The measurement of visual acuity in children: an evidence-based update.
Over the past decade, a number of large clinical trials have provided important information relating to the reliability and repeatability of commonly used paediatric tests of vision and their role in the diagnosis and management of paediatric ocular diseases. The aim of this review is to summarise recent findings on the use of paediatric visual acuity tests in clinical practice and to discuss the validity and accuracy of visual acuity measurements in infants and young children. We provide a broad overview of the benefits and challenges of measuring visual acuity in children and then discuss age-appropriate tests for measuring visual acuity in infants through to school-age children. We also discuss normative values for visual acuity in each age group and, where possible, provide comparisons of results between tests with a particular focus on the importance of optotype design.


A comparative study of LaBr3(Ce(3+)) and CeBr3 based gamma-ray spectrometers for planetary remote sensing applications.
The recent availability of large volume cerium bromide crystals raises the possibility of substantially improving gamma-ray spectrometer limiting flux sensitivities over current systems based on the lanthanum tri-halides, e.g., lanthanum bromide and lanthanum chloride, especially for remote sensing, low-level counting applications or any type of measurement characterized by poor signal to noise ratios. The Russian Space Research Institute has developed and manufactured a highly sensitive gamma-ray spectrometer for remote sensing observations of the planet Mercury from the Mercury Polar Orbiter (MPO), which forms part of ESA's BepiColombo mission. The Flight Model (FM) gamma-ray spectrometer is based on a 3-in. single crystal of LaBr3(Ce(3+)) produced in a separate crystal development programme specifically for this mission. During the spectrometers development, manufacturing, and qualification phases, large crystals of CeBr3 became available in a subsequent phase of the same crystal development programme. Consequently, the Flight Spare Model (FSM) gamma-ray spectrometer was retrofitted with a 3-in. CeBr3 crystal and qualified for space. Except for the crystals, the two systems are essentially identical. In this paper, we report on a comparative assessment of the two systems, in terms of their respective spectral properties, as well as their suitability for use in planetary mission with respect to radiation tolerance and their propensity for activation. We also contrast their performance with a Ge detector representative of that flown on MESSENGER and show that: (a) both LaBr3(Ce(3+)) and CeBr3 provide superior detection systems over HPGe in the context of minimally resourced spacecraft and (b) CeBr3 is a more attractive system than LaBr3(Ce(3+)) in terms of sensitivities at lower gamma fluxes. Based on the tests, the FM has now been replaced by the FSM on the BepiColombo spacecraft. Thus, CeBr3 now forms the central gamma-ray detection element on the MPO spacecraft.


Inhibitor-resistant TEM (IRT) beta-lactamases with different substitutions at position 244.
A novel inhibitor-resistant TEM (IRT) beta-lactamase was detected in an Escherichia coli isolate resistant to amoxicillin-clavulanate and susceptible to cephalothin. The substrate and inhibitor profiles of this beta-lactamase were similar to those of IRT-1 and IRT-2. The novel IRT's bla gene was sequenced, and the deduced amino acid sequence showed the amino acid replacement Arg for His-244 of the TEM-1 sequence. Substitutions for Arg-244 have been reported in three TEM-1 mutants: IRT-1 (which corresponds to TEM-31) (Cys), IRT-2/TEM-30 (Ser), and TEM-41 (Thr). We designated this novel beta-lactamase, which corresponds to TEM-51, IRT-15.


[A method of isolation and preparation of the radial artery for direct revascularization of the myocardium].
The authors describe a technique of the isolation, preparation and use of the radial artery for the aortocoronary shunting for ischemic heart disease. The method is anatomically valid and approbated in 300 operations on the open heart. Safety and efficiency of using the radial artery is due to its not traumatic isolation, original preparing for shunting and medicamental prevention of its spasm.


Surface immobilization of plant cells.
A novel technique has been developed to immobilize plant cells. The cells are deposited on a surface of man-made fibrous material that provides for strong binding of the plant tissue biomass growing in the submerged culture. The immobilized plant cells remain fully viable. Relatively uniform biomass loadings of up to 20 mg d.w. plant cells/cm(2) support material have been attained. All plant cells from the inoculum suspension became attached within the first 24-48 h depending on the support matrix configuration and hydraulic culture conditions. The advantages and scale-up potential of this technique are discussed and compared to other culturing modes.


A New Double Stranded RNA Suppresses Bladder Cancer Development by Upregulating p21 (Waf1/CIP1) Expression.
We have previously demonstrated that miR-1180-5p has potent ability to upregulate p21 expression by targeting promoter and inhibit bladder cancer. This prompted us to conjecture that a candidate dsRNA (dsP21-397) with perfect complementarity to the miR-1180-5p target site of p21 promoter may also trigger p21 expression. Transfection of dsP21-397 into T24 and EJ cells significantly activated p21 expression at 72 h and the activation presented in a time-course and dose-dependent manner. Moreover, the p21-activated activities of dsP21-397 and miR-1180-5p are not significantly different. Overexpression of p21 downregulated Cyclin D1, CDK4/6, and Cyclin A2 expression, and thereby induced cell cycle arrest and inhibited proliferation. Moreover, dsP21-397 suppressed bladder cancer largely depended on manipulating p21. In conclusion, our study identifies a pair of miRNA-dsRNA mediating endogenous p21 overexpression.


Association of plasma concentration of small heat shock protein B7 with acute coronary syndrome.
Heat shock proteins (HSPs) act as chaperones and have a protective function in cardiovascular diseases. The clinical association of a novel small HSPB7 with cardiovascular disease, however, has not been reported. The aim of this study was to investigate the potential biological functions of HSPB7 and its relationship with acute coronary syndrome (ACS). A mouse myocardial infarction (MI) model and samples from clinical human subjects were used to determine plasma HSPB7 concentration after acute MI. The associations of plasma HSPB7 concentration with ACS and other risk factors of coronary artery disease were analyzed. Plasma HSPB7 concentration was found to be rapidly elevated in mice after coronary artery ligation. In addition, plasma HSPB7 concentration was significantly higher in patients with ACS than in control patients with non-cardiac chest pain (5.1 ng/ml vs. 2.9 ng/ml, P<0.001). Plasma HSPB7 was detected as early as 1-3 h after the onset of symptoms and remained detectable up to 24h. Furthermore, in patients presenting to the emergency department with acute chest pain, HSPB7 level was an independent risk factor of ACS (adjusted odds ratio, 7.44; 95% confidence interval: 1.91-28.93, P<0.01). HSPB7 is a potential early biomarker after MI and serves as an independent risk factor of ACS in patients with acute chest pain.


Kinetic studies on the reduction of cytochrome c. Reaction with dihydroxy conjugated compounds (catechols and quinols).
The kinetics of reduction of cytochrome c by catechol(s), quinol(s) and related compounds were investigated by stopped-flow spectrophotometry. Studies on the influence of pH on the rates indicate that only deprotonated forms of these compounds act as reducing agents, with the dianionic forms being the most effective. The pH-independent second-order rate constants are reported. Hammett treatment of the effects of substituents on the aromatic ring structure of the reductants show that for electron transfer to occur the charge on the deprotonated species must not be withdrawn on to the substituents. Possible sites for electron donation to cytochrome c are discussed, and the results indicate that the haem edge is a likely candidate.


The gene therapy journey for hemophilia: are we there yet?
Since the isolation and characterization of the genes for FVIII and FIX some 30 years ago, a longstanding goal of the field has been development of successful gene therapy for the hemophilias. In a landmark study published in 2011, Nathwani et al demonstrated successful conversion of severe hemophilia B to mild or moderate disease in 6 adult males who underwent intravenous infusion of an adeno-associated viral (AAV) vector expressing factor IX. These 6 subjects have now exhibited expression of FIX at levels ranging from 1% to 6% of normal for periods of > 2 years. This review discusses obstacles that were overcome to reach this goal and the next steps in clinical investigation. Safety issues that will need to be addressed before more widespread use of this approach are discussed. Efforts to extend AAV-mediated gene therapy to hemophilia A, and alternate approaches that may be useful for persons with severe liver disease, who may not be candidates for gene transfer to liver, are also discussed.


Aging in healthy men impairs recombinant human luteinizing hormone (LH)-stimulated testosterone secretion monitored under a two-day intravenous pulsatile LH clamp.
Testosterone (Te) depletion in aging men in principle could reflect deficits in the hypothalamus, pituitary gland, or testis. Available pharmacological studies of possible failure of Leydig cell steroidogenesis remain inconclusive. The objective of the study was to assess Te secretion in older and young men in response to near physiological LH stimulation. Pulsatile i.v. infusion of recombinant human LH was administered for 2 d to stimulate Te secretion during suppression of endogenous LH concentrations with a potent selective GnRH receptor antagonist (ganirelix). SUBJECTS/CONTEXT: Healthy older (aged 60-73 yr, n = 8) and young (19-30 yr, n = 13) men were studied in an academic setting. Pulsatile LH and Te concentrations on the second day of exogenous LH stimulation were measured. Serum ganirelix concentrations and infused LH pulse increments were similar by age. In contrast, older subjects manifested: 1) reduced mean Te concentrations (P = 0.016), Te peak heights (P = 0.014), increments (P = 0.010), summed areas (P < 0.013), and interpeak Te concentrations (P = 0.023); 2) decreased Te to LH concentration ratios (P = 0.002); 3) diminished LH-Te feed-forward synchrony (P = 0.020); and 4) a blunted amplitude (P = 0.036) and advanced phase (P = 0.013) of diurnal Te rhythms. A novel regimen of pulsatile LH stimulation for 48 h during GnRH receptor blockade unmasks deficits in pulsatile, basal, synchronous, and nyctohemeral Te secretion in healthy older men. These findings do not exclude concomitant defects in GnRH outflow and/or Te-negative feedback in the aging male.


Contactless Video-Based Heart Rate Monitoring of a Resting and an Anesthetized Pig.
Heart rate (HR) is a vital bio-signal that is relatively easy to monitor with contact sensors and is related to a living organism's state of health, stress and well-being. The objective of this study was to develop an algorithm to extract HR (in beats per minute) of an anesthetized and a resting pig from raw video data as a first step towards continuous monitoring of health and welfare of pigs. Data were obtained from two experiments, wherein the pigs were video recorded whilst wearing an electrocardiography (ECG) monitoring system as gold standard (GS). In order to develop the algorithm, this study used a bandpass filter to remove noise. Then, a short-time Fourier transform (STFT) method was tested by evaluating different window sizes and window functions to accurately identify the HR. The resulting algorithm was first tested on videos of an anesthetized pig that maintained a relatively constant HR. The GS HR measurements for the anesthetized pig had a mean value of 71.76 bpm and standard deviation (SD) of 3.57 bpm. The developed algorithm had 2.33 bpm in mean absolute error (MAE), 3.09 bpm in root mean square error (RMSE) and 67% in HR estimation error below 3.5 bpm. The sensitivity of the algorithm was then tested on the video of a non-anaesthetized resting pig, as an animal in this state has more fluctuations in HR than an anaesthetized pig, while motion artefacts are still minimized due to resting. The GS HR measurements for the resting pig had a mean value of 161.43 bpm and SD of 10.11 bpm. The video-extracted HR showed a performance of 4.69 bpm in MAE, 6.43 bpm in RMSE and 57% in . The results showed that HR monitoring using only the green channel of the video signal was better than using three color channels, which reduces computing complexity. By comparing different regions of interest (ROI), the region around the abdomen was found physiologically better than the face and front leg parts. In summary, the developed algorithm based on video data has potential to be used for contactless HR measurement and may be applied on resting pigs for real-time monitoring of their health and welfare status, which is of significant interest for veterinarians and farmers.


Addressing the public health burden caused by the nutrition transition through the Healthy Foods North nutrition and lifestyle intervention programme.
Dietary inadequacies, low levels of physical activity, excessive energy intake and high obesity prevalence have placed Inuit and Inuvialuit populations of the Canadian Arctic at increased risk of chronic disease. An evidence-based, community participatory process was used to develop Healthy Foods North (HFN), a culturally appropriate nutrition and physical activity intervention programme that aimed to reduce risk of chronic disease and improve dietary adequacy amongst Inuit/Inuvialuit in Nunavut and the Northwest Territories. HFN was implemented over the course of 12 months in a series of seven phases between October 2008 and 2009 (Nunavut) and June 2008 and 2009 (Northwest Territories). Combining behaviour change and environmental strategies to increase both the availability of healthful food choices in local shops and opportunities for increasing physical activity, HFN promoted the consumption of traditional foods and nutrient-dense and/or low energy shop-bought foods, utilisation of preparation methods that do not add fat content, decreased consumption of high-energy shop-bought foods, and increased physical activity. Messages identified in the community workshops, such as the importance of family eating and sharing, were emphasised throughout the intervention. Intervention components were conducted by community staff and included working with shops to increase the stocking of healthy foods, point of purchase signage and promotion in shops and community settings, pedometer challenges in the workplace and use of community media (e.g. radio and cable television advertisements) to reinforce key messages. HFN represents an innovative multilevel approach to the reduction of chronic disease risk factors amongst Inuit and Inuvialuit, based on strong collaboration with local agencies, government and institutions.


Enzyme-linked immunosorbent assay reactivity of torovirus-like particles in fecal specimens from humans with diarrhea.
Toroviruses are recognized enteric pathogens of cattle and horses; in humans, similar pleomorphic particles have been described, but doubt has been raised concerning their identity as viruses. We screened fecal samples from humans with diarrhea for the presence of torovirus-like particles (TVLPs) by electron microscopy and subsequently used an enzyme-linked immunosorbent assay (ELISA) with bovine torovirus reference reagents to test for the presence of torovirus antigens. To add another selection criterion to this heterologous ELISA, we enriched the TVLPs from the stool specimens by using sucrose density gradients before testing. The results of ELISA and EM correlated significantly, the ELISA having a sensitivity of 68% and a specificity of 86% (chi-square, P < 0.0001). In the gradient, peaks of ELISA reactivity were found at a buoyant density of 1.16 g/ml and were parallel to those found when using bovine torovirus. Furthermore, in 50% of the ELISA-positive gradients, a hemagglutinin for human group O erythrocytes comigrated with the peaks of ELISA reactivity. We were unable to isolate human TVLPs in human colonic tumor or rectal tumor cells. We cloned and sequenced amplification products obtained by low-stringency polymerase chain reaction amplification using consensus primers mapping to the 3' end of the genome of animal toroviruses, but found no significant homologies with animals torovirus sequences. Rabbits were inoculated with material from the gradient peak fractions of human stool specimens, and their sera were assayed for immunologic comparison with bovine torovirus as a reference. A two-way antigenic cross-reactivity was seen between human TVLP and bovine torovirus reagents when tested by ELISA. The rabbit antisera to human TVLP detected a higher number of electron microscopy-positive stool specimens than did the rabbit antisera to bovine torovirus. The application of these assays and reagents should help to elucidate the roles of TVLPs and toroviruses in diarrheal disease in humans.


Alternative model for mechanism-based inhibition of Escherichia coli ribonucleotide reductase by 2'-azido-2'-deoxyuridine 5'-diphosphate.
Ribonucleotide reductase (RDPR) from Escherichia coli is composed of two subunits, R1 and R2, and catalyzes the conversion of nucleotides to deoxynucleotides. The mechanism of inactivation of RDPR by 2'-azido-2'-deoxynucleoside 5'-diphosphate (N3UDP) has been examined using a variety of isotopically labeled derivatives: (1'-, 2'-, 3'-, or 4'-[2H])-N3UDPs and 2'-[15N3, 13C]-N3UDP. Electron paramagnetic resonance (EPR) and electron spin echo envelope modulation (ESEEM) spectroscopy studies using these compounds indicate that the 2' carbon-nitrogen bond to the azide moiety is cleaved prior to or upon formation of the nitrogen-centered radical derived from the azide moiety of N3UDP. EPR studies reveal no hyperfine interactions of the nitrogen-centered radical with the 1', 2', 3', or 4' hydrogens of N3UDP. ESEEM studies however, reveal that the 1' and 4' deuterons are 3.3 +/- 0.2 and 2.6 +/- 0.3 A, respectively, from the nitrogen-centered radical. Further support for carbon-nitrogen bond cleavage is derived from studies of the interaction of oxidized R1, C225SR1, and C462SR1 with R2 and N3UDP. In all three cases, in contrast to the results with the wild type R1, azide is detected. Nitrogen-centered radical is not observed with either oxidized R1 or C225SR1 but is observed with C462SR1. These results suggest that C225 is required for the conversion of azide into N2 and a nitrogen-centered radical. The dynamics of the inactivation of RDPR by N3UDP have also been examined. Use of [3'-2H]N3UDP reveals an isotope effect of approximately 2 on the loss of the tyrosyl radical and the rate of inactivation of RDPR. In both cases the kinetics are complex, suggesting multiple modes of inactivation. In addition, several modes of inactivation are required to explain the observation that loss of the tyrosyl radical is slower than the rate of inactivation. Studies using [5'-3H]N3UDP reveal that the rapid inactivation is the result of the formation of a tight noncovalent complex between modified nucleotide, nitrogen-centered radical and RDPR. Destruction of the nitrogen-centered radical is a slow process which appears to be accompanied by decomposition of the modified nucleotide into PPi, uracil, and 2-methylene-3(2H)-furanone. The latter covalently modifies R1 and ultimately leads to loss of approximately 50% of the activity of R1.


A standardized letter of recommendation for residency application.
Emergency medicine (EM) program directors have expressed a desire for more evaluative data to be included in application materials. This is consistent with frustrations expressed by program directors of multiple specialties, but mostly by those in specialties with more competitive matches. Some of the concerns about traditional narrative letters of recommendation included lack of uniform information, lack of relative value given for interval grading, and a perception of ambiguity with regard to terminology. The Council of Emergency Medicine Residency Directors established a task force in 1995 that created a standardized letter of recommendation form. This form, to be completed by EM faculty, requests that objective, comparative, and narrative information be reported regarding the residency applicant.


Dietary diversity and associated factors among school-aged children and adolescents in Lokossa district of southern Benin: a cross-sectional study.
The main objective of this study was to assess the prevalence of dietary diversity and associated factors. Cross-sectional study. Lokossa district, southern Benin. A survey conducted in a probabilistic sample of 612 students (345 boys and 267 girls), aged 8-17 years old from 26 primary schools. Dietary Diversity Scores were calculated by summing the number of food groups consumed by the schoolchildren and adolescents over a 24-hour recall period. Adequate dietary diversity can be assigned to a consumption that is greater than or equal to five food groups, and inadequate dietary diversity can be assigned to a consumption that is lower than five food groups. Descriptive statistics such as frequency, mean and SD were computed. Statistical analysis was performed on the data to determine which variables were associated with dietary diversity as well as the results of the adjusted OR with a 95% CI. A p<0.05 was considered statistically significant. The proportion of schoolchildren and adolescents with inadequate dietary diversity was 25.8% (95% CI 15.1% to 40.5%). Schoolchildren and adolescents living in rural areas, having low household socioeconomic status, eating breakfast less than 5 days per week and no eating school meals were significantly associated with inadequate dietary diversity. The results of this study revealed that the diet among schoolchildren and adolescents lacked diversity and is associated with socioeconomic status, rural living, eating breakfast and school meals. Public health interventions, such as school meal programmes in rural and isolated areas, in association with poverty-reducing programmes and nutrition education, are recommended to improve the quality of diet and limit the consequences of poor diet diversity.


Free vascularized lateral femoral cutaneous nerve graft with anterolateral thigh flap for reconstruction of facial nerve defects.
Wide resection of a malignant tumor in the parotid gland often results in loss of a long segment of facial nerve, as well as a soft-tissue defect. With conventional nerve grafts, functional recovery of the facial nerve is poor in cases with risk factors that might inhibit nerve regeneration, such as a history of irradiation and a recipient bed scarred from previous operations. For such cases, a vascularized nerve graft is reported to be more effective than a nonvascularized nerve graft. This paper describes the first successful use of a free vascularized lateral femoral cutaneous nerve graft combined with an anterolateral thigh flap to repair the facial nerve and a soft-tissue defect. This method is technically simple, has minimal donor-site morbidity, and typically results in successful nerve recovery.


Acute somatomedin response to growth hormone: radioreceptor assay versus radioimmunoassay.
The acute somatomedin (SM) response to GH therapy has been examined in 21 GH-deficient children using a placental membrane radioreceptor assay (RRA) which measures a variety of SMs and a RIA specific for SM-C and insulin-like growth factor I (IGF-I). Plasma for determination of SM peptide content was obtained before initiation of therapy and 13 h after each of four daily injections of GH (0.1 U/kg). An additional SM determination was performed after 6 weeks of GH therapy (0.1 U/kg, three times per week) in seven of the subjects. RRA and RIA SM determinations were performed on the same acid-chromatographed sample and were compared to an acid-chromatographed pooled plasma standard. The 4 days of GH therapy resulted in an increase in SM levels from 0.39 +/- 0.24 to 1.18 +/- 0.62 (+/- SD) U/ml, determined by RIA. A single injection of GH resulted in a significant rise in plasma SM levels, measured by either RRA or RIA (P less than 0.001). Subjects who responded poorly to two injections of GH also had low SM levels after 4 days and even after 6 weeks of GH therapy. The RRA resulted in consistently higher value than the RIA. This difference was even greater when results were compared to a pure IGF-I/SM-C standard. The SM peptide contents determined by RRA and RIA were strongly correlated, not only for the group, but also among the determinations for each individual subject. However, the consistently higher values observed when the SM peptide content was measured by RRA compared to that measured by RIA and the variability in the RRA to RIA ratio among individual subjects suggest that the IGF-I/SM-C RIA measures only one of a number of GH-dependent SM peptides.


Feline genetics: clinical applications and genetic testing.
DNA testing for domestic cat diseases and appearance traits is a rapidly growing asset for veterinary medicine. Approximately 33 genes contain 50 mutations that cause feline health problems or alterations in the cat's appearance. A variety of commercial laboratories can now perform cat genetic diagnostics, allowing both the veterinary clinician and the private owner to obtain DNA test results. DNA is easily obtained from a cat via a buccal swab with a standard cotton bud or cytological brush, allowing DNA samples to be easily sent to any laboratory in the world. The DNA test results identify carriers of the traits, predict the incidence of traits from breeding programs, and influence medical prognoses and treatments. An overall goal of identifying these genetic mutations is the correction of the defect via gene therapies and designer drug therapies. Thus, genetic testing is an effective preventative medicine and a potential ultimate cure. However, genetic diagnostic tests may still be novel for many veterinary practitioners and their application in the clinical setting needs to have the same scrutiny as any other diagnostic procedure. This article will review the genetic tests for the domestic cat, potential sources of error for genetic testing, and the pros and cons of DNA results in veterinary medicine. Highlighted are genetic tests specific to the individual cat, which are a part of the cat's internal genome.


Statistical Analysis of Hurst Exponents of Essential/Nonessential Genes in 33 Bacterial Genomes.
Methods for identifying essential genes currently depend predominantly on biochemical experiments. However, there is demand for improved computational methods for determining gene essentiality. In this study, we used the Hurst exponent, a characteristic parameter to describe long-range correlation in DNA, and analyzed its distribution in 33 bacterial genomes. In most genomes (31 out of 33) the significance levels of the Hurst exponents of the essential genes were significantly higher than for the corresponding full-gene-set, whereas the significance levels of the Hurst exponents of the nonessential genes remained unchanged or increased only slightly. All of the Hurst exponents of essential genes followed a normal distribution, with one exception. We therefore propose that the distribution feature of Hurst exponents of essential genes can be used as a classification index for essential gene prediction in bacteria. For computer-aided design in the field of synthetic biology, this feature can build a restraint for pre- or post-design checking of bacterial essential genes. Moreover, considering the relationship between gene essentiality and evolution, the Hurst exponents could be used as a descriptive parameter related to evolutionary level, or be added to the annotation of each gene.


Nonsaturating Linear Magnetoresistance Manifesting Two-Dimensional Transport in Wet-Chemical Patternable Bi2O2Te Thin Films.
Two-dimensional (2D) materials with exotic transport behaviors have attracted extensive interest in microelectronics and condensed matter physics, while scaled-up 2D thin films compatible with the efficient wet-chemical etching process represent realistic advancement toward new-generation integrated functional devices. Here, thickness-controllable growth and chemical patterning of high-quality Bi2O2Te continuous films are demonstrated. Noticeably, except for an ultrahigh mobility (∼45074 cm2 V-1 s-1 at 2 K) and obvious Shubnikov-de Hass quantum oscillations, a 2D transport channel and large linear magnetoresistance are revealed in the patterned Bi2O2Te films. Investigation implies that the linear magnetoresistance correlates with the inhomogeneity described by P. B. Littlewood's theory and EMT-RRN theory developed recently. These results not only reveal the nonsaturating linear magnetoresistance in high-quality Bi2O2Te but shed light on understanding the corresponding physical origin of linear magnetoresistance in 2D high-mobility semiconductors and providing a pathway for the potential application in multifunctional electronic devices.


Deliberative effectiveness in municipal sanitation and health councils: a study in Belo Horizonte-MG and in Belém-PA.
Deliberation in municipal councils of sanitation and health is the object of this study. Deliberation is understood as decision making and argumentative process, from the formulations of Rousseau, Habermas and Cohen. The proposed objective was to evaluate the effectiveness of the deliberative action of the councils of Belo Horizonte (MG) and Belém (PA). The evaluation included the study of variables defining the degree of institutionalization of the councils and revealing the dynamics of the deliberative process developed in them. The internal regulations of each council and the minutes and resolutions produced by them during the 2012-2014 triennium were consulted. The results showed that the four councils, in the period and according to the defined criteria of analysis, are far from the degree of deliberative effectiveness desired, considering the purposes of the social control in sanitation and in health, arranged by the specific legislation of each area. Even with broader experience, considering their years of participatory pedagogical exercise, health councils were no more effective than neophyte sanitation councils.


The association between family history of mental disorders and general cognitive ability.
There is an emerging literature linking cognitive ability with a wide range of psychiatric disorders. These findings have led to the hypothesis that diminished 'cognitive reserve' is a causal risk factor for psychiatric disorders. However, it is also feasible that a family history of mental disorders may confound this relationship, by contributing to both a slight impairment in cognitive ability, and an increased risk of psychiatric disorder. On the basis of a large, population-based sample of young adult male conscripts (n=160 608), we examined whether the presence of a family history of a range of mental disorders was associated with cognitive ability, as tested by the Børge Priens Prøve. In those with no individual-level history of mental disorder, a family-level history of a mental disorder was associated with a slight reduction in cognitive ability. In general, this pattern was found regardless of the nature of the psychiatric disorder in the family. Our study suggests that shared familial factors may underpin both cognitive ability and the risk of a wide range of psychiatric disorders. Convergent evidence from epidemiology and genetics suggests that shared genetic factors underpin an unexpectedly diverse range of psychiatric disorders. On the basis of the findings of the current study, we speculate that these same shared genetic factors also contribute to general cognitive ability.


Modeling employer self-insurance decisions after the Affordable Care Act.
To present a microsimulation model that addresses the methodological challenge of estimating the firm decision to self-insure. The model considers the risk that the firm bears when self-insuring and the opportunity to mitigate that risk by purchasing stop-loss insurance. The model makes use of a structural, utility maximization framework to account for numerous aspects of the firm decision, and a multinomial probit to reproduce the elasticity of the firm's demand for health insurance. Our simulations provide three important conclusions. First, they project significant increases in self-insurance rates among small firms--presumably induced by the desire to avoid ACA's rate-banding and risk adjustment regulations-only if generous stop-loss policies become widely available. Second, they show that this increase would be due to this hypothetical adoption of widespread, generous reinsurance by the market and not by passage of the ACA. Third, even with a substantial increase of self-insurance rates among small firms, they project negligible adverse selection in the exchanges, as indicated by our finding that the increase in exchange premium is less than 0.5% when assuming very generous stop-loss policies after implementation of the ACA.


Quantification of User Driving Behavior in Motorized Mobility Scooters using CNN-based Head Pose Estimation Algorithm.
There is a growing concern regarding the driving safety of Motorized Mobility Scooters (MMSs) for the elderly and mobility-impaired individuals. Although various research has made progress in sensor-based driving assistance systems to identify environmental hazards, few studies focus on investigating the impact of user behavior on MMS driving. In this paper, a driving status logging (DSL) system is developed to measure the user's behavior while driving. A cross-correlation analysis is implemented to quantify the temporal relationship between the head movement and steering operation in the driving of MMSs. The preliminary results suggest that the head movement can be used as an appropriate index to predict the intended steering operation in the driving of MMSs. Moreover, the quantified head-steering lag time provides the possibility to identify the hazardous driving pattern of MMS users.Clinical Relevance- The investigation of user behavior has the potential to improve the safety of MMSs. In this study, the user behavior in the driving of MMSs was quantitatively measured using the developed DSL system. Consequently, the temporal relationship between head movement and steering operation was first quantified in MMS-related research. These outcomes provide valuable insights into developing behavioral interventions to address the user's risky behavior patterns, thereby promoting the driving safety of MMSs.


Innovative designs for trials informing the care of cardiac surgical patients: part I.
Randomized clinical trials, now commonplace and regarded as top-tier evidence, are actually a recent development. The first randomized trial took place in 1948, just six decades ago. As anticipated from a relatively young field, rapid progress continues in response to an ever-increasing number of medical questions that demand answers. We examine evolving methodologies in cardiac anesthesia clinical trials, focusing on the transition towards larger sample sizes, increasing use of pragmatic trial designs, and the innovative adoption of real-time automated enrollment and randomization. We highlight how these changes enhance the reliability and feasibility of clinical trials. Recent understanding in clinical trial methodology acknowledges the importance of large sample sizes, which increase the reliability of findings. As illustrated by P value fragility, small trials can mislead despite statistical significance. Pragmatic trials have gained prominence, offering real-world insights into the effectiveness of various treatments. Additionally, the use of real-time automated enrollment and randomization, particularly in situations where obtaining prior consent is impractical is an important methodological advance. The landscape of cardiac anesthesia clinical trials is rapidly evolving, with a clear trend towards large sample sizes and innovative approaches to enrollment. Recent developments enhance the quality and applicability of research findings, thus providing robust guidance to clinicians.


A cascade process for directly converting nitriles (RCN) to cyanamides (RNHCN) via SO2F2-activated Tiemann rearrangement.
A simple, mild and practical process for the direct conversion of nitriles to cyanamides was newly discovered and exhibited a wide substrate scope as well as great functional group-tolerability (36 examples). In this efficient strategy, the in situ generated amidoximes obtained from the reaction of nitriles with hydroxylamine subsequently underwent Tiemann rearrangement, producing the corresponding cyanamides with great isolated yields under SO2F2. Additionally, the control experiments reportedly shed light on the tentative mechanism involved in the formation and elimination of the key intermediate: a sulfonyl ester.


A melanocyte-specific gene, Pmel 17, maps near the silver coat color locus on mouse chromosome 10 and is in a syntenic region on human chromosome 12.
Melanocytes preferentially express an mRNA species, Pmel 17, whose protein product cross-reacts with anti-tyrosinase antibodies and whose expression correlates with the melanin content. We have now analyzed the deduced protein structure and mapped its chromosomal location in mouse and human. The amino acid sequence deduced from the nucleotide sequence of the Pmel 17 cDNA showed that the protein is composed of 645 amino acids with a molecular weight of 68,600. The Pmel 17 protein contains a putative leader sequence and a potential membrane anchor segment, which indicates that this may be a membrane-associated protein in melanocytes. The deduced protein contains five potential N-glycosylation sites and relatively high levels of serine and threonine. Three repeats of a 26-amino acid motif appear in the middle of the molecule. The human Pmel 17 gene, designated D12S53E, maps to chromosome 12, region 12pter-q21; and the mouse homologue, designated D12S53Eh, maps to the distal region of mouse chromosome 10, a region also known to carry the coat color locus si (silver).


Internal jugular phlebectasia in an African adult.
Jugular vein phlebectasia is a rare venous anomaly commonly presenting as a unilateral neck swelling in children and adults. Its aetiology is unknown and its detection may have increased with availability of better imaging facilities. Due to its rarity, a high index of suspicion is required once other causes of neck swelling are excluded. The few reported cases are mainly in children and non-Africans adults. The authors report the case of a 54-year-old Nigerian woman presenting for the first time with a progressive, intermittent, painless right neck swelling, which was demonstrated on Doppler ultrasound and CT angiography to be an internal jugular phlebectasia. She had satisfactory surgical excision of the dilated segment for cosmetic reasons.


Small molecule tools for functional interrogation of protein tyrosine phosphatases.
The importance of protein tyrosine phosphatases (PTPs) in the regulation of cellular signalling is well established. Malfunction of PTP activity is also known to be associated with cancer, metabolic syndromes and autoimmune disorders, as well as neurodegenerative and infectious diseases. However, a detailed understanding of the roles played by the PTPs in normal physiology and in pathogenic conditions has been hampered by the absence of PTP-specific small molecule agents. In addition, the therapeutic benefits of modulating this target class are underexplored as a result of a lack of suitable chemical probes. Potent and specific PTP inhibitors could significantly facilitate functional analysis of the PTPs in complex cellular signal transduction pathways and may constitute valuable therapeutics in the treatment of several human diseases. We highlight the current challenges to and opportunities for developing PTP-specific small molecule agents. We also review available selective small molecule inhibitors developed for a number of PTPs, including PTP1B, TC-PTP, SHP2, lymphoid-specific tyrosine phosphatase, haematopoietic protein tyrosine phosphatase, CD45, PTPβ, PTPγ, PTPRO, Vaccinia H1-related phosphatase, mitogen-activated protein kinase phosphatase-1, mitogen-activated protein kinase phosphatase-3, Cdc25, YopH, mPTPA and mPTPB.


Pebbled Trachea: A Case Series and Literature Review of Tracheobronchopathia Osteochondroplastica.
We report a series of three cases diagnosed with tracheobronchopathia osteochondroplastica on bronchoscopy and computed tomography (CT) chest. Most patients were diagnosed incidentally on evaluation for chronic cough. The association of this entity with chronic bacterial infections and tuberculosis is an intriguing entity that was observed in our patients. Nodular, ulcerative, and calcific lesions in the trachea are bronchoscopic findings seen in quite a few other conditions posing diagnostic challenges. However, the classical bronchoscopic appearance with CT imaging in an appropriate clinical context can lead to an accurate diagnosis of this condition. We describe this array of cases with varying clinical presentations, their associations, and deliberate the literature reviews on this rare entity.


Synergism between thrombin and adrenaline (epinephrine) in human platelets. Marked potentiation of inositol phospholipid metabolism.
We have studied synergism between adrenaline (epinephrine) and low concentrations of thrombin in gel-filtered human platelets prelabelled with [32P]Pi. Suspensions of platelets, which did not contain added fibrinogen, were incubated at 37 degrees C to measure changes in the levels of 32P-labelled phosphatidylinositol 4,5-bisphosphate (PIP2), phosphatidylinositol 4-phosphate (PIP) and phosphatidate (PA), aggregation and dense-granule secretion after stimulation. Adrenaline alone (3.5-4.0 microM) did not cause a change in any parameter (phosphoinositide metabolism, aggregation and dense-granule secretion), but markedly enhanced the thrombin-induced responses over a narrow range of thrombin concentrations (0.03-0.08 units/ml). The thrombin-induced hydrolysis of inositol phospholipids by phospholipase C, which was measured as the formation of [32P]PA, was potentiated by adrenaline, as was the increase in the levels of [32P]PIP2 and [32P]PIP. The presence of adrenaline caused a shift to the left for the thrombin-induced changes in the phosphoinositide metabolism, without affecting the maximal levels of 32P-labelled compounds obtained. A similar shift by adrenaline in the dose-response relationship was previously demonstrated for thrombin-induced aggregation and dense-granule secretion. Also, the narrow range of concentrations of thrombin over which adrenaline potentiates thrombin-induced platelet responses is the same for changes in phosphoinositide metabolism and physiological responses (aggregation and dense-granule secretion). Our observations clearly indicate that adrenaline directly or indirectly influences thrombin-induced changes in phosphoinositide metabolism.


Safety-in-numbers: An updated meta-analysis of estimates.
Safety-in-numbers denotes the tendency for the number of accidents to increase less than in proportion to traffic volume. This paper updates a meta-analysis of estimates of safety-in-numbers published in 2017 (Elvik and Bjørnskau, Safety Science, 92, 274-282). Nearly all studies find safety-in-numbers, but the numerical estimates vary considerably. As virtually all studies are cross-sectional, it is not possible to determine if safety-in-numbers represents a causal relationship. Meta-regression analysis was performed to identify factors which may explain the large heterogeneity of estimates of safety-in-numbers. It was found that safety-in-numbers tends to be stronger for pedestrians than for cyclists, and stronger at the macro-level (e.g. citywide) than at the micro-level (e.g. in junctions). Recent studies find a stronger tendency towards safety-in-numbers than older studies.


Progress towards machine learning reaction rate constants.
Quantum and classical reaction rate constant calculations come at the cost of exploring potential energy surfaces. Due to the "curse of dimensionality", their evaluation quickly becomes unfeasible as the system size grows. Machine learning algorithms can accelerate the calculation of reaction rate constants by predicting them using low cost input features. In this perspective, we briefly introduce supervised machine learning algorithms in the context of reaction rate constant prediction. We discuss existing and recently created kinetic datasets and input feature representations as well as the use and design of machine learning algorithms to predict reaction rate constants or quantities required for their computation. Amongst these, we first describe the use of machine learning to predict activation, reaction, solvation and dissociation energies. We then look at the use of machine learning to predict reactive force field parameters, reaction rate constants as well as to help accelerate the search for minimum energy paths. Lastly, we provide an outlook on areas which have yet to be explored so as to improve and evaluate the use of machine learning algorithms for chemical reaction rate constants.


Evidence for direct protein kinase-C mediated modulation of N-methyl-D-aspartate receptor current.
Protein kinase-C (PKC) activation differentially affects currents from N-methyl-D-aspartate (NMDA) type glutamate receptors depending upon their subunit composition. Experiments using chimeras initially indicated that the cytoplasmic C-terminal tails of NR2B (responsive to PKC) and NR2C (unresponsive to PKC) subunits contain the amino acid residues responsible for the observed disparity of PKC effects. However, truncation and point mutation experiments have suggested that PKC action on NMDA receptors may be entirely indirect, working via the phosphorylation of associated proteins. Here we suggest that PKC does, in fact, affect NR2B/NR1-011 NMDA currents by direct phosphorylation of the NR2B tail at residues S1303 and S1323. Replacement of either of these residues with Ala severely reduces PKC potentiation. To verify that S1303 and S1323 are sites of direct phosphorylation by PKC, synthetic peptides from the regions surrounding these sites were used as substrates for in vitro assays with purified rat brain PKC. These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels. The direct action of PKC on certain NMDA receptor subtypes may be important in any physiological or pathological process where PKC and NR2B/NR1 receptors interact.


Contact-based social contagion in multiplex networks.
We develop a theoretical framework for the study of epidemiclike social contagion in large scale social systems. We consider the most general setting in which different communication platforms or categories form multiplex networks. Specifically, we propose a contact-based information spreading model, and show that the critical point of the multiplex system associated with the active phase is determined by the layer whose contact probability matrix has the largest eigenvalue. The framework is applied to a number of different situations, including a real multiplex system. Finally, we also show that when the system through which information is disseminating is inherently multiplex, working with the graph that results from the aggregation of the different layers is inaccurate.


Radioautographic localization of beta-adrenergic receptors in the rat ventral prostate.
Previous studies performed with crude homogenates have demonstrated the presence of beta-adrenergic receptors in the rat ventral prostate. The precise localization of these receptors in prostatic tissue, however, has not been determined. The present study describes the localization of beta-adrenergic receptors using in vitro radioautography. beta-adrenergic receptors are present exclusively in the epithelial cells, while no receptors could be detected in the stromal cells. The silver grains mostly are associated with the apical pole of the glandular cells and are much less concentrated in the basal nuclear region of the epithelium. Very low concentrations of grains are found in the lumen of the acini. Castration caused a dramatic fall in the receptor concentration, while treatment with dihydrotestosterone reversed these effects. The specific presence of beta-adrenergic receptors in prostatic epithelial cells and their control by androgens suggest that they could play a physiologic role in androgen action in prostatic tissue. Moreover, the level and activity of beta-adrenergic receptors could be used as parameters of prostatic activity.


Unauthorized practice: teaching pelvic examination on women under anesthesia.
Medical ethics evolved over the past half-century. This brought close reexamination and scrutiny of medical education and the "hands-on training" of future medical practitioners. Likewise societal opinions have intensified regarding the rights of patients, especially those deemed less likely to express their humiliation if they should discover themselves in compromising positions during treatment. Informed consent is modern medico-legal terminology; if the public felt that all patients were treated with the self-determination and dignity required by current HIPAA regulations, then there would be no reason to legislate such requirements. Law professor Robin Fretwell Wilson, Esq., and obstetrics and gynecology professor Nancy G. Chescheir, MD, present evidence and opinions from the legal and medical perspectives regarding conducting pelvic exams on anesthetized women without or with vague consent.


Multiplex PCR analysis of virulence genes and their influence on antibiotic resistance in Enterococcus spp. isolated from broiler chicken.
Enterococcus spp. are opportunistic pathogens that cause lameness in broiler chickens, resulting in serious economic losses worldwide. Virulence of Enterococcus spp. is associated with several putative virulence genes including fsr, efm, esp, cylA, cad1, ace, gelE, and asa1. In this study, multiplex polymerase chain reaction (PCR) for the simultaneous detection of these virulence genes in Enterococcus spp. was developed, and detection limits for E. faecium, E. faecalis, and E. hirae were 64.0 pg/μL, 320.0 pg/μL, and 1.6 ng/μL DNA, respectively. Among 80 Enterococcus isolates tested, efm and cad1 were detected in all 26 E. faecium samples, and only cad1 was observed in E. hirae. Additionally, the presence of virulence genes in 25 E. faecalis isolates were 100% for cad1, 88.0% for gelE, 64.0% for fsr, 44.0% for asa1, 16.0% for cylA, and 4.0% for esp. No virulence genes were found in E. gallinarum isolates. A total of 49 isolates were resistant to tigecycline and to at least 2 different classes of antibiotics. The most prevalent resistance was to ciprofloxacin (73.5%), quinupristin/dalfopristin (55.1%), and tetracycline (49.0%). No strains were resistant to vancomycin or linezolid. This is the first multiplex PCR assay to simultaneously detect eight virulence genes in Enterococcus spp., and the method provides diagnostic value for accurate, rapid, and convenient detection of virulence genes. Additionally, we report the prevalence of virulence genes and antimicrobial resistance in Enterococcus isolates from commercial broiler chickens suffering lameness.


Neural correlates of evaluating self and close-other in physical, academic and prosocial domains.
Behavioral studies showed that self-concept can be distinguished into different domains, but few neuroimaging studies have investigated either domain-specific or valence-specific activity. Here, we investigated whether evaluating self- and mother-traits in three domains (physical, academic, prosocial) relies on similar or distinct brain regions. Additionally, we explored the topical discussion in the literature on whether vmPFC activity during self-evaluations is induced by valence or importance of traits. Participants evaluated themselves and their mothers on positive and negative traits in three domains. Across all domains, evaluating traits resulted in right dlPFC, left middle temporal cortex, bilateral thalamus, and right insula activity. For physical traits, we found specific neural activity in brain regions typically implicated in mentalizing (dmPFC, IPL). For academic traits, we found a brain region typically implicated in autobiographical memories (PCC), and for prosocial traits, social brain regions (temporal pole, TPJ) were activated. Importantly, these patterns were found for both self and mother evaluations. Regarding valence, rACC/vmPFC showed stronger activation for positive than for negative traits. Interestingly, activation in this region was stronger for highly important traits compared to low/neutral important traits. Thus, this study shows that distinct neural processes are activated for evaluating positive and negative traits in different domains.


Two EguCBF1 genes overexpressed in Eucalyptus display a different impact on stress tolerance and plant development.
Two C-repeat binding factor genes (EguCBF1a/b), isolated from E. gunnii and differentially cold-regulated, were constitutively overexpressed in a cold-sensitive Eucalyptus hybrid. In addition to the expected improvement on freezing tolerance, some resulting transgenic lines (EguCBF1a-OE and EguCBF1b-OE) exhibited a decrease in stomata density and an over-accumulation of anthocyanins also observed to a lesser extent in a cold-acclimated control plant. Given that the induction of five putative CBF target genes was observed in CBF-overexpressing lines as well as in the cold-acclimated control line, these phenotypes might be related to cold acclimation. In comparison with the control plant, the most altered transgenic line (EguCBF1a-OE A1 line), exhibited reduced growth and better water retention capacity. This modified phenotype includes reduced leaf area and thickness associated with a decrease in cell size, as well as a higher oil gland density and a wax deposition on the cuticle. Surprisingly, the EguCBF1b-OE B9 line, with a level of transgene expression equivalent to the A1 line, showed a less marked phenotype, suggesting a difference in transactivation efficiency between EguCBF1A and B factors. The features of these transgenic lines provide the first signs of adaptive mechanisms controlled by CBF transcription factors in an evergreen broad-leaved tree. These data also open new prospects towards genetic improvement on Eucalyptus for freezing tolerance.


Medical comorbidity in psychiatric inpatients: relation to clinical outcomes and hospital length of stay.
Medical comorbidity is common in psychiatric inpatients and may be associated with substantial impairment and mortality. Few studies have examined the relation between this comorbidity and psychiatric outcomes. A series of 950 admissions to the Johns Hopkins Hospital Phipps Psychiatric Service were rated by attending psychiatrists at admission and discharge on symptom and functional measures. A subset was also evaluated on the General Medical Health Rating, a valid and reliable measure of seriousness of medical comorbidity. Attending psychiatrists were also asked at discharge whether medical comorbidity had been a focus of care during the hospitalization; medical comorbidity had been a focus of care in about 20% of the patients. Serious active medical comorbidity was present in 15% of patients on admission and 12% at discharge. Medical comorbidity was associated with a 10%-15% increase in psychiatric symptoms and functional impairment at discharge, even after adjustment for admission clinical status. In addition, when comorbidity had been a focus of care during the hospitalization, length of stay was prolonged by 3.25 days on average. Medical comorbidity has measurable effects on the psychiatric outcomes of psychiatric inpatients and in some cases prolongs hospital stay. Psychiatrists should redouble their efforts to detect and treat this comorbidity and should consider whether special inpatient units might be needed to care for psychiatric patients with complex medical comorbidity.


[The anthropogenic transformation of natural foci of leptospirosis].
The problems connected with epizootic consequences of the anthropogenic transformation of the landscape with respect to leptospirosis are discussed. The conclusion on changes produced by hydromelioration in the terrain, specific and etiological features of natural foci is made. Irrigation farming facilitates the formation and spread of natural foci, while drainage of a humid territory leads to the localization and suppression of such foci.


The emergence of delusional companions in Alzheimer's disease: an unusual misidentification syndrome.
Misidentifications in the course of organic diseases, including Alzheimer's disease (AD), have been associated with right sided brain dysfunction. The reasons for this association might be clarified by investigating the contribution of neurobiological, cognitive and emotional factors to distinctive types of misidentification. This study reports the cases of three patients with AD presenting a novel misidentification delusion in which objects with intrinsically comforting associations, soft toys, were experienced as sentient and triggered associated behaviours. Investigations included regional cerebral blood flow (rCBF) measurements with HMPAO SPECT and a comprehensive clinical and neuropsychological assessment. All three patients showed a distinctive pattern of rCBF with dysfunction centred in the right parietal area and severe visuospatial and visuoperceptive processing deficits, with relatively preserved memory and language abilities. These findings support the hypothesis that this type of misidentification delusion may be facilitated by right sided regional brain dysfunction involving visuoperceptual processing. Other historical and cognitive data from these patients suggests that the appearance of the symptom may be determined by the coexistence of a more widespread disorder of reality processing, which interacts with cognitive and psychogenic factors.


The learning curve for surgical margins after open radical prostatectomy: implications for margin status as an oncological end point.
Surgical margin status is commonly used as an end point for surgical learning. We examined the surgical margin learning curve and investigated whether surgical margins are a good marker for oncological outcome. The study cohort included 7,765 patients with prostate cancer treated with radical prostatectomy by 1 of 72 surgeons at a total of 4 major American academic medical centers. We calculated the learning curve for surgical margins and a concordance probability between the surgeon rates of positive surgical margins and 5-year biochemical recurrence. A positive surgical margin was identified in 2,059 patients (27%). On multivariate analysis surgeon experience was strongly associated with surgical margin status (p = 0.017). The probability of a positive surgical margin was 40% for a surgeon with 10 prior cases, which decreased to 25% for a surgeon with 250 (absolute difference 15%, 95% CI 11 to 18). Learning curves differed dramatically among surgeons. For surgeon pairs the surgeon with the superior positive surgical margin rate also had the better biochemical recurrence rate only 58% of the time. We noted a learning curve for surgical margins after open radical prostatectomy. The poor concordance between surgeon margin and recurrence rates suggests that while margins clearly matter and efforts should be made to decrease positive margin rates, surgical margin status is not a strong surrogate for cancer control. These results have implications for using the margin rate to evaluate changes in surgical technique and as surgeon feedback.


Opioids in chronic non-cancer pain: systematic review of efficacy and safety.
Opioids are used increasingly for chronic non-cancer pain. Controversy exists about their effectiveness and safety with long-term use. We analysed available randomised, placebo-controlled trials of WHO step 3 opioids for efficacy and safety in chronic non-cancer pain. The Oxford Pain Relief Database (1950-1994) and Medline, EMBASE and the Cochrane Library were searched until September 2003. Inclusion criteria were randomised comparisons of WHO step 3 opioids with placebo in chronic non-cancer pain. Double-blind studies reporting on pain intensity outcomes using validated pain scales were included. Fifteen randomised placebo-controlled trials were included. Four investigations with 120 patients studied intravenous opioid testing. Eleven studies (1025 patients) compared oral opioids with placebo for four days to eight weeks. Six of the 15 included trials had an open label follow-up of 6-24 months. The mean decrease in pain intensity in most studies was at least 30% with opioids and was comparable in neuropathic and musculoskeletal pain. About 80% of patients experienced at least one adverse event, with constipation (41%), nausea (32%) and somnolence (29%) being most common. Only 44% of 388 patients on open label treatments were still on opioids after therapy for between 7 and 24 months. The short-term efficacy of opioids was good in both neuropathic and musculoskeletal pain conditions. However, only a minority of patients in these studies went on to long-term management with opioids. The small number of selected patients and the short follow-ups do not allow conclusions concerning problems such as tolerance and addiction.


[Multiple urethral lithiasis. Report of a case].
To report a case of multiple urethral calculi, an uncommon urological condition in our setting. The clinical, radiological and therapeutic aspects are discussed and the literature is briefly reviewed. A 77-year-old male consulted at the emergency services of our hospital for dysuria, pollakiuria and difficulty in voiding. The patient also referred and indurated area in the penile ventral aspect. Radiological examination disclosed three calculi in the penile urethra with were successfully removed by meatotomty and urethrolithotomy. The patient is currently asymptomatic. Urethral calculus is uncommon in developed countries. "Milking" is not advocated due to the high incidence of urethral injury. Treatment is by simple urethrolithotomy in combination with other techniques (urethroplasty, diverticulectomy, etc.), if required.


Perinatal and early-life factors associated with stable and unstable trajectories of psychopathic traits across childhood.
This study aimed to identify perinatal and early-life factors associated with trajectories of psychopathic traits across childhood. Participants were 1631 children (51.5% girls) from the Quebec Longitudinal Study of Child Development. A wide range of perinatal and early-life factors were assessed from pregnancy to age 2.5 years using medical files and mothers' reports. Psychopathic traits were assessed via teachers' reports at ages 6, 7, 8, 10, and 12 years. Latent class growth analyses and multinomial logistic regressions controlling for child sex were conducted. Two-way interaction effects between perinatal/early-life factors and child sex were explored. Four trajectories of psychopathic traits were identified: High-stable (4.48%), Increasing (8.77%), Decreasing (11.46%), and Low-stable (75.29%). A few perinatal factors and most child-level and family-level early-life factors significantly increased the odds of following the High-stable v. the Low-stable trajectory. Higher levels of psychotropic exposures during pregnancy, socioeconomic adversity, child's physical aggression, child's opposition, mother's depressive symptoms, and hostile parenting increased the likelihood of following the Increasing instead of the Low-stable trajectory. Higher socioeconomic adversity, mother's depressive symptoms, and inconsistent parenting were associated with membership to the High-stable instead of the Decreasing trajectory. Most associations were not moderated by child sex. These results shed light on the perinatal and early-life factors that are associated with specific pathways of psychopathic traits during childhood and suggest that different factors could be targeted to prevent the exacerbation (v. low and stable levels) or the stability at high levels (v. attenuation) of these traits.


Wogonin inhibits hepatoma cell proliferation by targeting miR-27b-5p/YWHAZ axis.
Wogonin (5,7-dihydroxy-8-methoxyflavone), a natural flavonoid compound in herbal plants, can suppress growth in hepatocellular carcinoma (HCC). However, the microRNA (miRNA) expression profiles that are influenced by wogonin have not been thoroughly described. To explore the novel miRNAs and the biological mechanism underlying the effect of wogonin on HCC cells. The effect of wogonin on Huh7 cell growth was assessed both in vitro and in vivo. The expression profiles of miRNAs were obtained by small RNA sequencing. Luciferase reporter experiment and bioinformatics analysis were conducted to determine whether tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ) can bind to miR-27b-5p. Effects of the ectopic expression of YWHAZ and miR-27b-5p on Huh7 cells proliferation and apoptosis were evaluated. Furthermore, the cell cycle, apoptosis and multiple signaling pathway-related molecules were detected by Western blot analysis. Wogonin substantially inhibited the growth of Huh7 cells both in vitro and in vivo. Seventy miRNAs exhibited greater than twofold changes in wogonin-treated cells. Upregulation of miR-27b-5p inhibited Huh7 cell proliferation, and the anticancer effect of wogonin was reversed after miR-27b-5p knockdown. miR-27b-5p directly targeted YWHAZ in HCC cells. The proliferation-inhibiting effect of miR-27b-5p was revoked by YWHAZ overexpression. Meanwhile, inhibition of HCC growth was achieved by downregulating YWHAZ. Wogonin exerted antitumor activity through multiple signaling molecules, such as focal adhesion kinase, protein kinase B, mammalian target of rapamycin and molecules related to apoptosis and cell cycle by upregulating miR-27b-5p and downregulating YWHAZ. Our findings suggest that miR-27b-5p/YWHAZ axis contributes to the inhibitory effect of wogonin in HCC by targeting related genes and multiple signaling pathways.


Quantification of heart valve regurgitation: a critical analysis from a theoretical and experimental point of view.
A theoretical analysis is presented regarding factors of importance for the determination of distance of intrusion of the regurgitant jet in heart valve regurgitation. The analysis is based on hydrodynamic theory. In the idealized model situation, for a circular hole, the intrusion of the regurgitant jet is linearly related to the product of the fluid mean velocity in the orifice and the diameter of the orifice. This was also shown to be true in an experimental fluid model. Thus, volume regurgitation cannot be quantified by the measurement of distance of intrusion of the regurgitant jet alone. On the other hand, an estimate of volume regurgitation can, in the idealized situation, be obtained if mean fluid velocity in the orifice, distance of intrusion of the jet and regurgitation time are known.


Glycogen synthase kinase-3 in neurodegeneration and neuroprotection: lessons from lithium.
For over fifty years lithium has been a fundamental component of therapy for patients with bipolar disorders. Lithium has been considered recently for its potential to alleviate neuronal loss and other neurodegeneration processes. For instance, lithium reduces the severity of some behavioral complications of Alzheimer's disease (AD). And there are growing indications that lithium may be of benefit to the underlying pathology of AD, as well as an array of other common CNS disorders, including stroke, Parkinson's disease, and Huntington's disease. Despite these demonstrated and prospective therapeutic benefits, lithium's mechanism of action remains elusive, and opinions differ regarding the most relevant molecular targets. Lithium inhibits several enzymes; significant among these are inositol monophosphatase (IMPase), glycogen synthase kinase-3 (GSK-3), and the proteasome. Most recent publications discussing the medical application of lithium have converged on GSK-3, so this article reviews data and discussions regarding the roles and interactions of GSK-3 with other proteins and its proposed role in the pathogenesis of Alzheimer's disease.


Prioritizing biomaterials for spinal disc implants by a fuzzy AHP and TOPSIS decision making method.
Considerable research has been focused on identifying the optimum biomaterial for spine implants. New technologies and materials have allowed surgeons to better grasp the biomechanical principles underpinning implant stability and function. An optimal biomaterial for total disc replacement (TDR) should include essential characteristics such as biocompatibility, long-term durability, the capacity to withstand mechanical stresses, and economic viability. Our research has focused on six biomaterials for TDR, including Ti-6Al-4V, CoCr alloy, stainless steel 316L, zirconia toughened alumina (ZTA), polyether ether ketone (PEEK) and ultra-high-molecular weight polyethylene (UHMWPE). Ten common properties, i.e., the Young's modulus, density, tensile strength, the expense of the manufacturing process, the cost of raw material, wear rate, corrosion resistance, thermal conductivity, fracture toughness and compressive strength were utilized to assess these six different materials. The purpose of this study was to evaluate and rank the six alternative biomaterials proposed for use in the endplates and articulating surface of a spinal TDR. To accomplish this, a multi-criteria decision-making approach, namely the fuzzy analytic hierarchy process (fuzzy AHP) and the Technique of Order Preference by Similarity to Ideal Solution (TOPSIS) was adopted to solve the model. For validation and robustness of the proposed method, sensitivity analysis was performed, and comparison was performed with fuzzy-VIKOR and fuzzy-MOORA methods. In light of the study's results, ZTA and Ti-6Al-4V were identified as the best suited materials for the articulating surface and endplates, respectively, in a spinal disc implant.


Readiness for orthognathic surgery: a survey of practitioner opinion.
The purpose of this study was to determine if a general consensus exists among orthodontists regarding the features of an adequate presurgical setup. A questionnaire was developed to assess the importance of 12 criteria for surgical readiness. Each criterion was rated on a 5-point scale (1 = Unimportant, 5 = Critical). This questionnaire was sent to 104 randomly selected, board-certified orthodontists in the United States and Puerto Rico. Usable questionnaires were returned by 57 respondents (55% response rate). The highest and most consistent ratings were given for Arch Compatibility in the transverse dimension (mean = 4.66, SD = 0.55), Crossbite (mean = 4.57, SD = 0.63), and Torque of the Anterior Teeth (mean = 4.38, SD = 0.73). Further analysis showed a correlation between surgical experience of the orthodontist and a higher rating of importance for Torque of the Mandibular Teeth (Spearman r = 0.38), Torque of the Maxillary Teeth (Spearman r = 0.37), and Torque of the Anterior Teeth (Spearman r = 0.28). These results suggest that as orthodontists gain surgical experience, they attribute more importance to correcting the torque of the teeth. Also, the relatively large differences in opinion regarding presurgery orthodontic setup support a need for further research and/or educational effort regarding what criteria are important before surgery.


Metabolism of thyroid hormones by the isolated perfused rabbit kidney.
The metabolism of thyroxine and triiodothyronine in the isolated perfused rabbit kidney was monitored by specific radioimmunoassay for each hormone. The amount of thyroxine catabolised was proportional to the amount added initially and no saturation effects were observed over a wide range (3.9-82 nmol). After addition of thyroxine alone, triiodothyronine could be detected in the perfusion medium within 10 minutes but only much later in the urine. It was proposed that circulating thyroxine contributes indirectly to the level of urinary triiodothyronine.


Multi-Modal Characterization of the Coagulopathy Associated With Extracorporeal Membrane Oxygenation.
Extracorporeal membrane oxygenation is used to stabilize severe cardiocirculatory and/or respiratory failure. However, extracorporeal membrane oxygenation is associated with a coagulopathy characterized by thromboembolic and hemorrhagic complications. This study aimed to characterize the pathomechanism of the extracorporeal membrane oxygenation-associated coagulopathy and identify options to optimize its monitoring and therapy. Prospective observational clinical trial. ICU of a university hospital. Patients treated with venovenous extracorporeal membrane oxygenation (n = 10) due to acute respiratory distress syndrome and patients treated with venoarterial extracorporeal membrane oxygenation (n = 8) due to cardiocirculatory failure. One patient per group (venovenous extracorporeal membrane oxygenation or venoarterial extracorporeal membrane oxygenation) had surgery before extracorporeal membrane oxygenation. Blood was sampled before, and 1, 24, and 48 hours after extracorporeal membrane oxygenation implantation. Point-of-care tests (thrombelastometry/platelet aggregometry), conventional coagulation tests, whole blood counts, and platelet flow cytometry were performed. Even before extracorporeal membrane oxygenation, plasmatic coagulation and platelet aggregation were impaired due to systemic inflammation, liver failure, anticoagulants (heparins, phenprocoumon, apixaban), and antiplatelet medication. During extracorporeal membrane oxygenation, hemodilution and contact of blood components with artificial surfaces and shear stress inside extracorporeal membrane oxygenation additionally contributed to coagulation and platelet defects. Fibrinogen levels, fibrin polymerization, platelet activation, and microparticle release were increased in venovenous extracorporeal membrane oxygenation compared to venoarterial extracorporeal membrane oxygenation patients. Point-of-care results were available faster than conventional analyses. Bleeding requiring blood product application occurred in three of 10 venovenous extracorporeal membrane oxygenation patients and in four of eight venoarterial extracorporeal membrane oxygenation patients. No thrombotic events were observed. In-hospital mortality was 30% for venovenous extracorporeal membrane oxygenation and 37.5% for venoarterial extracorporeal membrane oxygenation patients. The extracorporeal membrane oxygenation-associated coagulopathy is a multifactorial and quickly developing syndrome. It is characterized by individual changes of coagulation parameters and platelets and is aggravated by anticoagulants. The underlying factors of the extracorporeal membrane oxygenation-associated coagulopathy differ between venovenous extracorporeal membrane oxygenation and venoarterial extracorporeal membrane oxygenation patients and are best diagnosed by a combination of point-of-care and conventional coagulation and platelet analyses. Therapy protocols for treating extracorporeal membrane oxygenation-associated coagulopathy should be further validated in large-scale prospective clinical investigations.


Near-equal compressibility of liver oil and seawater minimises buoyancy changes in deep-sea sharks and chimaeras.
Whereas upper ocean pelagic sharks are negatively buoyant and must swim continuously to generate lift from their fins, deep-sea sharks float or swim slowly buoyed up by large volumes of low-density oils in their livers. Investigation of the pressure, volume, temperature (PVT) relationships for liver oils of 10 species of deep-sea Chondrichthyes shows that the density difference between oil and seawater, Δρ, remains almost constant with pressure down to full ocean depth (11 km, 1100 bar), theoretically providing buoyancy far beyond the maximum depth of occurrence (3700 m) of sharks. However, Δρ does change significantly with temperature and we show that the combined effects of pressure and temperature can decrease buoyancy of oil by up to 10% between the surface and 3500 m depth across interfaces between warm southern and cold polar waters in the Rockall Trough in the NE Atlantic. This increases drag more than 10-fold compared with neutral buoyancy during horizontal slow swimming (0.1 m s-1), but the effect becomes negligible at high speeds. Chondrichthyes generally experience positive buoyancy change during ascent and negative buoyancy change during descent, but contrary effects can occur at interfaces between waters of different densities. During normal vertical migrations buoyancy changes are small, increasing slow-speed drag no more than 2- to 3-fold. Equations and tables of density, pressure and temperature are provided for squalene and liver oils of Chimaeriformes (Harriotta raleighana, Chimaera monstrosa, Hydrolagus affinis), Squaliformes (Centrophorus squamosus, Deania calcea, Centroscymnus coelolepis, Centroscyllium fabricii, Etmopterus spinax) and Carcharhiniformes (Apristurus laurussonii, Galeus murinus).


Fluorescence molecular imaging for identification of high-grade dysplasia in patients with head and neck cancer.
High-grade dysplasia is associated with a risk of malignant transformation, and it is necessary to distinguish from normal epithelium or low-grade dysplasia, especially in the intraoperative setting. We hypothesize that an anti-epidermal growth factor receptor (EGFR) contrast agent can be used to differentiate high-grade dysplasia from low-grade dysplasia and normal epithelium. Patients with biopsy proven head and neck squamous cell carcinoma (HNSCC) were enrolled in a clinical trial using systemically injected fluorescently labeled anti-EGFR antibody (panitumumab-IRDye800CW) (NCT02415881). Paraffin embedded tumor specimens from 11 patients were evaluated by fluorescence histopathology. Hematoxylin and eosin (H&E) slides were reviewed by a board-certified pathologist, and regions of invasive squamous cell carcinoma, high-grade dysplasia and low-grade dysplasia were delineated. EGFR expression was assessed for each patient by way of immunohistochemistry. 11 patients were included in the study with a total of 219 areas on tissue sections analyzed; 68 normal epithelium, 53 low-grade dysplasia, 48 high-grade dysplasia, and 50 malignant regions. The signal-to-background ratio (SBR) increased proportionally with increasing grade of dysplasia; normal epithelium (1.5 ± 0.1), low-grade dysplasia (1.8 ± 0.1), high-grade dysplasia: (2.3 ± 0.2). High-grade dysplasia had a significantly higher SBR when compared to normal or low-grade dysplasia (p < 0.05). Fluorescence histopathology positively correlated with EGFR expression by immunohistochemistry, which also increased proportionally with increasing degree of dysplasia. Molecular imaging with an anti-EGFR agent can successfully discriminate high-grade dysplastic lesions from low-grade dysplasia and normal epithelium.


Association between C-reactive protein and generalized anxiety disorder in stable coronary heart disease patients.
Comprehensive evaluation of major depressive disorder (MDD), anxiety disorder, and MDD in conjunction with anxiety disorder in stable coronary heart disease (CHD) patients, including cardiac biomarkers such as C-reactive protein (CRP), troponin T (TnT), and amino-terminal pro-B-type brain natriuretic peptide (NT-proBNP). Cross-sectional study of a consecutive series of 120 stable CHD outpatients (n = 30 with MDD, n = 30 with anxiety disorder, n = 30 with MDD and anxiety disorder, n = 30 with no psychiatric disorder). Psychiatric diagnoses were established by using the structured clinical interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders-IV). Binomial logistic regression analyses using cut-off scores of biomarkers as dependent variables showed associations between CRP and generalized anxiety disorder (GAD) (P = 0.04), and education (P = 0.004), whereas MDD, and MDD and anxiety disorder did not reach the significance level. TnT showed relationships with hyperlipidaemia (P = 0.009), history of obesity or overweight (P = 0.04), and education (P = 0.04). NT-proBNP was associated with type II diabetes (P = 0.005). After adjusting for relevant demographic, medical, and psychiatric co-variables, CRP was associated with GAD.


Pathogens in water: value and limits of correlation with microbial indicators.
This article discusses the value and limitations of using microbial indicators to predict occurrence of enteric pathogens in water. Raw or treated sewage is a primary source of fecal contamination of the receiving surface water or groundwater; hence, understanding the relationship between pathogens and indicators in sewage is an important step in understanding the correlation in receiving waters. This article presents three different datasets representing different concentrations of pathogens and microbial indicators: sewage containing high concentrations of pathogens and indicators, surface water with variable concentrations, and groundwater with low concentrations. In sewage, even with very high levels of microorganisms, no mathematical correlation can predict the type or concentration of any pathogen. After discharge in the environment, direct correlation becomes biologically improbable as dilution, transport, and different inactivation rates occur in various environments. In surface waters, advanced statistical methods such as logistic regression have provided some level of predictability of the occurrence of pathogens but not specific counts. In groundwater, the continuous absence of indicators indicates an improbable occurrence of pathogen. In contrast, when these indicators are detected, pathogen occurrence probability increases significantly. In groundwater, given the nature and dissemination pattern of pathogenic microorganisms, a direct correlation with fecal microbial indicators is not observed and should not be expected. However, the indicators are still useful as a measure of risk. In summary, many pathogens of public health importance do not behave like fecal microbial indicators, and there is still no absolute indicator of their presence, only a probability of their co-occurrence.


SPIN90 Modulates Long-Term Depression and Behavioral Flexibility in the Hippocampus.
The importance of actin-binding proteins (ABPs) in the regulation of synapse morphology and plasticity has been well established. SH3 protein interacting with Nck, 90 kDa (SPIN90), an Nck-interacting protein highly expressed in synapses, is essential for actin remodeling and dendritic spine morphology. Synaptic targeting of SPIN90 to spine heads or dendritic shafts depends on its phosphorylation state, leading to blockage of cofilin-mediated actin depolymerization and spine shrinkage. However, the physiological role of SPIN90 in long-term plasticity, learning and memory are largely unknown. In this study, we demonstrate that Spin90-knockout (KO) mice exhibit substantial deficits in synaptic plasticity and behavioral flexibility. We found that loss of SPIN90 disrupted dendritic spine density in CA1 neurons of the hippocampus and significantly impaired long-term depression (LTD), leaving basal synaptic transmission and long-term potentiation (LTP) intact. These impairments were due in part to deficits in AMPA receptor endocytosis and its pre-requisites, GluA1 dephosphorylation and postsynaptic density (PSD) 95 phosphorylation, but also by an intrinsic activation of Akt-GSK3β signaling as a result of Spin90-KO. In accordance with these defects, mice lacking SPIN90 were found to carry significant deficits in object-recognition and behavioral flexibility, while learning ability was largely unaffected. Collectively, these findings demonstrate a novel modulatory role for SPIN90 in hippocampal LTD and behavioral flexibility.


Evolutionary conservation of primate lymphocryptovirus microRNA targets.
Epstein-Barr virus (EBV) and rhesus lymphocryptovirus (rLCV) are closely related gammaherpesviruses in the lymphocryptovirus subgroup that express viral microRNAs (miRNAs) during latent infection. In addition to many host mRNAs, EBV miRNAs are known to target latent viral transcripts, specifically those encoding LMP1, BHRF1, and EBNA2. The mRNA targets of rLCV miRNAs have not been investigated. Using luciferase reporter assays, photoactivatable cross-linking and immunoprecipitation (PAR-CLIP), and deep sequencing, we demonstrate that posttranscriptional regulation of LMP1 expression is a conserved function of lymphocryptovirus miRNAs. Furthermore, the mRNAs encoding the rLCV EBNA2 and BHRF1 homologs are regulated by miRNAs in rLCV-infected B cells. Homologous to sites in the EBV LMP1 and BHRF1 3'-untranslated regions (UTRs), we also identified evolutionarily conserved binding sites for the cellular miR-17/20/106 family in the LMP1 and BHRF1 3'UTRs of several primate LCVs. Finally, we investigated the functional consequences of LMP1 targeting by individual EBV BART miRNAs and show that select viral miRNAs play a role in the previously observed modulation of NF-κB activation.


A Negative Slope Conductance of the Persistent Sodium Current Prolongs Subthreshold Depolarizations.
Neuronal subthreshold voltage-dependent currents determine membrane properties such as the input resistance (Rin) and the membrane time constant (τm) in the subthreshold range. In contrast with classical cable theory predictions, the persistent sodium current (INaP), a non-inactivating mode of the voltage-dependent sodium current, paradoxically increases Rin and τm when activated. Furthermore, this current amplifies and prolongs synaptic currents in the subthreshold range. Here, using a computational neuronal model, we showed that the creation of a region of negative slope conductance by INaP activation is responsible for these effects and the ability of the negative slope conductance to amplify and prolong Rin and τm relies on the fast activation of INaP. Using dynamic clamp in hippocampal CA1 pyramidal neurons in brain slices, we showed that the effects of INaP on Rin and τm can be recovered by applying an artificial INaP after blocking endogenous INaP with tetrodotoxin. Furthermore, we showed that injection of a pure negative conductance is enough to reproduce the effects of INaP on Rin and τm and is also able to prolong artificial excitatory post synaptic currents. Since both the negative slope conductance and the almost instantaneous activation are critical for producing these effects, the INaP is an ideal current for boosting the amplitude and duration of excitatory post synaptic currents near the action potential threshold.


Toward the understanding of national culture in the success of non-pharmaceutical technological interventions in mitigating COVID-19 pandemic.
This study conceptually explores the relationship between a nation's culture and the success of utilizing various digital technologies to mitigate the spread of a pandemic, such as novel coronavirus (COVID-19). In the absence of a cure or vaccine of COVID-19, the national governments and public health authorities have been aggressively utilizing digital technologies to mitigate the pandemic spread. Given the urgency caused by COVID-19, this study highlights the importance of considering a country's national culture in evaluating the efficacy of a given digital technology, despite how promising or groundbreaking it may sound, in combating the spread of an infectious disease. Relying on the two critical dimensions of national culture, power distance and individualism/collectivism, this study proposes a framework that describes how people from different countries, depending on their prevalent national cultural values, would be receptive (or intolerant) to using government-run technology solutions meant for curbing the pandemic spread.


Do European people with type 1 diabetes consume a high atherogenic diet? 7-year follow-up of the EURODIAB Prospective Complications Study.
Individuals with type 1 diabetes have a high risk of developing cardiovascular diseases, and it has been reported that they consume a high atherogenic diet. We examined how nutrient intake and adherence to current European nutritional recommendations evolved in a large cohort of European individuals with type 1 diabetes over a period of 7 years. We analysed data from the EURODIAB Prospective Complications Study, a European multicentre prospective cohort study. Standardized 3-day dietary records were employed in individuals with type 1 diabetes. One thousand one hundred and two patients (553 men, 549 women, baseline age 33 ± 10 years, duration 15 ± 9 years) had complete nutritional data available at baseline and after 7 years. We calculated mean differences in reported nutrients over time and adjusted these for age, gender, HbA1c and BMI with ANOVA models. Compared to baseline, there were minor changes in nutrients. Reported protein (-0.35% energy (en), fat (-1.07% en), saturated fat (-0.25% en) and cholesterol (-7.42 mg/1000 kcal) intakes were lower, whereas carbohydrate (+1.23% en) and fibre (+0.46 g/1000 kcal) intakes were higher at the 7-year follow-up. European recommendations for adequate nutrient intakes were followed in individuals with type 1 diabetes for protein (76% at baseline and 78% at follow-up), moderately for fat (34, 40%), carbohydrate (34, 41%) and cholesterol (39, 47%), but poorly for fibre (1.4, 2.4%) and saturated fat (11, 13%). European individuals with type 1 diabetes consume a high atherogenic diet as few patients met recommendations for dietary fibre and saturated fat. This study showed minor changes in dietary nutrients and energy intakes over a period of 7 years. Nutrition education needs particular focus on strategies to increase dietary fibre and reduce saturated fat to exploit their potential benefit.


Dyslipidemia in patients with type 2 diabetes. relationships between lipids, kidney disease and cardiovascular disease.
Type 2 diabetes mellitus is a leading cause of morbidity and mortality. Cardiovascular disease (CVD) is the most prevalent complication and primarily accounts for the excess morbidity and mortality in diabetic patients, but microvascular complications, such as kidney disease and retinopathy, are frequent and contribute to the total disease burden. Lipid abnormalities in patients with type 2 diabetes are a major problem and associated with the increased risk of CVD. The most common pattern of dyslipidemia in these patients consists of elevated levels of triglycerides and low levels of high-density lipoprotein cholesterol. Low-density lipoprotein levels in these patients are often similar to that of the nondiabetic population, although there may be important qualitative differences in the pattern that contribute to the increased risk of CVD. Abnormal levels of urinary albumin occur in 30-40% of patients with type 2 diabetes and the presence of kidney disease enhances the mortality from CVD. Microalbuminuria, an early marker of diabetic nephropathy, is an independent risk factor for CVD. The increased levels of urinary albumin secretion may represent a more generalized vascular damage than renal microvascular injury alone. This Review focuses on the significance of diabetic dyslipidemia and microalbuminuria to CVD risk as well as to kidney complications. We also discuss the role of aggressive therapy to ameliorate vascular injury in the diabetic patient and reduce or prevent the cardiovascular and renal consequences of the disease.


Mouse embryonic stem cell-derived cells reveal niches that support neuronal differentiation in the adult rat brain.
A neurogenic niche can be identified by the proliferation and differentiation of its naturally residing neural stem cells. However, it remains unclear whether "silent" neurogenic niches or regions suitable for neural differentiation, other than the areas of active neurogenesis, exist in the adult brain. Embryoid body (EB) cells derived from embryonic stem cells (ESCs) are endowed with a high potential to respond to specification and neuralization signals of the embryo. Hence, to identify microenvironments in the postnatal and adult rat brain with the capacity to support neuronal differentiation, we transplanted dissociated EB cells to conventional neurogenic and non-neurogenic regions. Our results show a neuronal differentiation pattern of EB cells that was dependent on the host region. Efficient neuronal differentiation of EB cells occurred within an adjacent region to the rostral migratory stream. EB cell differentiation was initially patchy and progressed toward an even distribution along the graft by 15-21 days post-transplantation, giving rise mostly to GABAergic neurons. EB cells in the striatum displayed a lower level of neuronal differentiation and derived into a significant number of astrocytes. Remarkably, when EB cells were transplanted to the striatum of adult rats after a local ischemic stroke, increased number of neuroblasts and neurons were observed. Unexpectedly, we determined that the adult substantia nigra pars compacta, considered a non-neurogenic area, harbors a robust neurogenic environment. Therefore, neurally uncommitted cells derived from ESCs can detect regions that support neuronal differentiation within the adult brain, a fundamental step for the development of stem cell-based replacement therapies.


Pain Sensitivity and its Relation to Spreading on the Body, Intensity, Frequency, and Duration of Pain: A Cross-Sectional Population-based Study (SwePain).
Individuals with chronic pain often report increased pain sensitivity compared with pain-free individuals; hence, it is crucial to determine whether and how different pain characteristics influence or interact with pain sensitivity. An alternative to experimental pain sensitivity testing is the self-reported pain sensitivity questionnaire (PSQ), which captures pain sensitivity in various body areas.This study compares PSQ in individuals with and without pain and clarifies how pain sensitivity relates to spreading of pain on the body, and to intensity, frequency, duration of pain and to age and sex. A total of 5905 individuals with pain and 572 individuals without pain from the general population in southeastern Sweden completed and returned a postal questionnaire. The mean PSQ score was 3.9 (95% confidence interval [CI], 3.88-3.98) in individuals with pain and 3.5 (95% CI, 3.38-3.64) in pain-free individuals. Hence, PSQ was the highest among individuals with pain, with a difference of 0.4 (95% CI, 0.30-0.56). There was a considerable variation in the PSQ values (mean=3.5; SD=1.54) among pain-free individuals. Pain sensitivity was positively related to spreading, intensity, and frequency of pain, with a correlation coefficient of 0.3. PSQ was higher in widespread pain, 4.5 (95% CI, 4.27-4.69) in women and 4.3 (95% CI, 3.94-4.71) in men, than in local pain, 3.7 (95% CI, 3.61-3.91) in women and 3.8 (95% CI, 3.66-3.95) in men. The score for women with regional pain was between local and widespread pain at 4.0 (95% CI, 3.95-4.11) and that for men with regional pain was 3.8 (95% CI, 3.69-3.87), which is equal to that of local pain. The positive association between pain sensitivity and spreading of pain on the body provides some evidence that the extent of spreading may be related to the degree of pain sensitivity. Before clinical use of PSQ, psychometric development and further research are needed.


Mediator-dependent secondary injury after unilateral blunt thoracic trauma.
The pathophysiologic sequence leading to respiratory failure after chest trauma can be an inevitable consequence of the primary injury or a secondary, mediator-driven inflammatory process. To distinguish between these alternatives, a simple cross-transfusion experiment was performed. A captive bolt gun injured the chest of anesthetized pigs that were mechanically ventilated with FiO2 = .21, .50, or .50 plus indomethacin (5 mg/kg intravenous; 15 min before injury). Tube thoracostomy immediately followed. After 30 min, blood from these injured donors was transfused into three matched groups of naive recipients (n = 8, 6, and 4, respectively) for a 33% exchange transfusion. Two control groups received blood from uninjured donors with tube thoracostomies only (FiO2 = .21, n = 7; FiO2 = .50, n = 10). Within 15-30 min after transfusion, in recipients from injured donors versus controls, lung compliance was decreased 20%, stroke volume and cardiac output were decreased 50%, and pulmonary vascular resistance was increased >300% (all p < .05). These changes recovered to baseline within 60-90 min. The stable metabolite of thromboxane A2, thromboxane B2, increased >500% in plasma within 15 min and remained elevated for >120 min. All responses were similar at 21 % or 50% O2, which suggests that hypoxia per se is not a cause of mediator production. All responses were eliminated by indomethacin. By 24 h, histologic changes included atelectasis in 3/3 recipients from injured donors versus 0/3 recipients from uninjured donors. We conclude that 1) blunt chest trauma releases blood borne mediators, including prostanoids; 2) these mediators can cause secondary cardiopulmonary changes in naive recipients similar to those produced by chest trauma; 3) the progression to trauma-induced respiratory failure is multifactorial; 4) early pharmacologic intervention, rather than supportive care alone, may benefit some victims of severe chest trauma.