Post-Transcriptional and Post-translational Regulation of Central Carbon Metabolic Enzymes in Cancer.
Malignant transformation of cells requires specific adaptations of cellular metabolism to support growth and survival. Alterations in cancer central carbon metabolism including aerobic glycolysis, elevated glutaminolysis, dysregulated tricarboxylic acid cycle and pentose phosphate pathway, facilitate cancer development by maintaining viability and building new biomass. Although a variety of oncogenes or tumor suppressors contribute to these rewiring, accumulating evidence suggests that both post-transcriptional and post-translational modifications (PTMs) also orchestrate the tightly controlled regulation of cancer metabolic adaptations, broadening the biological mechanisms of cancer metabolic reprogramming. Micro RNA, one kind of posttranscriptional modification, mediates transcriptional silencing of various metabolic enzymes. Additional, different kinds of PTMs play important roles in cancer metabolic rewiring by affecting the function, interaction or stability of target proteins. We survey recent studies demonstrating PTMs at lysine residues and microRNAs that are involved in reprogramming of cancer central carbon metabolism, and summarize the effect of these modifications according to different parts of central carbon metabolic pathway. Moreover, we provide an updated overview of the compounds or agents targeting central carbon metabolism in cancer. Given that the heterogeneity of cancer biology, a combination of these novel therapeutics and standard chemotherapeutic agents may obtain better benefit and overcome drug resistance. Finally, this review discusses the challenges and some new steps that may further advance this field.


Group memory rehabilitation for people with multiple sclerosis: a feasibility randomized controlled trial.
To assess the feasibility and effectiveness of a group memory rehabilitation programme combining compensation and restitution strategies. Randomized controlled trial. Community. People with multiple sclerosis who reported memory difficulties were recruited. A group memory rehabilitation programme, comprising ten 1.5-hour sessions, was compared with a waiting list control. The primary outcome was the Everyday Memory Questionnaire. Secondary outcomes included the General Health Questionnaire 28 and MS Impact Scale administered four and eight months after randomization. In addition, those in the intervention group gave feedback about the intervention. Forty-eight participants were recruited. They were aged 34-72 years (mean 54.3, SD 11.0) and 33 (69%) were women. There were no significant differences between the two groups on the Everyday Memory Questionnaire or MS Impact Scale (P > 0.05) at four or eight months after randomization. However, the intervention group reported significantly better mood than controls on the GHQ-28 at eight months (P = 0.04). Participants showed minimal benefit from the memory rehabilitation programme on quantitative measures but the intervention was well received, as indicated by positive feedback at the end of the intervention. There was no significant effect of the intervention on memory but there was a significant effect on mood. The results suggest a larger scale study is justified.


A double-blind placebo-controlled study of lithium in hospitalized aggressive children and adolescents with conduct disorder.
A subgroup of children and adolescents with conduct disorder are characterized by severe and persistent aggression. Although there is no agreed on treatment for such aggression, lithium carbonate has shown promise in some studies involving children. Our study was designed to critically assess the efficacy of lithium in the treatment of aggression in children and adolescents using a measure specific for aggression. Subjects were inpatients with conduct disorder hospitalized because of severe and chronic aggression. A parallel-groups design was used in this double-blind, placebo-controlled trial with randomization to lithium or placebo. Only those who met the aggression criterion during the 2-week placebo-baseline period were randomized to 4 weeks of treatment. Outcome measures included Clinical Global Impressions, the Global Clinical Judgements (Consensus) Scale, and the Overt Aggression Scale. Eighty-six inpatients enrolled in the study; 40 (33 male and 7 female; median age, 12.5 years) entered and completed the treatment phase. Lithium was statistically and clinically superior to placebo. Sixteen of 20 subjects in the lithium group were responders on the Consensus ratings vs 6 of 20 in the placebo group (P=.004). Ratings on the Overt Aggression Scale decreased significantly for the lithium group vs the placebo group (P=.04). More than half of the subjects in the lithium group experienced nausea, vomiting, and urinary frequency. Lithium is a safe and effective short-term treatment for aggression in inpatients with conduct disorder, although its use is associated with adverse effects.


The diversity of interest in later-life entrepreneurship: Results from a nationally representative survey of Americans aged 50 to 70.
While older entrepreneurs are more likely to be male, white, and have higher levels of human, social, and financial capital, we know less about interest in later-life entrepreneurship. This study estimates entrepreneurial interest in a nationally representative sample of Americans aged 50 to 70 using partial proportional odds modeling. We estimate that more than 31 million older Americans have some interest in entrepreneurship and reveal key predictors of this interest (e.g., younger age). Importantly, the findings indicate that a more diverse group of older adults are interested in entrepreneurship than have become entrepreneurs, suggesting the need for additional research on the potential disparities between entrepreneurial interest and action in later life.


Development of hemagglutination assays II. Enhancement in the sensitivity of an RPHA test for HBsAg.
Studies were undertaken to enhance the sensitivity of a previously developed RPHA test for HBsAg. A net increase in sensitivity of approximately 3-fold was achieved by modifying the elution procedure used to purify chimpanzee anti-HBs by affinity chromatography. A further 3- or 4-fold sensitivity increase was achieved by increasing the volume of specimen tested. A concomitant increase in nonspecific agglutination usually observed with increased specimen size was avoided by incubating the reaction mixture at 37 or 45 degrees C. Evaluation of the test in detection of HBsAg in blood obtained from volunteer donors indicates that the materials produced at the New York Blood Center using the modified test protocol compare favorably with a commercial RPHA test. Modifications which did not contribute toward enhancing sensitivity are also reported.


Teleost TLR22 recognizes RNA duplex to induce IFN and protect cells from birnaviruses.
TLR22 occurs exclusively in aquatic animals and its role is unknown. Herein we show that the fugu (Takifugu rubripes) (fg)TLR3 and fgTLR22 link the IFN-inducing pathway via the fg Toll-IL-1R homology domain-containing adaptor protein 1(fgTICAM-1, or TRIF) adaptor in fish cells. fgTLR3 resides in endoplasmic reticulum and recognizes relatively short-sized dsRNA, whereas fgTLR22 recognizes long-sized dsRNA on the cell surface. On poly(I:C)-stimulated fish cells, both recruit fgTICAM-1, which in turn moves from the TLR to a cytoplasmic signalosome region. Thus, fgTICAM-1 acts as a shuttling platform for IFN signaling. When fish cells expressing fgTLR22 are exposed to dsRNA or aquatic dsRNA viruses, cells induce IFN responses to acquire resistance to virus infection. Thus, fish have a novel TICAM-1-coupling TLR that is distinct from the mammalian TLR3 in cellular localization, ligand selection, and tissue distribution. TLR22 may be a functional substitute of human cell-surface TLR3 and serve as a surveillant for infection with dsRNA virus to alert the immune system for antiviral protection in fish.


Improved spectrophotometric analysis of fullerenes C60 and C70 in high-solubility organic solvents.
Fullerenes are among a number of recently discovered carbon allotropes that exhibit unique and versatile properties. The analysis of these materials is of great importance and interest. We present previously unreported spectroscopic data for C60 and C70 fullerenes in high-solubility solvents, including error bounds, so as to allow reliable colorimetric analysis of these materials. The Beer-Lambert-Bouguer law is found to be valid at all wavelengths. The measured data were highly reproducible, and yielded high-precision molar absorbance coefficients for C60 and C70 in o-xylene and o-dichlorobenzene, which both exhibit a high solubility for these fullerenes, and offer the prospect of improved extraction efficiency. A photometric method for a C60/C70 mixture analysis was validated with standard mixtures, and subsequently improved for real samples by correcting for light scattering, using a power-law fit. The method was successfully applied to the analysis of C60/C70 mixtures extracted from fullerene soot.


Hip-abductor fatigue influences sagittal plane ankle kinematics and shank muscle activity during a single-leg forward jump.
Diminished hip abductor strength decreases postural control which is a parameter that is associated with an increased risk of ankle sprains. In our study we evaluated the influence of hip abductor fatigue on sagittal plane ankle kinematics and shank muscle activity during a single-leg forward jump. Sagittal ankle plane kinematics are important in ankle sprains but less studied than frontal plane kinematics. Therefore, we evaluated differences in sagittal ankle kinematics (12-camera motion capture system) and lower limb surface electromyographic muscle activity in 20 healthy, recreationally active adults (9 females, 11 males, mean age 30.3 SD 4.0 years, mean BMI 23.6 SD 2.8 kg/m2) before and after a hip abductor fatigue protocol (200-ms prior, at and in the 250-ms following initial contact (IC)). After fatigue, the maximal ankle plantar-flexion angle decreased prior to IC (median 3.8° [interquartile range 0.1, 7.2], p = 0.014), at IC (4.1° [-0.3, 5.0], p = 0.027) and post IC (4.1° [-1.3, 5.0] p = 0.036). Gastrocnemius activity onset was delayed (-28.0 ms [-44.0, 0.0], p < 0.01). Average activity of the tibialis anterior increased prior to IC (pre-fatigue 19.32% [14.89, 33.45], post-fatigue 28.95% [18.49, 34.81], p < 0.05). Hip-abductor fatigue influenced sagittal ankle kinematics and shank muscle activity during single-leg landings.


Ammonia synthesis on BaTiO2.5H0.5: computational insights into the role of hydrides.
Perovskite oxyhydrides such as BaTiO2.5H0.5 have been found to be able to catalyze NH3 synthesis, but the mechanism and the role of the catalyst's lattice hydrides in the catalytic reaction remain unknown. Here we employ first principles density functional theory to investigate the mechanism of ammonia synthesis and the role of lattice hydrides on a prototypical perovskite oxyhydride, BaTiO2.5H0.5 (BTOH). Two mechanistic hypotheses, the distal and alternating pathways, have been tested on the Ti2O2 termination of the BTOH (210) surface, previously determined to be the most stable surface termination under the reaction conditions considered. In the distal pathway, H atoms hydrogenate N2 to form the *N-NHx key intermediates, followed by N-N bond breaking. In the alternating pathway, H atoms hydrogenate N2 in an alternating fashion to form the *NHx-NHy intermediates before N-N bond breaking and formation of co-adsorbed *NHx/*NHy on the surface. We find that the subsurface hydride vacancy formed after reaction of *N2 with the lattice hydride is key to the distal pathway, leading to surface nitride formation after breaking the *N-NH3 bond, while the neighboring surface Ti sites are key to bridging and stabilizing the *NNH intermediate in the alternating pathway. In both pathways, desorption of NH3 is the most uphill in energy. Our results provide important insights into the role of hydrides and surface vacancies in hydrogenation reactions over BTOH, which will be useful to guide future spectroscopic experiments such as operando IR and inelastic neutron scattering to verify the key intermediates.


Screening and enrolling subjects in a randomized clinical trial involving implant dentures.
When planning and budgeting for a clinical trial, researchers have few references to help them estimate how many volunteers will need to be screened, how long the screening process may take, and how much it may cost to enroll sufficient qualified subjects. The purpose of this study was to analyze the time and costs involved in recruiting, screening, and enrolling subjects for a randomized clinical trial examining patient satisfaction with mandibular dentures retained by 1 or 2 implants. Data collected included age and sex of volunteers, recruiting sources, length of time and costs of recruiting and screening volunteers, and reasons for inclusion or exclusion. Results were analyzed using Pearson chi-square tests. We estimated that we would need to screen 180 volunteers over a period of 4 years at an estimated total cost of CAN$47,664.00 to enroll 86 subjects. Instead, we had to screen 220 volunteers at a direct cost of $63,324.81. We excluded 28% of volunteers, while 32% declined participation and 40% agreed to participate in the study. Volunteers were most commonly excluded because of technical problems with their existing dentures, while they were most likely to decline participation because of perceived surgical risks with implants. Those who agreed to participate most commonly cited anticipation of a more secure mandibular denture as their reason for enrolling. We had to screen more volunteers at a higher cost than anticipated, with only 40% of those screened meeting inclusion criteria and agreeing to participate in the trial.


Hypocholesterolemic effects of mevinolin in patients with heterozygous familial hypercholesterolemia.
We have evaluated the hypolipidemic effects of mevinolin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol biosynthesis in 13 patients with heterozygous familial hypercholesterolemia (FH). Patients were maintained on a low-cholesterol diet and received sequentially increasing doses of 5, 10, 20, and 40 mg of mevinolin twice daily for a period of 1 mo on each dose. Plasma concentrations of low density lipoprotein cholesterol decreased by 19.8% on the 5 mg twice daily dose (P less than 0.05 vs. base line), 28.4% on 10 mg of mevinolin twice daily (P less than 0.05 vs. 5 mg twice daily), 35% on 20 mg of mevinolin twice daily (P less than 0.05 vs. 10 mg twice daily), and 37.7% on 40 mg of mevinolin twice daily (not statistically different from 20 mg twice daily). Concentrations of high density lipoprotein cholesterol remained stable on all doses of mevinolin whereas plasma triglyceride levels fell significantly on the 20 mg (-30.7%) and 40 mg (-34.3%) twice daily doses of mevinolin. Mevinolin was well tolerated and all patients completed the study period. Side effects during the period of study were limited to transient insomnia and headaches in two patients, transient increases in alkaline phosphatase in three patients, and a modest but sustained increase in alkaline phosphatase in a fourth patient. These results indicate that mevinolin is an effective hypolipidemic agent in patients with heterozygous FH but that the optimal doses in these patients are greater than those previously reported in normal volunteers. If long-term safety can be satisfactorily established, mevinolin offers considerable promise in the therapy of heterozygous FH.


GDF-15 and Hepcidin Levels in Nonanemic Patients with Impaired Glucose Tolerance.
Aims. Growth Differentiation Factor-15 (GDF-15) has been suggested as one of the regulators of hepcidin, an important regulatory peptide for iron deposition. Current data is conflicting about the relationship between hepcidin and disorders of glucose metabolism. We aimed to investigate serum hepcidin and GDF-15 concentrations and their associations with each other, in nonanemic subjects with impaired glucose tolerance (IGT) in comparison with the nonanemic subjects with normal glucose tolerance (NGT). Methods. Thirty-seven subjects with IGT and 32 control subjects with NGT, who were age-, gender-, and body mass index- (BMI-) matched, were included in the study. Results. Serum GDF-15 levels were significantly higher in IGT compared to NGT. There were no differences in hepcidin, interleukin-6, and high sensitive C-reactive protein levels between the groups. We found a positive correlation between GDF-15 and hepcidin levels. There were also positive correlations between GDF-15 and age, uric acid, creatinine, and area under the curve for glucose (AUC-G). Hepcidin was correlated positively with ferritin levels. In the multiple regression analysis, GDF-15 concentrations were independently associated with age, uric acid, and AUC-G. Conclusions. Impaired glucose tolerance is associated with increased GDF-15 levels even in the absence of anemia, but the levels of hepcidin are not significantly altered in prediabetic state.


Clinical relevance of vilazodone treatment in patients with major depressive disorder: categorical improvement in symptoms.
To assess clinically relevant symptom improvement in patients with major depressive disorder (MDD) receiving vilazodone by using the Montgomery-Asberg Depression Rating Scale (MADRS), a clinician-rated scale used to measure MDD symptom severity and improvement. Pooled data from 2 positive, phase 3, 8-week, double-blind, randomized, placebo-controlled trials in patients with MDD were analyzed. Patients received vilazodone 40 mg/d or placebo; post hoc analyses were conducted on study completers. Depression symptom improvement was evaluated by analyzing the proportions of patients who shifted from the baseline MADRS single-item symptom severity category of ≥ 2 (mild to severe symptoms) to an end-of-study category < 2 (minimal to no symptoms) or from ≥ 4 (moderate to severe symptoms) to ≤ 2 (mild to no symptoms). The proportion of patients who shifted from anxious depression to no anxious depression was also analyzed. The percentage of patients who completed these studies with severity category shift from baseline ≥ 2 to end of study < 2 was significantly higher for vilazodone versus placebo on all MADRS items (odds ratio [OR] range, 1.4-1.7, P < .05) except reduced appetite (OR = 1.3, P = .232). A significantly greater proportion of vilazodone-treated versus placebo-treated patients shifted from baseline ≥ 4 to end of study ≤ 2 on MADRS items of apparent sadness, reported sadness, inner tension, reduced sleep, and lassitude (OR range, 1.5-2.0, P < .05). Additionally, a significantly greater proportion of vilazodone-treated versus placebo-treated patients shifted from anxious depression at baseline to no anxious depression at end of study (OR = 1.5, P = .031). These results suggest that vilazodone treatment is associated with clinically relevant changes in depression symptoms in patients with MDD. ClinicalTrials.gov identifiers: NCT00285376 and NCT00683592.


Mechanism of Enhanced Immature Dengue Virus Attachment to Endosomal Membrane Induced by prM Antibody.
Dengue virus (DENV) particles are released from cells in different maturation states. Fully immature DENV (immDENV) is generally non-infectious, but can become infectious when complexed with anti-precursor membrane (prM) protein antibodies. It is unknown how anti-prM antibody-coated particles can undergo membrane fusion since the prM caps the envelope (E) protein fusion loop. Here, we determined cryoelectron microscopy (cryo-EM) maps of the immDENV:anti-prM complex at different pH values, mimicking the extracellular (pH 8.0) or endosomal (pH 5.0) environments. At pH 5.0, there are two structural classes with fewer antibodies bound than at pH 8.0. These classes may represent different maturation states. Molecular simulations, together with the measured high-affinity pr:antibody interaction (versus the weak pr:E interaction) and also the low pH cryo-EM structures, suggest how antibody:pr complex can dislodge from the E protein at low pH. This exposes the E protein fusion loop enhancing virus interaction with endosomes.


[Expert consensus on navigation-guided unilateral delayed zygomatic fractures reconstruction techniques].
The zygoma is located in the medial and lateral parts of the face, supporting the midfacial contour. The forward projection of the zygoma and the zygomatic arch expose them to frequent injury. Fractures of the zygoma can lead to displacement of the zygoma and the zygomatic arch, causing facial collapse deformity. For delayed zygomatic fractures, the loss of normal anatomical landmarks, caused by the malunion of the fracture lines and remodeling of the bony contour, makes it difficult to determine the correct positions of the zygomatic bones. In such cases, using traditional surgical methods, ideal and steady outcomes with satisfactory midface symmetry have been difficult to obtain. Nowadays, the application of digital surgical software and surgical navigation help surgeons to perform accurate preoperative simulations to obtain ideal 3-dimensional (3D) virtual surgical plans, and achieve accurate reduction by intraoperative navigation systems, which increase the accuracy and predictability of fracture reduction outcomes. Experts from the Oral and Maxillofacial Surgery Committee of the Chinese Stomatological Association have fully discussed and formulated an expert consensus on navigation-guided unilateral delayed zygomatic fracture reconstruction techniques, to standardize the clinical operation procedures and promote the application.


Effects of increased daily physical activity on mental health and depression biomarkers in postmenopausal women.
[Purpose] Little is known about the effectiveness of daily physical activity on depression biomarkers in older adults. This study aimed to investigate the effects of increased daily physical activity for 8 weeks on depression biomarkers in postmenopausal women. [Participants and Methods] Thirty-eight postmenopausal females were randomly assigned into a control or an active group and were asked to wear a uniaxial accelerometer for 8 weeks. Blood samples were obtained at baseline and at the end of the intervention. During the intervention, the active group was asked to increase their physical activity level above their usual lifestyle whereas those in the control group maintained their daily lifestyle. [Results] After the 8-week intervention, the step counts of the participants in the active group increased. The serum concentration of the brain-derived neurotrophic factor and serotonin increased significantly in the active group, but not in the control group, as compared with baseline values. The serum concentration of derivatives of reactive oxygen metabolites and biological antioxidant potential did not change after the intervention in either group. [Conclusion] These findings may suggest that promotion of daily physical activity in postmenopausal women has a positive impact on depression without any change in oxidative stress.


Association of DNA topoisomerase I and RNA polymerase I: a possible role for topoisomerase I in ribosomal gene transcription.
RNA polymerase I preparations purified from a rat hepatoma contained DNA topoisomerase activity. The DNA topoisomerase associated with the polymerase had an Mr of 110,000, required Mg2+ but not ATP, and was recognized by anti-topoisomerase I antibodies. When added to RNA polymerase I preparations containing topoisomerase activity, anti-topoisomerase I antibodies were able to inhibit the DNA relaxing activity of the preparation as well as RNA synthesis in vitro. RNA polymerase II prepared by analogous procedures did not contain topoisomerase activity and was not recognized by the antibodies. The topoisomerase I: polymerase I complex was reversibly dissociated by column chromatography on Sephacryl S200 in the presence of 0.25 M (NH4)2SO4. Topoisomerase I was immunolocalized in the transcriptionally active ribosomal gene complex containing RNA polymerase I in situ. These data indicate that topoisomerase I and RNA polymerase I are tightly complexed both in vivo and in vitro, and suggest a role for DNA topoisomerase I in the transcription of ribosomal genes.


Impairments in Food Oral Processing in Patients Treated for Tongue Cancer.
Patients surgically treated for oral cancer are affected by several underestimated deglutition disorders risk factors. This study aims to characterize the level of these food oral processing (FOP) impairments in a group of patients treated by surgery for tongue cancer. Twenty-seven consecutive patients surgically treated for tongue cancer were evaluated concerning their chewing capacity (Mastication-test), and responded to questions concerning their capacity to bite, chew and manipulate food with their tongue, and their quality of life. According to the Mastication-test, 16 patients suffered total FOP incapacities (TI group), characterized by high tumor stage, invasive carcinological surgery and necessity of reconstructive surgery; 12 patients were partially or not impaired (PI/NI-group). Tongue movement score and number of dental units were lower in the TI group than in the PI/NI-group. Subjective FOP criteria were clearly impaired in the TI group and correlated with a poor oral health-related quality of life. One year after surgery, there is a decrease in BMI for TI group patients while the PI group patients had a significant increase in BMI. All patients surgically treated for oral cancer suffered FOP impairments, but not with the same severity. Totally impaired subjects are at higher risk from long-term malnutrition. Functional evaluation of FOP should form part of the post-operative follow-up for all patients suffering from tongue cancer, using a quick combined evaluation of chewing efficiency, oral health quality of life and nutritional status.


Obesity and Outcomes of Kawasaki Disease and COVID-19-Related Multisystem Inflammatory Syndrome in Children.
Obesity may affect the clinical course of Kawasaki disease (KD) in children and multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. To compare the prevalence of obesity and associations with clinical outcomes in patients with KD or MIS-C. In this cohort study, analysis of International Kawasaki Disease Registry (IKDR) data on contemporaneous patients was conducted between January 1, 2020, and July 31, 2022 (42 sites, 8 countries). Patients with MIS-C (defined by Centers for Disease Control and Prevention criteria) and patients with KD (defined by American Heart Association criteria) were included. Patients with KD who had evidence of a recent COVID-19 infection or missing or unknown COVID-19 status were excluded. Patient demographic characteristics, clinical features, disease course, and outcome variables were collected from the IKDR data set. Using body mass index (BMI)/weight z score percentile equivalents, patient weight was categorized as normal weight (BMI <85th percentile), overweight (BMI ≥85th to <95th percentile), and obese (BMI ≥95th percentile). The association between adiposity category and clinical features and outcomes was determined separately for KD and MIS-C patient groups. Of 1767 children, 338 with KD (median age, 2.5 [IQR, 1.2-5.0] years; 60.4% male) and 1429 with MIS-C (median age, 8.7 [IQR, 5.3-12.4] years; 61.4% male) were contemporaneously included in the study. For patients with MIS-C vs KD, the prevalence of overweight (17.1% vs 11.5%) and obesity (23.7% vs 11.5%) was significantly higher (P < .001), with significantly higher adiposity z scores, even after adjustment for age, sex, and race and ethnicity. For patients with KD, apart from intensive care unit admission rate, adiposity category was not associated with laboratory test features or outcomes. For patients with MIS-C, higher adiposity category was associated with worse laboratory test values and outcomes, including a greater likelihood of shock, intensive care unit admission and inotrope requirement, and increased inflammatory markers, creatinine levels, and alanine aminotransferase levels. Adiposity category was not associated with coronary artery abnormalities for either MIS-C or KD. In this international cohort study, obesity was more prevalent for patients with MIS-C vs KD, and associated with more severe presentation, laboratory test features, and outcomes. These findings suggest that obesity as a comorbid factor should be considered at the clinical presentation in children with MIS-C.


Testing a behavioral intervention to improve adherence to adjuvant endocrine therapy (AET).
Adjuvant endocrine therapy (AET) is used to prevent recurrence and reduce mortality for women with hormone receptor positive breast cancer. Poor adherence to AET is a significant problem and contributes to increased medical costs and mortality. A variety of problematic symptoms associated with AET are related to non-adherence and early discontinuation of treatment. The goal of this study is to test a novel, telephone-based coping skills training that teaches patients adherence skills and techniques for coping with problematic symptoms (CST-AET). Adherence to AET will be assessed in real-time for 18 months using wireless smart pill bottles. Symptom interference (i.e., pain, vasomotor symptoms, sleep problems, vaginal dryness) and cost-effectiveness of the intervention protocol will be examined as secondary outcomes. Participants (N = 400) will be recruited from a tertiary care medical center or community clinics in medically underserved or rural areas. Participants will be randomized to receive CST-AET or a general health education intervention (comparison condition). CST-AET includes ten nurse-delivered calls delivered over 6 months. CST-AET provides systematic training in coping skills for managing symptoms that interfere with adherence. Interactive voice messaging provides reinforcement for skills use and adherence that is tailored based on real-time adherence data from the wireless smart pill bottles. Given the high rates of non-adherence and recent recommendations that women remain on AET for 10 years, we describe a timely trial. If effective, the CST-AET protocol may not only reduce the burden of AET use but also lead to cost-effective changes in clinical care and improve breast cancer outcomes. Trials registration: ClinicalTrials.gov, NCT02707471, registered 3/3/2016.


Normative spatiotemporal gait parameters in older adults.
While factor analyses have characterized pace, rhythm and variability as factors that explain variance in gait performance in older adults, comprehensive analyses incorporating many gait parameters have not been undertaken and normative data for many of those parameters are lacking. The purposes of this study were to conduct a factor analysis on nearly two dozen spatiotemporal gait parameters and to contribute to the normative database of gait parameters from healthy, able-bodied men and women over the age of 70. Data were extracted from 294 participants enrolled in the Mayo Clinic Study of Aging. Spatiotemporal gait data were obtained as participants completed two walks across a 5.6-m electronic walkway (GAITRite(®)). Five primary domains of spatiotemporal gait performance were identified: a "rhythm" domain was characterized by cadence and temporal parameters such as stride time; a "phase" domain was characterized by temporophasic parameters that constitute distinct divisions of the gait cycle; a "variability" domain encompassed gait cycle and step variability parameters; a "pace" domain was characterized by parameters that included gait speed, step length and stride length; and a "base of support" domain was characterized by step width and step width variability. Several domains differed between men and women and differed across age groups. Reference values of 23 gait parameters are presented which researchers or clinicians can use for assessing and interpreting gait dysfunction in aging persons.


The hypotensive effects of propofol at different sampling sites in cardiopulmonary bypass model.
Although propofol has been widely used the uncertainties about its pharmacokinetics and pharmacodynamics are still in existence especially on acute infusion model. This study was designed to observe the changes of the arterial and superior vena cava blood concentrations of propofol during cardiopulmonary bypass and to see whichever site is more appropriate for pharmacodynamic studies of propofol. Eight patients undergoing cardiopulmonary bypass were infused rapidly with propofol. Samples were collected concurrently from bypass arterial side (Ca) and superior vena cava (Cv) side at 0, 0.5, 1, 1.5, 2, 5, 10, 20, 30, and 40 minutes after infusion and analyzed with high pressure liquid chromatography (HPLC). Arterial blood pressure was also recorded at the same time. After administration, the concentration at Ca side was significantly higher than that at the corresponding Cv side from 0.5 to 5 min. The concentration at Ca side peaked at 0.5 min, then decreased rapidly and crossed the Cv curve at approximately 10 min. Thereafter Cv side concentration was slightly higher than that of Ca side. The mean arterial blood pressure decreased significantly from 1 to 20 min after injection. The change in Cv side was significantly consistent with the blood pressure change in the distribution phase (r = 0.78, r2 = 0.61 P < 0.001) (0 to 5 min). There was a significant arteriovenous concentration difference of propofol after a rapid infusion in the cardiopulmonary bypass model. The hypotensive effect of propofol in the distribution phase can be predicted better on Cv side.


Identification of risk factors for bleeding during treatment of acute venous thromboembolism with heparin or low molecular weight heparin.
In a prospective double-blind trial, we treated 194 patients with acute venous thromboembolism with heparin or low molecular weight heparin (LMWH; Fragmin). To evaluate the most important prognostic factors for bleeding, the presenting clinical features of the patients, the patients' anticoagulant responses, and the doses of the drugs were analyzed using univariate and multivariate regression analyses. No significant differences in clinical risk factors associated with bleeding were observed between heparin and LMWH. The univariate analyses ranked the parameters in the following order of importance: World Health Organization (WHO) performance status, history of bleeding tendency, cardiopulmonary resuscitation, recent trauma or surgery, leukocyte counts, platelet counts, duration of symptoms, and body surface area. Patients with WHO grade 4 had an eightfold increase in risk of bleeding as compared with WHO grade 1. Assessment of the individual contribution of each variable using multivariate regression analysis showed that the WHO performance status was the most important independent factor predicting major bleeding. A history of a bleeding tendency, recent trauma or surgery, and body surface area were also independent risk factors. The risk of bleeding was influenced by two factors related to the treatment, the patient's anticoagulant response as measured with the anti-Xa assay and the dose of the drug expressed as U/24 h/m2. An increased risk of bleeding was only observed at mean anti-Xa levels greater than 0.8 U/mL for both drugs. Significantly more major bleedings occurred in patients treated with high doses of the drugs, an observation that was independent of the concomitant anti-Xa levels. It should be considered whether choosing an appropriate initial dose adapted to the patient's body surface area and clinical risk factors can improve the efficacy to safety ratio of heparin treatment.


Bacopa monnieri (L.) exerts anti-inflammatory effects on cells of the innate immune system in vitro.
Bacopa monnieri (L., BM) is a traditional Ayurvedic medicinal herb recognised for its efficacy in relieving acute pain and inflammation, as related to selective inhibition of cyclo-oxygenase-2 (COX-2) enzyme and consequent reduction in COX-2-mediated prostanoid mediators. BM is also associated with cognitive enhancing (nootropic) activity including improving memory free recall, observed after prolonged intake (>3 months). It is likely that the time frame required to exert an effect in the brain reflects regulation by BM of chronic inflammation and oxidative stress associated with aging and chronic diseases, and other polypharmacological effects. We report down-regulation by BM of NO and TNF-α in stimulated RAW 246.7 macrophages and of IFN-γ in stimulated human blood cells. Furthermore, in human blood cells, IL-10 was slightly elevated indicating polarisation towards a regulatory T cell phenotype. These results provide further supportive evidence to justify the clinical evaluation of BM for managing diseases involving chronic systemic and brain inflammation driven by the innate immune system.


Environmental and genetic determinants of tobacco use: methodology for a multidisciplinary, longitudinal family-based investigation.
This article describes the ongoing collaborative effort of six research teams to operationalize and execute an integrative approach to the study of gene x environment interactions in the development of tobacco dependence. At the core of the project is a longitudinal investigation of social and behavioral risk factors for tobacco use in individuals who were, on average, 13 years of age at intake and for whom smoking outcomes extending from early adolescence to young adulthood have been characterized previously (current average age of the cohort is 29 years). The conceptual framework for the integrative approach and the longitudinal investigation on which the study is based is presented. A description is also provided of the methods used to: (a) recruit participants and families to provide DNA samples and information on tobacco use; (b) assess participants for relevant tobacco-related phenotypes including smoking history, current use of tobacco, and nicotine metabolism; (c) assess the quality of the DNA samples collected from participants for genome-wide scanning and candidate gene analysis; (d) examine several research questions concerning the role of genetic and environmental factors in the onset and maintenance of tobacco use; and (e) ensure adherence to local and federal guidelines for ethical and legal investigations of genotypic associations with tobacco-related phenotypes in families. This investigation is unique among ongoing studies of the genetics of tobacco dependence in the extent to which equal importance has been assigned to both phenotypic and genotypic measurements.


Gradients in fiber shortening and metabolism across ischemic left ventricular wall.
Blood flow, metabolism, and fiber shortening in various layers of left ventricular wall were studied during the initial 5 min of ischemia. In open-chest dogs (n = 51) ischemia was induced by coronary arterial stenosis (median value of mean perfusion pressure distal to stenosis 3.3 kPa). Epicardial deformation measurements with an inductive technique allowed estimation of fiber shortening in inner (eendo,est) and outer layers (eepi) of left ventricular free wall during the ejection phase. The decrease of eendo,est occurred within a few seconds after onset of stenosis, whereas eepi started to decrease 30 s later. After 1 min, eendo,est diminished to zero concomitantly with a reduction of blood flow and creatine phosphate content in the inner layers by 68 and 46%, respectively. In contrast a 60% reduction of eepi was associated with a decrease in blood flow of only 32% and no significant decrease in creatine phosphate in the outer layers. H+ and inorganic phosphate were released simultaneously into the local venous blood starting within 1 min of ischemia. During the initial 5 min of ischemia the content of ATP and glycogen remained unchanged across the ischemic wall. Present results indicate that the decrease of fiber shortening in the inner layers is associated with severe metabolic dearrangements, as reflected by the depletion of creatine phosphate. They also indicate that, during coronary arterial stenosis, impaired fiber shortening in the outer layers may result from the impairment of mechanical function in the inner layers, rather than from metabolic disturbances in the outer layers themselves.


Combined pulmonary fibrosis and emphysema in connective tissue disease.
This review discusses combined pulmonary fibrosis and emphysema (CPFE) in the setting of connective tissue disease. CPFE is a recently identified syndrome in smokers or ex-smokers characterized by dyspnea often severe, preserved lung volumes, severely impaired gas exchanges, and an increased risk of pulmonary hypertension associated with a dismal prognosis, and possibly lung cancer. It may be encountered in the setting of connective tissue diseases, especially rheumatoid arthritis and systemic sclerosis, with generally similar features as 'idiopathic' (tobacco-related) CPFE. The diagnosis is based on the presence of both emphysema predominating in the upper lobes and frequently paraseptal, and interstitial abnormalities suggesting pulmonary fibrosis in the lower lung zones with velcro crackles at auscultation. Pathologic radiological correlations are difficult owing to various pathology and difficulties in identifying honeycombing at chest high-resolution computed tomography in the setting of coexistent emphysema. Tobacco smoking is associated with an increased risk of developing most of the individual components of the syndrome (i.e. emphysema, pulmonary fibrosis, pulmonary hypertension, rheumatoid arthritis, and pulmonary fibrosis among patients with rheumatoid arthritis). CPFE impacts modalities of follow-up for pulmonary function and detection of pulmonary hypertension especially in systemic sclerosis. The syndrome of CPFE is a distinct pulmonary manifestation in the spectrum of lung diseases associated with connective tissue diseases, especially in smokers or ex-smokers.


The Multifaceted Role of Macrophages in Oncolytic Virotherapy.
One of the cancer hallmarks is immune evasion mediated by the tumour microenvironment (TME). Oncolytic virotherapy is a form of immunotherapy based on the application of oncolytic viruses (OVs) that selectively replicate in and induce the death of tumour cells. Virotherapy confers reciprocal interaction with the host's immune system. The aim of this review is to explore the role of macrophage-mediated responses in oncolytic virotherapy efficacy. The approach was to study current scientific literature in this field in order to give a comprehensive overview of the interactions of OVs and macrophages and their effects on the TME. The innate immune system has a central influence on the TME; tumour-associated macrophages (TAMs) generally have immunosuppressive, tumour-supportive properties. In the context of oncolytic virotherapy, macrophages were initially thought to predominantly contribute to anti-viral responses, impeding viral spread. However, macrophages have now also been found to mediate transport of OV particles and, after TME infiltration, to be subjected to a phenotypic shift that renders them pro-inflammatory and tumour-suppressive. These TAMs can present tumour antigens leading to a systemic, durable, adaptive anti-tumour immune response. After phagocytosis, they can recirculate carrying tissue-derived proteins, which potentially enables the monitoring of OV replication in the TME. Their role in therapeutic efficacy is therefore multifaceted, but based on research applying relevant, immunocompetent tumour models, macrophages are considered to have a central function in anti-cancer activity. These novel insights hold important clinical implications. When optimised, oncolytic virotherapy, mediating multifactorial inhibition of cancer immune evasion, could contribute to improved patient survival.


Evaluating time points for measuring recovery after major trauma in adults.
To evaluate recovery after major trauma over a 24-month time frame. Measuring disability after injury is seen as increasingly important but requires knowledge not only of the measures that should be implemented but also of the critical time points for follow-up. Six hundred sixty-two adult major trauma patients from 2 level 1 trauma centers (October 2006 to March 2007) were followed up by telephone at 6-, 12-, 18-, and 24 months after injury. SF-12, Glasgow Outcome Scale-Extended (GOS-E), pain scores, and return to work (RTW) were collected. Multilevel mixed-effects regression models were fitted to analyze change in outcomes over time. Six hundred seventeen (93%) were followed up for at least 1 time point. Functional recovery (GOS-E = 8) [odds ratio (OR) 3.1, 95% CI: 1.9, 5.0] and RTW (OR 2.4, 95% CI: 1.4, 4.0) improved, and physical health (PCS-12) scores were better (mean difference 1.9, 95% CI: 0.9, 2.9), from 6 to 12 months after injury, but changed little from 12 months. Pain scores were unchanged from 6 to 12 months but were higher at 18 months than at 12 months (OR 1.8, 95% CI: 1.2, 2.8). SF-12 mental health (MCS-12) scores decreased until 18 months but improved from 18 to 24 months (mean difference 1.5, 95% CI: 0.2, 2.8). The rate of recovery differed by injury group and age. Different patterns of recovery were evident for each outcome, and there was a variation in the rate of recovery for some subgroups. The selection of time points for follow-up requires consideration of the outcome measurements of interest and the population being studied.


Prioritization of Medical Errors in Patient Safety Management: Framework Using Interval-Valued Intuitionistic Fuzzy Sets.
Medical errors negatively affect patients, healthcare professionals, and healthcare establishments. Therefore, all healthcare service members should be attentive to medical errors. Research has revealed that most medical errors are caused by the system, rather than individuals. In this context, guaranteeing patient safety and preventing medical faults appear to be basic elements of quality in healthcare services. Healthcare institutions can create internal regulations and follow-up plans for patient safety. While this is beneficial for the dissemination of patient safety culture, it poses difficulties in terms of auditing. On the other hand, the lack of a standard patient safety management system, has led to great variation in the quality of the provided service among hospitals. Therefore, this study aims to create an index system to create a standard system for patient safety by classifying medical errors. Due to the complex nature of healthcare and its processes, interval-valued intuitionistic fuzzy logic is used in the proposed index system. Medical errors are prioritized, based on the index scores that are generated by the proposed model. Because of this systematic study, not only can the awareness of patient safety perception be increased in health institutions, but their present situation can also be displayed, on the basis of each indicator. It is expected that the outcomes of this study will motivate institutions to identify and prioritize their future improvements in the patient safety context.


Isolation and identification of ecdysteroid phosphates and acetylecdysteroid phosphates from developing eggs of the locust, Schistocerca gregaria.
Maturing eggs of the desert locust, Schistocerca gregaria, contain a variety of ecdysteroid (insect moulting hormone) conjugates and metabolites, four of which have been previously isolated from polar extracts and identified as ecdysonoic acid, 20-hydroxyecdysonoic acid, 3-acetylecdysone 2-phosphate and ecdysone 2-phosphate. In the present study we have isolated eight additional ecdysteroids from similar late-stage eggs by high-performance liquid chromatography. The 22-phosphate esters of ecdysone, 2-deoxyecdysone, 20-hydroxyecdysone and 2-deoxy-20-hydroxyecdysone, all of which were first identified as ecdysteroid components of newly-laid eggs of S. gregaria, were identified by co-chromatography with authentic compounds and by physicochemical techniques. The remaining compounds were identified as 3-acetyl-20-hydroxyecdysone 2-phosphate, 3-epi-2-deoxyecdysone 3-phosphate, 3-acetylecdysone 22-phosphate and 2-acetylecdysone 22-phosphate by fast atom bombardment mass spectrometry, p.m.r. spectroscopy and analysis of the steroid moieties after enzymic hydrolysis. The latter two compounds, after isolation, are susceptible to nonenzymic acetyl migration and deacetylation to give mixtures of ecdysone 22-phosphate and its 2- and 3-acetate derivatives. The possible role and significance of these ecdysteroid conjugates with respect to the control of hormone titres in insect eggs is discussed.


Keeping the (kinase) party going: SLP-76 and ITK dance to the beat.
The Tec-family protein tyrosine kinase IL-2-inducible T cell kinase (ITK) mediates T cell activation, as does the adaptor protein SLP-76 (SH2-domain-containing leukocyte protein of 76 kD), which forms a complex with ITK and other intracellular signaling enzymes. One of these enzymes is phospholipase C-gamma1 (PLC-gamma1), which mediates T cell receptor (TCR)-stimulated intracellular calcium mobilization leading to the activation of transcription factors such as nuclear factor of activated T cells. The Src-family tyrosine kinase Lck and the Syk-family tyrosine kinase zeta chain-associated protein kinase of 70 kD (ZAP-70), together with ITK, are necessary for the phosphorylation of PLC-gamma1 in response to TCR stimulation. ITK is thought to phosphorylate a specific tyrosine residue of PLC-gamma1 that is required for its activation. The mechanism of activation of ITK appears to involve the interaction between SLP-76 and ITK, which not only initiates ITK activity but is also important to maintain the kinase activity of ITK. This suggests that SLP-76 acts as more than a neutral adaptor in mediating T cell activation; SLP-76 also directly influences the kinase activity of ITK, allowing ITK to phosphorylate PLC-gamma1.


On the impact of discreteness and abstractions on modelling noise in gene regulatory networks.
In this paper, we explore the impact of different forms of model abstraction and the role of discreteness on the dynamical behaviour of a simple model of gene regulation where a transcriptional repressor negatively regulates its own expression. We first investigate the relation between a minimal set of parameters and the system dynamics in a purely discrete stochastic framework, with the twofold purpose of providing an intuitive explanation of the different behavioural patterns exhibited and of identifying the main sources of noise. Then, we explore the effect of combining hybrid approaches and quasi-steady state approximations on model behaviour (and simulation time), to understand to what extent dynamics and quantitative features such as noise intensity can be preserved.


Degenerative cervical myelopathy: Diagnosis and management in primary care.
To raise awareness about degenerative cervical myelopathy (DCM) and to help family physicians identify, diagnose, and manage DCM more effectively. A PubMed search was conducted for articles published between 1970 and October 2017, using the terms cervical myelopathy and degenerative spinal cord injury with family medicine or primary care. Owing to limited knowledge of DCM in primary care, along with the large variability of the disease, the diagnosis of DCM is often missed or delayed. The natural course of DCM presents as a stepwise decline, with symptoms ranging from muscle weakness to complete paralysis. All individuals with signs and symptoms should be referred to a spine surgeon for consideration of surgery; those with mild DCM might be offered conservative treatment but should receive a surgical evaluation and opinion nonetheless. Asymptomatic patients with evidence of cord compression on magnetic resonance imaging might need to be referred for assessment; however, surgery is not advised. It is critical to closely monitor asymptomatic individuals or those with mild DCM for neurologic deterioration. Degenerative cervical myelopathy is the most common cause of spinal cord dysfunction in adults. This review helps streamline its diagnosis in primary care, allowing for improved chances of early diagnosis and prevention of further neurologic decline among patients.


King and Pennel's free graft series: a defining moment revisited.
The free gingival graft is one of the most versatile and predictable procedures in current use. A review of the significant contributions leading to this procedure is presented. Reports of the free graft series of King and Pennel, as well as the reaction to its initial presentation by members of the Philadelphia Society of Periodontology, are introduced to the dental literature. The chronology of events leading to the rediscovery of the gingival graft procedure in the early 1960s suggests independent and nearly simultaneous clinical innovation took place in Sweden and the United States. Therefore, though fully acknowledging Hilding Björn's seminal contribution, substantial credit must be given to colleagues King and Pennel for introducing the gingival graft procedure to periodontics.


Symptomatic sclerosing haemangioma: a rare case of solitary pulmonary nodule in a young girl.
Sclerosing haemangioma (SH) is a rare benign lung tumour with distinctive variety of histological patterns. SH typically presents as asymptomatic peripheral, solitary well-circumscribed lesion in women with median age at diagnosis in the fifth decade. Preoperative diagnosis of this tumour is difficult, and sometimes even intraoperative frozen sections cannot differentiate it from malignant tumours. Here, we present our experiences in investigating its characteristics. We report a case of a 19-year-old girl who presented with chest pain, cough and sputum and off and on haemoptysis for 6 months. Anti-tubercular treatment was given but provided no relief. CT chest showed a well-defined hypodense solid mass lesion with a soft tissue alternation. Lobectomy was performed. Microscopy revealed a tumour comprising of two distinct populations of cells surface and stromal cells which disposed in papillary, solid, sclerotic and haemorrhagic growth patterns. Histology and immunohistochemistry confirmed the diagnosis of SH of the lung.


Preclinical Studies for Cartilage Repair: Recommendations from the International Cartilage Repair Society.
Investigational devices for articular cartilage repair or replacement are considered to be significant risk devices by regulatory bodies. Therefore animal models are needed to provide proof of efficacy and safety prior to clinical testing. The financial commitment and regulatory steps needed to bring a new technology to clinical use can be major obstacles, so the implementation of highly predictive animal models is a pressing issue. Until recently, a reductionist approach using acute chondral defects in immature laboratory species, particularly the rabbit, was considered adequate; however, if successful and timely translation from animal models to regulatory approval and clinical use is the goal, a step-wise development using laboratory animals for screening and early development work followed by larger species such as the goat, sheep and horse for late development and pivotal studies is recommended. Such animals must have fully organized and mature cartilage. Both acute and chronic chondral defects can be used but the later are more like the lesions found in patients and may be more predictive. Quantitative and qualitative outcome measures such as macroscopic appearance, histology, biochemistry, functional imaging, and biomechanical testing of cartilage, provide reliable data to support investment decisions and subsequent applications to regulatory bodies for clinical trials. No one model or species can be considered ideal for pivotal studies, but the larger animal species are recommended for pivotal studies. Larger species such as the horse, goat and pig also allow arthroscopic delivery, and press-fit or sutured implant fixation in thick cartilage as well as second look arthroscopies and biopsy procedures.


Single-event multilevel surgery in children with spastic diplegia: a pilot randomized controlled trial.
Single-event multilevel surgery is considered the standard of care to improve gait and functioning of children with spastic diplegic cerebral palsy. However, the evidence base is limited. This pilot study is the first randomized controlled trial of single-event multilevel surgery, to our knowledge. Nineteen children (twelve boys and seven girls with a mean age of nine years and eight months) with spastic diplegia were enrolled. Eleven children were randomized to the surgical group and eight, to the control group. The control group underwent a program of progressive resistance strength training. The randomized phase of the trial concluded at twelve months. The control group then exited the study and progressed to surgery, whereas the surgical group continued to be followed in a prospective cohort study. The primary outcome measures were the Gait Profile Score (GPS) and the Gillette Gait Index (GGI). Secondary outcome measures were gross motor function (Gross Motor Function Measure-66 [GMFM-66]), functional mobility (Functional Mobility Scale [FMS]), time spent in the upright position, and health-related quality of life (Child Health Questionnaire [CHQ]). A total of eighty-five surgical procedures were performed, with a mean of eight procedures per child (standard deviation, four). The surgical group had a 34% improvement in the GPS and a 57% improvement in the GGI at twelve months. The control group had a small nonsignificant deterioration in both indices. The between-group differences for the change in the GPS (-5.5; 95% confidence interval, -7.6 to -3.4) and the GGI (-218; 95% confidence interval, -299 to -136) were highly significant. The differences between the groups with regard to the secondary outcome measures were not significant at twelve months. At twenty-four months after surgery, there was a 4.9% increase in the GMFM-66 score and improvements in the FMS score, time spent in the upright position, and the physical functioning domain of the CHQ in the surgical group. This study provides Level-II evidence that single-event multilevel surgery improves the gait of children with spastic diplegic cerebral palsy twelve months after surgery. Improvements in other domains, including gross motor function and quality of life, were not observed until twenty-four months after surgery.


Insulin resistance syndrome blunts the mitochondrial anabolic response following resistance exercise.
Metabolic risk factors associated with insulin resistance syndrome may attenuate augmentations in skeletal muscle protein anabolism following contractile activity. The purpose of this study was to investigate whether or not the anabolic response, as defined by an increase in cumulative fractional protein synthesis rates (24-h FSR) following resistance exercise (RE), is blunted in skeletal muscle of a well-established rodent model of insulin resistance syndrome. Four-month-old lean (Fa/?) and obese (fa/fa) Zucker rats engaged in four lower body RE sessions over 8 days, with the last bout occurring 16 h prior to muscle harvest. A priming dose of deuterium oxide ((2)H(2)O) and (2)H(2)O-enriched drinking water were administered 24 h prior to euthanization for assessment of cumulative FSR. Fractional synthesis rates of mixed (-5%), mitochondrial (-1%), and cytosolic (+15%), but not myofibrillar, proteins (-16%, P = 0.012) were normal or elevated in gastrocnemius muscle of unexercised obese rats. No statistical differences were found in the anabolic response of cytosolic and myofibrillar subfractions between phenotypes, but obese rats were not able to augment 24-h FSR of mitochondria to the same extent as lean rats following RE (+14% vs. +28%, respectively). We conclude that the mature obese Zucker rat exhibits a mild, myofibrillar-specific suppression in basal FSR and a blunted mitochondrial response to contractile activity in mixed gastrocnemius muscle. These findings underscore the importance of assessing synthesis rates of specific myocellular subfractions to fully elucidate perturbations in basal protein turnover rates and differential adaptations to exercise stimuli in metabolic disease.


Elevated VGKC-complex antibodies in a boy with fever-induced refractory epileptic encephalopathy in school-age children (FIRES).
Fever-induced refractory epileptic encephalopathy in school-age children (FIRES) is a clinically recognized epileptic encephalopathy of unknown aetiology. Presentation in previously healthy children is characterized by febrile status epilepticus. A pharmacoresistant epilepsy ensues, occurring in parallel with dramatic cognitive decline and behavioural difficulties. We describe a case of FIRES in a 4-year-old boy that was associated with elevated voltage-gated potassium channel (VGKC) complex antibodies and a significant clinical and immunological response to immunomodulation. This case, therefore, potentially expands the clinical phenotype of VGKC antibody-associated disease to include that of FIRES. Prior to immunomodulation, neuropsychology assessment highlighted significant attention, memory, and word-finding difficulties. The UK version of the Wechsler Preschool and Primary Scale of Intelligence assessment indicated particular difficulties with verbal skills (9th centile). Immunomodulation was initially administered as intravenous methylprednisolone (followed by maintenance oral prednisolone) and later in the disease course as regular monthly intravenous immunoglobulin infusions and low-dose azathioprine. Now aged 6 years, the seizure burden in this child is much reduced, although increased seizure frequency is observed in the few days before his monthly immunoglobulin infusions. Formal IQ assessment has not been repeated but there is no clinical suggestion of further cognitive regression. VGKC complex antibodies have been reported in a range of central and peripheral neurological disorders (predominantly presenting in adulthood), and the identification of elevated VGKC complex antibodies, combined with the response to immunotherapies in this child, supports an autoimmune pathogenesis in FIRES with potential diagnostic and therapeutic implications.


Aromatic alpha-glycosides of mannose are powerful inhibitors of the adherence of type 1 fimbriated Escherichia coli to yeast and intestinal epithelial cells.
Adherence of bacteria via their surface lectins to host epithelial cells is considered an important initial event in bacterial pathogenesis. Mannose-specific (type 1) fimbriae are among the most commonly found lectins in enterobacteria. We studied the effect of aromatic alpha-glycosides of mannose on the agglutination of mannan-containing yeasts by different strains of Escherichia coli and on the adherence of the bacteria to guinea pig ileal epithelial cells. In both systems these compounds were considerably more effective inhibitors than methyl alpha-mannoside, with 4-methylumbelliferyl alpha-mannoside and p-nitro-o-chlorophenyl alpha-mannoside being the strongest inhibitors. Both compounds were approximately 400-times stronger inhibitors of yeast agglutination by E. coli O128 than was methyl alpha-mannoside and 1,000- and 470-fold stronger, respectively, than was methyl alpha-mannoside in inhibiting the adherence of the bacteria to ileal epithelial cells. 4-Methylumbelliferyl alpha-mannoside was 540 to 1,000 times more effective in inhibiting yeast agglutination by four additional strains of mannose-specific E. coli. It was also more efficient than methyl alpha-mannoside in removing adherent E. coli O128 from ileal epithelial cells. Our results provide further evidence that type 1 fimbriae of E. coli possess a hydrophobic region next to the mannose-binding site. The results suggest that 4-methylumbelliferyl alpha-mannoside and p-nitro-o-chlorophenyl alpha-mannoside are good candidates for the design of therapeutic agents that may prevent adherence in vivo and infection by E. coli strains that express type 1 fimbriae.


Distribution and determinants of sedentary lifestyles in the European Union.
Many studies have shown the health burden of a sedentary lifestyle. The main goal of this study was to determine the prevalence of sedentary lifestyles in the 15 Member States of the European Union (EU) and to identify the main correlates of a sedentary lifestyle. Nationally representative samples (n approximately 1000 subjects in each country; >15 years) completed a questionnaire concerning attitudes to physical activity, body weight, and health; in total 15 239 subjects. Sedentary people were defined in two ways: (1) those expending less than 10% of their leisure time expenditure in activities involving >/=4 metabolic equivalents (MET). (2) Those who did not practice any leisure-time physical activity and who also were above the median in the number of hours spent sitting down during leisure time. Logistic regression models were fitted to analyse the association between sedentary lifestyles and gender, age, body mass index (BMI), educational level, weight change in the last 6 months, and marital and smoking status. Percentages of sedentary lifestyles across European countries ranged between 43.3% (Sweden) and 87.8% (Portugal) according to the first definition. According to both definitions, a lower prevalence of sedentary lifestyle was found in Northern countries (especially Scandinavian countries) as compared with Mediterranean countries, whereas the prevalence was higher among older, obese, less educated, widowed/divorced individuals, and current smokers. Similar relative differences between countries and socio-demographic groups were found independently of the method used to define a sedentary lifestyle. Prevalence of sedentary lifestyle in the EU is high, especially among inhabitants of some Mediterranean countries, obese subjects, less-educated people, and current smokers. This high prevalence involves important public health burdens and preventive strategies are urgently needed.


The OBELIX project: early life exposure to endocrine disruptors and obesity.
The hypothesis of whether early life exposure (both pre- and early postnatal) to endocrine-disrupting chemicals (EDCs) may be a risk factor for obesity and related metabolic diseases later in life will be tested in the European research project OBELIX (OBesogenic Endocrine disrupting chemicals: LInking prenatal eXposure to the development of obesity later in life). OBELIX is a 4-y project that started in May 2009 and which has the following 5 main objectives: 1) to assess early life exposure in humans to major classes of EDCs identified as potential inducers of obesity (ie, dioxin-like compounds, non-dioxin-like polychlorinated biphenyls, organochlorine pesticides, brominated flame retardants, phthalates, and perfluorinated compounds) by using mother-child cohorts from 4 European regions with different food-contaminant exposure patterns; 2) to relate early life exposure to EDCs with clinical markers, novel biomarkers, and health-effect data related to obesity; 3) to perform hazard characterization of early life exposure to EDCs for the development of obesity later in life by using a mouse model; 4) to determine mechanisms of action of obesogenic EDCs on developmental programming with in vivo and in vitro genomics and epigenetic analyses; and 5) to perform risk assessments of prenatal exposure to obesogenic EDCs in food by integrating maternal exposure through food-contaminant exposure and health-effect data in children and hazard data in animal studies.


Using nutritional indices to study LOX3-dependent insect resistance.
Induced resistance to biotic attackers is thought to be mediated by responses elicited by jasmonic acid (JA), a subset of which are lipoxygenase 3 (LOX3) dependent. To understand the importance of LOX3-mediated insect resistance, we analysed the performance of Manduca sexta larvae on wild-type (WT) and on isogenic Nicotiana attenuata plants silenced in NaLOX3 expression and JA signalling, and we used Waldbauer nutritional indices to measure the pre- and post-ingestive effects. LOX3-mediated defenses reduced larval growth, consumption and frass production. These defenses reduced how efficiently late-instar larvae converted digested food to body mass (ECD). In contrast, LOX3-mediated defenses decreased approximate digestibility (AD) in early instar larvae without affecting the ECD and total food consumption. Larvae of all instars feeding on defended WT plants behaviourally compensate for their reduced body mass by consuming more food per unit of body mass gain. We suggest that larvae feeding on plants silenced in NaLOX3 expression (as-lox) initially increase their AD, which in turn enables them to consume more food in the later stages and consequently, to increase their ECD and efficiency of conversion of ingested food (ECI). We conclude that N. attenuata's oxylipin-mediated defenses are important for resisting attack from M. sexta larvae, and that Waldbauer nutritional assays reveal behavioural and physiological counter responses of insects to these plant defenses.


First-trial protective step performance before and after short-term perturbation practice in people with Parkinson's disease.
Protective steps are critical for fall prevention and are altered in people with Parkinson's disease (PD). Previous work suggests that perturbation training, in which patients are exposed to repeated slips, may improve protective postural responses. However, these studies typically take the average performance of several postural responses before and after training. To reduce falls in the community, training must improve protective stepping after the first perturbation exposure. To date, no investigations have examined whether first-trial protective stepping is improved after training in people with PD. First-trial protective stepping was measured in 14 people with PD and 9 healthy adults before and 24 h after 1 day of perturbation training. The primary outcome was margin of stability after a perturbation, a measure of protective stepping effectiveness. Margin of stability for the first perturbation was significantly (p = 0.001) improved on day 2 compared to before perturbation practice (day 1) in both groups. Furthermore, improvement in margin of stability was correlated with age and baseline stepping performance, such that older individuals and people with worse baseline performance showed the most pronounced improvement. Improving the first loss of balance after training is critical if such training is to reduce falls in people with PD. The observed improvement in first-trial protective stepping provides further support for perturbation training as a potential tool to improve protective steps and reduce falls in people with PD.


Thienopyridine derivatives (ticlopidine, clopidogrel) versus aspirin for preventing stroke and other serious vascular events in high vascular risk patients.
The most widely studied and prescribed antiplatelet agent for the prevention of stroke and other serious vascular events among high vascular risk patients is aspirin. Aspirin inhibits platelet activation by inhibiting platelet cyclooxygenase and thromboxane production, and reduces the odds of a serious vascular event by about a quarter. The thienopyridines (ticlopidine and clopidogrel) inhibit platelet activation by a different mechanism to aspirin (blocking the ADP receptor on platelets), and so may be more effective than aspirin. The objective of this review was to determine the effectiveness and safety of thienopyridine derivatives (ticlopidine and clopidogrel) versus aspirin for the prevention of serious vascular events (stroke, myocardial infarction (MI) or vascular death) in patients at high risk of such events, and specifically in patients with a previous TIA or ischaemic stroke. We searched the Cochrane Stroke Group trials register (most recent search: March 1999) and the Antithrombotic Trialists' database, and also contacted Sanofi pharmaceutical company. All unconfounded, double blind, randomised trials directly comparing ticlopidine or clopidogrel with aspirin in high vascular risk patients. Two reviewers independently extracted data and assessed trial quality. Additional data were sought from the principal investigators of the largest trial. Four trials involving a total of 22,656 high vascular risk patients were included. The trials were of high quality and comparable. Aspirin was compared with ticlopidine in three trials (3471 patients) and with clopidogrel in one trial (19,185 patients). Allocation to a thienopyridine was associated with a modest, yet statistically significant, reduction in the odds of a serious vascular event (12. 0% vs 13.0%; OR: 0.91, 95% CI: 0.84 to 0.98; 2p = 0.01), corresponding to the avoidance of 11 (95% CI: 2 to 19) serious vascular events per 1000 patients treated for about two years. There was also a reduction in stroke (5.7% vs 6.4%; OR: 0.88, 95% CI: 0.79 to 0.98; 7 [95% CI: 1 to 13] strokes avoided per 1000 patients treated for two years). Compared with aspirin, thienopyridines produced a significant reduction in the odds of gastrointestinal haemorrhage and other upper gastrointestinal upset, but a significant increase in the odds of skin rash and of diarrhoea. However, the increased odds of skin rash and diarrhoea were greater for ticlopidine than for clopidogrel. Allocation to ticlopidine, but not clopidogrel, was associated with a significant increase in the odds of neutropenia (2.3% vs 0.8%; OR: 2.7, 95% CI: 1.5 to 4.8). In the subset of patients with TIA/ischaemic stroke, the results were similar to those for all patients combined. However, since these patients are at particularly high risk of stroke, allocation to a thienopyridine was associated with a larger absolute reduction in stroke (10.4% vs 12.0%; OR: 0.86, 95% CI: 0.75 to 0.97; 16 [95% CI: 3 to 28] strokes avoided per 1000 patients treated for two years). The available randomised evidence shows that the thienopyridine derivatives are modestly but significantly more effective than aspirin in preventing serious vascular events in patients at high risk (and specifically in TIA/ischaemic stroke patients), but there is uncertainty about the size of the additional benefit. The thienopyridines are also associated with less gastrointestinal haemorrhage and other upper gastrointestinal upset than aspirin, but an excess of skin rash and diarrhoea. The risk of skin rash and diarrhoea is greater with ticlopidine than with clopidogrel. Ticlopidine, but not clopidogrel, is associated with an excess of neutropenia and of thrombotic thrombocytopenic purpura.


The Social Prioritization Index and Tobacco Use Among Young Adult Bar Patrons.
Social benefits likely play a role in young adult tobacco use. The Social Prioritization Index (SPI) was developed to measure the degree to which young adults place a great importance on their social lives. We examined the usefulness of this measure as a potential predictor of tobacco use controlling for demographics and tobacco-related attitudes. Young adults completed cross-sectional surveys between 2012 and 2014 in bars in seven U.S. cities (N = 5,503). The SPI is a 13-item scale that includes personality items and information on how frequently participants attend bars and how late they stay out. Three step-by-step multinomial regression models were run using the SPI as a predictor of smoking status (nondaily and daily smoking vs. nonsmoking): (1) SPI as the sole predictor, (2) SPI and demographics, and (3) SPI, demographics, and tobacco-related attitude variables. Next, we conducted an exploratory factor analysis to examine if the number of items in SPI could be reduced and retain its strong relationship with smoking. Higher scores on the SPI were related to an increased probability of being a Nondaily Smoker (odds ratio = 1.09, 95% confidence interval [1.04, 1.14], p < .001) or Daily Smoker (odds ratio = 1.14, 95% confidence interval [1.07, 1.22], p < .0001) compared to a Nonsmoker, controlling for demographics and other tobacco-related attitudes. The SPI and reduced SPI were independently related to young adult tobacco use. The measure's brevity, ease of use, and strong association with tobacco use may make it useful to tobacco and other prevention researchers.


Direct actions of angiopoietin-1 on human endothelium: evidence for network stabilization, cell survival, and interaction with other angiogenic growth factors.
Angiopoietin-1 (Ang-1) is a recently described angiogenic protein that activates the endothelial Tie 2 receptor. Disruption of the Ang-1 gene shows that it has an indispensable role in blood vessel development, but it is not clear what specific effects, if any, Ang-1 has on endothelial cell (EC) phenotypes. Here, we show that Ang-1 dose-dependently stabilizes HUVEC network organization for up to 48 hours; this action of Ang-1 is dependent on Tie-2 receptor activation, because a soluble form of the Tie2-, but not the Tie1-receptor, completely blocks the effects of Ang-1. Moreover, we show that Ang-1 potentiates the actions of other angiogenic growth factors. Ang-1 markedly increases the survival of vascular networks (up to 96 hours) exposed to either vascular endothelial growth factor or endothelial cell growth supplement, a form of acidic fibroblast growth factor. In addition, Ang-1 prevents apoptotic death in HUVEC triggered by withdrawal of endothelial cell growth supplement. Collectively, these data are consistent with the idea that Ang-1 directly acts on human EC and interacts with other angiogenic molecules to stabilize vascular structures by promoting the survival of differentiated ECs.


Combined density functional theory and Landauer approach for hole transfer in DNA along classical molecular dynamics trajectories.
We investigate in detail the charge transport characteristics of DNA wires with various sequences and lengths in the presence of solvent. Our approach combines large-scale quantum/classical molecular dynamics (MD) simulations with transport calculations based on Landauer theory. The quantum mechanical transmission function of the wire is calculated along MD trajectories and thus encodes the influence of dynamical disorder arising from the environment (water, backbone, counterions) and from the internal base dynamics. We show that the correlated fluctuations of the base pair dynamics are crucial in determining the transport properties of the wire and that the effect of fluctuations can be quite different for sequences with low and high static disorders (differences in base ionization potentials). As a result, in structures with high static disorder as is the case of the studied Dickerson dodecamer, the weight of high-transmissive structures increases due to dynamical fluctuations and so does the calculated average transmission. Our analysis further supports the basic intuition of charge-transfer active conformations as proposed by Barton et al. [J. Am. Chem. Soc. 126, 11471 (2004)]. However, not DNA conformations with good stacking contacts leading to large interbase hopping values are necessarily the most important, but rather those where the average fluctuation of ionization potentials along the base stack is small. The reason behind this is that the ensemble of conformations leads to average electronic couplings, which are large enough for sufficient transmission. On the other hand, the alignment of onsite energies is the critical parameter which gates the charge transport.


Diabetic cardiomyopathy.
Prior to 1972, the increased cardiovascular morbidity and mortality that diabetics endure had been attributed to vascular disease. In 1972, Rubler et al. proposed the existence of a diabetic cardiomyopathy based on their expereince with four adult diabetic patients who suffered from congestive heart failure (CHF) in the absence of discernable coronary artery disease, valvular or congenital heart disease, hypertension, or alcoholism. Alternative explanations for CHF, such as anemia and vascular and renal disease in these four patients, gave rise to criticisms, but a wave of subsequent studies in the 1970s and 1980s provided credence to this new disease entity. This review of the studies done since 1972 appears to support the concept of a diabetic cardiomyopathy independent of atherosclerotic cardiovascular disease. The exact mechanism is still questionable, and several mechanisms have been proposed including small and microvascular disease, autonomic dysfunction, metabolic derangements, and interstitial fibrosis. However, the weight of evidence leans toward the development of fibrosis, possibly caused by the accumulation of a peroxidase acid schiff (PAS)-positive glycoprotein, leading to myocardial hypertrophy and diastolic dysfunction.


Factors affecting the life expectancy in malignant pleural mesothelioma: Our 10 years of studies and experience.
Malignant pleural mesothelioma (MPM) is an aggressive tumor with a poor prognosis. In our study, we aimed to investigate the specific clinical, laboratory, and radiological features of the tumor and the prognostic effect of SUVmax (maximum standardized uptake values) according to PET/CT (positron emission tomography). Demographic, therapeutic, clinical, and survival information of patients diagnosed with histologically-validated pleural mesothelioma in our hospital between January 2010 to December 2019 will be retrospectively scanned from the hospital records. A total of 116 patients, 61 men (52.6%), and 55 women (47.4%), were analyzed. Thirty five patients (30.2%) were over the age of 65. Percentage of patients over 65 years of age, neutrophil count, and PET SUV Max values, asbestos exposure and pleural thickening rate were significantly higher in the deceased patients' group than in the living patients' group (P = .042, P = .039, P = .002, P = .004, P = .037). T stage (tumor stage), N stage (lymph nodes stage), metastasis stage, and Grade distribution were significantly higher in the deceased patients' group than in the living patients' group (P < .000, P < .000, P = .003, P < .000). The rates of chemotherapy and surgical treatment, right lung location, and epithelioid pathology were significantly lower in the deceased patients' group compared to the living patients' group (P = .016, P = .030, P = .018, P = .008). The mean follow-up time was 13 months. Key determinants of survival in MPM include age, male gender, neutrophil increase, pleural thickening, high PET SUV max values, stage, histological type, asbestos exposure, and treatment regimen.


Hyperbaric treatment deviations for U.S. Navy divers: Spinal DCS.
The United States Navy (USN) developed and refined standardized oxygen treatment tables for diving injuries, but USN tables may not address all situations of spinal decompression sickness (DCS). We describe a detailed recompression treatment regimen that deviated from standard USN protocol for an active-duty USN diver with a severe, delayed presentation of spinal cord DCS. A USN diver surfaced from his second of three dives on a standard Navy 'no-Decompression' Air SCUBA dive (Max depth 101 fsw utilizing a Navy Dive Computer) and developed mid-thoracic back pain, intense nausea, paresthesias of bilateral feet, and penile erection. Either not recognizing the con- stellation of symptoms as DCS and after resolution of the aforementioned symptoms, he completed the third planned dive (essentially an in-water recompression). Several hours later, he developed paresthesias and numbness of bilateral feet and legs and bowel incontinence. He presented for hyperbaric treatment twenty hours after surfacing from the final dive and was diagnosed with severe spinal DCS. Based on the severity of clinical presentation and delay to treatment, the initial and follow-on treatments were modified from standard USN protocol. MRI of the spine four days after initial presentation demonstrated a 2.2 cm lesion at the T4 vertebral level extending caudally. Follow-up examinations over two years demonstrated almost complete return of motor and sensory function; however, the patient continued to suffer fecal incontinence and demonstrated an abnormal post-void residual urinary volume. An atypical presenting symptom, a discussion of MRI findings, and clinical correlations to the syndrome of spinal DCS are discussed throughout treatment and long-term recovery of the patient.


Immunogenicity of a recombinant measles-HIV-1 clade B candidate vaccine.
Live attenuated measles virus is one of the most efficient and safest vaccines available, making it an attractive candidate vector for a HIV/AIDS vaccine aimed at eliciting cell-mediated immune responses (CMI). Here we have characterized the potency of CMI responses generated in mice and non-human primates after intramuscular immunisation with a candidate recombinant measles vaccine carrying an HIV-1 insert encoding Clade B Gag, RT and Nef (MV1-F4). Eight Mauritian derived, MHC-typed cynomolgus macaques were immunised with 10(5) TCID(50) of MV1-F4, four of which were boosted 28 days later with the same vaccine. F4 and measles virus (MV)-specific cytokine producing T cell responses were detected in 6 and 7 out of 8 vaccinees, respectively. Vaccinees with either M6 or recombinant MHC haplotypes demonstrated the strongest cytokine responses to F4 peptides. Polyfunctional analysis revealed a pattern of TNFα and IL-2 responses by CD4+ T cells and TNFα and IFNγ responses by CD8+ T cells to F4 peptides. HIV-specific CD4+ and CD8+ T cells expressing cytokines waned in peripheral blood lymphocytes by day 84, but CD8+ T cell responses to F4 peptides could still be detected in lymphoid tissues more than 3 months after vaccination. Anti-F4 and anti-MV antibody responses were detected in 6 and 8 out of 8 vaccinees, respectively. Titres of anti-F4 and MV antibodies were boosted in vaccinees that received a second immunisation. MV1-F4 carrying HIV-1 Clade B inserts induces robust boostable immunity in non-human primates. These results support further exploration of the MV1-F4 vector modality in vaccination strategies that may limit HIV-1 infectivity.


Surgical drain after open or laparoscopic splenectomy: is it needed or contraindicated?
The Authors report their experience with the routine use of surgical drainage in a large series of splenectomies. Benefits and risks related to surgical drains have been always discussed, with some surgeons in favor of them and skeptic others considering not physiological their use. After splenectomy, their use is also largely debated, especially because of susceptibility of operated patients to infections. Two thousand nine cases have been reviewed. Indications for splenectomy, performed either by open or laparoscopic approach, included idiopathic thrombocytopenic purpura in 137 patients (65,4%), splenic lymphoma in 36 (17,2%), hereditary spherocytosis in 15 (7,4%), β-thalassemia in 8 (3,7%), other diseases in 13 (6,1%). "Active" or "passive" drains were placed in 80% and 20% of cases, respectively. Drains were removed 2-3 days after surgery in 90,2%, within 10 days in 4,3%, within 2 months in 0,4% of cases. In 2 cases a post-operative bleeding, detected through the drainage, required re-operation. One patient developed a subphrenic abscess, successfully treated by a percutaneous drainage. One case of pancreatic fistula was observed. In Authors' experience, the use of drains after splenectomy does not affect the risk of subsequent infectious complications, independently on the type of the drainage system used. Early removal of drains in this series might have played an important role in the very low incidence of abdominal infections reported. The use of surgical drains after splenectomy might play an important role to early detect post-operative bleeding, as it happened in 2 cases of this series.


Food-based dietary guidelines can be developed and tested using linear programming analysis.
Effective food-based dietary guidelines (FBDGs) are required to combat micronutrient deficiencies. This study aimed to develop a rigorous approach for designing population-specific FBDGs. A 4-phase approach based on linear programming analysis was used to design, test, and refine the FBDGs. This was illustrated for Malawian children. In phase I, the objective function minimized the difference in the energy contributed by different food groups between modeled and observed diets for 16 observed diet types, while preferentially selecting foods most often consumed. Constraints ensured nutrient adequacy and diet palatability. In phase II, the meal/snack patterns of the phase I modeled diets were examined to develop season-specific FBDGs. In phase III, the robustness of these FBDGs, for ensuring a nutritionally adequate diet, was tested. The objective function, in this analysis, minimized selected nutrient levels in the modeled diets (i.e., chose the "worst-case scenario"), while respecting the FBDGs, palatability, and energy constraints. The FBDGs were refined in phase IV. In the Malawian example used to illustrate our approach, the FBDGs promoted daily consumption of maize flour, small dry fish (>or=20 g), leaf relish, and 2-3 snacks. The last mentioned included mangoes, in the food-shortage season, and pumpkin in the food-plenty season. In addition, legume relish was recommended in the food-shortage season. The approach presented here can be used to design and then test the robustness of FBDGs for meeting nutrient recommendations.


Association between spectral electroencephalography power and autism risk and diagnosis in early development.
Autism spectrum disorder (ASD) has its origins in the atypical development of brain networks. Infants who are at high familial risk for, and later diagnosed with ASD, show atypical activity in multiple electroencephalography (EEG) oscillatory measures. However, infant-sibling studies are often constrained by small sample sizes. We used the International Infant EEG Data Integration Platform, a multi-site dataset with 432 participants, including 222 at high-risk for ASD, from whom repeated measurements of EEG were collected between the ages of 3-36 months. We applied a latent growth curve model to test whether familial risk status predicts developmental trajectories of spectral power across the first 3 years of life, and whether these trajectories predict ASD outcome. Change in spectral EEG power in all frequency bands occurred during the first 3 years of life. Familial risk, but not a later diagnosis of ASD, was associated with reduced power at 3 months, and a steeper developmental change between 3 and 36 months in nearly all absolute power bands. ASD outcome was not associated with absolute power intercept or slope. No associations were found between risk or outcome and relative power. This study applied an analytic approach not used in previous prospective biomarker studies of ASD, which was modeled to reflect the temporal relationship between genetic susceptibility, brain development, and ASD diagnosis. Trajectories of spectral power appear to be predicted by familial risk; however, spectral power does not predict diagnostic outcome above and beyond familial risk status. Discrepancies between current results and previous studies are discussed. LAY SUMMARY: Infants with an older sibling who is diagnosed with ASD are at increased risk of developing ASD themselves. This article tested whether EEG spectral power in the first year of life can predict whether these infants did or did not develop ASD.


Generation of CdS nano-necklaces and NiS nanotubes templated by sugar-appended hydrogel.
A new hydrogel based on glucose-appended Schiff base derivative has been employed as the template to synthesize CdS and NiS nanostructures with different morphologies. The FT-IR and UV-vis results revealed that H-bonding and pi-pi interaction played important roles in the formation of original hydrogel fibers. The study of mineralization mechanism suggested that the inorganic ions were firstly adsorbed at the surface of the hydrogel fibers due to the hydrophilic affinity with the hydrophilic glucose groups. With the penetration of H2S gas, the preformed CdS or NiS nanoparticles on the surface of the fibers acted as the growing points for the continuous growth. And the different adsorption abilities of the metal ions at the hydrogel fibers resulted in the formation of CdS nano-necklaces and NiS nanotubes.


Nutrition and Nutraceuticals in Neuroinflammatory and Brain Metabolic Stress: Implications for Neurodegenerative Disorders.
A steep rise in the incidences of neurodegenerative disorders could be the combined effect of several non-genetic factors such as increased life expectancy, environmental pollutants, lifestyle, and dietary habits, as population-level genetic change require multiple generations. Emerging evidence suggests that chronic over-nutrition induces brain metabolic stress and neuroinflammation, and are individually known to promote neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Although the association of metabolic disorders such as diabetes, hypertension, dyslipidemia, and atherosclerosis with the dietary habits is well known, neuronal implications of diet and nutritional factors is still in its infancy. Transcriptomics and proteomics-based studies support the view that nutraceuticals target multiple neuroprotective pathways in a slow but effective manner without causing severe adverse effects, and may represent the future of tackling neurodegenerative disorders. In this article we i) review the diet/dietary supplement connection with brain metabolic stress and neuroinflammation and ii) summarize current knowledge of the effects of nutraceuticals on neurodegenerative disorders.


Ontogenetic transition of wound healing pattern in rat skin occurring at the fetal stage.
Full-thickness excisional wounds were made in the dorsal skin of rat fetuses at day 16 and day 18 of gestation. A small patch of skin surrounding the open wound was cut out, mounted on a plastic ring and incubated in an organ culture system. In the presence of serum, the open wound in the day-16 fetal skin closed within three days of culture. During the wound-closure process, no new structures were formed in the wound space, and no conspicuous changes were noted in the histological architecture of the surrounding skin during culture, indicating that the wound closure may result from a centripetal movement of the surrounding skin only. In contrast, the size of the open wound in the day-18 fetal skin remained almost unchanged for one week, but a thin acellular network spread over the wound space within one day of culture. The predominant component of the network was cross-linked fibrin, as disclosed by scanning electron microscopy and sodium dodecylsulfate-polyacrylamide gel electrophoresis followed by immunoblotting. The network served as a scaffold for the ingrowth of fibroblast-like cells. These stage-dependent differences in fetal wound healing were consistent with an in vivo study showing that the day-16 wound was covered with the surrounding skin itself, whereas the day-18 wound was covered with newly formed epidermis and invaded by inflammatory cells. The present investigation strongly indicates the prenatal occurrence of a fetal-to-adult transition in the wound-healing pattern of rat skin.


Ontogeny of endocrine responses to methadone in rats.
The effects of methadone (METH) on serum levels of prolactin (PRL), growth hormone (GH), corticosterone (CS) and TSH were determined in developing rats. METH increased PRL, GH and CS and decreased TSH at all ages tested, but the time course and magnitude of these effects changed during ontogeny. METH effects on day 10 were lower in magnitude than those observed in adults. In 20 day old pups, METH effects on GH and CS were comparable to those of adults, but TSH effects were still blunted. METH effects on hormone secretion in both 10 and 20 day old pups lasted longer than those observed in adults. Naloxone blocked all hormonal responses in adults, but did not completely block METH effects on CS secretion in 10 day old pups.


SPARC Regulates Transforming Growth Factor Beta Induced (TGFBI) Extracellular Matrix Deposition and Paclitaxel Response in Ovarian Cancer Cells.
TGFBI has been shown to sensitize ovarian cancer cells to the cytotoxic effects of paclitaxel via an integrin receptor-mediated mechanism that modulates microtubule stability. Herein, we determine that TGFBI localizes within organized fibrillar structures in mesothelial-derived ECM. We determined that suppression of SPARC expression by shRNA decreased the deposition of TGFBI in mesothelial-derived ECM, without affecting its overall protein expression or secretion. Conversely, overexpression of SPARC increased TGFBI deposition. A SPARC-YFP fusion construct expressed by the Met5a cell line co-localized with TGFBI in the cell-derived ECM. Interestingly, in vitro produced SPARC was capable of precipitating TGFBI from cell lysates dependent on an intact SPARC carboxy-terminus with in vitro binding assays verifying a direct interaction. The last 37 amino acids of SPARC were shown to be required for the TGFBI interaction while expression of a SPARC-YFP construct lacking this region (aa 1-256) did not interact and co-localize with TGFBI in the ECM. Furthermore, ovarian cancer cells have a reduced motility and decreased response to the chemotherapeutic agent paclitaxel when plated on ECM derived from mesothelial cells lacking SPARC compared to control mesothelial-derived ECM. In conclusion, SPARC regulates the fibrillar ECM deposition of TGFBI through a novel interaction, subsequently influencing cancer cell behavior.