Effect of sex hormones on renal estrogen and angiotensin type 1 receptors in female and male rats.
Although the mechanisms are not understood, evidence suggests that 17beta-estradiol (E2) confers protection from cardiovascular and renal complications in many diseases. We have reported that E2 decreases angiotensin type 1 receptors (AT1Rs) in different tissues and hypothesize that E2 exerts tonic inhibition on AT1Rs, reducing effects of ANG II. This study determined the effects of E2 and dihydrotestosterone (DHT) on cortical estrogen receptors (ERs) and glomerular AT1R binding in rats. Animals underwent sham operation, ovariectomy (Ovx) or orchidectomy (Cas) and were treated (Ovx +/- E2; Cas +/- DHT) for 3 wk. Cortical ERalpha protein was 2.5 times greater, and ERbeta was 80% less in females vs. males (P < 0.01). Glomerular AT1R binding was lower in females than males [4,657 +/- 838 vs. 7,457 +/- 467 counts per minute (cpm), P < 0.01]. Ovx reduced ERalpha protein by 50%, whereas E2 increased ERalpha expression after Ovx. The decrease in cortical ERalpha in Ovx rats was associated with a significant increase in AT1R binding (6,908 +/- 609 cpm), and E2 prevented this increase. There was no change in ERalpha or AT1R binding following Cas +/- DHT (25 mg) treatment, although Cas did elevate cortical ERbeta (P < 0.01). Interestingly, the high dose DHT (200 mg) elevated ERalpha 150% above intact levels and profoundly decreased AT1R binding (1,824 +/- 705 cpm, P < 0.001 vs. intact male). This indicates that under normal conditions, glomerular AT1R binding is significantly greater in male than female animals, which may be important in development of cardiovascular and renal disease in males. Furthermore, E2 regulates ERalpha and is inversely associated with glomerular AT1R binding, supporting our hypothesis that E2 tonically suppresses AT1Rs and suggesting a potential mechanism for the protective effects of estrogen.


Photoaggravated pityriasis rubra pilaris.
Pityriasis rubra pilaris (PRP) is a rare papulosquamous condition with an estimated incidence of one in 35,000 to one in 50,000. Psoralen and ultraviolet A (UVA) therapy has been used in its treatment but some patients are reported to be clinically photosensitive. We describe the photoinvestigation of a patient with PRP in whom sensitivity to broadband UVA was demonstrated.


[Enhanced lymphocyte proliferative response to house dust mite in the older but not in the younger asthmatic children].
Allergen-specific lymphocyte proliferation was measured by flow cytometry in 16 children with atopic dermatitis (AD). 26 with bronchial asthma (BA) and 13 non-atopic controls. Although the level of mite-S.I.F. (stimulation index measured by flow cytometry) in the younger AD children (2-7 y) was significantly higher than that in the non-atopic subjects (189.6 +/- 70.7 vs 113.9 +/- 11.0, p < 0.02), there was no elevation in the younger BA children (122.6 +/- 23.4). It is therefore likely that the elevated mite-S.I.F. level is related to the development of the allergic cellular inflammation representing the pathology of AD, rather than the IgE-mediated allergic reaction as a mechanism of childhood BA. Because the level of mite-specific IgE antibody in the younger BA children is elevated (93.6 +/- 41.2 PRU/ml), the result also indicates that mite-specific peripheral T lymphocytes do not play a critical role in stimulating the mite-specific IgE synthesis. On the contrary, the older BA children (8-15 y) showed an elevated mite-S.I.F. level (176.0 +/- 54.6) significantly higher than that in the non-atopic subjects (114.6 +/- 13.9, p < 0.05) as well as that in the younger BA children (p < 0.05). Because other investigators have reported that the level of mite-specific lymphocyte proliferation is increased in the adult BA patients, the transition from childhood BA to adult-type BA may start at the age of about 8 y.


Dietary rapeseed/canola-oil supplementation reduces serum lipids and liver enzymes and alters postprandial inflammatory responses in adipose tissue compared to olive-oil supplementation in obese men.
Obesity is associated with hyperlipidemia, hepatic steatosis, and low-grade inflammation. Studies have shown that MUFA as well as PUFA have beneficial effects on blood lipids and the inflammatory state. This study investigates the effects of a daily supplementation of either 50 g of rapeseed/canola (RA) or olive (OL) oil over 4 wk on serum lipids, serum liver enzymes, and inflammatory gene expression in subcutaneous (s. c.) adipose tissue in obese men. Consuming RA resulted in increased serum n-3 fatty acids and a reduction in total cholesterol, LDL cholesterol, and serum aspartate aminotransferase compared to OL. In s. c. adipose tissue, gene expression of the pro-inflammatory cytokine IL6 was reduced in RA compared to OL. However, after 4 h after a test meal, containing the appropriate oil, white bread, and 400 mL of liquid diet drink (835 kcal in total), gene expression of IL6, IL1B, and EMR1 (egf-like module containing Mucin-like hormone receptor-like 1) was increased in RA and of monocyte chemoattractant protein-1 (CCL2) in both RA and OL. This demonstrates that consuming RA for 4 wk improves serum lipids, liver enzymes, and basal inflammation in s. c. adipose tissue, but it mediates an acute pro-inflammatory response in adipose tissue upon consuming a meal.


[Breeding control and immobilizing effects of wood microingredients on house dust mites].
The possible effects of essential oils as wood microingredients on house dust mites (Tyrophagus putrescentiae, Dermatophagoides farinae and Dermatophagoides pteronyssinus) were investigated. 1. Whether small pieces of 5 types of wood had any control effect on mite breeding was studied. Mite breeding using only normal feed was compared with breeding using feed mixed with small pieces of wood. In addition, mite breeding using feed mixed with small pieces of wood with no essential oil was studied. 2. Effects of 6 different wood essential oils in immobilizing mites were studied with regard to respired and contact toxicities. 3. The immobilizing effects of 10 ingredients in Hinoki oil were also specifically studied with regard to contact toxicity. The results of the 3 experiments were as follows: 1) It was confirmed that the small pieces of Hinoki, cedar, pine and Lauan had control effects on mite breeding. However, the small pieces of spruce did not demonstrate an effect. Woods which had no essential oils had reduced or no breeding control effects. 2) It was confirmed that the 6 different wood essential oils had mite immobilizing effects associated with respired and contact toxicities. Rosewood oil, White Pine oil and Taiwan Hinoki oil had strong immobilizing effects. Hinoki oil, however, had only a weak effect. 3) Among the 10 ingredients of Hinoki oil, specifically Linalool, Geranyl acetate and alpha-Terpineol had strong mite immobilizing effects.


Porphyromonas gingivalis gingipains cause defective macrophage migration towards apoptotic cells and inhibit phagocytosis of primary apoptotic neutrophils.
Periodontal disease is a prevalent chronic inflammatory condition characterised by an aberrant host response to a pathogenic plaque biofilm resulting in local tissue damage and frustrated healing that can result in tooth loss. Cysteine proteases (gingipains) from the key periodontal pathogen Porphyromonas gingivalis have been implicated in periodontal disease pathogenesis by inhibiting inflammation resolution and are linked with systemic chronic inflammatory conditions such as rheumatoid arthritis. Efficient clearance of apoptotic cells is essential for the resolution of inflammation and tissue restoration. Here we sought to characterise the innate immune clearance of apoptotic cells and its modulation by gingipains. We examined the capacity of gingipain-treated macrophages to migrate towards and phagocytose apoptotic cells. Lysine gingipain treatment of macrophages impaired macrophage migration towards apoptotic neutrophils. Furthermore, lysine gingipain treatment reduced surface expression levels of CD14, a key macrophage receptor for apoptotic cells, which resulted in reduced macrophage interactions with apoptotic cells. Additionally, while apoptotic cells and their derived secretome were shown to inhibit TNF-α-induced expression by P. gingivalis lipopolysaccharide, we demonstrated that gingipain preparations induced a rapid inflammatory response in macrophages that was resistant to the anti-inflammatory effects of apoptotic cells or their secretome. Taken together, these data indicate that P. gingivalis may promote the chronic inflammation seen in periodontal disease patients by multiple mechanisms, including rapid, potent gingipain-mediated inflammation, coupled with receptor cleavage leading to defective clearance of apoptotic cells and reduced anti-inflammatory responses. Thus, gingipains represent a potential therapeutic target for intervention in the management of chronic periodontal disease.


Determinants of total and specific IgE in infants with atopic dermatitis. ETAC Study Group. Early Treatment of the Atopic Child.
ETAC (Early Treatment of the Atopic Child), a multi-centre predominantly European study to investigate the potential for cetirizine to prevent the development of asthma in infants with atopic dermatitis has completed enrollment: 817 children have been randomised to 18 months' treatment with either active or placebo and a subsequent 18 months of post-treatment follow-up. Results of the therapeutic effects will not be available for some time, but the study has provided an opportunity to investigate influences on sensitization to allergens in a large cohort of 1-2 years olds with already established atopic dermatitis, resident in different countries and in different environments. The study shows that in infants with atopic dermatitis, raised serum total IgE has significantly different determinants from that a specific allergen sensitization. In infancy, increased total IgE is more affected by factors increasing risk of intercurrent infection and non-specific airway inflammation, such as environmental tobacco smoke exposure (p < 0.001) and the use of gas cookers (p = 0.02). Specific allergen sensitization as represented by detectable IgE antibodies is influenced primarily by allergen exposure. In Sweden, low level exposure to allergens is associated with reduced specific allergen sensitization rates even though the infants already have atopic dermatitis.


Response to nivolumab combining radiotherapy and nimotuzumab in metastatic oral squamous cell carcinoma patient with strong PD-L1 expression: a case report.
Immune checkpoint inhibitors (ICIs) have been approved for the treatment of oral squamous cell carcinoma (OSCC). However, not all patients would benefit from ICIs. Thus, in order to improve the response rate, the efficacy and safety of combination immunotherapy is still under evaluation. We report a 71-year-old female patient with a recurrent metastatic oral cavity cancer. Immunohistochemical examination showed more than 50% of tumor cells to express the programmed cell death receptor ligand 1 (PD-L1). The patient received nivolumab plus radiotherapy and nimotuzumab. Both clinically and radiologically response was observed and the patient reached a partial response (PR). This is the first case describing the efficacy and safety of nivolumab plus radiotherapy and nimotuzumab in an OSCC patient with a strong PD-L1 expression, showing a tolerable safety profile and a promising response. The combination immunotherapy may be a potential treatment option for patients with OSCC.


How prior expectations shape multisensory perception.
The brain generates a representation of our environment by integrating signals from a common source, but segregating signals from different sources. This fMRI study investigated how the brain arbitrates between perceptual integration and segregation based on top-down congruency expectations and bottom-up stimulus-bound congruency cues. Participants were presented audiovisual movies of phonologically congruent, incongruent or McGurk syllables that can be integrated into an illusory percept (e.g. "ti" percept for visual «ki» with auditory /pi/). They reported the syllable they perceived. Critically, we manipulated participants' top-down congruency expectations by presenting McGurk stimuli embedded in blocks of congruent or incongruent syllables. Behaviorally, participants were more likely to fuse audiovisual signals into an illusory McGurk percept in congruent than incongruent contexts. At the neural level, the left inferior frontal sulcus (lIFS) showed increased activations for bottom-up incongruent relative to congruent inputs. Moreover, lIFS activations were increased for physically identical McGurk stimuli, when participants segregated the audiovisual signals and reported their auditory percept. Critically, this activation increase for perceptual segregation was amplified when participants expected audiovisually incongruent signals based on prior sensory experience. Collectively, our results demonstrate that the lIFS combines top-down prior (in)congruency expectations with bottom-up (in)congruency cues to arbitrate between multisensory integration and segregation.


The clinical and virological features of the first imported case causing MERS-CoV outbreak in South Korea, 2015.
In 2015, the largest outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) infection outside the Middle East occurred in South Korea. We summarized the epidemiological, clinical, and laboratory findings of the first Korean case of MERS-CoV and analyzed whole-genome sequences of MERS-CoV derived from the patient. A 68-year-old man developed fever and myalgia 7 days after returning to Korea, following a 10-day trip to the Middle East. Before diagnosis, he visited 4 hospitals, potentially resulting in secondary transmission to 28 patients. On admission to the National Medical Center (day 9, post-onset of clinical illness), he presented with drowsiness, hypoxia, and multiple patchy infiltrations on the chest radiograph. He was intubated (day 12) because of progressive acute respiratory distress syndrome (ARDS) and INF-α2a and ribavirin treatment was commenced. The treatment course was prolonged by superimposed ventilator associated pneumonia. MERS-CoV PCR results converted to negative from day 47 and the patient was discharged (day 137), following rehabilitation therapy. The complete genome sequence obtained from a sputum sample (taken on day 11) showed the highest sequence similarity (99.59%) with the virus from an outbreak in Riyadh, Saudi Arabia, in February 2015. The first case of MERS-CoV infection had high transmissibility and was associated with a severe clinical course. The patient made a successful recovery after early treatment with antiviral agents and adequate supportive care. This first case in South Korea became a super-spreader because of improper infection control measures, rather than variations of the virus.


Outcomes of patients with cirrhosis and hepatorenal syndrome type 1 treated with liver transplantation.
Hepatorenal syndrome type 1 (HRS1) is acute renal failure in the setting of advanced cirrhosis, and it results from hemodynamic derangements, which should be fully reversible after liver transplantation. However, the rate of hepatorenal syndrome (HRS) reversal and factors predicting renal outcomes after transplantation have not been fully elucidated. The aim of this study was to assess outcomes of HRS1 patients after liver transplantation and factors predicting HRS reversal. A chart review of all liver transplant patients with HRS1 (according to International Ascites Club criteria) at Toronto General Hospital from 2001 to 2010 was conducted. Patient demographic data, pretransplant and posttransplant laboratory data, and the presence of and time to posttransplant HRS reversal (serum creatinine < 1.5 mg/dL) were extracted from the center's transplant electronic database. Patients were followed until death or the end of the 2011 calendar year. Sixty-two patients (mean age, 54.7 ± 1.2 years; mean Model for End-Stage Liver Disease score, 35 ± 1) with HRS1 (serum creatinine, 3.37 ± 0.13 mg/dL) at liver transplant were enrolled. Thirty-eight patients received midodrine, octreotide, and albumin without success and subsequently received renal dialysis. One further patient received dialysis without pharmacotherapy. After liver transplantation, HRS1 resolved in 47 of 62 patients (75.8%) at a mean time of 13 ± 2 days. Patients without HRS reversal had significantly higher pretransplant serum creatinine levels (3.81 ± 0.34 versus 3.23 ± 0.14 mg/dL, P = 0.06), a longer duration of HRS1 {25 days [95% confidence interval (CI), 16-42 days] versus 10 days (95% CI, 10-18 days), P = 0.02}, a longer duration of pretransplant dialysis [27 days (95% CI, 13-41 days) versus 10 days (95% CI, 6-14 days), P = 0.01], and increased posttransplant mortality (P = 0.0045) in comparison with those whose renal function recovered. The only predictor of HRS1 nonreversal was the duration of pretransplant dialysis with a 6% increased risk of nonreversal with each additional day of dialysis. In conclusion, our study suggests that patients with HRS1 should receive a timely liver transplant to improve their outcome.


Societal interventions to prevent child abuse and neglect.
A framework for understanding child maltreatment in terms of complex and interacting factors from the individual to the societal level can aid in conceptualizing and implementing prevention efforts. Research on interventions at the societal level can guide a broad range of activities, increasing their effectiveness and viability. Fundamental approaches include evaluation of specific interventions and systems-level research on implementation and development of best practice in prevention activities for different portions of society. Research can indicate the roles that each individual, agency, organization, community, and level of government can play. The U.N. Convention on the Rights of the Child provides a useful framework for societal level change to improve the welfare of children and families.


Quantitative Analysis of Image Quality in Low-Dose Computed Tomography Imaging for COVID-19 Patients.
Computed tomography (CT) scan is one of the main tools to diagnose and grade COVID-19 progression. To avoid the side effects of CT imaging, low-dose CT imaging is of crucial importance to reduce population absorbed dose. However, this approach introduces considerable noise levels in CT images. In this light, we set out to simulate four reduced dose levels (60% dose, 40% dose, 20% dose, and 10% dose) of standard CT imaging using Beer-Lambert's law across 49 patients infected with COVID-19. Then, three denoising filters, namely Gaussian, bilateral, and median, were applied to the different low-dose CT images, the quality of which was assessed prior to and after the application of the various filters via calculation of peak signal-to-noise ratio, root mean square error (RMSE), structural similarity index measure, and relative CT-value bias, separately for the lung tissue and whole body. The quantitative evaluation indicated that 10%-dose CT images have inferior quality (with RMSE = 322.1 ± 104.0 HU and bias = 11.44% ± 4.49% in the lung) even after the application of the denoising filters. The bilateral filter exhibited superior performance to suppress the noise and recover the underlying signals in low-dose CT images compared to the other denoising techniques. The bilateral filter led to RMSE and bias of 100.21 ± 16.47 HU and - 0.21% ± 1.20%, respectively, in the lung regions for 20%-dose CT images compared to the Gaussian filter with RMSE = 103.46 ± 15.70 HU and bias = 1.02% ± 1.68% and median filter with RMSE = 129.60 ± 18.09 HU and bias = -6.15% ± 2.24%. The 20%-dose CT imaging followed by the bilateral filtering introduced a reasonable compromise between image quality and patient dose reduction.


Inhibitory control of active expiration by the Bötzinger complex in rats.
Contraction of abdominal muscles at the end of expiration during metabolic challenges (such as hypercapnia and hypoxia) improves pulmonary ventilation. The emergence of this active expiratory pattern requires the recruitment of the expiratory oscillator located on the ventral surface of the medulla oblongata. Here we show that an inhibitory circuitry located in the Bötzinger complex is an important source of inhibitory drive to the expiratory oscillator. This circuitry, mediated by GABAergic and glycinergic synapses, provides expiratory inhibition that restrains the expiratory oscillator under resting condition and regulates the formation of abdominal expiratory activity during active expiration. By combining experimental and modelling approaches, we propose the organization and connections within the respiratory network that control the changes in the breathing pattern associated with elevated metabolic demand. The expiratory neurons of the Bötzinger complex (BötC) provide inhibitory inputs to the respiratory network, which, during eupnoea, are critically important for respiratory phase transition and duration control. Here, we investigated how the BötC neurons interact with the expiratory oscillator located in the parafacial respiratory group (pFRG) and control the abdominal activity during active expiration. Using the decerebrated, arterially perfused in situ preparations of juvenile rats, we recorded the activity of expiratory neurons and performed pharmacological manipulations of the BötC and pFRG during hypercapnia or after the exposure to short-term sustained hypoxia - conditions that generate active expiration. The experimental data were integrated in a mathematical model to gain new insights into the inhibitory connectome within the respiratory central pattern generator. Our results indicate that the BötC neurons may establish mutual connections with the pFRG, providing expiratory inhibition during the first stage of expiration and receiving excitatory inputs during late expiration. Moreover, we found that application of GABAergic and glycinergic antagonists in the BötC caused opposing effects on abdominal expiratory activity, suggesting complex inhibitory circuitry within the BötC. Using mathematical modelling, we propose that the BötC network organization and its interactions with the pFRG restrain abdominal activity under resting conditions and contribute to abdominal expiratory pattern formation during active expiration observed during hypercapnia or after the exposure to short-term sustained hypoxia.


Suppression of spiral waves and spatiotemporal chaos by generating target waves in excitable media.
A method for suppressing spiral waves and spatiotemporal chaos in excitable media is proposed. Applying suitable periodic force to a single point, we can successfully suppress spiral waves as well as spatiotemporal chaos by generating target waves. After we turn off the external force, target waves finally disappear and the whole system which was in the state of spiral wave or spatiotemporal chaos goes to the spatially homogeneous steady state. It is shown that our control method is not sensitively model dependent. It works for a model for catalytic CO oxidation on platinum as well as for a model for cardiac muscle.


Differential Shannon entropies and correlation measures for Born-Oppenheimer electron-nuclear dynamics: numerical results and their analytical interpretation.
We study the Born-Oppenheimer dynamics within a model for a coupled electron-nuclear motion. Differential Shannon entropies are calculated from the time-dependent probability densities of the combined system and, using single particle densities, entropies for the electronic and nuclear degrees of freedom are derived. These functions provide information on details of the wave packet motion. From the entropies, we determine the mutual information which characterizes particle correlations. This quantity is compared to other measures of electron-nuclear entanglement. Numerical results are interpreted within an analytically solvable approach, and it is documented how these functions depend on properties of the Born-Oppenheimer wave function and, in particular, how dynamical effects like wave packet focusing and dispersion influence the correlation between the particles.


Mentoring Interventions and the Impact of Protective Assets on the Reproductive Health of Adolescent Girls and Young Women.
Adolescent girls and young women (AGYW) are disproportionately affected by HIV and AIDS and other negative reproductive health (RH) outcomes. Emerging evidence suggests that programs to build AGYW's assets can help reduce their vulnerability to poor RH. Mentoring interventions have demonstrated a positive impact on a variety of youth development outcomes, including the protective assets needed to circumvent poor RH outcomes. The purpose of this review was to understand the types of mentoring programs for AGYW that have demonstrated effectiveness in improving protective assets, and/or, RH knowledge, intentions, behaviors, or outcomes themselves. Interventions were identified through an electronic search of the peer-reviewed and the gray literature. Studies were excluded in stages based on reviews of titles, abstracts, and full text. A review of 491 publications yielded a total of 19 articles that were included in the final review. The majority of the publications examined the impact of the one-to-one mentoring model in the United States. However, a good proportion examined the impact of both one-on-one and group-based interventions globally. The few interventions that followed a group-based model demonstrated more promise; evaluations of this model demonstrated a positive impact on RH knowledge and behavior, academic achievement, financial behavior, and social networks, as well as reductions in the experience of violence. Group-based mentoring programs demonstrated the most promise in building AGYW's protective assets and improving their RH outcomes. The most successful interventions consisted of multiple components, including mentoring, that sought to directly improve AGYW's protective assets and met with more frequency over a longer duration. Despite the promising evidence, more research is needed to better understand the relationship between assets and RH; the characteristics of successful mentoring programs; and the influence mentoring alone has on RH outcomes, versus mentoring as part of a larger RH program.


The relationship between birth weight and congenital heart disease at Ahmed Gasim Cardiac Centre, Bahri, Sudan.
Low birth weight is a known comorbidity of congenital heart disease (CHD). This study examines the relationship between CHD and birth weight of singletons, while attempting to remove factors that influence birth weight, and assesses the impact of CHD on growth in later life. The main objective is to study the relationship between birthweight and CHD. This is a cross-sectional study of 141 samples, covering all patients who were referred to the Paediatric Echocardiography Lab at Ahmed Gasim Cardiac Centre between September and October 2016. Infants with genetic syndromes or other major extracardiac abnormalities were excluded. The findings of this study clearly demonstrate that infants with CHD are more likely to be of low birth weight than the general Sudanese population, by a factor of 2.6. Of the sample, 31.9% were born with low or very low birthweight. The mean birth weight of the cases was 2.59 kg, which is 17.3% and 542.4 g less than the national average. CHD that cause a decrement in birth weight in a descending order of severity were atrial septal defect (-721 g/23%), patent ductus arteriosus (-669 g/21%), ventricular septal defect (-610 g/19%), pulmonary stenosis (-548 g/13%) and tetralogy of Fallot (248 g/8%). Pre/postnatal growth impairment is a common feature among children with CHD. No statistically significant relationship was found between the degree of birth weight/weight to age decrement and the specific type of hemodynamic disturbance. Our results are comparable to other studies that have been undertaken. However, Sudanese patients display larger birthweight deficits than other populations.


Identification of the hub genes and transcription factor-miRNA axes involved in Helicobacter pylori-associated gastric cancer.
It has been previously reported that transcription factor-microRNA (TF-miRNA) axes play a significant role in the carcinogenesis of several types of malignant tumor. However, there is a lack of research into the differences in the mechanism of Helicobacter pylori (HP)-positive [HP(+)] and HP-negative [HP(-)] gastric cancer. The aim of the present study was to identify the hub genes and TF-miRNA axes, and to determine the potential mechanisms involved in HP-associated gastric cancer. HP-associated mRNA and miRNA data, as well as the corresponding clinical information, was downloaded from The Cancer Genome Atlas database. Differentially expressed genes (DEGs) and DE miRNAs (DEMs) were then identified from the HP(+) and HP(-) cancer mRNA and miRNA datasets, respectively. Subsequently, gene set enrichment analysis and the protein-protein interaction (PPI) networks were investigated using the ClusterProfiler packages. Lastly, TF-miRNA-DEG networks were constructed using the miRWalk online tool. A total of 1,050 DEGs and 13 DEMs were identified from the normalized mRNA and miRNA expression datasets, respectively. In addition, 180 Gene Ontology terms and 30 Kyoto Encyclopedia of Genes and Genomes pathways were found to be enriched, while 6 hub genes were identified from the PPI analysis. Furthermore, 7 TF-miRNA interactions and 181 TF-miRNA-DEG axes were constructed using an integrated bioinformatics approach, while 2 TF-miRNA interactions (ZEB1-miRNA-144-3p and PAX2-miRNA-592) were confirmed using reverse transcription-quantitative PCR in samples from enrolled patients. Moreover, the ZEB1-miRNA-144-3p axis was further validated based on dual luciferase reporter assay results. In summary, an integrated bioinformatics approach was used to screen the significant molecular and regulatory axes, which may provide a novel direction to investigate the pathogenesis of gastric cancer associated with HP.


Selection and validation of reference genes by RT-qPCR for murine cementoblasts in mechanical loading experiments simulating orthodontic forces in vitro.
Different structures and cell types of the periodontium respond to orthodontic tooth movement (OTM) individually. Cementoblasts (OC/CM) located in the immediate vicinity of the fibroblasts on the cement have found way to the centre of actual research. Here, we identify and validate possible reference genes for OC/CM cells by RT-qPCR with and without static compressive loading. We investigated the suitability of 3 reference genes in an in vitro model of cementoblast cells using four different algorithms (Normfinder, geNorm, comparative delta-Ct method and BestKeeper) under different confluences and time. Comparable to our previous publications about reference genes in OTM in rats and human periodontal ligament fibroblasts (hPDLF), Rpl22 in murine OC/CM cells appears as the least regulated gene so that it represents the most appropriate reference gene. Furthermore, unlike to the expression of our recommended reference genes, the expression of additionally investigated target genes changes with confluence and under loading compression. Based on our findings for future RT-qPCR analyses in OC/CM cells, Rpl22 or the combination Rpl22/Tbp should be favored as reference gene. According to our results, although many publications propose the use of Gapdh, it does not seem to be the most suitable approach.


Eel-pout (Zoarces viviparus L.) as a marine bioindicator.
Several elements and metal species were analyzed in eel-pout or viviparous blenny (Zoarces viviparus). The analytical data demonstrate that fish muscle is a suitable bioindicator for mercury (Hg) and arsenic (As). About 90% of the total Hg content is present in the fish muscle in the form of methyl mercury. Due to higher concentration levels, the liver is more useful for monitoring Pb and TI. No biomagnification of some trace elements, such as Cd, Ni or Co, were observed in eel-pout. More information is necessary to decide about the use of eel-pout for long-time monitoring programs.


EZH2-regulated DAB2IP is a medulloblastoma tumor suppressor and a positive marker for survival.
Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements, the molecular mechanisms driving medulloblastoma are not fully understood and further elucidation could provide cues to improve outcome prediction and therapeutic approaches. Here, we conducted a meta-analysis of mouse and human medulloblastoma gene expression data sets, to identify potential medulloblastoma tumor suppressor genes. We identified DAB2IP, a member of the RAS-GTPase-activating protein family (RAS GAP), and showed that DAB2IP expression is repressed in medulloblastoma by EZH2-induced trimethylation. Moreover, we observed that reduced DAB2IP expression correlates significantly with a poor overall survival of patients with medulloblastoma, independent of metastatic stage. Finally, we showed that ectopic DAB2IP expression enhances stress-induced apoptosis in medulloblastoma cells and that reduced expression of DAB2IP in medulloblastoma cells conveys resistance to irradiation-induced cell death. These results suggest that repression of DAB2IP may at least partly protect medulloblastoma cells from apoptotic cell death. Moreover, DAB2IP may represent a molecular marker to distinguish patients with medulloblastoma at high risk from those with a longer survival prognosis.


Digoxin and risk of death in adults with atrial fibrillation: the ATRIA-CVRN study.
Digoxin remains commonly used for rate control in atrial fibrillation, but limited data exist supporting this practice and some studies have shown an association with adverse outcomes. We examined the independent association between digoxin and risks of death and hospitalization in adults with incident atrial fibrillation and no heart failure. We performed a retrospective cohort study of 14,787 age, sex, and high-dimensional propensity score-matched adults with incident atrial fibrillation and no previous heart failure or digoxin use in the AnTicoagulation and Risk factors In Atrial fibrillation-Cardiovascular Research Network (ATRIA-CVRN) study within Kaiser Permanente Northern and Southern California. We examined the independent association between newly initiated digoxin and the risks of death and hospitalization using extended Cox regression. During a median 1.17 (interquartile range, 0.49-1.97) years of follow-up among matched patients with atrial fibrillation, incident digoxin use was associated with higher rates of death (8.3 versus 4.9 per 100 person-years; P<0.001) and hospitalization (60.1 versus 37.2 per 100 person-years; P<0.001). Incident digoxin use was independently associated with a 71% higher risk of death (hazard ratio, 1.71; 95% confidence interval, 1.52-1.93) and a 63% higher risk of hospitalization (hazard ratio, 1.63; 95% confidence interval, 1.56-1.71). Results were consistent in subgroups of age and sex and when using intent-to-treat or on-treatment analytic approaches. In adults with atrial fibrillation, digoxin use was independently associated with higher risks of death and hospitalization. Given other available rate control options, digoxin should be used with caution in the management of atrial fibrillation.


Neural adaptive control for vibration suppression in composite fin-tip of aircraft.
In this paper, we present a neural adaptive control scheme for active vibration suppression of a composite aircraft fin tip. The mathematical model of a composite aircraft fin tip is derived using the finite element approach. The finite element model is updated experimentally to reflect the natural frequencies and mode shapes very accurately. Piezo-electric actuators and sensors are placed at optimal locations such that the vibration suppression is a maximum. Model-reference direct adaptive neural network control scheme is proposed to force the vibration level within the minimum acceptable limit. In this scheme, Gaussian neural network with linear filters is used to approximate the inverse dynamics of the system and the parameters of the neural controller are estimated using Lyapunov based update law. In order to reduce the computational burden, which is critical for real-time applications, the number of hidden neurons is also estimated in the proposed scheme. The global asymptotic stability of the overall system is ensured using the principles of Lyapunov approach. Simulation studies are carried-out using sinusoidal force functions of varying frequency. Experimental results show that the proposed neural adaptive control scheme is capable of providing significant vibration suppression in the multiple bending modes of interest. The performance of the proposed scheme is better than the H(infinity) control scheme.


Nanocomposite hydrogels for cartilage tissue engineering: a review.
The loss of cartilaginous tissues is an important challenge to orthopaedic surgeons. Injury to cartilage tissue due to its properties is along with movement difficulties. Tissue engineering is a developing field that can be used for regeneration or replacement of damaged tissues. In this field, an appropriate scaffold that support the recruitment, adhesion, proliferation and differentiation of cells is necessary. Hydrogels recently considered as materials that resemble the extracellular matrix (ECM) and efficiently replace defective tissues, but they have limited mechanical strength. So nanomaterials are embedded in the hydrogel's matrix to improve their properties. Nanoparticles, such as organic/polymeric and inorganic (hydroxyapatite, clay, graphene and metallic nanoparticles), can be used as fillers to reinforce the hydrogel matrix. Utilizing those nanocomposites could help in better performance of hydrogels applicable in cartilage regeneration practices. This review presents some of nanocomposite hydrogel (NCH) systems that used in cartilage tissue engineering.


[Zheng Meijian's Sha yu yi yu (Random Medical Talks in Leisure Time) and his new ideas on pulse-taking].
Zheng Meijian, a doctor of Xin'an district in the reign of Qianlong Emperor of the Qing Dynasty, left his manuscript Sha yu yi yu (Random Medical Talks in Leisure Time), and was handed down in his family for generations. Sha yu yi yu was published in the Anhui Yixue of Issue 20, 1959, with horizontal layout and punctuation. The book records Zheng Meijian's understanding for the medicine, especially his new ideas on the cunkou pulse, with its underlying corresponding relationship among cun-guan-chi and zang-fu which should be combined with meridian and collateral system, claiming that the pulse taken superficially was corresponding to fu, while that taken deeply, to zang. He classified the strength of the fingers in pulse-taking into 8 levels, and advocated flexible application of pulse-taking. All his opinions had an important reference value for theoretical research and clinical application of pulse-taking.


Challenges to conquer from the gender perspective in medicine: The case of spondyloarthritis.
Diagnostic delay is well-known in spondyloarthritis and studies have demonstrated a longer deferral in women. The aim of this study was to explore whether diagnostic delay of spondyloarthritis depends on clinical manifestations expressed by patients according to sex or whether it is related to a doctor's misdiagnosis bias. A cross-sectional study of 96 men and 54 women with spondyloarthritis was performed at Alicante University General Hospital in Spain using a semistructured interview and clinical records. Comparative sex analysis were done via Student's T and Mann-Whitney U tests for parametric and nonparametric continuous variables, chi-square and Fisher's exact tests for unpaired categorical variables, and McNemar's test for paired ones. The median diagnostic delay in women 7.5 (11.5) years is higher than men 4 (11) years, with a difference close to statistical significance (p = 0.053). A total of 30.2% of men received a first correct diagnosis of spondyloarthritis versus 11.1% of women (p = 0.016), indicating that men have higher probability of not having a misdiagnosis of spondyloarthritis (odds ratio = 3.5; 1.3-9). Eleven different health services referred male patients to the rheumatology clinic but only six in the case of female. No sex differences were detected in patients' manifestations of back pain at onset. However, medical records registered differences (women 44.4%, men 82.1%; p < 0.001). There were differences between patients (women 57.7%, men 35.2%; p = 0.008) and medical records in peripheral signs/symptoms at onset (women 55.6%, men 17.9%; p < 0.001). The few differences of self-reported manifestations between both sexes with spondyloarthritis as compared with their clinical records (more axial pain in men and more peripheral pain in women) suggests that the professionals' annotations reflect what they expect according to Literature, which could explain the higher misdiagnosis and diagnostic delay in women with spondyloarthritis.


Relationship between aided preferred listening level and long-term listening range.
The long-term listening range was defined as extending, at any frequency, from the threshold of audibility to the upper limit of the comfortable loudness range. The relationship between the aided preferred listening level and the long-term listening range was investigated by analyzing data obtained from 16 hearing impaired subjects. Results support a tentative conclusion that the aided preferred listening level is equal to the midpoint of the long-term listening range. Application of this relationship to the specification of frequency/gain function is discussed.


Identification of specific chemoattractants and genetic complementation of a Borrelia burgdorferi chemotaxis mutant: flow cytometry-based capillary tube chemotaxis assay.
Measuring the chemotactic response of Borrelia burgdorferi, the bacterial species that causes Lyme disease, is relatively more difficult than measuring that of other bacteria. Because these spirochetes have long generation times, enumerating cells that swim up a capillary tube containing an attractant by using colony counts is impractical. Furthermore, direct counts with a Petroff-Hausser chamber is problematic, as this method has a low throughput and necessitates a high cell density; the latter can lead to misinterpretation of results when assaying for specific attractants. Only rabbit serum and tick saliva have been reported to be chemoattractants for B. burgdorferi. These complex biological mixtures are limited in their utility for studying chemotaxis on a molecular level. Here we present a modified capillary tube chemotaxis assay for B. burgdorferi that enumerates cells by flow cytometry. Initial studies identified N-acetylglucosamine as a chemoattractant. The assay was then optimized with respect to cell concentration, incubation time, motility buffer composition, and growth phase. Besides N-acetylglucosamine, glucosamine, glucosamine dimers (chitosan), glutamate, and glucose also elicited significant chemoattractant responses, although the response obtained with glucose was weak and variable. Serine and glycine were nonchemotactic. To further validate and to exploit the use of this assay, a previously described nonchemotactic cheA2 mutant was shown to be nonchemotactic by this assay; it also regained the wild-type phenotype when complemented in trans. This is the first report that identifies specific chemical attractants for B. burgdorferi and the use of flow cytometry for spirochete enumeration. The method should also be useful for assaying chemotaxis for other slow-growing prokaryotic species and in specific environments in nature.


Technical Note: Characterization and correction of gradient nonlinearity induced distortion on a 1.0 T open bore MR-SIM.
Distortions in magnetic resonance imaging (MRI) compromise spatial fidelity, potentially impacting delineation and dose calculation. We characterized 2D and 3D large field of view (FOV), sequence-independent distortion at various positions in a 1.0 T high-field open MR simulator (MR-SIM) to implement correction maps for MRI treatment planning. A 36 × 43 × 2 cm(3) phantom with 255 known landmarks (∼1 mm(3)) was scanned using 1.0 T high-field open MR-SIM at isocenter in the transverse, sagittal, and coronal axes, and a 465 × 350 × 168 mm(3) 3D phantom was scanned by stepping in the superior-inferior direction in three overlapping positions to achieve a total 465 × 350 × 400 mm(3) sampled FOV yielding >13 800 landmarks (3D Gradient-Echo, TE/TR/α = 5.54 ms/30 ms/28°, voxel size = 1 × 1 × 2 mm(3)). A binary template (reference) was generated from a phantom schematic. An automated program converted MR images to binary via masking, thresholding, and testing for connectivity to identify landmarks. Distortion maps were generated by centroid mapping. Images were corrected via warping with inverse distortion maps, and temporal stability was assessed. Over the sampled FOV, non-negligible residual gradient distortions existed as close as 9.5 cm from isocenter, with a maximum distortion of 7.4 mm as close as 23 cm from isocenter. Over six months, average gradient distortions were -0.07 ± 1.10 mm and 0.10 ± 1.10 mm in the x and y directions for the transverse plane, 0.03 ± 0.64 and -0.09 ± 0.70 mm in the sagittal plane, and 0.4 ± 1.16 and 0.04 ± 0.40 mm in the coronal plane. After implementing 3D correction maps, distortions were reduced to <1 pixel width (1 mm) for all voxels up to 25 cm from magnet isocenter. Inherent distortion due to gradient nonlinearity was found to be non-negligible even with vendor corrections applied, and further corrections are required to obtain 1 mm accuracy for large FOVs. Statistical analysis of temporal stability shows that sequence independent distortion maps are consistent within six months of characterization.


Total metabolic tumor volume as a survival predictor for patients with diffuse large B-cell lymphoma in the GOYA study.
This retrospective analysis of the phase III GOYA study investigated the prognostic value of baseline metabolic tumor volume parameters and maximum standardized uptake values for overall and progression-free survival (PFS) in treatment-naïve diffuse large B-cell lymphoma. Baseline total metabolic tumor volume (determined for tumors >1 mL using a threshold of 1.5 times the mean liver standardized uptake value +2 standard deviations), total lesion glycolysis, and maximum standardized uptake value positron emission tomography data were dichotomized based on receiver operating characteristic analysis and divided into quartiles by baseline population distribution. Of 1,418 enrolled patients, 1,305 had a baseline positron emission tomography scan with detectable lesions. Optimal cut-offs were 366 cm3 for total metabolic tumor volume and 3,004 g for total lesion glycolysis. High total metabolic tumor volume and total lesion glycolysis predicted poorer PFS, with associations retained after adjustment for baseline and disease characteristics (high total metabolic tumor volume hazard ratio: 1.71, 95% confidence interval [CI]: 1.35- 2.18; total lesion glycolysis hazard ratio: 1.46; 95% CI: 1.15-1.86). Total metabolic tumor volume was prognostic for PFS in subgroups with International Prognostic Index scores 0-2 and 3-5, and those with different cell-of-origin subtypes. Maximum standardized uptake value had no prognostic value in this setting. High total metabolic tumor volume associated with high International Prognostic Index or non-germinal center B-cell classification identified the highest-risk cohort for unfavorable prognosis. In conclusion, baseline total metabolic tumor volume and total lesion glycolysis are independent predictors of PFS in patients with diffuse large B-cell lymphoma after first-line immunochemotherapy.


CRISPR-Mediated Knockout of Cybb in NSG Mice Establishes a Model of Chronic Granulomatous Disease for Human Stem-Cell Gene Therapy Transplants.
Chronic granulomatous disease (CGD) is characterized by defects in the production of microbicidal reactive oxygen species (ROS) by phagocytes. Testing of gene and cell therapies for the treatment of CGD in human hematopoietic cells requires preclinical transplant models. The use of the lymphocyte-deficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse strain for human hematopoietic cell xenografts to test CGD therapies is complicated by the presence of functional mouse granulocytes capable of producing ROS for subsequent bacterial and fungal killing. To establish a phagocyte-defective mouse model of X-linked CGD (X-CGD) in NSG mice, clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 was utilized for targeted knockout of mouse Cybb on the X-chromosome by microinjection of NSG mouse zygotes with Cas9 mRNA and CRISPR single-guide RNA targeting Cybb exon 1 or exon 3. This resulted in a high incidence of indel formation at the CRISPR target site, with all mice exhibiting deletions in at least one Cybb allele based on sequence analysis of tail snip DNA. A female mouse heterozygous for a 235-bp deletion in Cybb exon 1 was bred to an NSG male to establish the X-CGD NSG mouse strain, NSG.Cybb[KO]. Resulting male offspring with the 235 bp deletion were found to be defective for production of ROS by neutrophils and other phagocytes, and demonstrated increased susceptibility to spontaneous bacterial and fungal infections with granulomatous inflammation. The establishment of the phagocyte-defective NSG.Cybb[KO] mouse model enables the in vivo assessment of gene and cell therapy strategies for treating CGD in human hematopoietic cell transplants without obfuscation by functional mouse phagocytes, and may also be useful for modeling other phagocyte disorders in humanized NSG mouse xenografts.


The mechanisms and functions of spontaneous neurotransmitter release.
Fast synaptic communication in the brain requires synchronous vesicle fusion that is evoked by action potential-induced Ca(2+) influx. However, synaptic terminals also release neurotransmitters by spontaneous vesicle fusion, which is independent of presynaptic action potentials. A functional role for spontaneous neurotransmitter release events in the regulation of synaptic plasticity and homeostasis, as well as the regulation of certain behaviours, has been reported. In addition, there is evidence that the presynaptic mechanisms underlying spontaneous release of neurotransmitters and their postsynaptic targets are segregated from those of evoked neurotransmission. These findings challenge current assumptions about neuronal signalling and neurotransmission, as they indicate that spontaneous neurotransmission has an autonomous role in interneuronal communication that is distinct from that of evoked release.


Experimental and numerical iInvestigations of effects of silica colloids on transport of strontium in saturated sand columns.
Transport experiments with strontium were conducted using saturated sand columns in the presence and absence of silica colloids, and numerical modeling was performed with modeling results compared to experimental data. The experiments were aimed at testing the hypothesis that under certain chemical conditions colloids act as movement-retarding agents and yield a larger effective retardation factor for the migrating contaminant. Four individual experiments were conducted to identify conditions where the mobility of silica colloids is increased or decreased, and a similar set was conducted for strontium transport in the absence of colloids. Mobility of colloids was found to increase with decreasing ionic strength and increasing pH, with the ionic strength having the more significant impact. The reverse effect was obtained for strontium. Based on these results, two additional experiments were conducted where both colloids and strontium were injected at the column inlet. Results showed that under certain conditions of ionic strength and pH (I = 3.0 x 10(-2) M and pH = 4-5.4) colloids retarded the movement of strontium. The retardation effect was obtained in two experiments under slightly modified conditions, which confirms the role of colloids as retarding agents. Afinite difference numerical model was used to (a) simulate mobile breakthrough curves and compare to experimental data and (b) estimate the model parameters describing cotransport of strontium and colloids. The model accurately predicted arrival time and the overall shape of the breakthrough curves.


Toward a Phenomenological Assessment of Values in Alcohol Misuse.
Alcohol misuse emerges from a complex range of psychopathological experiences and personal and cultural values. For this reason, understanding the reasons why a person seeks treatment is crucial to effective care. This study aimed to identify the values which guide the decision-making process of persons seeking voluntary hospitalization for treatment for alcohol misuse, as well as the values of significant others. A phenomenological investigation was conducted through interviews with 25 individuals (and family members) who had voluntarily admitted themselves to a hospital in São Paulo, Brazil, with the objective of maintaining abstinence from alcohol dependence. The main factors that determined the treatment-seeking decision were damage to social relationships and fear of illness and deterioration of the physical condition; the factors related to treatment expectations were restoring personality and awareness of morbidity; and the single factor considered most important to the success of the treatment was willpower. The results of this study contribute to developing strategies for bringing care closer to the patient's perspective of the disease and encourage their active participation in the formulation of care.


The microbial oxidation of methanol. The prosthetic group of the alcohol dehydrogenase of Pseudomonas sp. M27: a new oxidoreductase prosthetic group.
1. The purified alcohol dehydrogenase of Pseudomonas sp. M27, whose action is independent of nicotinamide nucleotides, has absorption peaks at 280mmu and at 350mmu with little or no absorption at or above 450mmu. 2. It does not fluoresce, but green-fluorescent material, diffusible on dialysis, is produced when the enzyme is treated with acid or alkali or when it is boiled. 3. Evidence is presented that the enzyme is not a flavoprotein. 4. Kinetic studies show a correlation between enzyme inactivation by acid, alkali or heat and liberation of the fluorescent material. 5. Some purification of the fluorescent material was achieved, but definite identification was not possible; the major component has a fluorescence maximum at about 460mmu with excitation maxima at about 260mmu and 365mmu. 6. Data are given (including absorption and fluorescence spectra) that support the suggestion that the prosthetic group of the enzyme is a pteridine derivative. 7. Possible mechanisms of action of the enzyme are discussed.


Open source board based acoustofluidic transwells for reversible disruption of the blood-brain barrier for therapeutic delivery.
Blood-brain barrier (BBB) is a crucial but dynamic structure that functions as a gatekeeper for the central nervous system (CNS). Managing sufficient substances across the BBB is a major challenge, especially in the development of therapeutics for CNS disorders. To achieve an efficient, fast and safe strategy for BBB opening, an acoustofluidic transwell (AFT) was developed for reversible disruption of the BBB. The proposed AFT was consisted of a transwell insert where the BBB model was established, and a surface acoustic wave (SAW) transducer realized using open-source electronics based on printed circuit board techniques. In the AFT device, the SAW produced acousto-mechanical stimulations to the BBB model resulting in decreased transendothelial electrical resistance in a dose dependent manner, indicating the disruption of the BBB. Moreover, SAW stimulation enhanced transendothelial permeability to sodium fluorescein and FITC-dextran with various molecular weight in the AFT device. Further study indicated BBB opening was mainly attributed to the apparent stretching of intercellular spaces. An in vivo study using a zebrafish model demonstrated SAW exposure promoted penetration of sodium fluorescein to the CNS. In summary, AFT effectively disrupts the BBB under the SAW stimulation, which is promising as a new drug delivery methodology for neurodegenerative diseases.


[Establishment of monoclonal antibodies against purified mucin from human pancreatic cell line].
Thirty four murine monoclonal antibodies were produced against mucin which was isolated from nude mouse xenografts of the SW1990 pancreatic adenocarcinoma cell line. Twelve of them reacted with formalin-fixed SW1990 cells. The antigenic determinants of these antibodies were composed of carbohydrates and their immunoreactivities were predominant at CsCl fraction #6. The remaining 22 antibodies did not react with formalin-fixed cells, 5 epitope specificities of which antibodies are present in the polypeptide part or the part of linkage between oligosaccharide and polypeptide and the immunoreactivities were predominant at CsCl fraction #5. Immunohistochemical study showed that the incidence of epitope expression of the latter 22 antibodies were higher in pancreatic cancer tissues and lower in normal pancreatic tissues than that of the former 12 antibodies. The incidence of Nd2 (one of the 22 antibodies) expression was highest in pancreatic cancer tissues and lowest in normal tissues. ELISA showed that Nd2 antigen was non-secreting type. In vivo tumor distribution studies showed that Nd2 antibody tended to accumulate in cancer tissues. These results seem to support the clinical availability of Nd2.


Restoration of heart rate turbulence by titrated beta-blocker therapy in patients with advanced congestive heart failure: positive correlation with enhanced vagal modulation of heart rate.
Heart rate turbulence (HRT) is a powerful novel predictor for cardiovascular mortality. Chronic congestive heart failure is associated with abnormal HRT. Whether antiadrenergic beta-blocker therapy can restore control of HRT in patients with chronic congestive heart failure is unknown. A 24-hour Holter ECG recording was obtained before and 1 and 3 months after titrated addition of atenolol therapy in 10 consecutive patients with advanced congestive heart failure. Two parameters derived from HRT, turbulence slope (TS) and turbulence onset (TO), and time- and frequency-domain heart rate variability (HRV) parameters (SDNN, RMSSD, VLF, LF, HF) from 24-hour ECG were compared before and after beta-blocker therapy, together with the same parameters in age-matched normal control. Results showed that TS (3.1 +/- 2.2 vs 6.2 +/- 3.0; P = 0.001) and all HRV parameters were increased after 3 months of atenolol treatment. No changes in TO were evident (0.6 +/- 0.5 vs -0.2 +/- 1.3; P = 0.13). The improvement of TS and the vagally mediated parameters of mean R-R interval, RMSSD, and the HF component of HRV were positively correlated. Abnormal HRT caused by chronic congestive heart failure can be restored by beta-blocker therapy. The evolution of TS was positively correlated with measures of vagal modulation of heart rate.


Cooperative Membrane Damage as a Mechanism for Pentamidine-Antibiotic Mutual Sensitization.
Most Gram-positive-selective antibiotics have low activity against Gram-negative bacteria due to the presence of an outer membrane barrier. There is, therefore, interest in developing combination therapies that can penetrate the outer membrane (OM) with known antibiotics coupled with membrane-active sensitizing adjuvants. However, two unanswered questions hinder the development of such combination therapies: the sensitization spectrum of the sensitizer and the mechanism of antibiotic-sensitizer mutual potentiation. Here, with pentamidine as an example, we screened a library of 170 FDA-approved antibiotics in combination with pentamidine, a compound known to disturb the OM of Gram-negative bacteria. We found that four antibiotics, minocycline, linezolid, valnemulin, and nadifloxacin, displaced enhanced activity in combination with pentamidine against several multidrug-resistant Gram-negative bacteria. Through a descriptor-based structural-activity analysis and multiple cell-based biochemical assays, we found that hydrophobicity, partial charge, rigidity, and surface rugosity were key factors that affected sensitization via a cooperative membrane damage mechanism in which lipopolysaccharides and phospholipids were identified as sites of synergy. Finally, in vitro experiments showed that the linezolid-pentamidine combination slowed the generation of drug resistance, and there was also potent activity in in vivo experiments. Overall, our results highlight the importance of the physicochemical properties of antibiotics and cooperative membrane damage for synergistic pentamidine-antibiotic drug combinations.


Syringo-Subarachnoid Shunt Placement: A Minimally Invasive Technique Using Fixed Tubular Retractors-Three Case Reports and Literature Review.
Placement of a syringo-subarachnoid shunt as a surgical management for syringomyelia has been well described in the literature. Good results in terms of clinical and radiological improvement have been documented especially for posttraumatic syringomyelia. Traditionally, this has been performed using open approaches which are fraught with risks of cerebrospinal fluid leak, delayed wound healing, and increased postoperative pain. With the help of minimally invasive techniques that are currently being used to treat various degenerative spinal disorders, most of these complications may be minimized. However, few reports in literature describe similar approaches for accessing intradural intramedullary spinal cord lesions and especially for syringomyelia. Retrospective case review: using a 22-mm tubular retractor, a laminotomy was performed, durotomy done, and spinal cord identified. Myelotomy was performed at the dorsal root entry zone, syrinx visualized and entered, followed by placement of syringo-subarachnoid shunt. Three male patients aged 44, 57, and 37 underwent placement of syringo-subarachnoid shunts using minimally invasive fixed tubular retractors. Indications included posttraumatic or postsurgical spinal cord syrinx. Follow-up period was 1 year in all cases. There were no neurological or technique-related complications. All patients showed clinical improvement upon subsequent follow up. Our clinical experience on the treatment of syringomyelia via a minimally invasive fixed tubular retractor is presented. We find that this is an ideal approach for placement of syringo-subarachnoid shunts, as it provides direct access to the lesion with minimal collateral damage and wound-related complications. 4. Relevant - in demonstrating the effectiveness of an already established procedure through a novel, minimally invasive approach which has the potential to significantly reduce the overall morbidity, in view of the inherent approach-related benefits as compared to conventional open approaches.


Focus on Communications: Communicating the Message: Clarifying the Controversies About Caffeine.
Today's "coffee culture" and the widespread availability of caffeine-containing foods and beverages fuel the ongoing study of caffeine and its subsequent coverage by the media. Although the media has become influential in communicating health and nutrition information to the public, coverage of emerging science, such as the study of caffeine, does not necessarily bring clarity or improved understanding for consumers. This article highlights the current knowledge of caffeine's effects on health, with emphasis on the most common areas of interest and confusion. To address persistent misperceptions about caffeine, this article also accentuates the need for nutrition professionals to help put the findings of caffeine research into perspective and suggests practical ways to do this.


Tubaramure, a Food-Assisted Integrated Health and Nutrition Program, Reduces Child Stunting in Burundi: A Cluster-Randomized Controlled Intervention Trial.
Food-assisted maternal and child health and nutrition (FA-MCHN) programs are widely used to address undernutrition, but little is known about their effectiveness in improving child linear growth. We assessed the impact of Burundi's Tubaramure FA-MCHN program on linear growth. The program targeted women and their children during the first 1000 d and included 1) food rations, 2) strengthening of health services and promotion of their use, and 3) behavior change communication (BCC). A second objective was to assess the differential effect when varying the timing and duration of receiving food rations. We used a 4-arm, cluster-randomized controlled study to assess program impact with the use of cluster fixed-effects double-difference models with repeated cross-sectional data (baseline and follow-up 4 y later with ∼3550 children in each round). Treatment arms received food rations (corn-soy blend and micronutrient-fortified vegetable oil) for the first 1000 d (T24), from pregnancy through the child reaching 18 mo (T18), or from birth through the child reaching 24 mo ["no food during pregnancy" (TNFP)]. All treatment arms received BCC for the first 1000 d. The control arm received no food rations or BCC. Stunting (height-for-age z score <2 SDs) increased markedly from baseline to follow-up, but Tubaramure had a significant (P < 0.05) beneficial effect in the T24 [7.4 percentage points (pp); P < 0.05], T18 (5.7 pp; P < 0.05), and TNFP (4.6; P = 0.09) arms; the differences in effect across arms were not significant (P > 0.01). Secondary analyses showed that the effect was limited to children whose mother and head of household had some primary education and who lived in households with above-median assets. FA-MCHN programs are an effective development tool to improve child linear growth and can protect children from political and economic shocks in vulnerable countries such as Burundi. A better understanding of how to improve the nutritional status of children in the worst-off households is needed. This trial was registered at www.clinicaltrials.gov as NCT01072279.


Phosphatidylinositol and inositol involvement in Alzheimer amyloid-beta fibril growth and arrest.
A key pathological feature of Alzheimer's disease is the formation and accumulation of amyloid fibres. The major component is the 39 to 42 residue amyloid-beta peptide (Abeta) which is an internal proteolytic fragment of the integral membrane amyloid precursor protein. Aggregation of Abeta into insoluble amyloid fibres is a nucleation-dependent event that may be modulated by the presence of amyloid-associated molecules. Fibril formation is also associated with neurotoxicity which may be the result of specific Abeta interactions with membrane proteins and/or lipids. Using circular dichroism spectroscopy, tyrosine fluorescence spectroscopy and electron microscopy, we have examined the binding of Abeta peptides 1-40 (Abeta40) and 1-42 (Abeta42) to the glycolipid, phosphatidylinositol (PI), and different inositol headgroups. At pH 6.0 and in the presence of PI vesicles, both Abeta40 and Abeta42 adopted an amyloidogenic beta-structure. In contrast, at neutral pH only Abeta42 folded into a beta-structure in the presence of PI vesicles. To determine whether the induction of beta-structure stemmed from interactions with the headgroup of PI, the effects of inositol derivatives on Abeta were also examined. At pH 7.0, myo-inositol was sufficient to induce beta-structure in Abeta42 but had no effect on the conformation of Abeta40. Myo-inositol may promote beta-structure as a result of its ability to be both a hydrogen-bond donor and acceptor. Mono-, di- and triphosphorylated forms of inositol had reduced ability to induce beta-structure in both peptides. The results from this study indicate that interaction of Abeta40 and Abeta42 with PI acts as a seed for fibril formation while myo-inositol stabilizes a soluble Abeta42 micelle.


An interactive learning environment for health care professionals.
This article summarizes experiences to date with building and deploying a clinical simulator that medical students use as part of a 3rd year primary care rotation. The simulated microworld helps students and health care professionals gain experience with and learn meta-cognitive skills for the care of complex patient populations that require treatment in the biopsychosocial-value dimensions. We explain lessons learned and next steps resulting from use of the program by over 300 users to date.


Effects of miR-155 on proliferation and apoptosis by regulating FoxO3a/BIM in liver cancer cell line HCCLM3.
MiR-155 has been shown to be up-regulated in hepatocellular carcinoma (HCC) patients. B-cell lymphoma-2 (Bcl-2) interacting mediator of cell death (BIM) regulates cell proliferation and apoptosis, as its down-regulation is involved in HCC onset. Transcriptional factor FoxO3a mediates BIM expression and is related to HCC pathogenesis. Bioinformatics analysis showed targeted regulation of FoxO3a by miR-155. This study aims to investigate whether miR-155 plays a role in mediating FoxO3a/BIM signal pathway and HCC occurrence. HCC patients were collected for tumor and adjacent tissues, in which microRNA-155 (miR-155) and FoxO3a expressions were examined. In vitro cultured HCCLM3, HepG2 and L-02 cells were tested for basal apoptotic rate by flow cytometry and were compared for miR-155 and FoxO3a expression. Dual-luciferase reporter gene assay demonstrated the targeted relationship between miR-155 and FoxO3a. HCCLM3 cells were treated with miR-155 inhibitor and/or FoxO3a-pMD18-T. Cell apoptosis and proliferation were examined by using flow cytometry and MTT assays, respectively. Western blot and spectrometry assay were employed to quantify the FoxO3a, BIM expressions, and caspase activity. Compared to adjacent tissues, HCC tissues had significantly higher miR-155 and significantly lower FoxO3a expression (p<0.05). HCCLM3 and HepG2 cells had significantly lower FoxO3a expression and basal apoptotic rate compared to L02 cells, whilst miR-155 level was significantly higher (p<0.05). MiR-155 targeted and inhibited 3'-UTR of FoxO3a, increasing BIM expression, caspase-3, and caspase-9 activities, and enhancing cell apoptosis and weakening proliferation. HCC tissues elevated the miR-155 and suppressed the FoxO3a expressions. MiR-155 targeted and inhibited FoxO3a expression to suppress the BIM, depress caspase-3 and caspase-9 activities, therefore inhibiting the HCC cell apoptosis and facilitating proliferation.


External validation of an emergency department triage algorithm for chest pain patients.
We aimed to externally validate an emergency department triage algorithm including five hierarchical clinical variables developed to identify chest pain patients at low risk of having an acute coronary syndrome justifying delayed rather than immediate evaluation. In a single-centre cohort enrolling 29,269 consecutive patients presenting with chest pain, the performance of the algorithm was compared against the emergency department discharge diagnosis. In an international multicentre study enrolling 4069 patients, central adjudication by two independent cardiologists using all data derived from cardiac work-up including follow-up served as the reference. Triage towards 'low-risk' required absence of all five clinical 'high-risk' variables: history of coronary artery disease, diabetes, pressure-like chest pain, retrosternal chest pain and age above 40 years. Safety (sensitivity and negative predictive value (NPV)) and efficacy (percentage of patients classified as low risk) was tested in this initial proposal (Model A) and in two additional models: omitting age criteria (Model B) and allowing up to one (any) of the five high-risk variables (Model C). The prevalence of acute coronary syndrome was 9.4% in the single-centre and 28.4% in the multicentre study. The triage algorithm had very high sensitivity/NPV in both cohorts (99.4%/99.1% and 99.9%/99.1%, respectively), but very low efficacy (6.2% and 2.7%, respectively). Model B resulted in sensitivity/NPV of 97.5%/98.3% and 96.1%/89.4%, while efficacy increased to 14.2% and 10.4%, respectively. Model C resulted in sensitivity/NPV of 96.7%/98.6% and 95.2%/91.3%, with a further increase in efficacy to 23.1% and 15.5%, respectively. A triage algorithm for the identification of low-risk chest pain patients exclusively based on simple clinical variables provided reasonable performance characteristics possibly justifying delayed rather than immediate evaluation in the emergency department.


Ultrathin Broadband Germanium-Graphene Hybrid Photodetector with High Performance.
Germanium-based photodetector is a key component in silicon based photonics because of its unique properties of response at telecommunication band and compatibility with CMOS techniques. However, the limitations of low quantum efficiency and high surface recombination in ultrathin germanium film, especially in the near-infrared range, put huge obstructions on the road toward applications. Nowadays, practical applications require more nanoscale devices with lower power consumption as well as higher responsivity and response speed. In this work, we first demonstrate a germanium-graphene hybrid structure photodetector that consists of an ultrathin 20 nm germanium layer and a monolayer graphene. The photodetector can achieve a broadband detection from ultraviolet to near-infrared range. A conductive gain of 155 and a responsivity of 66.2 A W-1 are achieved, which is about 3 orders of magnitude higher than pure graphene photodetectors and about 4 times larger than pure germanium photodetectors. Such enhancement owes to effective generation, separation and transfer of photogenerated carriers at material interface. The photodetector based on germanium--graphene hybrid structure presents a new paradigm for the realization of small but high performance device in the process of integration in silicon-based optical chips. And it offers new opportunities for imaging, sensing, and other optoelectronic field applications.


BTG2: a rising star of tumor suppressors (review).
B-cell translocation gene 2 (BTG2), the first gene identified in the BTG/TOB gene family, is involved in many biological activities in cancer cells acting as a tumor suppressor. The BTG2 expression is downregulated in many human cancers. It is an instantaneous early response gene and plays important roles in cell differentiation, proliferation, DNA damage repair, and apoptosis in cancer cells. Moreover, BTG2 is regulated by many factors involving different signal pathways. However, the regulatory mechanism of BTG2 is largely unknown. Recently, the relationship between microRNAs and BTG2 has attracted much attention. MicroRNA-21 (miR-21) has been found to regulate BTG2 gene during carcinogenesis. In this review, we summarize the latest findings in the investigations of biological functions of BTG2 and regulation of its expression, with an emphasis on miR-21 in regulation of BTG2 gene in various cancers. B-cell translocation gene 2 (BTG2), also known as PC3 or TIS21, belongs to the antiproliferative (APRO) gene family. Several studies have demonstrated that BTG2 is involved in a large number of physiological and pathological processes, such as cell differentiation, proliferation, apoptosis, and other cellular functions, acting as a tumor suppressor. In this review, we summarize the latest findings in BTG2 studies, highlighting the mechanisms for the regulatory effects of microRNAs (miRNAs) on BTG2 gene expression in the most common human cancers.


Benefits and demerits of antihypertensive therapy by high-dose calcium channel blocker in severely hypertensive rats.
This study examined the protective effects of a calcium channel blocker, nisoldipine (NSL), against organ damage secondary to severe hypertension. Severe hypertension was induced in male 7-week-old spontaneously hypertensive rats (n = 21) by heminephrectomy and substitution of 1% NaCl solution for drinking water. They were fed a chow containing 0%, 0.03% (low dose) or 0.1% (high dose) NSL for 12 weeks. The systolic blood pressures after 12 weeks were 228 mmHg in the control group, 201 in the low dose NSL group and 188 in the high dose NSL group. Body weight gain was blunted in the high dose NSL group (at 12 weeks: control 289g; low dose NSL 286; high dose NSL 263, p < 0.04). Although a further reduction in cardiac weight was seen in the high dose NSL rate (low NSL -5.2%, p < 0.05; high NSL -9%, p < 0.01), reductions in aortic thickness did not differ between the 2 doses (low NSL -18%, p < 0.001; high NSL -17%, p < 0.001). Moreover, dose-dependent effects of NSL treatment were absent for such endpoints as plasma creatinine (low NSL -15%, p < 0.04; high NSL -17%, p < 0.05), glomerular filtration rate (low NSL +21%, p < 0.05; high NSL +20%, p < 0.03) and urinary protein excretion (low NSL -22%, p < 0.05; high NSL -29%, p < 0.02). Thus, a high dose calcium channel blocker hampered growth and did not further improve vascular wall thickening or renal injury in severely hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)


Antibody Response to Paramyxoviruses in Paget's Disease of Bone.
Paget's disease of bone (PDB) is a common skeletal disorder characterised by focal abnormalities of increased and disorganised bone turnover. Genetic factors play a central role in the pathogenesis of PDB but environmental factors also contribute. Measles virus (MV), respiratory syncytial virus (RSV) and canine distemper virus (CDV) have all been implicated as potential disease triggers but the data are conflicting. Since chronic paramyxovirus infection with measles is known to be accompanied by increased production of antiviral antibodies, we have analysed circulating concentrations of antibodies to MV, CDV, and RSV as well as mumps, rubella and varicella zoster virus (VZV) in 463 patients with PDB and 220 aged and gender-matched controls. We also studied the relation between viral antibody concentrations and various markers of disease severity and extent in 460 PDB patients. A high proportion of cases and controls tested positive for antiviral antibodies but there was no significant difference in circulating antibody concentrations between PDB cases and controls for MV, CDV, RSV, rubella or VZV. However, mumps virus antibody levels were significantly higher in the PDB cases (mean ± SD = 3.1 ± 0.84 vs. 2.62 ± 0.86. p < 0.001). There was no association between disease severity and circulating antibody concentrations to any of the viruses. In conclusion, we found no evidence to suggest that PDB is associated with abnormalities of immune response to measles or other paramyxoviruses, although there was evidence of a greater antibody response to mumps. The results do not support that hypothesis that PDB is associated with a persistent infection with measles or other paramyxoviruses.


Bright light therapy for depression: a review of its effects on chronobiology and the autonomic nervous system.
Bright light therapy (BLT) is considered among the first-line treatments for seasonal affective disorder (SAD), yet a growing body of literature supports its use in other neuropsychiatric conditions including non-seasonal depression. Despite evidence of its antidepressant efficacy, clinical use of BLT remains highly variable internationally. In this article, we explore the autonomic effects of BLT and suggest that such effects may play a role in its antidepressant and chronotherapeutic properties. After providing a brief introduction on the clinical application of BLT, we review the chronobiological effects of BLT on depression and on the autonomic nervous system in depressed and non-depressed individuals with an emphasis on non-seasonal depression. Such a theory of autonomic modulation via BLT could serve to integrate aspects of recent work centered on alleviating allostatic load, the polyvagal theory, the neurovisceral integration model and emerging evidence on the roles of glutamate and gamma-hydroxybutyric acid (GABA).


Association of body mass index and Trp64Arg polymorphism of the beta3-adrenoreceptor gene and leptin level in Tehran Lipid and Glucose Study.
In this study the association between beta3-adrenoceptor gene polymorphism and serum concentration of leptin with body mass index (BMI) is investigated. Using subjects in the Tehran Lipid and Glucose Study, genotyping of the Trp64Arg polymorphism of the beta3-adrenoreceptor gene was performed using a restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) technique was used and the association with obesity was investigated. At total of 197 men and 204 women were divided into four groups (BMI<20, 20< or =BMI<25, 25< or =BMI<30, BMI< or =30) and 97, 98, 104 and 102 subjects, respectively, were placed randomly in the four groups. Leptin level was determined by an enzyme immunoassay (EIA) method and FBS, HDL-C, triglyceride and total cholesterol levels were determined by an enzyme colorimetric method. Body mass index (BMI) was also measured. The A (Arg) allele frequency was 0.08 among the population and its presence was significantly associated with increase of leptin level (AA/TA, 30.5+/-24.8 ng/mL; TT, 22.6+/-20.9 ng/mL; P=0.014) but there was no significant association with increased BMI (AA/TA, 27+/-5.6 kg/m2; TT, 25.4+/-5.5 kg/m2; P=0.072). These data show that the presence of the Arg64 allele at the beta3-adenoceptor gene locus is related to increase in leptin level in this population, but is not related to body mass index.


Nanoparticles made of π-conjugated compounds targeted for chemical and biological applications.
Semiconducting organic nanoparticles have recently attracted increasing attention in the chemical and biomedical fields. Such nanoparticles are mainly composed of π-conjugated compounds. They possess the properties of easy synthesis, facile tuning, less toxicity and more biocompatibility relative to the existing inorganic nanoparticles. In addition, they show advantages such as brighter fluorescence, higher photostability and higher biocompatibility, compared with classical fluorescent organic dyes. In this review, we summarize the latest advances in the development of organic nanoparticles made of π-conjugated compounds, including preparation methods, material design, nanoparticle fabrication and surface functionalization for chemical and biological applications. Especially, we focus on the applications of semiconducting organic nanoparticles in chemical and biological sensing by monitoring the fluorescence signal, as nanocarriers for drug/gene delivery, in photothermal and photodynamic therapy, and in photoacoustic imaging. Finally, the challenges and perspectives for the future development of organic nanoparticles based on π-conjugated compounds are also discussed.


[Primary immunodeficiency and inherited bone marrow failure syndrome in adults].
Primary immunodeficiency is a group of heterozygous disorders with intrinsic defects in immune cells or molecules associated with immune function. Inherited bone marrow failure syndrome is characterized by at least one defective hematopoietic cell lineage. Clinical symptoms in these patients are usually observed in childhood, but the symptoms may infrequently first occur in adulthood. Although these patients tend to develop autoimmune diseases and cancer in adulthood, recent treatment advances can ensure long-term survival. Therefore, diagnosis should not be delayed, and disease management with a view to lifelong treatment should have a long-term outlook. Therefore, we need to fully understand the pathogenesis of associated underlying complications.


Temnothorax albipennis migration inspired semi-flocking control for mobile sensor networks.
Mobile sensor networks (MSNs) are utilized in many sensing applications that require both target seeking and tracking capabilities. Dynamics of mobile agents and the interactions among them introduce new challenges in designing robust cooperative control mechanisms. In this paper, a distributed semiflocking algorithm inspired by Temnothorax albipennis migration model is proposed to address the above issues. Mobile agents under the control of the proposed semiflocking algorithm are capable of detecting targets faster and tracking them with lower energy consumption when compared with existing MSN motion control algorithms. Furthermore, the proposed semiflocking algorithm can operate energy-efficiently on both flat and uneven terrains. Simulation results demonstrate that the proposed semiflocking algorithm can provide promising performances in target seeking and tracking applications of MSNs.


Social Determinant of Health Framework to Examine the Impact of COVID-19 on Latino Health.
Evaluated how COVID-19 impacted Latino health across social, economic, and emotional dimensions and differentiated whether adverse COVID-19-related effects persisted across respondents. In both English and Spanish, a cross-sectional survey was conducted in the USA from June 2021 to April 2022. Chi-square tests, Z-tests, and T-tests were used to test for significant differences between Spanish- and English-speaking respondents. Multiple linear regressions were carried out to understand whether previously established determinants of health for Latinos accounted for greater COVID-19-related adversity across social, economic, and mental health dimensions. English as a primary language was significantly related to greater adverse emotional/mental health COVID-19 experiences after controlling for other social determinants of health factors (β = - 0.355, p < 0.001). Individuals who reported worrying about housing loss were significantly more likely to experience more adverse economic adversity due to COVID-19 (β = - 0.234, p < 0.001). Household income < $35,000 (β = 0.083, p < 0.05), having more than 5 people living in the same home (β = -0.102, p < 0.05), and work-related transportation barriers (β = - 0.114, p < 0.05) all increased the likelihood of household-related stressors occurring because of the pandemic. The study highlights the heterogeneity in the Latino community and the key social, economic, and community-level factors most strongly correlated with adverse COVID-19-related outcomes.


Cytokeratin 19 (CK19) expression by thyroid neoplasms in a Nigerian tertiary health centre.
despite the observed appreciable sensitivity and specificity of the use of CK19 in predicting thyroid malignancies, there is still a paucity of information about its uses in Nigeria. Current information across the world is also scarce. This study was to review the histopathological diagnosis of thyroid neoplasms seen in Obafemi Awolowo University Teaching Hospital Complex (OAUTHC), Ile Ife, using cytokeratin 19 immunohistochemical marker. a retrospective study of fifty-six cases of thyroid neoplasm seen over a period of twenty years was conducted. The tissue samples were subjected to immunohistochemical staining for CK19 using monoclonal antibodies. The expression of the markers on the various thyroid neoplasms was assessed histologically. the expression of CK19 was significantly higher in malignant thyroid neoplasms compared to benign neoplasms (p<0.05). The sensitivity and specificity for cytokeratin 19 were 90.0% and 75.0% respectively. diffuse immunohistochemical expression of CK19 is a strong indicator of thyroid malignancy. This biomarker can help in the diagnosis of thyroid neoplasms especially those with incomplete or equivocal histomorphology features.


Pharmacokinetic Evidence from the HIRIF Trial To Support Increased Doses of Rifampin for Tuberculosis.
Rifamycins exhibit concentration-dependent killing of Mycobacterium tuberculosis; higher exposures potentially induce better outcomes. We randomized 180 tuberculosis patients in Peru to receive rifampin at 10, 15, or 20 mg/kg/day. A total of 168 had noncompartmental pharmacokinetic analyses; 67% were sampled twice, and 33% were sampled six times. The doses administered were well tolerated. The median area under the concentration-time curve from 0 to 6 h (interquartile range) was 24.9 (17.6 to 32.1), 43.1 (30.3 to 57.5), or 55.5 (35.7 to 73.2) h · μg/ml. The median maximum drug concentration in serum in the experimental arms reached the target of 8 μg/ml. Continued investigation of higher rifampin doses is warranted. (This study has been registered at ClinicalTrials.gov under registration no. NCT01408914.).


In vitro-in vivo correlation of the pharmacokinetics of vinpocetine.
Vinpocetine is extensively metabolized in rats, dogs and humans, and the plasma clearance approximates the hepatic plasma flow in each of the species. In vitro degradation studies with hepatocytes have shown that the activity of human hepatocytes is about one order of magnitude higher than the activity of dog hepatocytes, and two orders of magnitude higher than that of rat hepatocytes. These differences can explain the differences in bioavailabilities of vinpocetine in the three species (52% in rats, 21.5+/-19.3% in dogs and 6.2+/-1.9% in humans). In dogs and humans, the compound seems to be metabolized exclusively in the liver whereas in rats extrahepatic metabolism seems also to be important. The in vivo clearance predicted from the activity of hepatocytes is in good agreement with the values measured in vivo in the case of humans and dogs. The estimated values for bioavailability showed good correlation with in vivo data in each species if the free drug ratio was assumed to equal 1.


Premises for fowl sperm preservation based on applied bioenergetics.
The primary goal of this work was to test whether the sperm mobility assay could be used to derive mathematical relationships from which predictions could be made about sperm cell function. A precondition was random sampling from a pool of sperm. This precondition was met by centrifuging mobile sperm through 12% (wt/vol) Accudenz containing the Ca(2+) chelator 1,2-bis-(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) and then holding washed sperm at 20°C within buffered potassium chloride. These 2 conditions rendered washed sperm immobile at 20°C. Resumption of sperm mobility was independent of time (P > 0.8558) when sperm were reactivated at body temperature with 2 mM Ca(2+) in isotonic sodium chloride at pH 7.4. Reactivated sperm mobility was 93% of the prewash control. Subsequent experiments served to define a dose response, predict optimal conditions for in vitro sperm mobility, and show how sperm can recover from an imposed non-physiological condition. Thus, functions were derived from which predictions were made. Whereas the utility of BAPTA treatment was confirmed in a new context, such utility did not address the question of whole-cell Ca(2+) flux during sperm cell manipulation. This issue is pivotal for the application of bioenergetics to fowl sperm preservation. Therefore, the secondary goal of this research was to investigate sperm cell Ca(2+) flux using a simulation of conditions encountered by sperm during centrifugation through 12% (wt/vol) Accudenz. These conditions included a temperature of 30°C, a Ca(2+) sink, and no exogenous substrate. Sperm motion was measured with a Hobson SpermTracker. Data points conformed to parabolic functions when motile concentration and velocity were plotted as functions of time. In each case, maximums were observed, e.g., 26 min for motile concentration. The upswing was attributed to a redistribution of intracellular Ca(2+) whereas the downswing was attributed to sperm cell Ca(2+) depletion. A pronounced isothermal increase was observed for each variable when the Ca(2+) sink was overcome with exogenous Ca(2+). Experimental outcomes supported four testable premises applicable to fowl sperm preservation research: 1) the importance of sperm mobility phenotype, 2) the relationship between mitochondrial Ca(2+) cycling and sperm mobility, 3) the utility of the sperm mobility assay for predicting experimental outcomes, and 4) understanding mitochondrial Ca(2+) cycling in terms of whole-cell Ca(2+) flux.


Direct Monitoring of Exogenous γ-Hydroxybutyric Acid in Body Fluids by NMR Spectroscopy.
γ-Hydroxybutyric acid (GHB) is a popular drug increasingly associated with cases of drug-facilitated sexual assault (DFSA). Currently, expanding procedures of analysis and having forensic evidence of GHB intake in a long term are mandatory. Up to now, most studies have been performed using GC/MS and LC-MS as analytical platforms, which involve significant manipulation of the sample and, often, indirect measurements. In this work, procedures used in NMR-based metabolomics were applied to a GHB clinical trial on urine and serum. Detection, identification, and quantification of the drug by NMR methods were surveyed, as well as the use of NMR-based metabolomics for the search of potential surrogate biomarkers of GHB consumption. Results demonstrated the suitability of NMR spectroscopy, as a robust nondestructive technique, to fast and directly monitor (detect, identify, and quantify) exogenous GHB in almost intact body fluids and its high potential in the search for metabolites associated with GHB intake.


It May Not Be So Typical: Distinguishing Frontotemporal Dementia From Behavioral Variant Alzheimer's Disease.
The Banner Alzheimer's Institute Case Conference is a weekly event in which physicians and staff discuss challenging and/or teaching cases of patients seen in clinical settings. These conferences are attended by a multidisciplinary group that includes Banner Alzheimer's Institute dementia specialists, community physicians (internal medicine, family medicine, and radiology), neuropsychologists, physician assistants, nurse practitioners, social workers, medical students, residents, and fellows. The Banner Alzheimer's Institute is located in Phoenix, Arizona, and it has an ambitious mission: to end Alzheimer's disease without losing a generation, set a new standard of care for patients and families, and forge a model of collaboration in biomedical research. The Institute provides high-level care and treatment for patients affected by Alzheimer's disease, dementia, and related disorders. In addition, the Institute offers extensive support services for families and many unique and rewarding research opportunities.


Integrated information theory (IIT) 4.0: Formulating the properties of phenomenal existence in physical terms.
This paper presents Integrated Information Theory (IIT) 4.0. IIT aims to account for the properties of experience in physical (operational) terms. It identifies the essential properties of experience (axioms), infers the necessary and sufficient properties that its substrate must satisfy (postulates), and expresses them in mathematical terms. In principle, the postulates can be applied to any system of units in a state to determine whether it is conscious, to what degree, and in what way. IIT offers a parsimonious explanation of empirical evidence, makes testable predictions concerning both the presence and the quality of experience, and permits inferences and extrapolations. IIT 4.0 incorporates several developments of the past ten years, including a more accurate formulation of the axioms as postulates and mathematical expressions, the introduction of a unique measure of intrinsic information that is consistent with the postulates, and an explicit assessment of causal relations. By fully unfolding a system's irreducible cause-effect power, the distinctions and relations specified by a substrate can account for the quality of experience.


The impact of professional learning communities on pre-service teachers' professional commitment.
While in-service teachers' professional commitment has gained significant attention in recent years, researches on pre-service teachers' professional commitment is still insufficient, particularly with regard to the effect that professional learning communities play on pre-service teachers' professional commitment. In this context, this study employed mixed methods to investigate the impact of workshops for teaching competitions as a professional learning community on pre-service teachers' professional commitment in China. A questionnaire survey was administered to pre-service teachers who had workshop experiences (n = 43) and their classmates who did not have workshop experiences (n = 98) to examine the effect of workshops for teaching competitions as a professional learning community on pre-service teachers' professional commitment. Follow-up qualitative interviews with 5 pre-service teachers with workshop experiences were conducted to explain the reasons behind such effects. The results showed that workshop experiences had significant and positive effects on pre-service teachers' professional commitment and the characteristics of shared vision, collaboration, and reflective dialogue affected their professional commitment from three perspectives: commitment to teaching as a career, personal time investment, and interest in professional development.


New isopimarane diterpene and new cineole type glucoside from Nepeta prattii.
Together with sixteen known compounds, a new isopimarane diterpene (prattol) and a new cineole type glucoside were isolated from Nepeta prattii. Their structures were elucidated on the basis of spectral methods as isopimar-15-en-3 beta,8 beta,20-triol, and (1R, 2R, 4S)-1,8-epoxy-p-methan-2-O-beta-D-glucopyranosyl(1-->6)-beta- D-glucopyranoside.