Antibacterial effectiveness meets improved mechanical properties: Manuka honey/gellan gum composite hydrogels for cartilage repair.
Biomaterials for cartilage repair are still far from clinical requirements, even if several studies recently focused on this topic. In this respect, Nature-derived hydrogels are a promising class of scaffolds for cartilage tissue engineering, mimicking the native cellular microenvironment. However, they frequently lack mechanical features required for cartilage applications and are commonly subjected to infection threat. This work describes the innovative use of Manuka honey as molecular spacer for preparing gellan gum-based composites with intrinsic antibacterial properties and superior compressive Young's modulus in respect of several Nature-derived gels based on chitosan, hyaluronic acid or alginate. The addition of Manuka honey made hydrogels able to inhibit the proliferation of S. aureus and S. epidermidis clinical isolates. Furthermore, no cytotoxic effects were detected on human mesenchymal stem cells seeded on the hydrogels. Moreover, chondrogenesis experiments showed a consistent expression of collagen II and high synthesis of GAGs and proteoglycans, thus indicating the formation of cartilage matrix. Overall, these data suggest that the developed smart composites have a great potential as tools for cartilage tissue engineering.


Symptomatic Diverticular Disease in Patients With Severely Reduced Kidney Function: Higher Rates of Complications and Transfusion Requirement.
The prevalence of diverticulosis is increasing with 5-10% of patients developing diverticulitis and 5-15% developing symptomatic bleeding. Diverticulitis can result in abscess, perforation, fistula, or obstruction. Bleeding has combined morbidity and mortality rates of 10-20%. The purpose of this study was to compare diverticulitis-related complications and transfusion requirements for diverticular bleeding in patients with normal to moderately reduced kidney function (glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2) and patients with severe renal impairment (GFR < 30 mL/min/1.73 m2), and identify factors associated with these outcomes. We retrospectively reviewed records of all patients with diverticulitis and diverticular bleeding treated at our hospital from January 1, 2011 to July 31, 2016. Patients were evaluated for baseline characteristics, GFR, baseline hemoglobin, medications, comorbidities, length of stay (LOS), presence of perforations or abscesses and the need for transfusion. Of the 291 patients included, males were 167 (58%). Perforations and abscesses complicating diverticulitis developed in 31/136 (23%) of patients with GFR ≥ 30 mL/min/1.73 m2, and in 13/26 (50%) of patients with GFR < 30 mL/min/1.73 m2 (odds ratio (OR): 3.4; 95% confidence interval (CI): 1.423 - 8.06; P = 0.0073). Mean LOS (days) was 6.3 ± 4 in the GFR ≥ 30 mL/min/1.73 m2 group and 8.5 ± 4.4 in GFR < 30 mL/min/1.73 m2 group (P = 0.0001). Blood transfusion for diverticular bleeding occurred in 11/78 (14%) of patients with GFR ≥ 30 mL/min/1.73 m2 and in 22/51 (43%) of patients with GFR < 30 mL/min/1.73 m2 (OR: 4.6; 95% CI: 1.99 - 10.76; P = 0.0004). Among patients who needed transfusion, mean LOS was 8.5 ± 2.5 in GFR ≥ 30 mL/min/1.73 m2 group and 9 ± 5 in those with GFR < 30 mL/min/1.73 m2 (P = 0.04). There were no differences in age, gender or race between the study groups. There was a significant increase in complicated diverticulitis cases, transfusion requirements for diverticular bleeding and LOS in patients with severely reduced kidney function compared to patients with normal-moderately reduced renal function.


Effects of Cervical Extension on Deformation of Intervertebral Disk and Migration of Nucleus Pulposus.
We theorized that active cervical extension should influence the position of the nucleus pulposus (NP) within the intervertebral disk (IVD) in the sagittal plane. Although several studies on the lumbar IVD have been conducted, there are no quantitative data for in vivo positional changes of the NP in the cervical IVD. To evaluate the influence and mechanism of cervical extension on the deformation and migration of IVD and NP in the sagittal plane and understand underlying mechanisms of the extension maneuver. Asymptomatic subjects underwent magnetic resonance imaging while supine with their cervical spines in neutral and extended positions. Academic medical center. Ten young, healthy male participants (age range 19-30 years; mean 22.4 ± 1.64 years). T2-weighted sagittal images from C3-C4 to C6-C7 of subjects in both neutral and extension positions were analyzed. Deformation of IVD and positional change of NP were quantified and compared between neutral and extension positions. Intersegmental angles between vertebrae, horizontal positions of anterior and posterior IVD and NP margins, IVD outer and inner heights, and sagittal morphology of NP were quantified and compared between the neutral and extension positions. Correlations between the measured parameters and segmental extension angle were also investigated. Anterior and posterior IVD margins moved posteriorly with respect to the vertebral body in extension. Both NP margins remained unchanged relative to the vertebral body but moved anteriorly with respect to the IVD. IVD outer and inner heights in the anterior region increased in extension, and morphological changes of the NP were less noticeable when compared with its relative migration within the IVD. Most of the intradiskal changes were linearly correlated with the segmental extension angle. Cervical extension induces anterior migration of the NP away from the posterior disk margin and may have a clinical effect on diskogenic neck pain resulting from internal disk disruption. Not applicable.


Cryopreservation of adventitious shoot tips of Paraisometrum mileense by droplet vitrification.
Gesneriaceae family contains numerous species endemic to China, and many of them are listed as endangered species. There is a need for a simple and efficient method for long-term conservation of these species. The study aimed to establish an efficient procedure for cryopreserving Paraisometrum mileense, a critically endangered species endemic to Yunnan, China. Effects of sucrose concentration of preculture solution, duration of sucrose preculture, duration of plant vitrification solution 2 (PVS2) treatment, and cold acclimation on regeneration of cryopreserved adventitious shoot tips (ASTs) were assessed. Among different sucrose preculture regimes tested, preculture with 0.3M sucrose for 24h resulted in best regeneration of cryopreserved ASTs. PVS2 treatment also affected regeneration considerably with the maximum survival of ASTs after incubation in PVS2 for 90 min at 0 degrees C. With the optimised parameters, the level of shoot regeneration from cryopreserved ASTs reached 86%. No morphological abnormalities were observed during one year's growth of the plantlets developing from cryopreserved ASTs. Procedure established in this research is a promising technique for the cryopreservation of ASTs of this species.


Four-wave mixing in fibers with random birefringence.
Parametric amplification is made possible by four-wave mixing. In low-birefringence fibers the birefringence axes and strength vary randomly with distance. Light-wave propagation in such fibers is governed by the Manakov equation. In this paper the Manakov equation is used to study degenerate and nondegenerate four-wave mixing. The effects of linear and nonlinear wavenumber mismatches, and nonlinear polarization rotation, are included in the analysis. Formulas are derived for the initial quadratic growth of the idler power, and the subsequent exponential growth of the signal and idler powers (which continues until pump depletion occurs). These formulas are valid for arbitrary pump and signal polarizations.


The nature and functional significance of dentin extracellular matrix proteins.
Odontoblasts are responsible for formation of predentin, which is transformed to dentin when apatite crystals are formed and the fibrillar matrix becomes mineralized. Odontoblasts are specialized cells that synthesize and secrete a unique set of non-collagenous proteins (NCPs), as well as the collagenous matrix largely comprised of type I collagen. The NCPs consist of dentin specific and mineralized tissue specific proteins, as well as other proteins that are found in a variety of tissues. Three dentin specific proteins have been recognized to date: dentin phosphoprotein (DPP), also called phosphophoryn, AG1 (dentin matrix protein 1, Dmp1) and dentin sialoprotein (DSP). DPP appears to be made by odontoblasts and appears at the mineralization front within a short time. It may be secreted via odontoblastic processes. DPP binds to collagen and potentially initiates formation of apatite crystals. A second DPP function appears to be to bind to the 100 face of growing apatite crystals and to inhibit or slow their growth; thus, DPP may play a dual role by initiating mineralization and then affecting the crystal growth and perhaps the habit of the crystals. Although no function has been ascribed to AG1 or DSP, they should prove to be important markers for the odontoblast phenotype. A recent unique finding is that two separate genes appear to code for more than one DSP mRNA; other transcripts may result from differential splicing. Examples of mineralized tissue specific proteins expressed by osteoblasts as well as odontoblasts are bone sialoprotein (BSP) and osteocalcin. Some NCPs expressed by osteoblasts, odontoblasts and several other tissues include osteopontin (OPN) and the chondroitin sulfate containing proteoglycans, decorin and biglycan. We propose that characterization of odontoblasts in tissues and cultures should rely upon utilization of sets of markers for the above NCPs and their mRNAs. Similar approaches are commonly used in investigations on osteoblasts. Finally, dentin (like bone) contains other molecules such as growth factors, and serum derived proteins, found within the matrix; no functional significance has yet been placed upon this finding. Future experiments should focus upon the elucidation of the three dimensional structures of the collagenous fibrillar network and of the NCPs to determine the relationships to mineralization. The role played by odontoblasts in controlling extracellular events, such as by selective secretory routes, will require careful exploration.


Price and niche wars in a free-market economy of software agents.
One scenario of the future of computation populates the Internet with vast numbers of software agents providing, trading, and using a rich variety of information goods and services in an open, free-market economy. An essential task in such an economy is the retailing or brokering of information: gathering it from the right producers and distributing it to the right consumers. This article investigates one crucial aspect of brokers' dynamical behavior, their price-setting mechanisms, in the context of a simple information-filtering economy. We consider only the simplest cases in which a broker sets its price and product parameters based solely on the system's current state, without explicit prediction of the future. Analytical and numerical results show that the system's dynamical behavior in such "myopic" cases is generally an unending cycle of disastrous competitive "wars" in price/product space. These in turn are directly attributable to the existence of multiple peaks in the brokers' profitability landscapes, a feature whose generality is likely to extend far beyond our model.


Multivariate analysis of genetic variation.
Multiple factor analysis was used to interpret geographical variation of gene frequencies. Allelic frequencies at three loci (two esterase loci, Esr and Esh, and a malic dehydrogenase locus) from ants (Pogonomyrmex barbatus) collected throughout Texas and reported by Johnsonet al. (1969) were reexamined for patterns of correlation with five environmental measurements: mean January temperature, mean July temperature, mean annual precipitation, elevation, and annual growing season. These measurements and the associated gene frequencies at each sampling location were subjected to factor analysis. Variables highly correlated with the same factor were hypothesized to be causally related. Both orthogonal and oblique rotations of the factor solution provided four factors with essentially the same interpretation. Variation at the Esh locus was associated with a continuum from cold-wet to hot-dry. Variation at the Mdh locus and some of that at the Esr locus was related to the severity of winter months. Other allelic frequencies at the Esr locus had high correlations with a third factor which seemed to be independent of the environmental measurements. None of the allelic frequencies had high correlations with the fourth factor which was interpretable as an altitudinal gradient.


Nitric oxide and renal and cardiac dysfunction in cirrhosis.
Nitric oxide (NO) has diverse physiological and pathophysiological effects. The roles of NO in the renal and cardiac dysfunction found in cirrhosis are reviewed. In the kidneys of experimental animals with cirrhosis, several lines of evidence speak in favour of an enhanced production of NO, through the activation of both endothelial constitutive and inducible isoforms of NO synthase. In contrast with the situation in normal animals, inhibition of NO synthesis in rats with cirrhosis improves sodium and water excretion via blood pressure-dependent and -independent mechanisms, which indicates that the renal sodium and water retention of cirrhosis is related to an excess of NO production. The deleterious effect of excessive NO on the kidney may be mediated by peroxynitrite, a potent oxidant that is readily formed whenever superoxide anions and the *NO radical are produced together. The peroxidation of arachidonic acid by peroxynitrite leads to the formation of F(2a)-isoprostanes, which are powerful renal vasoconstrictors. F(2a)-isoprostane levels are correlated with the severity of liver injury during cirrhosis. However, whether peroxynitrite or F(2a)-isoprostanes are the elusive mediator of the NO-induced renal alterations in cirrhosis remains to be firmly established. NO is also involved in cardiac contractility, probably in the normal heart as well as in disease conditions such as non-cirrhotic and cirrhotic cardiomyopathy. In the latter state, evidence suggests that inducible NO synthase attenuates ventricular contractility, mediated by cGMP. Another gas that transduces its signal through cGMP, carbon monoxide, is also likely to play a role in cirrhotic cardiomyopathy, but the nature of the interaction between NO and carbon monoxide in this syndrome remains unclear.


Aspartate and maltose-binding protein interact with adjacent sites in the Tar chemotactic signal transducer of Escherichia coli.
The Tar protein of Escherichia coli is a chemotactic signal transducer that spans the cytoplasmic membrane and mediates responses to the attractants aspartate and maltose. Aspartate binds directly to Tar, whereas maltose binds to the periplasmic maltose-binding protein, which then interacts with Tar. The Arg-64, Arg-69, and Arg-73 residues of Tar have previously been shown to be involved in aspartate sensing. When lysine residues are introduced at these positions by site-directed mutagenesis, aspartate taxis is disrupted most by substitution at position 64, and maltose taxis is disrupted most by substitution at position 73. To explore the spatial distribution of ligand recognition sites on Tar further, we performed doped-primer mutagenesis in selected regions of the tar gene. A number of mutations that interfere specifically with aspartate taxis (Asp-), maltose taxis (Mal-), or both were identified. Mutations affecting residues 64 to 73 or 149 to 154 in the periplasmic domain of Tar are associated with an Asp- phenotype, whereas mutations affecting residues 73 to 83 or 141 to 150 are associated with a Mal- phenotype. We conclude that aspartate and maltose-binding protein interact with adjacent and partially overlapping regions in the periplasmic domain of Tar to initiate attractant signalling.


Development and standardization of tinnitus handicap inventory in malayalam.
Tinnitus is defined as the perception of sound mainly due to the activity within the central nervous system without any mechanical, vibratory activity within the cochlea. Administration of tinnitus related questionnaires along with the audiological test battery is recommended in routine clinical practice. Tinnitus Handicap Inventory (THI) is one of the useful and widely recognized tools for quantifying the impact of tinnitus on daily life. India, being a multilingual country with a multicultural background, there is no such inventories available in many of the local Indian languages except in Tamil and Kannada. The English THI was translated to Malayalam by a faculty who is qualified and proficient in Malayalam language. Then the translated THI was given to 40 native Malayalam speakers for content validity. The final THI-M was administered on 50 tinnitus patient. Obtained data was then subjected for statistical analysis using SPSS Statistics 17.0. Reliability statistics revealed an alpha score of 0.855 for the overall inventory. Across the three subscales, i.e. emotional, functional and catastrophic, a global alpha score of 0.766, 0.693 and 0.630, respectively. The alpha score remained the same even after deleting any single item. The results of the current study conclude that, THI-M has a good reliability/internal consistency as per the Cronbach's alpha score. THI-M can be considered as a reliable tool that can be used across the State by Hearing Professionals in assessment and management.


Weight Gain in Women at Midlife: A Concise Review of the Pathophysiology and Strategies for Management.
Weight gain accompanied by an increased tendency for central fat distribution is common among women in midlife. These changes are a result of aging, decreasing estrogen levels after menopause, and other unique influences in menopausal women that interfere with the adoption of healthy lifestyle measures. Central obesity, in particular, results in several adverse metabolic consequences, including dysglycemia, dyslipidemia, hypertension, and cardiovascular disease. Given that cardiovascular disease is the leading cause of death in postmenopausal women, the importance of weight management in midlife cannot be overemphasized. In addition, weight gain in midlife contributes to other health risks including cancer, arthritis, mood disorders, and sexual dysfunction. It is imperative that primary care physicians screen midlife women for overweight/obesity and offer appropriate advice and referral. In addition to counseling regarding lifestyle change, behavioral modification, and psychological support, it is important to address the unique barriers to adoption of healthy lifestyle measures in postmenopausal women, including the presence of vasomotor symptoms, mood disorders, and sleep disturbance. When indicated, menopausal hormone therapy should be considered to manage bothersome symptoms. Despite its favorable influence on body fat distribution, menopausal hormone therapy cannot be recommended as a treatment for central obesity in midlife women.


Emotional care experienced by hospitalised patients: development and testing of a measurement instrument.
This paper describes the development and preliminary psychometric testing of an instrument that evaluates the emotional care experienced by patients during hospitalisation. Previous qualitative work using the Grounded Theory method identified the characteristics of interpersonal interactions that hospitalised patients perceived to be therapeutic. Three conditions were associated with the patient's experience of emotional comfort: the patient's perceived Level of Security, Level of Knowing and Level of Personal Value. Questions relating to each of these conditions were included in this new instrument. Instrument development and psychometric testing. Preliminary psychometric testing was carried out in four phases: construction of the instrument; assessment of face and content validity; testing for clarity and feasibility for use with hospitalised patients; assessment of reliability, construct validity of the tool and assessment of the internal structure. A hospital-wide survey was carried out and the instrument was completed by a total sample of 132 patients. Two of the three sub-scales achieved an internal consistency estimate of at least 0.70. The construct validity of the tool confirmed the previously identified characteristics of patients in need of additional emotional care. Exploratory factor analysis established two of the sub-scales and identified a fourth sub-scale which was named 'Level of Connection'. Encouraging reliability and validity estimates were obtained and the instrument was improved. Further testing with larger samples is recommended. This questionnaire, which is completed by hospitalised patients, differs from other instruments because it evaluates the interactions of all hospital staff rather than only nursing staff. This instrument can be used to identify patients who may be in need of additional emotional care and to evaluate the effectiveness of interventions directed at improving the emotional well-being of patients.


Disentangling the relationship between sedentariness and obesity: Activity intensity, but not sitting posture, is associated with adiposity in women.
The relationship between free-living sedentary behaviour (SB) and obesity is unclear. Studies may arrive at disparate conclusions because of inconsistencies and limitations when defining and measuring free-living SB. The aim of this cross-sectional study was to examine whether the relationship between SB and adiposity differed depending on the way SB was operationally defined and objectively measured. Sixty-three female participants aged 37.1 years (SD = 13.6) with a body mass index (BMI) of 29.6 kg/m2 (SD = 4.7) had their body composition measured (BodPod, Concord, CA) then were continuously monitored for 5-7 days with the SenseWear Armband (SWA; sleep and activity intensity) and the activPAL (AP; posture). Data from both activity monitors were analysed separately and integrated resulting in a third measure of SB (activity intensity and posture; SEDINT). SB outputs were compared according to week or weekend day averages then correlated against body composition parameters after adjusting for moderate-to-vigorous physical activity (MVPA). SEDSWA resulted in the most sedentary time 11.74 h/day (SD = 1.60), followed by SEDAP 10.16 h/day (SD = 1.75) and SEDINT 9.10 h/day (SD = 1.67). There was a significant positive association between SEDSWA and body mass [r(61) = 0.29, p = .02], BMI [r (61) = 0.33, p = .009] and fat mass [r(61) = 0.32, p = .01]. SEDAP and SEDINT were not associated with any of the indices of adiposity. Correlations between SB and adiposity were non-significant when controlling for MVPA. The relationship between SB and adiposity differed depending on how SB was operationally defined and measured, and was dependent on MVPA. The definition of SB based on a sitting posture (SEDAP) was not strongly related to body fat, whereas the accumulation of any behaviour (sitting or standing) with an intensity of <1.5 METs (SEDSWA) (offset by the presence of MVPA) was positively associated with indices of adiposity. These data suggest that the postural element of SB (sitting) is not sufficient for the accumulation of adiposity, rather activities requiring low EE (<1.5 METs) and the absence of MVPA, regardless of posture, are associated with higher fat mass.


Development and validation of an index of musculoskeletal functional limitations.
While musculoskeletal problems are leading sources of disability, there has been little research on measuring the number of functionally limiting musculoskeletal problems for use as predictor of outcome in studies of chronic disease. This paper reports on the development and preliminary validation of a self administered musculoskeletal functional limitations index. We developed a summary musculoskeletal functional limitations index based upon a six-item self administered questionnaire in which subjects indicate whether they are limited a lot, a little or not at all because of problems in six anatomic regions (knees, hips, ankles and feet, back, neck, upper extremities). Responses are summed into an index score. The index was completed by a sample of total knee replacement recipients from four US states. Our analyses examined convergent validity at the item and at the index level as well as discriminant validity and the independence of the index from other correlates of quality of life. 782 subjects completed all items of the musculoskeletal functional limitations index and were included in the analyses. The mean age of the sample was 75 years and 64% were female. The index demonstrated anticipated associations with self-reported quality of life, activities of daily living, WOMAC functional status score, use of walking support, frequency of usual exercise, frequency of falls and dependence upon another person for assistance with chores. The index was strongly and independently associated with self-reported overall health. The self-reported musculoskeletal functional limitations index appears to be a valid measure of musculoskeletal functional limitations, in the aspects of validity assessed in this study. It is useful for outcome studies following TKR and shows promise as a covariate in studies of chronic disease outcomes.


Standing on textured surfaces: effects on standing balance in healthy older adults.
standing on textured surfaces or wearing textured shoe insoles can alter balance performance. This evidence, although inconclusive, offers a potential intervention for improving balance in older adults. This study explored the effect of standing on textured surfaces on double-limb balance in older adults and changes in muscle activity as a possible mechanism of effect. 50 healthy older adults (29 female, age mean [1SD] 75.1 [5.0]) stood quietly in six conditions-eyes open and closed on two different textured surfaces and a smooth surface control. Mediolateral sway, anterior-posterior sway and centre of pressure velocity were extracted from a force platform and lower limb muscle activity collected using surface electromyography (EMG) over 30 s. for mediolateral range with eyes closed, there was a statistically significant effect of texture (F [2, 47] = 3.840, P = 0.033). This was attributed to a 9.2% decrease with Texture 1 compared with Control. No such effects were seen in any other balance variable or lower limb EMG activity for either visual condition. the results suggest an effect of standing on textured surfaces on mediolateral sway in older adults, supporting further work to develop the therapeutic benefits of textured surfaces as an intervention to improve balance.


Goal management training and psychoeducation / mindfulness for treatment of executive dysfunction in Parkinson's disease: A feasibility pilot trial.
As there is currently no pharmacological treatment for Parkinson's Disease Mild Cognitive Impairment (PD-MCI) with executive dysfunctions, specific cognitive interventions must be investigated. Most previous studies have tested bottom-up cognitive training programs but have not shown very good results. The aim of this study was to test ease of implementation, differential safety and preliminary efficacy of two top-down (strategy-learning) home-based, individualized, cognitive interventions: Goal Management Training (GMT), adapted for PD-MCI (Adapted-GMT), and a psychoeducation program combined with mindfulness exercises (PSYCH-Mind). This was a single-blind block-randomized between-group comparative study. Twelve PD-MCI with mild executive dysfunctions were divided in four blocks and randomly assigned to any of the two interventions. The participants were included if they had PD-MCI diagnosis (no dementia), with stabilized medication. Both groups (Adapted-GMT and PSYCH-mind) received five intervention sessions each lasting 60-90 minutes for five weeks. Measures were collected at baseline, mid-point, one-week, four-week and 12-week follow-ups. Executive functions were assessed with the Dysexecutive questionnaire (DEX) and the Zoo Map Test (ZMT). Quality of life (QoL) and psychiatric symptoms were also evaluated. Repeated measures ANCOVAs (mixed linear analysis) were applied to all outcomes. There was one drop out, and both interventions were feasible and acceptable. Despite the small sample size limiting statistical power, patients of both groups significantly improved executive functions per the DEX-patient (Time: F(4,36) = 2.96, p = 0.033, CI95%: 10.75-15.23) and DEX-caregiver scores (Time: F(4,36) = 6.02, p = 0.017, CI95%: 9.63-17.23). Both groups significantly made fewer errors between measurement times on the ZMT (Time: F(3,36) = 16.66, p = 0.001, CI95%: 1.07-2.93). However, QoL significantly increased only in PSYCH-Mind patients at four-week follow-up (interaction Time*Group: F(4,36) = 5.31, p = 0.002, CI95%: 15.33-25.61). Both interventions were easily implemented and proved to be safe. Because both interventions are arguably cost-effective, these pilot findings, although promising, need to be replicated in large samples. NCT04636541.


Structures, NMR Spectroscopic Features, and Cytotoxic Properties of Oligomeric Hellinoyl (m-GO-m-GOG)-Type Ellagitannins from the Galls of Tamarix aphylla.
Ellagitannin oligomers are large molecules habitually showing complex NMR spectra that are sometimes misinterpreted and lead to incorrect structures. Understanding the NMR spectroscopic features of a group of ellagitannins would overcome these inadequacies. In this study, investigation of the galls of Tamarix aphylla led to the isolation of three new ellagitannin oligomers, phyllagallins T1 (1), T2 (2), and Q1 (3), a known monomer nilotinin M4 (4), four known dimers, nilotinins D7 (5) and D8 (6), hirtellin B (7), and tamarixinin A (8), and a simple phenolic, dehydrotrigallic acid (9). 1D and 2D NMR, HRESI-TOFMS, and ECD experiments show that compounds 1-8 are hellinoyl-type ellagitannins. The NMR spectroscopic features of this type of ellagitannins and the reasons for the abnormal upfield shifts of glucose anomeric proton and hellinoyl moiety proton signals are established considering the experimental results as well as quantum chemical calculation on a simple hellinoyl-type monomer, phyllagallin M2. Based on these results, the NMR assignments reported previously by a different research group for bracteatinin T1 and hirtellin T3 are revised. A cytotoxicity study against human oral squamous cell carcinoma cell lines (Ca9-22, HSC-2, and HSC-4) and human mesenchymal normal oral cells (HGF, HPC, and HPLF) showed cytotoxic effects with tumor-specificity higher than 5.2, 3.0, 1.6, and 2.0 for compounds 5, 2, 9, and 3, respectively.


Polymeric Nanoparticle Versus Liposome Formulations: Comparative Physicochemical and Metabolomic Studies as L-Carnitine Delivery Systems.
L-Carnitine has attracted much more attention especially in the treatment of crucial diseases such as diabetes, regional slimming, and obesity because of its metabolic activities. However, because of its short half-life, low bioavailability, and inability to be stored in the body, frequent dosing is required. In this study, L-carnitine-loaded liposome (lipo-carnitine) and PLGA nanoparticle (nano-carnitine) formulations were prepared and characterized. For lipo-carnitine and nano-carnitine formulations, particle size values were 97.88 ± 2.96 nm and 250.90 ± 6.15 nm; polydispersity index values were 0.35 ± 0.01 and 0.22 ± 0.03; zeta potential values were 6.36 ± 0.54 mV and - 32.80 ± 2.26 mV; and encapsulation efficiency percentage values were 14.26 ± 3.52% and 21.93 ± 4.17%, respectively. Comparative in vitro release studies of novel formulations and solution of L-carnitine revealed that L-carnitine released 90% of its content at the end of 1st hour. On the other hand, lipo-carnitine and nano-carnitine formulations maintained a controlled-release profile for 12 h. The in vitro efficacy of the formulations on cardiac fibroblasts (CFs) was evaluated by metabolomic studies and pathway analysis. Besides the prolonged release, lipo-carnitine/nano-carnitine formulations were also found to be effective on amino acid, carbohydrate, and lipid metabolisms. As a result, innovative nano-formulations were successfully developed as an alternative to conventional preparations which are available on the market.


Sepsis-induced myocardial dysfunction.
Despite the fact that septic patients exhibit altered cardiac function, it is not considered a major pathology during sepsis. Thus, the molecular mechanisms underlying sepsis-induced myocardial dysfunction have not been studied extensively. In a polymicrobial septic rat model, +dP/dt and -dP/dt on day 1 were not altered but found depressed later, i.e., at 3 and 7 days postsepsis. Diastolic dysfunction characterized by an elevation of the time constant of left ventricular relaxation, tau, was evident at 1, 3, and 7 days postsepsis. Recent data from our laboratory demonstrated that sepsis-induced cardiodynamic alterations correlated with upregulation of TNF receptor-associated death domain, Bax, Smac (both mitochondrial and cytosolic fractions), total nuclear factor kappaB expression, p38-mitogen-activated protein kinase and c-Jun N-terminal kinase phosphorylation, and cytochrome c levels in the rat heart at 3 and 7 days postsepsis. Data from various laboratories emphasized that molecular myocardial alteration, which occurs during early and late stages of sepsis, needs to be elucidated thoroughly. A poor understanding of myocardial signaling during early sepsis could be one of the main reasons for limited success of pharmacotherapeutic options for sepsis. We anticipate that an increased understanding of pathophysiological mechanisms leading to sepsis-induced myocardial dysfunction would generate new enthusiasm among various research groups in this area of research.


Microevolution in island forms: the roles of drift and directional selection in morphological divergence of a passerine bird.
Theory predicts that in small isolated populations random genetic drift can lead to phenotypic divergence; however this prediction has rarely been tested quantitatively in natural populations. Here we utilize natural repeated island colonization events by members of the avian species complex, Zosterops lateralis, to assess whether or not genetic drift alone is an adequate explanation for the observed patterns of microevolutionary divergence in morphology. Morphological and molecular genetic characteristics of island and mainland populations are compared to test three predictions of drift theory: (1) that the pattern of morphological change is idiosyncratic to each island; (2) that there is concordance between morphological and neutral genetic shifts across island populations; and (3) for populations whose time of colonization is known, that the rate of morphological change is sufficiently slow to be accounted for solely by genetic drift. Our results are not consistent with these predictions. First, the direction of size shifts was consistently towards larger size, suggesting the action of a nonrandom process. Second, patterns of morphological divergence among recently colonized populations showed little concordance with divergence in neutral genetic characters. Third, rate tests of morphological change showed that effective population sizes were not small enough for random processes alone to account for the magnitude of microevolutionary change. Altogether, these three lines of evidence suggest that drift alone is not an adequate explanation of morphological differentiation in recently colonized island Zosterops and therefore we suggest that the observed microevolutionary changes are largely a result of directional natural selection.


Plasmodium vivax: polymorphism in the merozoite surface protein 1 gene from wild Colombian isolates.
The Plasmodium vivax merozoite surface protein-1 (PvMSP-1) has been considered a candidate for a malaria vaccine against erythrocytic stages. PvMSP-1 is immunogenic during natural infections and exhibits antigenic polymorphism. The extent of genetic polymorphism in a region between the so-called interspecies conserved blocks (ICBs) 2 and 4 of the PvMSP-1 was analyzed in 20 isolates taken from patients from two different areas in Colombia. Variation is unevenly distributed along this gene segment among the isolates. Comparative analysis of these sequences led to the definition of five sequence types (ST1 to 5). ST1 to ST4 exhibit a variation pattern associated with sequences present in the Salvador or Belem sequences. However, ST5 has clusters of sequence that have not been previously described. The changes found along the five variants confirm the important role of recombinational and/or gene conversion events in generating allelic diversity.


Ultrastructural examination of human periodontal pockets following the use of an oral irrigation device in vivo.
To date, there are no ultrastructural studies that have examined untreated chronic periodontal pockets immediately following dental debridement with an oral irrigation device. This study used both scanning electron microscopic and transmission electron microscopic methodology to examine previously untreated human periodontal pockets after their exposure to a pulsating oral irrigation with saline solution. A comparison of 16 untreated controls with 16 test specimens revealed qualitative differences in microbial morphotypes at various pocket depths. Control specimens at all pocket depths examined (0-6 mm), exhibited a mixed microbial flora consisting of cocci, short rods, and filamentous organisms. Specifically at 3- to 4-mm and 5- to 6-mm levels in control specimens, spirochetes, fusiforms, and branching organisms were obvious. In contrast, test specimens exhibited a few cocci and short rods at 0- to 2-mm and 3- to 4-mm levels and a mixed flora at the 5- to 6-mm level. There was no observable difference between control and test specimens concerning epithelial topography, cavitations, microulcerations, spatial relationships, and individual cell appearance. Both control and test specimens exhibited a mild spirochete invasion of the epithelial strata. Collectively these observations suggest that pulsating oral irrigation effects a qualitative change on subgingival plaque and is not injurious to the soft tissues.


Computer-aided drug discovery and development.
Computer-aided approaches have been widely used in pharmaceutical research to improve the efficiency of the drug discovery and development pipeline. To identify and design small molecules as clinically effective therapeutics, various computational methods have been evaluated as promising strategies, depending on the purpose and systems of interest. Both ligand and structure-based drug design approaches are powerful technologies, which can be applied to virtual screening for lead identification and optimization. Here, we review the progress in this field and summarize the application of some new technologies we developed. These state-of-the-art tools have been used for the discovery and development of active agents for various diseases, in particular for cancer therapies. The described protocols are appropriate for all drug discovery stages, but expertise is still needed to perform the studies based on the targets of interest.


Comparison of the Lactate Pro and Analox GM7 blood lactate analysers.
The purpose of this study was firstly, to determine the level of agreement between the Lactate Pro and Analox GM7 for the measurement of blood lactate, and secondly, to examine whether these analysers may be used interchangeably to identify lactate parameters routinely used in the physiological assessment of athletes. Twenty well-trained male cyclists performed an incremental cycle ergometry test; duplicate blood samples were taken simultaneously throughout the test for lactate determination using the two analysers. Power output and heart rate at LT, LT1, 2 mmol.L-1, and 4 mmol.L-1 were calculated from the lactate values obtained from the two analysers. There was a strong linear relationship between the two analysers (Lactate Pro=1.4541xAnalox GM7-0.1287; R2=0.969, p<0.001; SEE=0.704) though the Lactate Pro overestimated blood lactate when compared to the Analox GM7; 95% ratio limits of agreement (Lactate Pro/Analox GM7) were 1.40x//1.35. Differences were found between analysers for power output and heart rate at LT1 (p<0.01), 2 mmol.L-1 (p<0.001), and 4 mmol.L-1 (p<0.001); no differences were found between analysers for power output or heart rate at LT. In conclusion, the average difference in blood lactate concentration measured by the Lactate Pro and the Analox GM7 was 40%, with 95% of measures differing by between 4% and 89%. This poor level of agreement and the significant differences between the two analysers in power output and heart rate associated with a number of lactate parameters indicate that these analysers should not be used interchangeably.


Allele Phasing Greatly Improves the Phylogenetic Utility of Ultraconserved Elements.
Advances in high-throughput sequencing techniques now allow relatively easy and affordable sequencing of large portions of the genome, even for nonmodel organisms. Many phylogenetic studies reduce costs by focusing their sequencing efforts on a selected set of targeted loci, commonly enriched using sequence capture. The advantage of this approach is that it recovers a consistent set of loci, each with high sequencing depth, which leads to more confidence in the assembly of target sequences. High sequencing depth can also be used to identify phylogenetically informative allelic variation within sequenced individuals, but allele sequences are infrequently assembled in phylogenetic studies. Instead, many scientists perform their phylogenetic analyses using contig sequences which result from the de novo assembly of sequencing reads into contigs containing only canonical nucleobases, and this may reduce both statistical power and phylogenetic accuracy. Here, we develop an easy-to-use pipeline to recover allele sequences from sequence capture data, and we use simulated and empirical data to demonstrate the utility of integrating these allele sequences to analyses performed under the multispecies coalescent model. Our empirical analyses of ultraconserved element locus data collected from the South American hummingbird genus Topaza demonstrate that phased allele sequences carry sufficient phylogenetic information to infer the genetic structure, lineage divergence, and biogeographic history of a genus that diversified during the last 3 myr. The phylogenetic results support the recognition of two species and suggest a high rate of gene flow across large distances of rainforest habitats but rare admixture across the Amazon River. Our simulations provide evidence that analyzing allele sequences leads to more accurate estimates of tree topology and divergence times than the more common approach of using contig sequences.


Cadmium influences the 5-Fluorouracil cytotoxic effects on breast cancer cells.
The aim of the research was to evaluate a heavy metal, Cadmium (Cd), which was used to produce alterations in human breast cancer cell line MCF-7. Moreover, we analyzed both immunohistochemical and ultrastructural alterations induced by the antineoplastic drug, 5-Fluorouracil (5-FU), after exposure to different concentrations of Cadmium. Also, we compared the effects of these compounds on actin and tubulin cytoskeleton proteins. Under ultramicroscopic observation, control cells looked polymorphous with filopodia. In cells already treated with small concentrations of Cd, after brief times of incubation, we observed an intense metabolic activity with larger, clearer, and elongated mitochondria characterized by thin and numerous dilated cristae. 5-FU-treated cells showed cytotoxicity signs with presence of pore-like alterations in the cell membrane and evident degeneration of cytoplasm and cell nuclei. The addition of 5-FU (1.5 μM) to the cells treated with Cd (5 μM-20 μM) did not induce significant ultrastructural changes in comparison with cells treated only with Cd. In Cd+5FU-treated cells mitochondria with globular aspect and regular cristae indicated the active metabolic state. In cells treated only with Cd we observed alterations in actin distribution, while tubulin branched out throughout the cytoplasm. With the association of Cd+5FU, we observed less morphological alterations in both tubulin and actin cytoskeleton proteins. Although the mechanism remains unknown at present, our findings suggest that Cd prevents the cytotoxic effect of 5-FU on breast cancer cells. These preliminary results could have an important clinical application in patients with breast cancer.


Root Nodule Enzymes of Ammonia Assimilation in Alfalfa (Medicago sativa L.) : DEVELOPMENTAL PATTERNS AND RESPONSE TO APPLIED NITROGEN.
Nitrogenase-dependent acetylene reduction activity of glasshouse-grown alfalfa (Medicago sativa L.) decreased rapidly in response both to harvesting (80% shoot removal) and applied NO(3) (-) at 40 and 80 kilograms N per hectare. Acetylene reduction activity of harvested plants grown on 0 kilogram N per hectare began to recover by day 15 as shoot regrowth became significant. In contrast, acetylene reduction activity of all plants treated with 80 kilograms NO(3) (-)-N per hectare and harvested plants treated with 40 kilograms NO(3) (-)-N per hectare remained low for the duration of the experiment. Acetylene reduction of unharvested alfalfa treated with 40 kilograms N per hectare declined to an intermediate level and appeared to recover slightly by day 15. Changes in N(2)-fixing capacity were accompanied by similar changes in levels of nodule soluble protein.After an initial lag of 24 hours, specific activities of alfalfa nodule glutamine synthetase, NADH-glutamate synthase, and NAD-glutamate dehydrogenase (oxidative amination) decreased similar to but less rapidly than acetylene reduction activity. Increased specific activities of these nodule enzymes occurred as acetylene reduction activity increased and shoot growth resumed. The observed rates of glutamine synthetase and glutamate synthase were sufficient to assimilate ammonia produced via symbiotic N(2) fixation. Nodule NADH-dependent glutamate dehydrogenase (reductive amination) specific activity was not associated with changes in acetylene reduction activity.The data indicate that host plant glutamine synthetase and NADH-glutamate synthase function to assimilate symbiotically fixed N and that NADH-dependent glutamate dehydrogenase may function in ammonia assimilation during senescence in alfalfa nodules.


Seizure control and extent of mesial temporal resection.
Controversy exists about the extent of mesial temporal lobe resection that improves seizure control in patients with temporal lobe epilepsy. In this retrospective study, 70 patients with mesial temporal seizure activity (without evidence of tumor or vascular malformation) were surgically treated and followed for at least 2 years. The extent of mesial temporal resection was based on the findings of interictal and ictal discharges using depth electrodes, which were inserted preoperatively or intraoperatively by the orthogonal approach to the amygdaloid and hippocampal regions. Only the amygdala was resected along with the limited lateral neocortex if no epileptiform activity involved the hippocampus. The amount of hippocampal excision was determined by the extent of interictal seizure activity. The following groups became seizure free: all 8 patients with only amygdalar resection; 6 of 10 patients with amygdalar and < or = 1 cm hippocampal resection; 23 of 38 with 1-2 cm hippocampal removal, and 11 of 14 with > 2 cm hippocampal excision. In cases where there was no hippocampal resection, neuropsychological outcome compared favorably with controls. Our results suggest that although most patients with temporal lobe epilepsy require hippocampal resection of varying degrees, there is a subset in whom the amygdala may be the crucial element of a mesial temporal epileptogenic network. These patients can undergo a surgical resection sparing the hippocampus without compromising seizure outcome.


Using research to determine support for a policy on family presence during resuscitation.
National guidelines and professional organizations have recommended allowing family presence during resuscitation and bedside invasive procedures. Studies found that only 5% of critical care units have written policies. Periodic requests by family members prompted the creation of a task force, including nurses, physicians, and respiratory therapists, to develop this controversial policy. Before development, a research study of healthcare personnel attitudes, concerns, and beliefs toward family presence during cardiopulmonary resuscitation and bedside invasive procedures was done. This descriptive and correlational study showed support for family presence by critical care and emergency department nurses. Findings revealed both support and non-support for families to be present during resuscitative efforts. Providing family presence as an option offers an opportunity for reluctant healthcare team members to refuse their presence and an opportunity for those who support family presence to welcome the family.


Restoration of menses with nonpharmacologic therapy in college athletes with menstrual disturbances: a 5-year retrospective study.
Functional hypothalamic amenorrhea is common among female athletes and may be difficult to treat. Restoration of menses (ROM) is crucial to prevent deleterious effects to skeletal and reproductive health. To determine the natural history of menstrual disturbances in female college athletes managed with nonpharmacologic therapies including increased dietary intake and/or decreased exercise expenditure and to identify factors associated with ROM. A 5-yr retrospective study of college athletes at a major Division I university. 373 female athletes' charts were reviewed. For athletes with menstrual disturbances, morphometric variables were noted. Months to ROM were recorded for each athlete. Fifty-one female athletes (19.7%) had menstrual disturbances (14.7% oligomenorrheic, 5.0% amenorrheic). In all, 17.6% of oligo-/amenorrheic athletes experienced ROM with nonpharmacologic therapy. Mean time to ROM among all athletes with menstrual disturbances was 15.6 ± 2.6 mo. Total absolute (5.3 ± 1.1 kg vs. 1.3 ± 1.1 kg, p < .05) and percentage (9.3% ± 1.9% vs. 2.3% ± 1.9%, p < .05) weight gain and increase in body-mass index (BMI; 1.9 ± 0.4 kg/m2 vs. 0.5 ± 0.4 kg/m2, p < .05) emerged as the primary differentiating characteristics between athletes with ROM and those without ROM. Percent weight gain was identified as a significant positive predictor of ROM, OR (95% CI) = 1.25 (1.01, 1.56), p < .05. Nonpharmacologic intervention in college athletes with menstrual disturbances can restore regular menstrual cycles, although ROM may take more than 1 yr. Weight gain or an increase in BMI may be important predictors of ROM.


Characterization of the antioxidant status of the heterozygous manganese superoxide dismutase knockout mouse.
The antioxidant status of several tissues (liver, kidney, lung, brain, heart, muscle, stomach, and spleen) from heterozygous manganese superoxide dismutase (MnSOD) mutant mice (Sod2-/+) was characterized. The activity of MnSOD was decreased (30 to 80%) in all tissues examined. The levels of mRNA coding for the major antioxidant enzymes (CuZnSOD, catalase, and glutathione peroxidase) were not significantly altered in liver, kidney, heart, lung, or brain in the Sod2-/+ mice. The activities of the enzymes were not altered in any of these tissues, with the exception of a decrease in glutathione peroxidase activity in muscle in the Sod2-/+ mice compared to the Sod2+/+ mice. Thus, there was no up-regulation of the activities of the major antioxidant enzymes to compensate for the decrease in MnSOD activity. Reduced glutathione levels were 30 to 50% lower in the lung, brain, and muscle of the Sod2-/+ mice compared to the wild-type Sod2+/+ mice. In addition, the ratio of GSH/GSSG was decreased approximately 50% in Sod2-/+ muscle, indicating that the decrease in MnSOD activity in the Sod2-/+ mice results in some degree of oxidative stress in this tissue.


Muscular production of individuated finger movements: the roles of extrinsic finger muscles.
Individuated finger movements--those in which one or more fingers are moved relatively independently of the movement or posture of other body parts--are produced in part by the action of the extrinsic finger muscles. Flexion/extension movements of the fingers are particularly dependent on these extrinsic muscles, most of which are multitendoned. How can contraction of multitendoned muscles move one digit without producing equivalent motion in other digits? This question was addressed by recording EMG activity from muscles of the forearm as trained rhesus monkeys performed flexion and extension individuated movements of each digit of the hand and of the wrist. Recordings showed that during movements of different fingers, a given muscle could act as an agonist, antagonist, or stabilizer of the digits it serves. Furthermore, during a given finger movement, several different muscles typically were active. A three-level connection model was developed that computed the relative motion of the digits during each finger movement based on the changes in EMG activity in the recorded muscles. The model showed that EMG activity changes in the extrinsic finger muscles, and the thenar muscles, could account for most of the motion of both the instructed digit and noninstructed digits. These results indicate that individuated finger movements were produced not by independent sets of muscles acting on each digit, but by the activity of several muscles, many of which act on more than one digit, combined such that the net effect was movement of one digit more than others.


International Consensus Recommendations on Microtia, Aural Atresia and Functional Ear Reconstruction.
The aim of this report is to provide international recommendations for functional ear reconstruction in patients with microtia and aural atresia. All patients with microtia and external auditory atresia should be seen in the setting of a multidisciplinary team and agreed treatment outcomes should be measured, so that techniques, approaches, and results can be compared. The methods are expert opinion from the members of the International Microtia and Atresia Workgroup (IMAW). The consensus recommendations reported herein take into account the variability in practice patterns present among experts in the field; the degree of consensus was quantified by presenting the percentage of above authors who agree or partially agree with each statement. Recommendations include the definition and classification of microtia/atresia, treatment of microtia, treatment of congenital aural atresia, flowchart of functional ear reconstruction, and future research directions. Patients with microtia and aural atresia can be guided by the consensus recommendations provided herein.


Cardiomyocytes stimulate angiogenesis after ischemic injury in a ZEB2-dependent manner.
The disruption in blood supply due to myocardial infarction is a critical determinant for infarct size and subsequent deterioration in function. The identification of factors that enhance cardiac repair by the restoration of the vascular network is, therefore, of great significance. Here, we show that the transcription factor Zinc finger E-box-binding homeobox 2 (ZEB2) is increased in stressed cardiomyocytes and induces a cardioprotective cross-talk between cardiomyocytes and endothelial cells to enhance angiogenesis after ischemia. Single-cell sequencing indicates ZEB2 to be enriched in injured cardiomyocytes. Cardiomyocyte-specific deletion of ZEB2 results in impaired cardiac contractility and infarct healing post-myocardial infarction (post-MI), while cardiomyocyte-specific ZEB2 overexpression improves cardiomyocyte survival and cardiac function. We identified Thymosin β4 (TMSB4) and Prothymosin α (PTMA) as main paracrine factors released from cardiomyocytes to stimulate angiogenesis by enhancing endothelial cell migration, and whose regulation is validated in our in vivo models. Therapeutic delivery of ZEB2 to cardiomyocytes in the infarcted heart induces the expression of TMSB4 and PTMA, which enhances angiogenesis and prevents cardiac dysfunction. These findings reveal ZEB2 as a beneficial factor during ischemic injury, which may hold promise for the identification of new therapies.


Adherence to diabetes self care for white, African-American and Hispanic American telemedicine participants: 5 year results from the IDEATel project.
Adherence to diabetes self care is poor for Hispanic American and African-American patients. This study examined the change in adherence over time and in response to a telemedicine intervention for elderly diabetes patients in these groups compared to white diabetes patients. We also examined whether adherence mediated the effect of the intervention on glycemic control (A1c). The Informatics for Diabetes Education and Telemedicine project randomized medically underserved Medicare patients (n=1665) to telemedicine case management (televideo educator visits, individualized goal-setting/problem solving) or usual care. Hispanic and African-American educators delivered the intervention in Spanish if needed. Annual assessment included A1c and self-reported adherence (Summary of Diabetes Self-Care Activities scale). A simple model (only time and group terms) and a model with covariates (e.g., age) were examined for baseline and 5 years of follow-up. SAS PROC Mixed was used with non-linear terms to examine mediating effects of adherence on A1c, by performing tests of the mediating path coefficients. Over time, self-reported adherence improved for the treatment group compared to usual care (p<0.001). There was no significant interaction with racial/ethnic group membership, i.e., all groups improved. However, minority subjects were consistently less adherent than whites. Also, greater comorbidity and diabetes symptoms predicted poorer adherence, greater duration of diabetes and more years of education predicted better adherence. Adherence was a significant mediator of A1c (p<0.001). A unique, tailored telemedicine intervention was effective in achieving improved adherence to diabetes self care. However, African-American and Hispanic American participants were less adherent than white participants at all time points despite an individualized and accessible intervention. The finding that adherence did mediate glycemic control suggests that unique interventions for minority groups may be needed to overcome this disparity.


DNA polymerases beta and lambda as potential participants of TLS during genomic DNA replication on the lagging strand.
The main strategy used by pro- and eukaryotic cells for replication of damaged DNA is translesion synthesis (TLS). Here, we investigate the TLS process catalyzed by DNA polymerases beta and lambda on DNA substrates using mono- or dinucleotide gaps opposite damage located in the template strand. An analog of a natural apurinic/apyrimidinic site, the 3-hydroxy-2-hydroxymetylthetrahydrofuran residue (THF), was used as damage. DNA was synthesized in the presence of either Mg2+ or Mn2+. DNA polymerases beta and lambda were able to catalyze DNA synthesis across THF only in the presence of Mn2+. Moreover, strand displacement synthesis was not observed. The primer was elongated by only one nucleotide. Another unusual aspect of the synthesis is that dTTP could not serve as a substrate in all cases. dATP was a preferential substrate for synthesis catalyzed by DNA polymerase beta. As for DNA polymerase lambda, dGMP was the only incorporated nucleotide out of four investigated. Modified on heterocyclic base photoreactive analogs of dCTP and dUTP showed substrate specificity for DNA polymerase beta. In contrast, the dCTP analog modified on the exocyclic amino group was a substrate for DNA polymerase lambda. We also observed that human replication protein A inhibited polymerase incorporation by both DNA polymerases beta and lambda on DNA templates containing damage.


Sunlight inactivation of human viruses and bacteriophages in coastal waters containing natural photosensitizers.
Sunlight inactivation of poliovirus type 3 (PV3), adenovirus type 2 (HAdV2), and two bacteriophage (MS2 and PRD1) was investigated in an array of coastal waters to better understand solar inactivation mechanisms and the effect of natural water constituents on observed inactivation rates (k(obs)). Reactor scale inactivation experiments were conducted using a solar simulator, and k(obs) for each virus was measured in a sensitizer-free control and five unfiltered surface water samples collected from different sources. k(obs) values varied between viruses in the same water matrix, and for each virus in different matrices, with PV3 having the fastest and MS2 the slowest k(obs) in all waters. When exposed to full-spectrum sunlight, the presence of photosensitizers increased k(obs) of HAdV2, PRD1 and MS2, but not PV3, which provides evidence that the exogenous sunlight inactivation mechanism, involving damage by exogenously produced reactive intermediates, played a greater role for these viruses. While PV3 inactivation was observed to be dominated by endogenous mechanisms, this may be due to a masking of exogenous k(obs) by significantly faster endogenous k(obs). Results illustrate that differences in water composition can shift absolute and relative inactivation rates of viruses, which has important implications for natural wastewater treatment systems, solar disinfection (SODIS), and the use of indicator organisms for monitoring water quality.


Predicting probable Alzheimer's disease using linguistic deficits and biomarkers.
The manual diagnosis of neurodegenerative disorders such as Alzheimer's disease (AD) and related Dementias has been a challenge. Currently, these disorders are diagnosed using specific clinical diagnostic criteria and neuropsychological examinations. The use of several Machine Learning algorithms to build automated diagnostic models using low-level linguistic features resulting from verbal utterances could aid diagnosis of patients with probable AD from a large population. For this purpose, we developed different Machine Learning models on the DementiaBank language transcript clinical dataset, consisting of 99 patients with probable AD and 99 healthy controls. Our models learned several syntactic, lexical, and n-gram linguistic biomarkers to distinguish the probable AD group from the healthy group. In contrast to the healthy group, we found that the probable AD patients had significantly less usage of syntactic components and significantly higher usage of lexical components in their language. Also, we observed a significant difference in the use of n-grams as the healthy group were able to identify and make sense of more objects in their n-grams than the probable AD group. As such, our best diagnostic model significantly distinguished the probable AD group from the healthy elderly group with a better Area Under the Receiving Operating Characteristics Curve (AUC) using the Support Vector Machines (SVM). Experimental and statistical evaluations suggest that using ML algorithms for learning linguistic biomarkers from the verbal utterances of elderly individuals could help the clinical diagnosis of probable AD. We emphasise that the best ML model for predicting the disease group combines significant syntactic, lexical and top n-gram features. However, there is a need to train the diagnostic models on larger datasets, which could lead to a better AUC and clinical diagnosis of probable AD.


Children's risky play from an evolutionary perspective: the anti-phobic effects of thrilling experiences.
This theoretical article views children's risky play from an evolutionary perspective, addressing specific evolutionary functions and especially the anti-phobic effects of risky play. According to the non-associative theory, a contemporary approach to the etiology of anxiety, children develop fears of certain stimuli (e.g., heights and strangers) that protect them from situations they are not mature enough to cope with, naturally through infancy. Risky play is a set of motivated behaviors that both provide the child with an exhilarating positive emotion and expose the child to the stimuli they previously have feared. As the child's coping skills improve, these situations and stimuli may be mastered and no longer be feared. Thus fear caused by maturational and age relevant natural inhibition is reduced as the child experiences a motivating thrilling activation, while learning to master age adequate challenges. It is concluded that risky play may have evolved due to this anti-phobic effect in normal child development, and it is suggested that we may observe an increased neuroticism or psychopathology in society if children are hindered from partaking in age adequate risky play.


Does simplicity compromise accuracy in ACS risk prediction? A retrospective analysis of the TIMI and GRACE risk scores.
The Thrombolysis in Myocardial Infarction (TIMI) risk scores for Unstable Angina/Non-ST-elevation myocardial infarction (UA/NSTEMI) and ST-elevation myocardial infarction (STEMI) and the Global Registry of Acute Coronary Events (GRACE) risk scores for in-hospital and 6-month mortality are established tools for assessing risk in Acute Coronary Syndrome (ACS) patients. The objective of our study was to compare the discriminative abilities of the TIMI and GRACE risk scores in a broad-spectrum, unselected ACS population and to assess the relative contributions of model simplicity and model composition to any observed differences between the two scoring systems. ACS patients admitted to the University of Michigan between 1999 and 2005 were divided into UA/NSTEMI (n = 2753) and STEMI (n = 698) subpopulations. The predictive abilities of the TIMI and GRACE scores for in-hospital and 6-month mortality were assessed by calibration and discrimination. There were 137 in-hospital deaths (4%), and among the survivors, 234 (7.4%) died by 6 months post-discharge. In the UA/NSTEMI population, the GRACE risk scores demonstrated better discrimination than the TIMI UA/NSTEMI score for in-hospital (C = 0.85, 95% CI: 0.81-0.89, versus 0.54, 95% CI: 0.48-0.60; p<0.01) and 6-month (C = 0.79, 95% CI: 0.76-0.83, versus 0.56, 95% CI: 0.52-0.60; p<0.01) mortality. Among STEMI patients, the GRACE and TIMI STEMI scores demonstrated comparably excellent discrimination for in-hospital (C = 0.84, 95% CI: 0.78-0.90 versus 0.83, 95% CI: 0.78-0.89; p = 0.83) and 6-month (C = 0.72, 95% CI: 0.63-0.81, versus 0.71, 95% CI: 0.64-0.79; p = 0.79) mortality. An analysis of refitted multivariate models demonstrated a marked improvement in the discriminative power of the TIMI UA/NSTEMI model with the incorporation of heart failure and hemodynamic variables. Study limitations included unaccounted for confounders inherent to observational, single institution studies with moderate sample sizes. The GRACE scores provided superior discrimination as compared with the TIMI UA/NSTEMI score in predicting in-hospital and 6-month mortality in UA/NSTEMI patients, although the GRACE and TIMI STEMI scores performed equally well in STEMI patients. The observed discriminative deficit of the TIMI UA/NSTEMI score likely results from the omission of key risk factors rather than from the relative simplicity of the scoring system.


Novel middle-type Kenyon cells in the honeybee brain revealed by area-preferential gene expression analysis.
The mushroom bodies (a higher center) of the honeybee (Apis mellifera L) brain were considered to comprise three types of intrinsic neurons, including large- and small-type Kenyon cells that have distinct gene expression profiles. Although previous neural activity mapping using the immediate early gene kakusei suggested that small-type Kenyon cells are mainly active in forager brains, the precise Kenyon cell types that are active in the forager brain remain to be elucidated. We searched for novel gene(s) that are expressed in an area-preferential manner in the honeybee brain. By identifying and analyzing expression of a gene that we termed mKast (middle-type Kenyon cell-preferential arrestin-related protein), we discovered novel 'middle-type Kenyon cells' that are sandwiched between large- and small-type Kenyon cells and have a gene expression profile almost complementary to those of large- and small-type Kenyon cells. Expression analysis of kakusei revealed that both small-type Kenyon cells and some middle-type Kenyon cells are active in the forager brains, suggesting their possible involvement in information processing during the foraging flight. mKast expression began after the differentiation of small- and large-type Kenyon cells during metamorphosis, suggesting that middle-type Kenyon cells differentiate by modifying some characteristics of large- and/or small-type Kenyon cells. Interestingly, CaMKII and mKast, marker genes for large- and middle-type Kenyon cells, respectively, were preferentially expressed in a distinct set of optic lobe (a visual center) neurons. Our findings suggested that it is not simply the Kenyon cell-preferential gene expression profiles, rather, a 'clustering' of neurons with similar gene expression profiles as particular Kenyon cell types that characterize the honeybee mushroom body structure.


The Current State of Donor Human Milk Use and Practice.
Human milk contains nutrients and immune factors that promote health and growth of an infant. Donor human milk is recommended as the best alternative for infants whose mothers' breast milk is unavailable. This article describes the current status of donor human milk practice and suggests the areas of educational and research needs. Articles published in the last 10 years were reviewed, and findings were summarized under 4 themes: (1) women's knowledge and concerns about donor human milk use, (2) hospital practices, (3) cost-effectiveness, and (4) access and affordability of donor human milk. Women were concerned about donor human milk contamination, disease transmission, cost, and access to bank donor human milk, due to lack of knowledge and awareness of donor human milk benefits and its processing procedures. The absence of health care providers' support for donor human milk adds to the confusion. There is a rising trend of donor human milk use in hospitals for both healthy and vulnerable newborns and infants with varying policies on screening for donor human milk use, cost coverage, or consent procedure. However, a shortage of safe and affordable donor human milk is a barrier to its adoption. A standardized guideline is needed for hospitals regarding donor human milk implementation and cost coverage. Education programs for health care providers are needed to improve knowledge and understanding of donor human milk benefits and safety to provide guidance to parents. It is crucial to develop legislation expanding insurance coverage to achieve donor human milk equity and optimizing long-term human milk diet outcomes.


Regulation of Trypanosoma cruzi infection in mice by gamma interferon and interleukin 10: role of NK cells.
Gamma interferon (IFN-gamma) plays an important role in experimental Trypanosoma cruzi infections, presumably by controlling the early replication of parasites in host macrophages. In this work, we show that NK cells represent an important cell type responsible for the production of most of the IFN-gamma in the early stage of T. cruzi infection and that the in vivo treatment of mice with anti-NK1.1 monoclonal antibody made resistant animals susceptible to the infection. Through in vitro experiments, we demonstrate that normal splenocytes from euthymic or athymic nude mice cultivated for 48 h with live T. cruzi trypomastigotes produced elevated levels of IFN-gamma. In addition, NK-depleted splenocytes show a drastic reduction of IFN-gamma production in response to live T. cruzi trypomastigotes. We also demonstrated that IFN-gamma production is dependent on a factor secreted by adherent cells. Supernatants of spleen cells from athymic nude mice are able to induce IFN-gamma production by normal splenocytes when cultured with trypomastigotes. The addition of anti-interleukin-10 to these cultures resulted in a marked increase in IFN-gamma production. On the other hand, the absence of NK cells led to an increased secretion of interleukin-10 upon in vitro stimulation with T. cruzi. Taken together, these results suggest that NK cells are the major source of IFN-gamma that could be involved in limiting the replication of T. cruzi in host macrophages during the early acute phase of the infection.


Tehran dust storm early warning system: corrective measures.
On June 2, 2014 a sandstorm hit Tehran, the capital city of Iran which killed 5 and injured 44 people. The early warning system did not operate properly and the alarm was not transferred to at risk population and the related organizations in time and in a right manner. Additionally, people who were exposed to the winds didn't know the appropriate safety measures. Focusing much more on establishing EWS to alert the risk prone population timely and public education for taking safety measures when exposed to the disastrous situation is recommended.


Osteochondral autograft transplantation of the femoral head in sequelae of developmental dysplasia of hip: A case report and review of the literature.
Although osteochondral autograft transplantation (OAT) in the knee and ankle has gained much popularity on the other hand the technique has rarely been applied in the femoral head. In this article, we present a 15-year-old female patient with unstable chondral lesion on the right femoral head. She had a history of open reduction for developmental dysplasia which resulted in avascular necrosis. She had coxa magna, breva and trochanteric overgrowth along with an unstable chondral lesion on the superolateral part of the femoral head. She underwent OAT for chondral lesion, femoral head reshaping and relative neck lengthening. Her Harris Hip Score improved from 55 to 90 in the 18 months of follow-up. The case is unique in a way that the autografts were harvested from the anterior part of the same femoral head that was already intended to be removed during osteochondroplasty.


Extracellular vesicles shed by glioma cells: pathogenic role and clinical value.
Extracellular vesicles (EVs) are commonly used by normal and tumor cells for communication at long distances to exchange by complex molecular messages and deliver a variety of essential biomolecules. EVs (exosomes and microvesicles) released in large numbers by glioma cells represent a key mechanism of intercellular signaling. Tumor-derived EVs are produced to regulate all vital functions of tumor cells including growth, proliferation, migration, survival, malignancy, invasion, and resistance to host anti-tumor immunity and anti-cancer drugs. Glioma EVs were shown to carry a variety of biomolecules such as oncogenic growth factors, receptors, enzymes, transcription factors, signaling and immunomodulatory molecules, DNA of mutated and nonmutated oncogenes, RNA transcripts, and noncoding RNA including retrotransposons, vault RNA, and microRNAs. Glioma-derived EVs can be useful as a source of potential tumor-associated biomarkers essential for development and validation of new diagnostic and prognostic tools for glioma and glioblastoma. Tumor EVs are enriched with glioma antigens that could be helpful, for example, for development of new advanced anti-tumor immune vaccines based on autologous dendritic cells stimulated by tumor-specific antigens.


Effects of Reactive Oxygen Species on in vitro Filtration of Water and Albumin across Glomerular Basement Membrane.
Most of the interest in the glomerular basement membrane (GBM) stems from the observation that it undergoes morphological changes in renal disease. Studies on persistent proteinuria in experimental animal models have shown that the permeability properties of the GBM have been altered as a result of protein degradation and cross-linking of type IV collagen via its NC1 domains promoted by reactive oxygen species (ROS) and extrusion of tubular cell contents. We used the in vitro ultrafiltration technique to assess permeability properties of bare isolated GBM films to water and albumin in the Munich Wistar Fromter rat model of glomerular injury. Hydraulic permeability for water and albumin solutions and albumin fractional clearances were measured for rats treated with lisinopril [an angiotensin converting enzyme (ACE) inhibitor] and were compared with those measured for rats treated with dimethylthiouria (an ROS scavenger) and their control groups, at four pressure levels (50, 100, 200, and 300 mmHg). The ACE inhibitors and ROS scavengers treatment regimens for studied rats in addition to significantly lowering their systolic blood pressure and urinary protein excretion values to normal levels, have significantly increased their in vitro hydraulic and Darcy permeability, which is a measure of the intrinsic hydraulic conductance of the GBM, either in the absence or presence of albumin; in comparison with control animals. We believe that these favorable effects may derive from ROS scavenging beneficial effects that preserve the GBM protein structure by reducing entactin and laminin degradation and type IV collagen cross-linking.


Can urgency classification of the Manchester triage system predict serious bacterial infections in febrile children?
To evaluate the discriminative ability of the Manchester triage system (MTS) to identify serious bacterial infections (SBIs) in children with fever in the emergency department (ED) and to study the association between predictors of SBI and discriminators of MTS urgency of care. This prospective observational study included 1255 children with fever (1 month-16 years) attending the ED of the Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands in 2008-9. Triage urgency was determined with the MTS (urgency (U) level 1-5). The relationship between triage urgency and SBI was assessed with multivariable logistic regression, including effects of age, sex and temperature. Discriminative ability was assessed by receiver operating characteristic curve analysis. SBI prevalence was 11% (n=131, 95% CI 9% to 12%). The discriminative value of the MTS for predicting SBI was 0.57 (95% CI 0.52 to 0.62), and the MTS did not contribute to a model including age, sex and temperature. The sensitivity of the MTS (U1-2 vs U3-5) to detect SBI was 0.42 (95% CI 0.33 to 0.51) and specificity was 0.69 (95% CI 0.66 to 0.72). MTS high urgency discriminators include several known predictors of SBI, such as fever, work of breathing, meningism and oxygen saturation, but apply to non-SBI children as well. The MTS has poor discriminative ability to predict the presence of SBIs in children presenting with fever to the paediatric ED. Important predictors of SBI are represented within the MTS, but are used in a different way to classify urgency.


Ultraviolet Rayleigh-Mie lidar for daytime-temperature profiling of the troposphere.
A UV Rayleigh-Mie scattering lidar has been developed for daytime measurement of temperature and aerosol optical properties in the troposphere. The transmitter is a narrowband, injection-seeded, pulsed, third-harmonic Nd:YAG laser at an eye-safe wavelength of 355 nm. Two Fabry-Perot etalons (FPEs) with a dual-pass optical layout filter the molecular Rayleigh scattering components spectrally for retrieval of the temperature and provide a high rejection rate for aerosol Mie scattering in excess of 43 dB. The Mie signal is filtered with a third FPE filter for direct profiling of aerosol optical properties. The Mie scattering component in the Rayleigh signals, which will have influence on temperature measurements, is corrected by using a measure of aerosol scattering because of the relative insufficiency of Mie rejection of Rayleigh filters in the presence of dense aerosols or clouds, and the Mie rejection capability of system is thus improved. A narrowband interference filter is incorporated with the FPEs to block solar radiation. Also, the small field of view (0.1 mrad) of the receiver and the UV wavelength used enhance the ability of the lidar to suppress the solar background signal in daytime measurement. The system is relatively compact, with a power-aperture product of 0.18 W m(-2), and has a high sensitivity to temperature change (0.62%/K). Lidar measurements taken under different weather conditions (winter and summer) are demonstrated. Good agreement between the lidar and the radiosonde measurements was obtained in terms of lapse rates and inversions. Statistical temperature errors of less than 1 K up to a height of 2 km are obtainable, with an averaging time of approximately 12 min for daytime measurements.


Anemia in a middle aged female with aortitis: a case report.
Idiopathic aortitis is among the most common causes of non-infectious aortitis, which rarely presents with anemia. Here we report a case of a 49-year-old muhajir female who presented with shortness of breath and easy fatigability for the past 6 months. Physical examination revealed pallor and a diastolic murmur in the aortic region. Echocardiography showed thickened and calcified aortic and mitral valves, severe aortic regurgitation and dilatation of ascending aorta. She was advised aortic valve replacement and was referred to a haematologist due to concomitant anemia. Complete blood counts revealed haemoglobin: 7.7 gm/dl, mean corpuscular volume (MCV): 78 fl, mean corpuscular haemoglobin (MCH):23 pg, total white cell count: 9.0 × 10(9)/L and platelet count: 227 × 10(9)/L. Erythrocyte sedimentation rate (ESR) was 100 mm/hr. There was suspicion of myelodysplastic syndrome, but could not be confirmed as the patient refused bone marrow and cytogenetic studies. She was given erythropoietin, folic acid and ferrous sulphate. Following relatively prolonged therapy, her haemoglobin level increased to approximately 9.0 gm/dL. She was transfused with packed red cells and underwent aortic valve and ascending aorta replacement. The ascending aorta was dilated and aortic wall markedly thick and irregular. Histopathology of the resected aorta revealed granulomatous aortitis. She was prescribed prednisolone, which resulted in further incremental rise of haemoglobin to 13.1 gm/dL. One month later, she developed complaints of blurred vision in the right eye and was diagnosed with central retinal vein occlusion. She was treated with antiplatelet agents and her vision improved. After 3 months, she was asymptomatic and her haemoglobin level rose to 11.2 gm/dL without hematinic therapy or blood transfusion. She was begun on anticoagulant therapy and remains clinically stable. We report a case of idiopathic aortitis with presumed diagnosis of anemia of chronic disease exhibiting a transient response towards steroid therapy post-valvuloplasty.


Epidemiology of severity of temporomandibular disorders in Brazilian women.
To evaluate the severity of temporomandibular disorders (TMD) of women in the municipality of Araraquara (Brazil) as well as the contribution of the perception of oral health, mandibular functional limitation, and sociodemographic variables on the severity of TMD. The participants were interviewed by telephone. Information regarding age, marital status, economic level, education, and use and type of dental prostheses was surveyed. To evaluate TMD severity, mandibular functional limitation and perception of oral health, Fonseca's Anamnesic Index (IAF), the Mandibular Function Impairment Questionnaire (MFIQ), and the General Oral Health Assessment Index (GOHAI) were used. To evaluate the contribution of these variables on TMD severity, a structural equation model (SEM) was fitted to the data and assessed by usual goodness-of- fit indices. A total of 701 women with a mean age of 44.36 years (SD = 16.31) participated. According to the IAF, 59.6% (95% confidence interval = 56.0%-63.2%) of the women were classified as having TMD, of which 63.9% presented light, 26.8% moderate, and 9.3% severe TMD. Mandibular functional limitation was low in 91.0% of the women, moderate in 7.1%, and severe in 1.9%. Goodness-of-fit for the structural model was adequate. The predictors explained 43% of the variation in the TMD severity, with significant contributions of the variables dental prostheses (β = -.008; P = .006), perception of oral health (β = -.43; P < .001), and mandibular functional limitation (β = .014; P = 014). The severity of TMD among Brazilian women was greater in nonusers of dental prostheses and was also associated with greater mandibular functional limitation and poor perception of oral health.


Administration of Chlorella sp. microalgae reduces endotoxemia, intestinal oxidative stress and bacterial translocation in experimental biliary obstruction.
Endotoxemia has long been documented in obstructive jaundice, and altered intestinal barrier function is considered to be one of the important mechanisms for this phenomenon. The aim of this study was to investigate the role of different microalgae (Chlorella sp. and Spirulina sp.) extracts in intestinal barrier function and oxidative stress in experimentally jaundiced rats. A total of 60 male wistar rats were randomly divided into four groups of 15 each: I, sham operated; II, bile duct ligation (BDL); III, BDL+Chlorella sp.; IV, BDL+Spirulina sp. Rats were fed rat chow or microalgae extracts supplemented enteral diet ten days after sham operation or BDL. Main outcome measures were endotoxin concentrations in plasma, evidence of bacterial translocation (BT) in mesenteric lymph nodes (MLNs) and liver, oxidative stress, and histology. Compared to the group I, a significant increase in contamined MLNs, liver, and spleen samples and increased endotoxemia were noted in group II (P<0.01) but were significant reduced in group III (P<0.05). There was no significant difference in BT rate between the group II and group IV (P>0.05). Moreover, Chlorella sp. administration protected in jaundiced rats against oxidative stress, as demonstrated by reduction of intestinal lipid peroxidation, increase of the antioxidant reduced glutathione (GSH), and decrease of the oxidized glutathione (GSSG). The intestinal mucosa in control rats was atrophic with significantly decreased villous density and total mucosal thickness. Chlorella sp. caused a significant reduction in villous atrophy compared with controls. Chlorella sp. microalgae supplemented enteral diet has significant protective effects on intestinal mucosa barrier in obstructive jaundice, and reduces intestinal translocation of bacteria and endotoxin.


Global ecosystems and fire: Multi-model assessment of fire-induced tree-cover and carbon storage reduction.
In this study, we use simulations from seven global vegetation models to provide the first multi-model estimate of fire impacts on global tree cover and the carbon cycle under current climate and anthropogenic land use conditions, averaged for the years 2001-2012. Fire globally reduces the tree covered area and vegetation carbon storage by 10%. Regionally, the effects are much stronger, up to 20% for certain latitudinal bands, and 17% in savanna regions. Global fire effects on total carbon storage and carbon turnover times are lower with the effect on gross primary productivity (GPP) close to 0. We find the strongest impacts of fire in savanna regions. Climatic conditions in regions with the highest burned area differ from regions with highest absolute fire impact, which are characterized by higher precipitation. Our estimates of fire-induced vegetation change are lower than previous studies. We attribute these differences to different definitions of vegetation change and effects of anthropogenic land use, which were not considered in previous studies and decreases the impact of fire on tree cover. Accounting for fires significantly improves the spatial patterns of simulated tree cover, which demonstrates the need to represent fire in dynamic vegetation models. Based upon comparisons between models and observations, process understanding and representation in models, we assess a higher confidence in the fire impact on tree cover and vegetation carbon compared to GPP, total carbon storage and turnover times. We have higher confidence in the spatial patterns compared to the global totals of the simulated fire impact. As we used an ensemble of state-of-the-art fire models, including effects of land use and the ensemble median or mean compares better to observational datasets than any individual model, we consider the here presented results to be the current best estimate of global fire effects on ecosystems.


Southern Corn Rootworm (Coleoptera: Chrysomelidae) Adult Emergence and Population Growth Assessment After Selection With Vacuolar ATPase-A double-stranded RNA Over Multiple Generations.
The southern corn rootworm, Diabrotica undecimpunctata howardi Barber (Coleoptera: Chrysomelidae), was exposed over multiple generations to vacuolar (v)ATPase-A double-stranded (ds)RNA, first as adults and later, as neonate larvae. During adult selection, high mortality and lower fecundity were observed in the RNAi-selected cages after beetles were exposed to sublethal dsRNA concentrations that varied between LC40 and LC75. During larval selection, a delay in adult emergence and effects on population growth parameters were observed after neonates were exposed to sublethal dsRNA concentrations that varied between LC50 and LC70. Some of the parameters measured for adult emergence such as time to reach maximum linear adult emergence, time elapsed before attaining linear emergence, termination point of the linear emergence, and total days of linear emergence increase, were significantly different between RNAi-selected and control colonies for at least one generation. Significant differences were also observed in population growth parameters such as growth rate, net reproductive rate, doubling time, and generation time. After seven generations of selection, there was no indication that resistance evolved. The sublethal effects caused by exposures of southern corn rootworm to dsRNAs can affect important life history traits and fitness especially through delays in adult emergence and reduction in population growth. Although changes in susceptibility did not occur, the observation of sublethal effects suggests important responses to potential selection pressure. Assuming resistance involves a recessive trait, random mating between susceptible and resistant individuals is an important factor that allows sustainable use of transgenic plants, and delays in adult emergence observed in our studies could potentially compromise this assumption.


Effectiveness of interventions to prevent pre-frailty and frailty progression in older adults: a systematic review.
To summarize the best available evidence regarding the effectiveness of interventions for preventing frailty progression in older adults. Frailty is an age-related state of decreased physiological reserves characterized by an increased risk of poor clinical outcomes. Evidence supporting the malleability of frailty, its prevention and treatment, has been presented. The review considered studies on older adults aged 65 and over, explicitly identified as pre-frail or frail, who had been undergoing interventions focusing on the prevention of frailty progression. Participants selected on the basis of specific illness or with a terminal diagnosis were excluded. The comparator was usual care, alternative therapeutic interventions or no intervention. The primary outcome was frailty. Secondary outcomes included: (i) cognition, quality of life, activities of daily living, caregiver burden, functional capacity, depression and other mental health-related outcomes, self-perceived health and social engagement; (ii) drugs and prescriptions, analytical parameters, adverse outcomes and comorbidities; (iii) costs, and/or costs relative to benefits and/or savings associated with implementing the interventions for frailty. Experimental study designs, cost effectiveness, cost benefit, cost minimization and cost utility studies were considered for inclusion. Databases for published and unpublished studies, available in English, Portuguese, Spanish, Italian and Dutch, from January 2001 to November 2015, were searched. Critical appraisal was conducted using standardized instruments from the Joanna Briggs Institute. Data was extracted using the standardized tools designed for quantitative and economic studies. Data was presented in a narrative form due to the heterogeneity of included studies. Twenty-one studies, all randomized controlled trials, with a total of 5275 older adults and describing 33 interventions, met the criteria for inclusion. Economic analyses were conducted in two studies. Physical exercise programs were shown to be generally effective for reducing or postponing frailty but only when conducted in groups. Favorable effects on frailty indicators were also observed after the interventions, based on physical exercise with supplementation, supplementation alone, cognitive training and combined treatment. Group meetings and home visits were not found to be universally effective. Lack of efficacy was evidenced for physical exercise performed individually or delivered one-to-one, hormone supplementation and problem solving therapy. Individually tailored management programs for clinical conditions had inconsistent effects on frailty prevalence. Economic studies demonstrated that this type of intervention, as compared to usual care, provided better value for money, particularly for very frail community-dwelling participants, and had favorable effects in some of the frailty-related outcomes in inpatient and outpatient management, without increasing costs. This review found mixed results regarding the effectiveness of frailty interventions. However, there is clear evidence on the usefulness of such interventions in carefully chosen evidence-based circumstances, both for frailty itself and for secondary outcomes, supporting clinical investment of resources in frailty intervention. Further research is required to reinforce current evidence and examine the impact of the initial level of frailty on the benefits of different interventions. There is also a need for economic evaluation of frailty interventions.


Imaginal discs secrete insulin-like peptide 8 to mediate plasticity of growth and maturation.
Developing animals frequently adjust their growth programs and/or their maturation or metamorphosis to compensate for growth disturbances (such as injury or tumor) and ensure normal adult size. Such plasticity entails tissue and organ communication to preserve their proportions and symmetry. Here, we show that imaginal discs autonomously activate DILP8, a Drosophila insulin-like peptide, to communicate abnormal growth and postpone maturation. DILP8 delays metamorphosis by inhibiting ecdysone biosynthesis, slowing growth in the imaginal discs, and generating normal-sized animals. Loss of dilp8 yields asymmetric individuals with an unusually large variation in size and a more varied time of maturation. Thus, DILP8 is a fundamental element of the hitherto ill-defined machinery governing the plasticity that ensures developmental stability and robustness.


[Magnetoencephalographic responses to odor and non-odor by fast Fourier transformation analysis in humans].
Magnetoencephalographic (MEG) responses to odor (amyl-acetate) and non-odor stimuli for 1 second were recorded in 9 healthy volunteers (right handed) with a dual 37-channel SQUID (Magnes, Bti Co.) and evaluated by fast Fourier transformation analysis, with the following results: 1. On MEG analysis, the spectral density increase in the left mid-central region at a frequency of 7 Hz was significantly greater in response to odor than in response to non-odor stimuli. This greater increase is apparently related to the presence of the odor perception mechanism in the orbital frontal area, a major center of the olfactory system. 2. Both increased and decreased spectral density areas at a frequency of 8 Hz were observed over the right hemisphere when no stimuli was compared with non-odor and no stimulus compared with odor. These changes may reflect a high level of vigilance caused by stimulation. 3. When no stimulus was compared with non-odor stimulation, a significant spectral density increase at a frequency of 11 Hz was noted. Similar trends were observed at frequencies of 11 and 12 Hz when no stimulus was compared with odor. These findings indicated increased attention in response to random presentation of odor and non-odor. 4. Significant differences at frequencies from 14 to 24 Hz were noted in the contralateral hemisphere when no stimulus was compared with odor stimuli. MEG spectral densities at 21 and 22 Hz were also noted in the contralateral hemisphere when no stimulus was compared with non-odor stimulus. These differences apparently arise from the response of the somato-sensory cortex to non-odor stimuli and amyl-acetate. Alternation of MEG spectral densities at frequencies from 14 to 17 Hz and 23 to 24 Hz in the left hemisphere was noted when no stimulus was compared with non-odor and no stimulus was compared with odor. These results appear to be related to "emotions" of pleasantness and unpleasantness evoked by non-odor and odor.