesophagus, and gastric cardia. Two population based case-control studies were carried out. There were 491 cases of carcinoma of the oral cavity and pharynx, 235 of the larynx, and 404 of the oesophagus and gastric cardia. 724 controls were selected by random digit dialing. Personal interviews ascertained information on lifetime job histories, cigarette use, alcohol consumption, and other potential risk factors. The probability and level of exposure to PCE were estimated from the scientific literature. People who worked in dry cleaning tended to consume less alcohol and cigarettes than the general population. The adjusted odds ratio (OR) associated with ever having worked in dry cleaning was 1.6 (95% confidence interval (95% CI) = 0.6 to 4.4) for all cancer types together. The strongest associations were with laryngeal (OR 2.7; 95% CI 0.6 to 10.9) and oesophageal squamous cell carcinomas (OR 3.6; 95% CI 0.5 to 27.0). For laryngeal cancer, the relative risk increased with number of years employed in the dry cleaning industry (P = 0.14. The two cases of oesophageal squamous cell carcinomas had worked in dry cleaning for only a short time. Analyses of subsites showed higher risks for supraglottic laryngeal cancer (OR 5.7; 95% CI 1.0 to 32.1) and cancer of the tongue (OR 2.3; 95% CI 0.4 to 12.6). Analyses of exposure to PCE yielded similar results. These findings could easily be explained by chance; nevertheless, they are consistent with previous reports of excess risk of oesophageal, laryngeal, and tongue cancer, and suggest that previous studies of dry cleaners that could not control for alcohol and cigarette use may have underestimated the relative risks of such cancers.


Genomic organization and promoter identification of the human protein kinase CK2 catalytic subunit alpha (CSNK2A1).
The isolation and characterization of the complete gene coding for human protein kinase CK2 catalytic subunit alpha is described. The gene spans 70 kb and consists of 13 exons, and the exon/intron boundaries conform to the gt/ag rule. Exons range in size from 51 to 2960 bp, introns from 527 to around 34000 bp. The translation start site is located in Exon 2, the stop codon in Exon 13. Two transcription start sites were identified by primer extension analysis: The further 5'-located site defines position 1 of the gene, the second site is located at position 50. The 5' region of the CK2 alpha gene shows features of a housekeeping promoter, such as lack of a TATA box and presence of a CpG island and GC boxes. The region was analyzed by reporter gene assay, and promoter activity was detected within the region ranging from position -256 to 144. Six potential polyadenylation signals were identified in the 3' noncoding region of the CK2 alpha gene. As indicated by comparison with expressed sequence tags from the EMBL databank and by Northern-blot analysis, the most 3' located, active polyadenylation signal seems to be the fourth signal, defining the end of the gene.


Development of High Strength Particleboards from Hemp Shives and Corn Starch.
In the current study, high-strength boards for the construction industry were developed from renewable natural resources, fibrous hemp shives, and corn starch. During the research, the influence of the composition of the mixture, the processing of raw materials, and technological parameters on the operational properties of the board were evaluated. The influence of the binding material and the water content on the properties of the molded boards was evaluated. It was established that the rational amount of starch is 15% of the mass of the shives, and the amount of water is 10%. It has been established that with the proper selection of the forming parameters of the board, it is possible to avoid internal disintegration of the structure due to the water vapor pressure, increase the bending strength, and ensure uniform sintering of the board throughout the entire volume. It was found that additional processing of hemp shives can increase bending strength by more than 40%. Furthermore, during the processing of shives by chemical means, soluble substances are washed out, which reduces the density and thermal conductivity of the shives. Selection of a rational level of compression allowed us to increase the bending strength of the boards by 40%. The assessment of all factors made it possible to obtain boards with a bending strength of 40 MPa. The additives used made it possible to reduce the water absorption of the boards up to 16 times and obtain non-flammable boards. The thermal conductivity of the resulting boards varied from 0.07 to 0.095 W/(m·K). The analysis of macrostructure and microstructure allowed us to evaluate the process of the formation of bonds between hemp shives.


Respectful care of human dignity: how is it perceived by patients and nurses?
Dignified care protects the patient's rights and provides appropriate ethical care while improving the quality of nursing care. In this context, the opinions of nurses and patients who receive nursing care about dignified care are important. The aim of this study was to explore the opinions and experiences of Turkish patients and nurses about respectful care of human dignity. This descriptive cross-sectional study was conducted in Turkey. Participants were inpatients at cardiology, neurology and neurosurgery clinics and nurses working in these clinics. The data for the study were collected from face-to-face interviews using questionnaires. The percentages of characteristics and preferences of the participants were calculated, and the results were analysed using statistical tests. A total of 150 patients and 78 nurses participated in the study. The patients stated that the protection of their rights was the most important factor for dignified nursing care. The nurses stated that being careful to not expose the patients' body and being respectful of the patients' privacy were important in dignified nursing care. The age of the patient, duration of the disease, number of hospitalisations and length of time the nurses had been working at the clinic caused significant changes in the factors considered important in dignified care. Our findings provide a perspective on dignified care in the Turkish healthcare setting. There were some differences between patients and nurses in the factors considered important for dignified care. The discussion with patients and nurses related to care and practices that protect or detract from human dignity can provide insights to ethics.


The relationship between the claustrum and endopiriform nucleus: A perspective towards consensus on cross-species homology.
With the emergence of interest in studying the claustrum, a recent special issue of the Journal of Comparative Neurology dedicated to the claustrum (Volume 525, Issue 6, pp. 1313-1513) brought to light questions concerning the relationship between the claustrum (CLA) and a region immediately ventral known as the endopiriform nucleus (En). These structures have been identified as separate entities in rodents but appear as a single continuous structure in primates. During the recent Society for Claustrum Research meeting, a panel of experts presented data pertaining to the relationship of these regions and held a discussion on whether the CLA and En should be considered (a) separate unrelated structures, (b) separate nuclei within the same formation, or (c) subregions of a continuous structure. This review article summarizes that discussion, presenting comparisons of the cytoarchitecture, neurochemical profiles, genetic markers, and anatomical connectivity of the CLA and En across several mammalian species. In rodents, we conclude that the CLA and the dorsal endopiriform nucleus (DEn) are subregions of a larger complex, which likely performs analogous computations and exert similar effects on their respective cortical targets (e.g., sensorimotor versus limbic). Moving forward, we recommend that the field retain the nomenclature currently employed for this region but should continue to examine the delineation of these structures across different species. Using thorough descriptions of a variety of anatomical features, this review offers a clear definition of the CLA and En in rodents, which provides a framework for identifying homologous structures in primates.


Impaired Stat3 activation following localized inflammatory stimulus in IL-6-deficient mice.
Interleukin 6 (IL-6) and related gp130-signalling cytokines rapidly activate latent cytoplasmic Stat transcription factors and these are believed to play pivotal roles in the expression of downstream cytokine-responsive genes. We have previously shown in IL-6-deficient (-/-) mice that IL-6 is absolutely required for the transcriptional induction of acute phase response (APR) genes in the liver following localized tissue damage caused by subcutaneous injection of turpentine oil, but is not required when the inflammatory stimulus is administered systemically by intraperitoneal injection of bacterial lipopolysaccharide (LPS). In this paper we show that Stat3 is the only Stat factor induced in liver tissue upon localized inflammatory stimuli, and that its activation is virtually absent in IL-6 deficient mice. During LPS-induced inflammation both Stat1 and Stat3 are activated, and only minor kinetic alterations are detected in IL-6-/- mice. These defects are not due to altered intracellular signal transduction, since they could be complemented by injection of recombinant cytokines. These results establish a direct causal relationship in vivo between Stat activation and acute phase gene expression and define unique functions of IL-6 in Stat3 activation upon localized inflammation.


Impact and Cost-Effectiveness of Oncotype DX for Guiding Adjuvant Chemotherapy Decisions in Early Breast Cancer.
Oncotype DX is approved in multiple countries but its cost-effectiveness is a matter of considerable health debate. Lebanon is high-middle income country according to the World Bank classification however it is facing a mounting financial and health care burden from cancer. Therefore, we conducted a costeffectiveness analysis of Oncotype DX based Lebanese on real-life data. We updated a Canadian cost-effectiveness model of Oncotype DX by incorporating Lebanese data. The patient population was a real-life cohort of 82 women diagnosed with hormone receptor - positive and HER2 - negative early breast cancer. Overall, providing Oncotype DX to only intermediate Adjuvant! Online risk patients costs an additional $83 CAD (93,883 LBP) per additional QALY. From this point, extending provision to also cover high Adjuvant! Online risk patients costs an additional $736 CAD (831,578 LBP) per additional QALY. From this point, extending provision further to also cover low Adjuvant! Online risk patients (such that Oncotype DX is provided to all patients) costs an additional $14,562 CAD (16.46m LBP) per additional QALY. Given that most women in our population-based sample were classified as intermediate Adjuvant! Online risk patients, our study focused on this subset in the second analysis. Providing Oncotype DX to intermediate Adjuvant! Online risk patients has a relatively small additional cost compared to not providing Oncotype DX, and results in a relatively large QALY gain. The incremental cost per QALY is $2,022 CAD (2.29m LBP), implying that Oncotype DX is cost-effective for intermediate Adjuvant! Online risk patients if the willingness-to-pay for a QALY is greater than 2.29m LBP. As one of the few economic evaluations to date conducted using Lebanese data, this evaluation provides information to decision makers regarding the cost-effectiveness of providing Oncotype DX to Lebanese patients.


Infertility and abortion among first-lactation dairy cows seropositive or seronegative for Leptospira interrogans serovar hardjo.
To estimate the extent to which exposure to Leptospira hardjo before or at the time of first parturition was associated with infertility and abortion during the first lactation among dairy cows that had not been vaccinated for > or = 12 months. 207 first-lactation cows from a herd of 2,000 lactating cows. Cows were tested for antibodies to L hardjo within 40 days after calving. Time from calving to first breeding, time from calving to conception, number of breedings per conception, and risk of abortion were compared between cows seropositive for L hardjo and cows that were seronegative. For the 9 (4.3%) cows that were seropositive for L hardjo, median time from calving to conception (132.6 days) was significantly longer than time for seronegative cows (95.4 days). Cows that were seropositive were twice as likely (relative risk, 2.07) to fail to conceive as seronegative cows. Mean number of breedings required per conception for seropositive cows (3.4) was significantly higher than that for seronegative cows (2.1). The proportion of seropositive cows that aborted was not significantly different from the proportion of seronegative cows that aborted. Exposure of nonvaccinated dairy cows to L hardjo can be associated with a subsequent reduction in fertility, as indicated by a greater time from calving to conception and higher number of breedings required per conception. The efficacy of leptospiral vaccines should be assessed to determine whether vaccination will minimize herd infertility associated with L hardjo infection.


[Results of the socioeconomic study of the population of patients with schizophrenia].
The authors provide the results of an analysis of direct and indirect expenses for schizophrenic patients (n-386) depending on certain social factors. The analysis has shown a wide variability of expenses for patients depending on the level of education and skills, the character of work organization, familial status, and living conditions. The social parameters exerting the most essential influence on the magnitude and character of expenses for schizophrenic patients, incurred by the state have also been defined. Adequate financing of the appropriate social and rehabilitation programs may produce an appreciable effect on the patients social status, lead to a decrease of expenses for them, which later will warrant the primary expenses for the programs.


Changes in Behavior and Neural Dynamics across Adolescent Development.
Adolescence is an important developmental period, during which substantial changes occur in brain function and behavior. Several aspects of executive function, including response inhibition, improve during this period. Correspondingly, structural imaging studies have documented consistent decreases in cortical and subcortical gray matter volume, and postmortem histologic studies have found substantial (∼40%) decreases in excitatory synapses in prefrontal cortex. Recent computational modeling work suggests that the change in synaptic density underlie improvements in task performance. These models also predict changes in neural dynamics related to the depth of attractor basins, where deeper basins can underlie better task performance. In this study, we analyzed task-related neural dynamics in a large cohort of longitudinally followed subjects (male and female) spanning early to late adolescence. We found that age correlated positively with behavioral performance in the Eriksen Flanker task. Older subjects were also characterized by deeper attractor basins around task related evoked EEG potentials during specific cognitive operations. Thus, consistent with computational models examining the effects of excitatory synaptic pruning, older adolescents showed stronger attractor dynamics during task performance.SIGNIFICANCE STATEMENT There are well-documented changes in brain and behavior during adolescent development. However, there are few mechanistic theories that link changes in the brain to changes in behavior. Here, we tested a hypothesis, put forward on the basis of computational modeling, that pruning of excitatory synapses in cortex during adolescence changes neural dynamics. We found, consistent with the hypothesis, that variability around event-related potentials shows faster decay dynamics in older adolescent subjects. The faster decay dynamics are consistent with the hypothesis that synaptic pruning during adolescent development leads to stronger attractor basins in task-related neural activity.


Critical evaluation of established risk prediction models for acute respiratory distress syndrome in adult patients: A systematic review and meta-analysis.
To assess the performance of validated prediction models for acute respiratory distress syndrome (ARDS) by systematic review and meta-analysis. Eight databases (Medline, CINAHL, Embase, The Cochrane Library, CNKI, WanFang Data, Sinomed, and VIP) were searched up to March 26, 2023. Studies developed and validated a prediction model for ARDS in adult patients were included. Items on study design, incidence, derivation methods, predictors, discrimination, and calibration were collected. The risk of bias was assessed by the Prediction model Risk of Bias Assessment Tool. Models with a reported area under the curve of the receiver operating characteristic (AUC) metric were analyzed. A total of 25 studies were retrieved, including 48 unique prediction models. Discrimination was reported in all studies, with AUC ranging from 0.701 to 0.95. Emerged AUC value of the logistic regression model was 0.837 (95% CI: 0.814 to 0.859). Besides, the value in the ICU group was 0.856 (95% CI: 0.812 to 0.899), the acute pancreatitis group was 0.863 (95% CI: 0.844 to 0.882), and the postoperation group was 0.835 (95% CI: 0.808 to 0.861). In total, 24 of the included studies had a high risk of bias, which was mostly due to the improper methods in predictor screening (13/24), model calibration assessment (9/24), and dichotomization of continuous predictors (6/24). This study shows that most prediction models for ARDS are at high risk of bias, and the discrimination ability of the model is excellent. Adherence to standardized guidelines for model development is necessary to derive a prediction model of value to clinicians.


Mothers' protection of their children after discovering they have been sexually abused: an information-processing perspective.
The purpose of this study was to understand why some non-offending mothers did not protect their children consistently after they knew they were sexually abused. The sample included 85 mothers who were involved with child protective services: 48 mothers who protected their children consistently were compared to 37 mothers who did not. Several variables explained 47% of the variance in the multivariate analysis. If the mother did not ask the abuser whether the abuse occurred, attributed responsibility to the abuser, believed consistently that the abuse occurred, and was not a victim of domestic violence, then she was more likely to protect her child consistently. Some maternal characteristics believed to affect protectiveness, such as mothers' mental health and substance abuse, were not related to whether they protected their children consistently, whereas other variables, such as domestic violence, were. Researchers need to continue to examine these and other variables simultaneously, so that practitioners can better understand which children are most likely to receive inadequate protection. Practitioners should ask mothers whether they believe the abusers' behavior was sexual and abusive. If mothers do not perceive sexual abuse, then they will not believe abuse occurred or attribute responsibility to the abusers. Helping mothers understand the nature of sexual abuse may change their beliefs and attributions. If the abuser is the mother's partner and he has physically assaulted her, practitioners need to assess her willingness and ability, with adequate services and support, to restrict his access to her child.


Vasopressin: a new target for the treatment of heart failure.
Arginine vasopressin is a peptide hormone that modulates a number of processes implicated in the pathogenesis of heart failure. Numerous vasopressin antagonists are currently under development for the treatment of this syndrome. Preclinical and clinical data describing the effects of vasopressin and the vasopressin antagonists on both normal physiology and heart failure were reviewed. Through activation of V(1a) and V(2) receptors, vasopressin regulates various physiological processes including body fluid regulation, vascular tone regulation, and cardiovascular contractility. Vasopressin synthesis is significantly and chronically elevated in patients with heart failure despite the volume overload and reductions in plasma osmolality often observed in these patients. Vasopressin also appears to adversely effect hemodynamics and cardiac remodeling, while potentiating the effects of norepinephrine and angiotensin II. The selective V(2) and dual V(1a)/V(2) receptor antagonists tolvaptan and conivaptan, respectively, substantially increase free water excretion and plasma osmolality, reduce body weight, improve symptoms of congestion, and moderately increase serum sodium concentrations in patients with heart failure who present with symptoms of fluid overload. Tolvaptan effectively normalizes serum sodium concentrations in hyponatremic heart failure patients. Conivaptan significantly reduces pulmonary capillary wedge pressure without affecting systemic vascular resistance or cardiac output. The clinical significance of V(1a) receptor antagonism requires further investigation. Current preclinical and clinical findings with the vasopressin antagonists appear promising, however further evaluation in phase III clinical trials is necessary to define the role of vasopressin antagonism in the treatment of heart failure.


The Rolipram-Perillyl Alcohol Conjugate (NEO214) Is A Mediator of Cell Death through the Death Receptor Pathway.
Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis. Treatment with temozolomide, standard of care for gliomas, usually results in drug resistance and tumor recurrence. Therefore, there is a great need for drugs that target GBM. NEO214 was generated by covalently linking rolipram to perillyl alcohol (POH) via a carbamate bond to form the rolipram-perillyl alcohol conjugate. We show here that NEO214 is effective against both temozolomide-sensitive and temozolomide-resistant glioma cells. Furthermore, NEO214 is effective for different mechanisms of temozolomide resistance: overexpression of MGMT (O6-methylguanine methyl-transferase); deficiency in specific mismatch repair proteins; and overexpression of base excision repair (BER) proteins. NEO214-induced cytotoxicity involves apoptosis triggered by endoplasmic reticulum (ER) stress, as well as activating the Death Receptor 5 (DR5)/TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) pathway. In vitro studies show that glioma cells treated with NEO214 express DR5 and exhibit cell death in the presence of recombinant TRAIL, a growth factor constitutively produced by astrocytes. Our in vitro 3D coculture data show that induction of DR5 in glioma cells with NEO214 and TRAIL cause tumor cell death very effectively and specifically for glioma cells. In vivo studies show that NEO214 has antitumor efficacy in orthotropic syngeneic rodent tumor models. Furthermore, NEO214 has therapeutic potential especially for brain tumors because this drug can cross the blood-brain barrier (BBB), and is effective in the TRAIL-rich astrocyte microenvironment. NEO214 is a strong candidate for use in the treatment of GBMs.


Espresso Coffee for the Treatment of Somnolence in Parkinson's Disease: Results of n-of-1 Trials.
There is limited information available concerning the treatment of daytime somnolence associated with Parkinson's disease (PD); the most frequently applied therapeutic strategies include decreasing the dose of dopamine agonists or adding potential wake-promoting agents. There is recent data from a placebo-controlled trial concluding on a non-significant trend in favor of caffeine. We aimed to evaluate the efficacy of espresso-coffee in the treatment of daytime somnolence in PD. To evaluate the efficacy of espresso-coffee in the treatment of daytime somnolence in PD, we have conducted multiple single-patient (n-of-1) clinical trials comparing regular espresso coffee to decaffeinated coffee in PD patients presenting moderate to severe daytime somnolence defined as an Epworth Sleepiness Scale score >9. Each single-patient (n-of-1) trial included a sequence of three crossovers (two treatment periods separated by two days of washout). Four patients were included in the studies and three completed the three pairs of treatment periods. In two of the four patients, espresso coffee was considered beneficial. This study concludes that multiple single patient trials are feasible in PD and suggests that espresso-coffee may have a beneficial effect on daytime somnolence in some patients. These results cannot be generalized beyond the patients included in these trials.


The central role of selenium in the biochemistry and ecology of the harmful pelagophyte, Aureococcus anophagefferens.
The trace element selenium (Se) is required for the biosynthesis of selenocysteine (Sec), the 21st amino acid in the genetic code, but its role in the ecology of harmful algal blooms (HABs) is unknown. Here, we examined the role of Se in the biology and ecology of the harmful pelagophyte, Aureococcus anophagefferens, through cell culture, genomic analyses, and ecosystem studies. This organism has the largest and the most diverse selenoproteome identified to date that consists of at least 59 selenoproteins, including known eukaryotic selenoproteins, selenoproteins previously only detected in bacteria, and novel selenoproteins. The A. anophagefferens selenoproteome was dominated by the thioredoxin fold proteins and oxidoreductase functions were assigned to the majority of detected selenoproteins. Insertion of Sec in these proteins was supported by a unique Sec insertion sequence. Se was required for the growth of A. anophagefferens as cultures grew maximally at nanomolar Se concentrations. In a coastal ecosystem, dissolved Se concentrations were elevated before and after A. anophagefferens blooms, but were reduced by >95% during the peak of blooms to 0.05 nM. Consistent with this pattern, enrichment of seawater with selenite before and after a bloom did not affect the growth of A. anophagefferens, but enrichment during the peak of the bloom significantly increased population growth rates. These findings demonstrate that Se inventories, which can be anthropogenically enriched, can support proliferation of HABs, such as A. anophagefferens through its synthesis of a large arsenal of Se-dependent oxidoreductases that fine-tune cellular redox homeostasis.


Neutrophils influence melanoma adhesion and migration under flow conditions.
We have studied human melanoma cell (C8161) adhesion and migration in response to stimulation by soluble collagen IV (CIV) using a modified Boyden chamber. In this modified chamber, shear flow can be introduced over the cell-substrate interface, affecting tumor cell chemotactic migration through a microporous filter. A relatively high level of intercellular adhesion molecule-1 (ICAM-1) was found on C8161 cells. In contrast, levels of beta(2)-integrins (e.g., LFA-1 and Mac-1), the molecules that would be necessary for C8161 stable adhesion to the endothelium substrate, were found to be very low on these melanoma cells. As a result, C8161 transendothelial migration under a flow condition of 4 dyn/cm(2) decreased by 70% as compared to static migration. When human neutrophils (PMNs) were present in the tumor cell suspension, C8161 migration recovered by 85% over C8161 cells alone under the 4 dyn/cm(2) flow condition. Blocking ICAM-1 on C8161 cells or Mac-1 on PMNs significantly inhibited C8161-PMN adhesion and subsequent C8161 migration through the endothelium under flow conditions. In addition, increased interleukin-8 production and Mac-1 expression by PMNs were detected when they were co-cultured with C8161 melanoma cells. These results suggest that transmigration of C8161 cells under flow conditions can be influenced by PMNs, mediated by Mac-1/ICAM-1 adhesive interactions and enhanced by altered cytokine production.


Organ doses from CT localizer radiographs: Development, validation, and application of a Monte Carlo estimation technique.
The purpose of this study was to simulate and validate organ doses from different computed tomography (CT) localizer radiograph geometries using Monte Carlo methods for a population of patients. A Monte Carlo method was developed to estimate organ doses from CT localizer radiographs using PENELOPE. The method was validated by comparing dosimetry estimates with measurements using an anthropomorphic phantom imbedded with thermoluminescent dosimeters (TLDs) scanned on a commercial CT system (Siemens SOMATOM Flash). The Monte Carlo simulation platform was then applied to conduct a population study with 57 adult computational phantoms (XCAT). In the population study, clinically relevant chest localizer protocols were simulated with the x-ray tube in anterior-posterior (AP), right lateral, and PA positions. Mean organ doses and associated standard deviations (in mGy) were then estimated for all simulations. The obtained organ doses were studied as a function of patient chest diameter. Organ doses for breast and lung were compared across different views and represented as a percentage of organ doses from rotational CT scans. The validation study showed an agreement between the Monte Carlo and physical TLD measurements with a maximum percent difference of 15.5% and a mean difference of 3.5% across all organs. The XCAT population study showed that breast dose from AP localizers was the highest with a mean value of 0.24 mGy across patients, while the lung dose was relatively consistent across different localizer geometries. The organ dose estimates were found to vary across the patient population, partially explained by the changes in the patient chest diameter. The average effective dose was 0.18 mGy for AP, 0.09 mGy for lateral, and 0.08 mGy for PA localizer. A platform to estimate organ doses in CT localizer scans using Monte Carlo methods was implemented and validated based on comparison with physical dose measurements. The simulation platform was applied to a virtual patient population, where the localizer organ doses were found to range within 0.4%-8.6% of corresponding organ doses for a typical CT scan, 0.2%-3.3% of organ doses for a CT pulmonary angiography scan, and 1.1%-20.8% of organ doses for a low-dose lung cancer screening scan.


Identification of mutations allowing Natural Resistance Associated Macrophage Proteins (NRAMP) to discriminate against cadmium.
Each essential transition metal plays a specific role in metabolic processes and has to be selectively transported. Living organisms need to discriminate between essential and non-essential metals such as cadmium (Cd(2+) ), which is highly toxic. However, transporters of the natural resistance-associated macrophage protein (NRAMP) family, which are involved in metal uptake and homeostasis, generally display poor selectivity towards divalent metal cations. In the present study we used a unique combination of yeast-based selection, electrophysiology on Xenopus oocytes and plant phenotyping to identify and characterize mutations that allow plant and mammalian NRAMP transporters to discriminate between their metal substrates. We took advantage of the increased Cd(2+) sensitivity of yeast expressing AtNRAMP4 to select mutations that decrease Cd(2+) sensitivity while maintaining the ability of AtNRAMP4 to transport Fe(2+) in a population of randomly mutagenized AtNRAMP4 cDNAs. The selection identified mutations in three residues. Among the selected mutations, several affect Zn(2+) transport, whereas only one, E401K, impairs Mn(2+) transport by AtNRAMP4. Introduction of the mutation F413I, located in a highly conserved domain, into the mammalian DMT1 transporter indicated that the importance of this residue in metal selectivity is conserved among NRAMP transporters from plant and animal kingdoms. Analyses of overexpressing plants showed that AtNRAMP4 affects the accumulation of metals in roots. Interestingly, the mutations selectively modify Cd(2+) and Zn(2+) accumulation without affecting Fe transport mediated by NRAMP4 in planta. This knowledge may be applicable for limiting Cd(2+) transport by other NRAMP transporters from animals or plants.


Life-threatening events in respiratory medicine: misconnections of invasive and non-invasive ventilators and interfaces.
Both the parallel use of intensive care unit (ICU)-ventilators and ventilators dedicated to non-invasive ventilation (NIV), as well as the construction of some expiratory valves in single circuit breathing tubes may lead to misconnections which are potentially fatal for the patient. We demonstrate first a case of a misconnected expiratory valve in a patient with invasive home ventilation. In a second case, the mistaken connection of a non-invasive ventilator to an endotracheal tube leading to carbon dioxide (CO2)-rebreathing is demonstrated. A third case describes a patient with home non-invasive ventilation who had been delivered a non-vented mask out-of-hospital, likewise leading to CO2-rebreathing. Human error is the main reason for critical incidents in medicine and the most serious unintended events often involve mechanical ventilation. A regular instruction of medical staff and patients is necessary. The demonstrated misconnections are examples of latent errors "waiting to happen". To prevent these errors from being made in the future, technological solutions similar to the aviation effort to improve safety are needed.


A CRISPR/Cas9-mediated in situ complementation method for Phytophthora sojae mutants.
Phytophthora sojae is an important model species for oomycete functional genomics research. Recently, a CRISPR/Cas9-mediated genome-editing technology has been successfully established in P. sojae, which has been rapidly and widely applied in oomycete research. However, there is an emerging consensus in the biological community that a complete functional gene research system is needed such as developed in the investigations in functional complementation carried out in this study. We report the development of an in situ complementation method for accurate restoration of the mutated gene. We targeted a regulatory B-subunit of protein phosphatase 2A (PsPP2Ab1) to verify this knockout and subsequent complementation system. We found that the deletion of PsPP2Ab1 in P. sojae leads to severe defects in vegetative hyphal growth, soybean infection, and loss of the ability to produce sporangia. Subsequently, the reintroduction of PsPP2Ab1 into the knockout mutant remedied all of the deficiencies. This study demonstrates the successful implementation of an in situ complementation system by CRISPR/Cas9, which will greatly accelerate functional genomics research of oomycetes in the post-genomic era.


[Current situation of the most frequent zoonosis in Mexico].
Control and eradication of zoonoses is a priority because there can only be human health if there is animal health, and both will not exist if the environment is not healthy. This concept is called "One Health" Mexico has demonstrated its capacity to eradicate various zoonoses such as Venezuelan equine encephalitis, yellow fever cattle screwworm, and highly pathogenic avian influenza. Zoonoses and emerging and reemerging diseases and food-borne diseases are called neglected diseases. They provoke disease and diminish food security. Their presence is seen in marginalized populations with lags in their development that reflect the lack of equity in our society; these diseases are the product of the lack of attention to the social determinants of health and risk factors. Tackling these diseases should be comprehensive, with intersectoral, interdisciplinary, and transdisciplinary approaches. Government agencies located in the human/animal health environment interface do not have established limits of liability and there are overlapping and empty spots; legislation is insufficient to guarantee collaboration. It is urgent to have reforms and new forms of organizations, regionalized according to the epidemiological situation; at the municipal level, a priority is to formalize an effective service of veterinary public health. New impetuses to address the persistent social and health lags are proposed.


Bacteriologic efficacy of a three-day intramuscular ceftriaxone regimen in nonresponsive acute otitis media.
To determine the bacteriologic efficacy of ceftriaxone in nonresponsive acute otitis media in children. In a prospective study 92 patients ages 3 to 36 months (median, 11 months) with culture-proved nonresponsive acute otitis media were studied from January, 1995, through August, 1997. The patients were treated with intramuscular ceftriaxone (50 mg/kg/l/day) for 3 days. Middle ear fluid was aspirated for culture by tympanocentesis on day of enrollment (Day 1); a second tap was performed on Days 4 to 10. Additional middle ear fluid cultures were obtained if clinical relapse occurred. Bacteriologic failure was defined by positive culture on Days 4 to 10. Patients were followed until Day 17+/-2. Susceptibility was measured by E test. The main drugs administered before enrollment were amoxicillin (38%), amoxicillinclavulanate (25%) and cefaclor (20%). Organisms recovered (n=105) were: Haemophilus influenzae, 54; Streptococcus pneumoniae, 47; Moraxella catarrhalis, 2; and Streptococcus pyogenes, 2. Thirty-four (72%) of the 47 S. pneumoniae isolates were intermediately resistant to penicillin (MIC 0.1 to 1.0 microg/ml), but all were susceptible to ceftriaxone (MIC < 0.5 microg/ml). Bacteriologic eradication was achieved in 100 of 105 (95%) cases: 54 of 54 (10O%) H. influenzae, 43 of 47 (92%) S. pneumoniae, 1 of 2 (50%) M. catarrhalis and 2 of 2 (100%) S. pyogenes. Bacteriologic success (with no relapse) occurred in 13 of 13 (100%) penicillin-susceptible S. pneumoniae vs. 28 of 34 (82%) S. pneumoniae intermediately resistant to penicillin (4 cases of bacteriologic failure and 2 cases of relapse). A 3-day intramuscular ceftriaxone regimen is efficacious for the treatment of nonresponsive acute otitis media. The optimal duration of treatment in cases of nonresponsive acute otitis media and whether ceftriaxone is efficacious for the treatment of nonresponsive otitis media caused by S. pneumoniae highly resistant to penicillin is yet to be determined.


A pan-HPV vaccine based on bacteriophage PP7 VLPs displaying broadly cross-neutralizing epitopes from the HPV minor capsid protein, L2.
Current human papillomavirus (HPV) vaccines that are based on virus-like particles (VLPs) of the major capsid protein L1 largely elicit HPV type-specific antibody responses. In contrast, immunization with the HPV minor capsid protein L2 elicits antibodies that are broadly cross-neutralizing, suggesting that a vaccine targeting L2 could provide more comprehensive protection against infection by diverse HPV types. However, L2-based immunogens typically elicit much lower neutralizing antibody titers than L1 VLPs. We previously showed that a conserved broadly neutralizing epitope near the N-terminus of L2 is highly immunogenic when displayed on the surface of VLPs derived from the bacteriophage PP7. Here, we report the development of a panel of PP7 VLP-based vaccines targeting L2 that protect mice from infection with carcinogenic and non-carcinogenic HPV types that infect the genital tract and skin. L2 peptides from eight different HPV types were displayed on the surface of PP7 bacteriophage VLPs. These recombinant L2 VLPs, both individually and in combination, elicited high-titer anti-L2 IgG serum antibodies. Immunized mice were protected from high dose infection with HPV pseudovirus (PsV) encapsidating a luciferase reporter. Mice immunized with 16L2 PP7 VLPs or 18L2 PP7 VLPs were nearly completely protected from both PsV16 and PsV18 challenge. Mice immunized with the mixture of eight L2 VLPs were strongly protected from genital challenge with PsVs representing eight diverse HPV types and cutaneous challenge with HPV5 PsV. VLP-display of a cross-neutralizing HPV L2 epitope is an effective approach for inducing high-titer protective neutralizing antibodies and is capable of offering protection from a spectrum of HPVs associated with cervical cancer as well as genital and cutaneous warts.


HPV-Associated Squamous Cell Carcinoma of the Eyelid: Diagnostic Utility of p16 Immunohistochemistry and mRNA In Situ Hybridization.
High-risk (HR) Human papillomavirus (HPV) has been implicated in pathogenesis of squamous cell carcinomas (SCC) at several sites with mucocutaneous junctions, including the head and neck. SCC is the second most common eyelid malignancy. However, its association with transcriptionally active HR-HPV has not been adequately studied. Two index cases of eyelid HPV-associated SCC are described in detail. A retrospective cohort of eyelid SCC was examined for p16 immunoexpression. Cases demonstrating p16 positivity or equivocal staining were subjected to high-risk HPV mRNA in situ hybridization (ISH). Quantitative real-time PCR (qPCR) was performed in mRNA ISH-positive cases for HPV genotyping. The two index patients were older adult females, with upper eyelid tumours. On histology, both tumours were non-keratinizing SCC with trabecular and nested architecture reminiscent of oropharyngeal HPV-associated non-keratinizing SCC, prompting p16 immunohistochemistry, which was positive. HR-HPV mRNA ISH was positive, and qPCR detected HPV16 in both cases. Three of 20 (15%) archival cases showed p16 immunopositivity and two (10%) showed equivocal staining. However, mRNA ISH was negative. All cases showing p16 immunostaining and lacking HR-HPV were keratinizing SCCs. Thus, 9% of all eyelid SCC examined demonstrated HR-HPV. The prevalence of HR-HPV in eyelid SCC is low in Indian patients. HPV-associated SCC may mimic commoner eyelid carcinomas as it lacks overt keratinization. In basaloid-appearing eyelid carcinomas, p16 immunopositivity should be followed by reflex HR-HPV mRNA ISH, as p16 immunohistochemistry alone has low specificity. The prognostic role, if any, of HPV association needs further evaluation.


Using a stair horizontal-vertical illusion to increase foot clearance over an inconsistently taller stair-riser.
Stair falls can be caused by inconsistent stair dimensions. During ascent, inconsistently taller stair risers lead to reduced foot clearances as the inconsistency goes unnoticed. A stair horizontal-vertical illusion increases perceived riser heights and foot clearance and could offset reduced foot clearances over inconsistently taller risers, though this might impact other stair safety measures. Twelve participants (age: 22 (3) years) ascended a seven-step staircase under three conditions: i) all steps consistent in riser height (consistent), ii) a 1cm increase in step 5 riser height (inconsistent) and iii) a 1cm increase in step 5 riser height, superimposed with a stair horizontal-vertical illusion (illusion). Vertical foot clearance, foot overhang, and margins of stability were assessed over step 4, 5 and 6. Perceived riser height due to the illusion was determined through a computer perception test. A One-Way Repeated Measures ANOVA compared biomechanical variables between conditions. A One Sample t test compared perceived riser height to the true height. Over the inconsistent step 5, foot clearance reduced by 0.8cm compared to consistent. Illusion increased foot clearance by 1.1cm and decreased foot overhang by 4% compared to inconsistent. On step 4 the illusion led to more anterior instability compared to inconsistent. Illusion and inconsistent led to more mediolateral stability compared to consistent. The illusion increased perceived riser height by 12%. Foot clearance reductions over inconsistently taller risers can be offset by a stair horizontal-vertical illusion. Additional benefits included a safer foot overhang and unaffected stability over the inconsistent riser. Changes to step 4 stability might have resulted from leaning forward to look at the step 5 illusion. The stair horizontal-vertical illusion could be a practical solution for inconsistently taller stair risers, where a rebuild is usually the only solution.


Protein structure, stability and solubility in water and other solvents.
Proteins carry out the most difficult tasks in living cells. They do so by interacting specifically with other molecules. This requires that they fold to a unique, globular conformation that is only marginally more stable than the large ensemble of unfolded states. The folded state is stabilized mainly by the burial and tight packing of over 80% of the peptide groups and non-polar side chains. If life as we know it is to exist in a solvent other than water, the folded state must be stable and soluble in the new solvent. Our analysis suggests that proteins will be unstable in most polar solvents such as ethanol, extremely stable in non-polar solvents such as cyclohexane, and even more stable in a vacuum. Our solubility studies suggest that protein solubility will be markedly lower in polar solvents such as ethanol and that proteins will be essentially insoluble in non-polar solvents such as cyclohexane. For these and other reasons it seems unlikely that the life we know could exist in any solvent system other than water.


Using administrative sickness absence data as a marker of future disability pension: the prospective DREAM study of Danish private sector employees.
The aim of this study was to examine duration of sickness absence as a risk marker for future disability pension among all private sector employees in Denmark 1998-2004. All private sector employees receiving sickness absence compensation from the municipality in 1998, a total of 225 056 persons (39.2% women 61.8% men, age range 18-65, mean age 37.2), were followed in a national register to determine granted disability pension during the period 1 January 2001 through 31 December 2004. The authors excluded pensions in 1999 and 2000 to determine the status of sickness absence duration as an early risk marker. 5694 persons (2.5%) received disability pension during follow-up, more men (53.4%) than women (46.6%). There was a strong graded association between increasing length of absence and increasing risk of future disability pension. Significant differences were found between the younger and older age strata: men below 40 experiencing more than 26 weeks of sickness absence had a 16-fold risk of disability pension. The corresponding figure for men 40 years or older was approximately 7. For women, the corresponding figures were 12.6 and 6.7 respectively. The findings suggest that administratively collected data on sickness absence compensation are an important predictor of disability pension among private sector employees. The use of information on sick leave may improve the effectiveness of early interventions by policy makers, case managing authorities, employers and physicians.


Genomic and Phenotypic Characterization of Experimentally Selected Resistant Leishmania donovani Reveals a Role for Dynamin-1-Like Protein in the Mechanism of Resistance to a Novel Antileishmanial Compound.
The implementation of prospective drug resistance (DR) studies in the research-and-development (R&D) pipeline is a common practice for many infectious diseases but not for neglected tropical diseases (NTDs). Here, we explored and demonstrated the importance of this approach using as paradigms Leishmania donovani, the etiological agent of visceral leishmaniasis (VL), and TCMDC-143345, a promising compound of the GlaxoSmithKline (GSK) "Leishbox" to treat VL. We experimentally selected resistance to TCMDC-143345 in vitro and characterized resistant parasites at the genomic and phenotypic levels. We found that it took more time to develop resistance to TCMDC-143345 than to other drugs in clinical use and that there was no cross-resistance to these drugs, suggesting a new and unique mechanism. By whole-genome sequencing, we found two mutations in the gene encoding the L. donovani dynamin-1-like protein (LdoDLP1) that were fixed at the highest drug pressure. Through phylogenetic analysis, we identified LdoDLP1 as a family member of the dynamin-related proteins, a group of proteins that impacts the shapes of biological membranes by mediating fusion and fission events, with a putative role in mitochondrial fission. We found that L. donovani lines genetically engineered to harbor the two identified LdoDLP1 mutations were resistant to TCMDC-143345 and displayed altered mitochondrial properties. By homology modeling, we showed how the two LdoDLP1 mutations may influence protein structure and function. Taken together, our data reveal a clear involvement of LdoDLP1 in the adaptation/reduced susceptibility of L. donovani to TCMDC-143345. IMPORTANCE Humans and their pathogens are continuously locked in a molecular arms race during which the eventual emergence of pathogen drug resistance (DR) seems inevitable. For neglected tropical diseases (NTDs), DR is generally studied retrospectively once it has already been established in clinical settings. We previously recommended to keep one step ahead in the host-pathogen arms race and implement prospective DR studies in the R&D pipeline, a common practice for many infectious diseases but not for NTDs. Here, using Leishmania donovani, the etiological agent of visceral leishmaniasis (VL), and TCMDC-143345, a promising compound of the GSK Leishbox to treat VL, as paradigms, we experimentally selected resistance to the compound and proceeded to genomic and phenotypic characterization of DR parasites. The results gathered in the present study suggest a new DR mechanism involving the L. donovani dynamin-1-like protein (LdoDLP1) and demonstrate the practical relevance of prospective DR studies.


RNF170 protein, an endoplasmic reticulum membrane ubiquitin ligase, mediates inositol 1,4,5-trisphosphate receptor ubiquitination and degradation.
Inositol 1,4,5-trisphosphate (IP(3)) receptors are endoplasmic reticulum membrane calcium channels that, upon activation, are degraded via the ubiquitin-proteasome pathway. While searching for novel mediators of IP(3) receptor processing, we discovered that RNF170, an uncharacterized RING domain-containing protein, associates rapidly with activated IP(3) receptors. RNF170 is predicted to have three membrane-spanning helices, is localized to the ER membrane, and possesses ubiquitin ligase activity. Depletion of endogenous RNF170 by RNA interference inhibited stimulus-induced IP(3) receptor ubiquitination, and degradation and overexpression of a catalytically inactive RNF170 mutant suppressed stimulus-induced IP(3) receptor processing. A substantial proportion of RNF170 is constitutively associated with the erlin1/2 (SPFH1/2) complex, which has been shown previously to bind to IP(3) receptors immediately after their activation. Depletion of RNF170 did not affect the binding of the erlin1/2 complex to stimulated IP(3) receptors, whereas erlin1/2 complex depletion inhibited RNF170 binding. These results suggest a model in which the erlin1/2 complex recruits RNF170 to activated IP(3) receptors where it mediates IP(3) receptor ubiquitination. Thus, RNF170 plays an essential role in IP(3) receptor processing via the ubiquitin-proteasome pathway.


Fatty acids are crucial to fuel NK cells upon acute retrovirus infection.
Natural killer (NK) cells are cytotoxic innate immune cells, able to recognize and eliminate virus-infected as well as cancer cells. Metabolic reprogramming is crucial for their activity as they have enhanced energy and nutritional demands for their functions during an infection. Fatty acids (FAs) represent an important source of cellular energy and are essential for proliferation of immune cells. However, the precise role of FAs for NK cells activity in retrovirus infection was unknown. Here we show that activated NK cells increase the expression of the FA uptake receptor CD36 and subsequently the uptake of FAs upon acute virus infection. We found an enhanced flexibility of NK cells to utilize FAs as source of energy compare to naïve NK cells. NK cells that were able to generate energy from FAs showed an augmented target cell killing and increased expression of cytotoxic parameters. However, NK cells that were unable to generate energy from FAs exhibited a severely decreased migratory capacity. Our results demonstrate that NK cells require FAs in order to fight acute virus infection. Susceptibility to severe virus infections as it is shown for people with malnutrition may be augmented by defects in the FA processing machinery, which might be a target to therapeutically boost NK cell functions in the future.


Cardiac protein synthesis and degradation during thyroxine-induced left ventricular hypertrophy.
Assessment of cardiac protein metabolism in thyroxine-induced left ventricular hypertrophy requires measurements of both protein synthesis and degradation. In vivo protein degradative rates can best be measured as the difference between rates of protein synthesis and growth. Accordingly, rates of left ventricular protein accumulation were determined in growing rabbits, and in animals administered intravenous L-thyroxine (200 micrograms X kg-1 X day-1) for up to 15 days. Left ventricular protein fractional synthetic rates in euthyroid and thyroxine-treated rabbits were measured by continuous infusion of [3H]leucine (200 mu Ci/h X 6 h), and results converted to milligrams protein synthesized and degraded per day. Thyroxine administration produced left ventricular hypertrophy by increasing the rate of total protein synthesis (35.7 +/- 2.0, 71.0 +/- 7.0, and 62.6 +/- 4.0 mg of left ventricular protein synthesized per day for 0-, 3-, and 9-day, thyroxine-treated rabbits, respectively). However, the increased rate of total protein synthesis was greater than the measured rate of total protein accumulation (8.1 vs. 15.9 mg protein/day for euthyroid and thyroxine-treated animals), indicating that left ventricular protein degradative rates were increased as well. These studies indicate that accelerated proteolysis may be important in the molecular and architectural remodeling of the rapidly hypertrophying heart during thyrotoxicosis.


68Ga-Prostate-Specific Membrane Antigen-Avid Tubercular Lesions Mimicking Prostate Cancer Metastasis on Simultaneous Prostate-Specific Membrane Antigen PET/MRI.
Ga-prostate-specific membrane antigen (PSMA) has gained increasing interest as a target molecule in imaging of prostate cancer because of its selective overexpression in local prostate cancer lesions and metastasis. We report a case of a 62-year-old man with raised serum prostate-specific antigen levels who presented for Ga-PSMA HBED-CC simultaneous PET/MRI for prostate cancer evaluation. A PSMA-nonavid PI-RADS 5 (Prostate Imaging-Reporting and Data System) lesion was confirmed as adenocarcinoma on histopathology. The PSMA-avid lesions were noted in the calvarium and lung, with the calvarial lesion confirmed to be of tubercular etiology on biopsy, and both lesions subsequently responded to antitubercular treatment.


Inflammatory markers in cancer: Potential resources.
Cancer is a leading cause of death worldwide and a major burden on developing and less developed countries of the world with limited resources for prevention and effective treatment of cancer. Although cancer is multifactorial in origin, various epidemiological and experimental studies suggest that chronic inflammation has an important role in all stages of cancer, from initiation to progression and even survival of the patient. Inflammatory products like cytokines, chemokines, leucocytes, prostaglandins, cyclooxygenase, reactive oxygen and nitrogen species, metalloproteinase induce genetic and epigenetic changes in normal cells damaging its DNA, inhibiting its repair, altering transcription factors, preventing apoptosis, and stimulating angiogenesis, and thus resulting in carcinogenesis. Thus, these inflammatory mediators have a potential role to become cancer biomarkers for all stages of cancer as many of them can be measured in a cost-effective manner. However, large scale prospective trials are required to validate these potential cancer biomarkers. Nonetheless, a transition from potential to practical utilization of these markers will be an effective tool for the amelioration of cancer burden and mortality in a resource limited setting.


Women subjects in NIH-funded clinical research literature: lack of progress in both representation and analysis by sex.
The National Institutes of Health (NIH) issued guidelines in 1990 requiring the inclusion of women and minorities in all NIH-sponsored clinical research and revised these guidelines in 1994 to require analysis of clinical trial outcomes by sex of the subjects. To ascertain whether these guidelines are yet reflected in the scientific literature, we performed a survey of research articles published in major medical journals. All original research articles in the New England Journal of Medicine, the Journal of the American Medical Association, the Journal of the National Cancer Institute, and Circulation from the years 1993, 1995, 1997, and 1998 were examined. Articles were assessed for use of human subjects, source of funding, type of study (clinical trial or not), sex-relatedness of the disease or condition, inclusion of women as study subjects, and analysis of outcomes by sex of the subjects. Among NIH-funded, non-sex-specific studies, approximately one fifth of the studies published each year failed to include women as research subjects. This number did not improve significantly over the 5-year period analyzed. Only one quarter to one third of the studies that included women analyzed data by sex of the subjects, with no significant change over the time period studied. Although most clinical trials included women as study subjects, in only a small percentage of the trials were results analyzed by sex of the subjects, with no significant improvement over time. These data clearly show the need for increased awareness and monitoring of recruitment and retention of women in clinical research and for analysis of data by sex of the subjects to be carried out consistently.


[Heavy metals as a factor of possible environmentally caused illnesses in the Astrakhan region].
There are presented data about heavy metals as pollutants of the environment and the factors of environment-related diseases. There is given the brief information about the appearance of heavy metals in the environmental objects and the possible occurrence of diseases caused by trace elements deficiency in the region. There are discussed difficulties of the clinical and laboratory diagnosis, associated with general symptoms of many diseases and lack in the medical facilities the equipment for objective detection of heavy metals in human biosubstrates.


Double little toenails: Report of 4 familial cases.
Double little toenails, or accessory nails of the fifth toe, are a rare and particular deformity distinct from other nail dysplasias. We describe 4 cases of female patients, including a 6-year-old girl, experiencing this bilateral condition after birth. The nail anomaly shows an autosomal-dominant type of transmission that affects only female individuals. The subjects examined were from a family without marriages between blood relatives and without neuroectodermal hereditary diseases. The 4 patients had no bone alterations of the terminal phalanges of the fifth toe or alterations of the joints of the toes or hair. One patient had nail deformity associated with epilepsy; another patient, associated with an infection of an accessory nail.


Complete Clinicopathological Case Report of a Young Patient Dying of COVID-19-Related Stroke.
The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic has revealed diverse neurological manifestations of coronavirus disease 2019 (COVID-19). This case report begins with a background review of the neurological effects of COVID-19, focusing on stroke, neuroinflammation, and coagulopathy. It then describes the clinical course and autopsy findings of a young patient presenting with COVID-19-associated stroke. The formal neuropathological examination is presented, along with the systemic and brain histological features. Interesting aspects include multiterritory hemorrhagic infarctions, microinfarcts throughout the cortex and white matter, and prominent mixed inflammatory cell cuffing of intracerebral blood vessels distant from the infarcts.


Temperature measurements in a capacitive system of deep loco-regional hyperthermia.
Hyperthermia has been shown to be a medically useful procedure applicable for different indications. For the connection between clinical effects and heat, it is important to understand the actual temperatures achieved in the tissue. There are limited temperature data available when using capacitive hyperthermia devices even though this is worldwide the most widespread method for loco-regional heating. Hence, this study examines temperature measurements using capacitive heating. Bioequivalent phantoms were used for the measurements, which, however, do not consider perfusion in live tissue. In general, the required temperature impact for an effective cancer therapy should need an increase of 0.2°C/min, which has been achieved. In the described tests on the non-perfused dummy, on average, the temperature increases by approximately 2°C in the first 12 min. The temperature difference relative to the starting temperature was 10-12°C within a therapy time of 60 min (rising from the initial room temperature between 20-24°C and 32-34°C). The average deviation with three individual measurements each on different days in a specified localization was 2°C. The minimum temperature difference was 4.2°C, and the maximum value was reached in the liver with 10.5°C. These values were achieved with a moderate energy input of 60-150 watts, with much higher performance outputs still available. These results show that the tested capacitive device is capable of achieving quick temperature increase with a sufficient impact into the depth of a body.


Management of penile cancer patients during the COVID-19 pandemic: An eUROGEN accelerated Delphi consensus study.
To develop an international consensus on managing penile cancer patients during the COVID-19 acute waves. A major concern for patients with penile cancer during the coronavirus disease 2019 (COVID-19) pandemic is how the enforced safety measures will affect their disease management. Delays in diagnosis and treatment initiation may have an impact on the extent of the primary lesion as well as the cancer-specific survival because of the development and progression of inguinal lymph node metastases. A review of the COVID-19 literature was conducted in conjunction with analysis of current international guidelines on the management of penile cancer. Results were presented to an international panel of experts on penile cancer and infection control by a virtual accelerated Delphi process using 4 survey rounds. Consensus opinion was defined as an agreement of ≥80%, which was used to reconfigure management pathways for penile cancer. Limited evidence is available for delaying penile cancer management. The consensus rate of agreement was 100% that penile cancer pathways should be reconfigured, and measures should be developed to prevent perioperative nosocomial transmission of COVID-19. The panel also reached a consensus on several statements aimed at reconfiguring the management of penile cancer patients during the COVID-19 pandemic. The international consensus panel proposed a framework for the diagnostic and invasive therapeutic procedures for penile cancer within a low-risk environment for COVID-19.


Health benefits of cocoa.
In modern society, cocoa is being eaten as a confectionery, contrary to its medicinal use in the past. However, since the last decade, there has been a revival of talks about cocoa's health beneficial effects. Development has been made at the molecular level recently. This review discusses the recent progresses on potential health benefits of cocoa and/or its derivatives, with a focus on the areas that have been paid little attention so far, such as the role of cocoa in immune regulation, inflammation, neuroprotection, oxidative stress, obesity, and diabetes control. Thanks to the advancement in analytical technologies, the cocoa's metabolic pathways have now been properly mapped providing essential information on its roles. Cocoa helps in weight loss by improving mitochondrial biogenesis. It increases muscle glucose uptake by inserting glucose transporter 4 in skeletal muscles membrane. Because of its antioxidant properties, cocoa offers neuron protection and enhances cognition and positive mood. It lowers immunoglobulin E release in allergic responses. It can affect the immune response and bacterial growth at intestinal levels. It reduces inflammation by inhibiting nuclear factor-κB. Keeping in view the pleiotropic health benefits of cocoa, it may have the potential to be used for the prevention/treatment of allergies, cancers, oxidative injuries, inflammatory conditions, anxiety, hyperglycemia, and insulin resistance.


The clinical course of cervical carcinoma in situ diagnosed during pregnancy.
The objective was to determine the frequency with which regression or progression of disease without treatment occurred in women diagnosed with squamous cell cervical carcinoma in situ (CIS) during pregnancy. . A retrospective chart review of all women evaluated at the University of Iowa Colposcopy Clinic diagnosed with CIS during pregnancy from 1987 through 1992 was used. Thirty-four women were evaluated during pregnancy, of which 26 also had postpartum evaluation. All pathology reports of initial cytology and biopsies, as well as colposcopic impressions, were reviewed and compared to the same evaluations postpartum. Of the 26 women evaluated both antepartum and postpartum, only 1 was treated (cone biopsy) during pregnancy. She had disease suspicious for microinvasion. She was disease free postpartum. Of the remaining 25, 20 (80%) had persistent disease, 2 (8%) had either missed disease or progressive disease postpartum, and 3 (12%) resolved without treatment at postpartum evaluation. No statistical significance was found between route of delivery and persistence (P = 0.34). No statistical significance was found between smoking and persistence of disease (P = 1.0). In 46% of women the initial cytology was CIN I or II, and the initial colposcopic impression was found to underestimate the severity of the disease in 35% of cases. Two women were found to have invasive disease postpartum. There is a high persistence rate of CIS complicating pregnancy. Given the relatively high rate of underestimation of disease severity by both cytology and colposcopic impression, the use of routine biopsy at the time of colposcopy is recommended. Invasive disease may be encountered on postpartum evaluation.


[The standardization of conjugates for the indirect solid-phase immunoenzyme analysis reaction].
The comparative study of several batches of conjugates has revealed that enzyme immunoassay techniques can be used for the standardization of conjugates by their affinity level. The study has shown that this can be done only if the concentration of specific antibodies in the conjugate is known and the amount of the conjugate is in excess to that of the antigen adsorbed on the plate.


Expression of Flavodiiron Proteins Flv2-Flv4 in Chloroplasts of Arabidopsis and Tobacco Plants Provides Multiple Stress Tolerance.
With the notable exception of angiosperms, all phototrophs contain different sets of flavodiiron proteins that help to relieve the excess of excitation energy on the photosynthetic electron transport chain during adverse environmental conditions, presumably by reducing oxygen directly to water. Among them, the Flv2-Flv4 dimer is only found in β-cyanobacteria and induced by high light, supporting a role in stress protection. The possibility of a similar protective function in plants was assayed by expressing Synechocystis Flv2-Flv4 in chloroplasts of tobacco and Arabidopsis. Flv-expressing plants exhibited increased tolerance toward high irradiation, salinity, oxidants, and drought. Stress tolerance was reflected by better growth, preservation of photosynthetic activity, and membrane integrity. Metabolic profiling under drought showed enhanced accumulation of soluble sugars and amino acids in transgenic Arabidopsis and a remarkable shift of sucrose into starch, in line with metabolic responses of drought-tolerant genotypes. Our results indicate that the Flv2-Flv4 complex retains its stress protection activities when expressed in chloroplasts of angiosperm species by acting as an additional electron sink. The flv2-flv4 genes constitute a novel biotechnological tool to generate plants with increased tolerance to agronomically relevant stress conditions that represent a significant productivity constraint.


Early events of citrus greening (Huanglongbing) disease development at the ultrastructural level.
Citrus greening (Huanglongbing [HLB]) is one of the most destructive diseases of citrus worldwide. The causal agent of HLB in Florida is thought to be 'Candidatus Liberibacter asiaticus'. Understanding of the early events in HLB infection is critical for the development of effective measures to control the disease. In this work, we conducted cytopathological studies by following the development of the disease in citrus trees graft inoculated with 'Ca. L. asiaticus'-containing material under greenhouse conditions to examine the correlation between ultrastructural changes and symptom production, with the main objective of characterizing the early events of infection. Based on our observations, one of the first degenerative changes induced upon invasion of the pathogen appears to be swelling of middle lamella between cell walls surrounding sieve elements. This anatomical aberration was often observed in samples from newly growing flushes in inoculated sweet orange and grapefruit trees at the early "presymptomatic" stage of HLB infection. Development of symptoms and their progression correlated with an increasing degree of microscopic aberrations. Remarkably, the ability to observe the bacterium in the infected tissue also correlated with the degree of the disease progression. Large numbers of bacterial cells were found in phloem sieve tubes in tissue samples from presymptomatic young flushes. In contrast, we did not observe the bacteria in highly symptomatic leaf samples, suggesting a possibility that, at more advanced stages of the disease, a major proportion of 'Ca. L. asiaticus' is present in a nonviable state. We trust that observations reported here advance our understanding of how 'Ca. L. asiaticus' causes disease. Furthermore, they may be an important aid in answering a question: when and where within an infected tree the tissue serves as a better inoculum source for acquisition and transmission of the bacterium by its psyllid vector.


Microfluidic system for studying the interaction of nanoparticles and microparticles with cells.
Nanoparticles and microparticles have many potential biomedical applications ranging from imaging to drug delivery. Therefore, in vitro systems that can analyze and optimize the interaction of such particles with cells may be beneficial. Here, we report a microfluidic system that can be used to study these interactions. As a model system, we evaluated the interaction of polymeric nanoparticles and microparticles and similar particles conjugated to aptamers that recognize the transmembrane prostate specific membrane antigen (PSMA), with cells seeded in microchannels. The binding of particles to cells that expressed or did not express the PSMA (LNCaP or PC3, respectively) were evaluated with respect to changes in fluid shear stress, PSMA expression on target cells, and particle size. Nanoparticle-aptamer bioconjugates selectively adhered to LNCaP but not PC3 cells at static and low shear (<1 dyn/cm2) but not higher shear (approximately 4.5 dyn/cm2) conditions. Control nanoparticles and microparticles lacking aptamers and microparticle-aptamer bioconjugates did not adhere to LNCaP cells, even under very low shear conditions (approximately 0.28 dyn/cm2). These results demonstrate that the interaction of particles with cells can be studied under controlled conditions, which may aid in the engineering of desired particle characteristics. The scalability, low cost, reproducibility, and high-throughput capability of this technology is potentially beneficial to examining and optimizing a wide array of cell-particle systems prior to in vivo experiments.


Cytotoxicity of Group 5 Transition Metal Ditellurides (MTe2 ; M=V, Nb, Ta).
Much research effort has been put in to study layered compounds with transition metal dichalcogenides (TMDs) being one of the most studied compounds. Due to their extraordinary properties such as excellent electrochemical properties, tuneable band gaps, and low shear resistance due to weak van der Waals interactions between layers, TMDs have been found to have wide applications such as electrocatalysts for hydrogen evolution reactions, supercapacitors, biosensors, field-effect transistors (FETs), photovoltaics, and lubricant additives. In very recent years, Group 5 transition metal ditellurides have received an immense amount of research attention. However to date, little has been known of the potential toxicities posed by these materials. As such, we conducted the cytotoxicity study by incubating various concentrations of the Group 5 transition metal ditellurides (MTe2 ; M=V, Nb, Ta) with human lung carcinoma epithelial A549 cells for 24 hours and the remaining cell viabilities after treatment was measured. Our findings indicate that VTe2 is highly toxic whereas NbTe2 and TaTe2 are deemed to exhibit mild toxicities. This study constitutes an exemplary first step towards the understanding of the Group 5 transition metal ditellurides' toxicity effects in preparation for their possible future commercialisation.


Online CKD education for medical students, residents, and fellows: training in a new era.
CKD and its complications are associated with substantial morbidity and mortality. Studies have highlighted significant deficiencies in resident knowledge and awareness of CKD and its complications. There is a need to improve CKD education through medical school and residency. There is also a need to provide alternatives to traditional teaching methods to meet the challenges of learning in the context of work-hour restrictions and increasing workload among residents and fellows. Internet-based learning resources offer various educational tools, including websites, kidney blogs, online modules, and smartphone applications, which could potentially and efficiently advance CKD knowledge among medical trainees. In this review, we describe several online resources for CKD education that could be useful for medical students, residents, and fellows. Increased awareness of these tools and their utilization may significantly influence and hopefully improve the recognition and management of patients with CKD. Future studies may help evaluate the effectiveness of these online learning methods and their effect on CKD patient outcomes. In addition, in light of increased concern about nephrology workforce issues, the potential for these online tools to augment interest in nephrology careers should be investigated.


Automated segmentation and analysis of vascular structures in magnetic resonance angiographic images.
The accurate assessment of the presence and extent of vascular disease, and planning of vascular interventions based on MRA requires the determination of vessel dimensions. The current standard is based on measuring vessel diameters on maximum intensity projections (MIPs) using calipers. In order to increase the accuracy and reproducibility of the method, automated analysis of the 3D MR data is required. A novel method for automatically determining the trajectory of the vessel of interest, the luminal boundaries, and subsequent the vessel dimensions is presented. The automated segmentation in 3D uses deformable models, combined with knowledge of the acquisition protocol. The trajectory determination was tested on 20 in vivo studies of the abdomen and legs. In 93% the detected trajectory followed the vessel. The luminal boundary detection was validated on contrast-enhanced (CE) MRA images of five stenotic phantoms. The results from the automated analysis correlated very well with the true diameters of the phantoms used in the in vitro study (r = 0.999, P < 0.001). MRA and x-ray angiography (XA) of the phantoms also correlated well (r = 0.895, P < 0.001). The average unsigned difference between the MRA and XA measurements was 0.08 +/- 0.05 mm. In conclusion, the automated approach allows the accurate assessment of vessel dimensions in MRA images.


Demonstration of the bipartite nature of the genome of a single-stranded DNA plant virus by infection with the cloned DNA components.
Linear double-stranded (ds)DNA, obtained by excision of the cloned A and B components of tomato golden mosaic virus (TGMV) from recombinant plasmids, was found to infect plants and to elicit symptoms identical to those obtained with TGMV or TGMV DNA. Progeny virus isolated from plants infected with cloned DNA was infective and indistinguishable from TGMV on the basis of (a) its circular single-stranded (ss)DNA genome, (b) its capsid polypeptide, (c) its particle morphology and (d) serological identity. Southern blot analysis of DNA extracted from cells infected with cloned DNA, or TGMV DNA, revealed the same intracellular ss and dsDNA species, represented in both A and B components, except for a subgenomic, possibly defective, DNA, which was not detected in infections with cloned DNA. Infection with cloned DNA was achieved when cloned A and B components were both present, but not with either cloned A or B components separately. TGMV is the first DNA virus for which unequivocal proof of a bipartite genome has been obtained.


One Patient Is Not One Condition: Delivering Patient-Centered Care to Those With Multiple Chronic Conditions.
While patients with multiple chronic conditions account for the bulk of health care spending in many countries-71 cents of every dollar spent on US Medicare beneficiaries-medical research and care remain organized around singular diseases and specialties. This siloed approach places the burden of managing multiple conditions on patients, who often have difficulty navigating the health care system and following treatment recommendations. This helps explain why patients with multiple chronic conditions have more unplanned admissions to the hospital, worse health outcomes, and poorer quality of life. Longer life expectancies, aging populations, and the increasing incidence of chronic conditions will vastly increase the number of patients living with multiple conditions, placing strains not only on patients but on governments and businesses paying for their care. In Japan, for example, the elderly will make up more than a quarter of the population by 2018, putting tremendous pressure on the country's health system as chronic diseases become more prevalent with age. Pharmaceutical companies can play a pivotal role in addressing these issues by developing products, programs, and services geared to the unique physical, social, and emotional challenges patients with multiple chronic conditions face. Companies also can have a significant impact by promoting collaboration and communication among health system stakeholders, expanding the knowledge base about patients' experiences with multiple chronic conditions, and developing therapies and tools to help patients adhere to treatments and improve their quality of life.


Physiological and Morphological Responses of Okra (Abelmoschus esculentus L.) to Rhizoglomus irregulare Inoculation under Ample Water and Drought Stress Conditions Are Cultivar Dependent.
Okra is an important crop species for smallholder farmers in many tropical and subtropical regions of the world. Its interaction with mycorrhiza has been rarely studied, and little is known about its mycorrhizal dependency, especially under drought stress. In a glasshouse experiment, we investigated the effect of Arbuscular Mycorrhiza Fungi (AMF) inoculation on growth, evapotranspiration, mineral nutrition and root morphology of five okra cultivars under ample water and drought stress conditions. 'Khartoumia', 'HSD6719', 'HSD7058', 'Sarah' and 'Clemson Spineless'-cultivars commonly used by farmers in Sudan were chosen for their geographical, morphological and breeding background variations. The plants were either inoculated with R. irregulare or mock-inoculated. Seven weeks after seeding, the soil-water content was either maintained at 20% w/w or reduced to 10% w/w to impose drought stress. Drought stress resulted in plant P deficiency and decreased shoot dry biomass (DB), especially in HSD7058 and Clemson Spineless (69% and 56% decrease in shoot DB, in the respective cultivars). Plant inoculation with AMF greatly enhanced the shoot total content of P and the total DB in all treatments. The mycorrhizal dependency (MD)-the degree of total plant DB change associated with AM colonization-differed among the cultivars, irrespective of the irrigation treatment. Key determinants of MD were the root phenotype traits. Khartoumia (with the highest MD) had the lowest root DB, root-to-shoot ratio, and specific root length (SRL). Meanwhile, HSD6719 (with the lowest MD) had the highest respective root traits. Moreover, our data suggest a relationship between breeding background and MD. The improved cultivar Khartoumia showed the highest MD compared with the wild-type Sarah and the HSD7058 and HSD6719 landraces (higher MD by 46%, 17% and 32%, respectively). Interestingly, the drought-affected HSD7058 and Clemson Spineless exhibited higher MD (by 27% and 15%, respectively) under water-deficiency compared to ample water conditions. In conclusion, the mediation of drought stress in the okra plant species by AMF inoculation is cultivar dependent. The presence of AMF propagules in the field soil might be important for increasing yield production of high MD and drought susceptible cultivars, especially under drought/low P environments.


A critical role in structure-specific DNA binding for the acetylatable lysine residues in HMGB1.
The structure-specific DNA-binding protein HMGB1 (high-mobility group protein B1) which comprises two tandem HMG boxes (A and B) and an acidic C-terminal tail, is acetylated in vivo at Lys(2) and Lys(11) in the A box. Mutation to alanine of both residues in the isolated A domain, which has a strong preference for pre-bent DNA, abolishes binding to four-way junctions and 88 bp DNA minicircles. The same mutations in full-length HMGB1 also abolish its binding to four-way junctions, and binding to minicircles is substantially impaired. In contrast, when the acidic tail is absent (AB di-domain) there is little effect of the double mutation on four-way junction binding, although binding to minicircles is reduced approximately 15-fold. Therefore it appears that in AB the B domain is able to substitute for the non-functional A domain, whereas in full-length HMGB1 the B domain is masked by the acidic tail. In no case does single substitution of Lys(2) or Lys(11) abolish DNA binding. The double mutation does not significantly perturb the structure of the A domain. We conclude that Lys(2) and Lys(11) are critical for binding of the isolated A domain and HMGB1 to distorted DNA substrates.


Cognitive emotional processing across mood disorders.
While impairments in cognitive emotional processing are key to the experience of mood disorders, little is understood of their shared and distinct features across major depressive disorder (MDD) and bipolar disorder (BD). In this review, we discuss the similarities and differences in abnormal emotional processing associated with mood disorders across the cognitive domains of perception, attention, memory, and reward processing, with a particular focus on how these impairments relate to the clinical profile of the disorders. We consider behavioral and neuroimaging evidence, especially that of the growing consensus surrounding mood-congruent biases in cognition, in combination with state- and trait-related characteristics in an attempt to provide a more comprehensive and translational overview of mood disorders. Special consideration is given to the shared phenomenon of mood instability and its role as a potential transdiagnostic marker across the prodrome and maintenance of mood disorders.


The circle method for preoperative TAVI sizing in a Sievers type 0 stenotic bicuspid aortic valve.
The most common congenital cardiac anomaly, affecting an estimated 0.4-2.25% of the general population, is the bicuspid aortic valve. The "pure" bicuspid aortic valve (non-raphe-type or bicuspid aortic valve type 0) is composed of 2 cusps, morphologically and functionally. The shape of the bicuspid aortic valve annulus is often elliptical, is relatively larger than the tricuspid aortic valves, and probably shows severe eccentric calcification. This situation contributes to the difficulties in selecting the correct type and size of transcatheter heart valve when treating bicuspid aortic valve stenosis. Furthermore, it is often associated with a dilated, horizontal ascending aorta and effaced sinuses. The goal of our video tutorial is to present the contemporary circle method used in preoperative sizing during TAVI procedures in patients with a bicuspid aortic valve as well as certain technical considerations and useful advice. Although annular sizing is the main focus for most patients with a bicuspid aortic valve, some patients may need the supra-annular level of sizing. For a dedicated sizing and positioning approach for the SAPIEN 3 Ultra valve, experts in the field propose the circle method.


The origin of Darwin's "abominable mystery".
The phrase "Darwin's abominable mystery" is frequently used with reference to a range of outstanding questions about the evolution of the plant group today known as the angiosperms. Here, I seek to more fully understand what prompted Darwin to coin the phrase in 1879, and the meaning he attached to it, by surveying the systematics, paleobotanical records, and phylogenetic hypotheses of his time. In the light of this historical research, I argue that Darwin was referring to the origin only of a subset of what are today called angiosperms: a (now obsolete) group equivalent to the "dicotyledons" of the Hooker and Bentham system. To Darwin and his contemporaries, the dicotyledons' fossil record began abruptly and with great diversity in the Cretaceous, whereas the gymnosperms and monocotyledons were thought to have fossil records dating back to the Carboniferous or beyond. Based on their morphology, the dicotyledons were widely seen by botanists in Darwin's time (unlike today) as more similar to the gymnosperms than to the monocotyledons. Thus, morphology seemed to point to gymnosperm progenitors of dicotyledons, but this hypothesis made the monocotyledons, given their (at the time) apparently longer fossil record, difficult to place. Darwin had friendly disagreements about the mystery of the dicotyledons' abrupt appearance in the fossil record with others who thought that their evolution must have been more rapid than his own gradualism would allow. But the mystery may have been made "abominable" to him because it was seen by some contemporary paleobotanists, most notably William Carruthers, the Keeper of Botany at the British Museum, as evidence for divine intervention in the history of life. Subsequent developments in plant systematics and paleobotany after 1879 meant that Darwin's letter was widely understood to be referring to the abrupt appearance of all angiosperms when it was published in 1903, a meaning that has been attached to it ever since.


The relationship between estrogen, estrogen receptors and periodontal disease in adult women.
The literature supports the fact that estrogen plays an important role in skeletal maintenance and remodeling. Estrogen, acting through estrogen receptors in the cells of the periodontal ligament, has a regulatory interaction on bone dynamics through a complex set of basic multicellular units (BMUs). Deficiency of estrogen results in an increased number of BMUs and enhanced bone turnover. The impact of the changes in estrogen deficiency on bone dynamics is primarily mediated through osteoclasts, with greater interdiction of estrogen's actions on trabecular bone than on cortical bone. The purpose of this manuscript is to review the literature for evidence to support an association between estrogen and periodontal disease in adult women, as well as bone mineral density, and to help clarify the mechanism of action. We found in our review of all pertinent databases, including Cochrane, that there are few peer-reviewed clinical studies that examine the relationship between estrogen deficiency and periodontal disease, and bone mineral density (BMD) and periodontal disease. Thus, future research is needed to investigate these associations so that at-risk patients can be identified earlier to avoid functional and esthetic sequellae of periodontal disease.