Antinociceptive effect of prostatic acid phosphatase in a rat model of cancer-induced bone pain.
Cancer-induced bone pain (CIBP) is a severe chronic pain that is less than adequately controlled by conventional analgesics. Prostatic acid phosphatase (PAP) has been considered as a diagnostic marker for prostate cancer and its transmembrane isoform has been reported to play an antinociceptive effect in neuropathic and inflammatory pain. However, it remains unknown whether it has an analgesic effect on CIBP and what are the underlying mechanisms. In the present study, we tested whether PAP could alleviate the pain symptoms induced by bone cancer in a rat model. A randomized, double blind, and controlled rat animal trial. We first established a rat CIBP model and observed the spinal expression of PAP by immunofluorescence histochemistry and Western blot. Then, PAP (0.1, 0.3, or 1 μg) was intrathecally administered in the CIBP rats in a repeated manner from 15 to 18 days (once per day) after inoculation of tumor cells. On postoperative day (POD) 18, the mechanical paw withdrawal threshold was tested for checking the dose-effect curve and ED50 of the antinociceptive effect of PAP. In an another test, a single dose of ED50 of PAP was intrathecally injected on POD 15 to observe the time course of its effect. Furthermore, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (3 mg/kg), an adenosine A1 receptor antagonist, or dipyridamole (DIP) (10 μg), a nucleoside transporter inhibitor, was administered to the CIBP rats for exploring the analgesic mechanisms of PAP. The concentration of extracellular adenosine was also detected by microdialysis method after intrathecal injection of PAP (0.57 μg) and DIP (10 μg) in the CIBP rats. Finally, an in vivo electrophysiological study of the CIBP rats was performed to observe whether the electrically evoked response of spinal wide-dynamic-range (WDR) neurons could be affected by PAP (0.57 μg), DIP (10 μg), or DPCPX (10 μg). The expression of PAP in the spinal dorsal horn was significantly reduced in the CIBP rats, and intrathecal injection of PAP dose-dependently attenuated CIBP-induced mechanical allodynia via the adenosine A1 receptor. Simultaneously, intrathecal injection of PAP increased the extracellular concentration of spinal adenosine in the CIBP rats, as well as inhibited the neuronal responses of WDR neurons in deep layers within the spinal dorsal horn through the adenosine A1 receptor. Finally, the analgesic effect of PAP was potentiated by DIP, the nucleoside transporter inhibitor. It's not clear whether PAP's antinociceptive effect is mediated by other signaling molecules besides the adenosine A1 receptor. In addition, the long-term antinociceptive effect of intrathecal PAP is still not clear. Our study demonstrated that PAP was involved in the maintenance of CIBP and could effectively suppress central sensitization by increasing spinal extracellular adenosine concentrations to exert a significant antinociceptive effect via the adenosine A1 receptor in CIBP rats. Therefore, our experiments suggest that the endogenous enzyme PAP may be a promising candidate for CIBP treatment.


The role of chemotherapy in biliary tract carcinoma.
Cholangiocarcinoma is a rare malignancy associated with poor prognosis and high mortality. Surgical resection is the only chance for cure depending on careful patient selection. There are no well-conducted studies regarding the role of adjuvant chemotherapy. Preliminary data suggest that liver transplantation could offer long-term survival in selected patients when combined with neoadjuvant chemoradiotherapy. The literature regarding treatment results with specific regimens in the adjuvant setting is limited and no general recommendation can be given. In patients with locally advanced or metastatic disease, most studies are small, non-randomized phase II trials, and many studies comprise a mix of bile duct cancers, gallbladder cancer, and either pancreatic or hepatocellular cancers. In metastatic cancer, phase II studies with several cytotoxics, including gemcitabine, the platinums, and the fluoropyrimidines, have shown a modest and often short-lasting activity. No single chemotherapy agent or combination regimen can therefore be recommended as a standard of care at present. In this review, we give an overview of chemotherapy in the adjuvant, neoadjuvant, and advanced settings.


Contemporary approach to joint hypermobility and related disorders.
Joint hypermobility is a common, although largely ignored physical sign. Joint hypermobility is often asymptomatic but may be a feature of an underlying genetic disorder with systemic manifestations. The present article presents a comprehensive approach to considering joint hypermobility and clinically related issues in children and adults. Ehlers-Danlos syndrome (EDS) is an umbrella term for various Mendelian connective tissue disorders sharing joint hypermobility, skin hyperextensibility, and tissue fragility. Hypermobile EDS is the default diagnosis in many individuals and still lacks of any confirmatory test. There is also a continuous spectrum of phenotypes between asymptomatic, nonsyndromic joint hypermobility, and hypermobile EDS. In 2017, a new international classification of EDSs, joint hypermobility, and related disorders was published. EDSs are now classified in 13 different variants because of mutations in 19 genes. The gap between joint hypermobility and hypermobile EDS is filled by the descriptive diagnosis of 'hypermobility spectrum disorders'. Alongside the new criteria recommendations for the assessment and management of selected issues related to joint hypermobility such as fatigue and physical therapy have also been published by expert panels. Asymptomatic, nonsyndromic joint hypermobility, hypermobility spectrum disorders and EDS (particularly, the hypermobile type) are the most common phenotypes in children and adults with joint hypermobility. Their prompt recognition is crucial to the appropriate application of evidence-based management and the reduction in burden of ill health.


Gastric Cancer as Preventable Disease.
Gastric cancer, 1 of the 5 most common causes of cancer death, is associated with a 5-year overall survival rate less than 30%. A minority of cancers occurs as part of syndromic diseases; more than 90% of adenocarcinomas are considered as the ultimate consequence of a longstanding mucosal inflammation. Helicobacter pylori infection is the leading etiology of non-self-limiting gastritis, which may result in atrophy of the gastric mucosa and impaired acid secretion. Gastric atrophy establishes a field of cancerization prone to further molecular and phenotypic changes, possibly resulting in cancer growth. This well-understood natural history provides the clinicopathologic rationale for primary and secondary cancer prevention strategies. A large body of evidence demonstrates that combined primary (H pylori eradication) and secondary (mainly endoscopy) prevention efforts may prevent or limit the progression of gastric oncogenesis. This approach, which is tailored to different country-specific gastric cancer incidence, socioeconomic, and cultural factors, requires that the complementary competences of gastroenterologists, oncologists, and pathologists be amalgamated into a common strategy of health policy.


Crystallization and arrest mechanisms of model colloids.
We performed dynamic simulations of spheres with short-range attractive interactions for many values of interaction strength and range. Fast crystallization occurs in a localized region of this parameter space, but the character of crystallization pathways is not uniform within this region. Pathways range from one-step, in which a crystal nucleates directly from a gas, to two-step, in which substantial liquid-like clusters form and only subsequently become crystalline. Crystallization can fail because of slow nucleation from either gas or liquid, or because of dynamic arrest caused by strong interactions. Arrested states are characterized by the formation of networks of face-sharing tetrahedra that can be detected by a local common neighbor analysis.


Imaging modalities for the diagnosis of hepatic fibrosis and cirrhosis.
Non-invasive methods for liver fibrosis diagnosis are now commonly used as first-intention tests for liver fibrosis diagnosis in chronic liver diseases. Even morphological parameters provided by ultrasound is now challenged by blood fibrosis tests and transient elastography, in experienced hands, it performed well and in certain situations, imaging can still be useful to detect patients with fibrosis. In parallel, to ultrasound and Doppler imaging, various methodologies have been explored. Some of them remain confined to clinical research for the moment, as perfusion, MR diffusion-weighted imaging, intravoxel incoherent motion or acoustic structure quantification; others have already taken a place in clinical practice. Regarding fast growing of new technology some methods may become available for daily practice in the near future. Ultrasound tools or automated quantification of different physical parameters of imaging data could provide an opportunity for early diagnosis of liver diseases; MRI techniques could lead to the development of a "global" liver examination.


Reduction of residual amplitude modulation to 1 × 10⁻⁶ for frequency modulation and laser stabilization.
Active control and cancellation of residual amplitude modulation (RAM) in phase modulation of an optical carrier is one of the key technologies for achieving the ultimate stability of a laser locked to an ultrastable optical cavity. Furthermore, such techniques are versatile tools in various frequency modulation-based spectroscopy applications. In this Letter we report a simple and robust approach to actively stabilize RAM in an optical phase modulation process. We employ a waveguide-based electro-optic modulator (EOM) to provide phase modulation and implement an active servo with both DC electric field and temperature feedback onto the EOM to cancel both the in-phase and quadrature components of the RAM. This technique allows RAM control on the parts-per-million level where RAM-induced frequency instability is comparable to or lower than the fundamental thermal noise limit of the best available optical cavities.


Avoiding the high Bonferroni penalty in genome-wide association studies.
A major challenge in genome-wide association studies (GWASs) is to derive the multiple testing threshold when hypothesis tests are conducted using a large number of single nucleotide polymorphisms. Permutation tests are considered the gold standard in multiple testing adjustment in genetic association studies. However, it is computationally intensive, especially for GWASs, and can be impractical if a large number of random shuffles are used to ensure accuracy. Many researchers have developed approximation algorithms to relieve the computing burden imposed by permutation. One particularly attractive alternative to permutation is to calculate the effective number of independent tests, M(eff), which has been shown to be promising in genetic association studies. In this study, we compare recently developed M(eff) methods and validate them by the permutation test with 10,000 random shuffles using two real GWAS data sets: an Illumina 1M BeadChip and an Affymetrix GeneChip Human Mapping 500K Array Set. Our results show that the simpleM method produces the best approximation of the permutation threshold, and it does so in the shortest amount of time. We also show that M(eff) is indeed valid on a genome-wide scale in these data sets based on statistical theory and significance tests. The significance thresholds derived can provide practical guidelines for other studies using similar population samples and genotyping platforms.


Are sperm capacitation and apoptosis the opposite ends of a continuum driven by oxidative stress?
This chapter explores the possibility that capacitation and apoptosis are linked processes joined by their common dependence on the continued generation of reactive oxygen species (ROS). According to this model capacitation is initiated in spematozoa following their release into the female reproductive tract as a consequence of intracellular ROS generation, which stimulates intracellular cAMP generation, inhibits tyrosine phosphatase activity and enhances the formation of oxysterols prior to their removal from the sperm surface by albumin. The continued generation of ROS by capacitating populations of spermatozoa eventually overwhelms the limited capacity of these cells to protect themselves from oxidative stress. As a result the over-capacitation of spermatozoa leads to a state of senescence and the activation of a truncated intrinsic apoptotic cascade characterized by enhanced mitochondrial ROS generation, lipid peroxidation, motility loss, caspase activation and phosphatidylserine externalization. The latter may be particularly important in instructing phagocytic leukocytes that the removal of senescent, moribund spermatozoa should be a silent process unaccompanied by the generation of proinflammatory cytokines. These observations reveal the central role played by redox chemistry in defining the life and death of spermatozoa. A knowledge of these mechanisms may help us to engineer novel solutions to both support and preserve the functionality of these highly specialized cells.


Evaluation of the effectiveness of the photobiomodulation in the treatment of dentin hypersensitivity after basic therapy. A randomized clinical trial.
Dentin hypersensitivity (DH) in one of the most common causes of patient discomfort in the general population and its prevalence is higher in patients who have received basic or surgical periodontal treatment. Efficiency of the diode laser with different wavelengths has been studied by several authors, showing an improvement rate of the DH between 60-98%. The aim of the present study was to evaluate the effect of photobiomodulation (PBM) treatment on the reduction of DH after non surgical periodontal treatment. A randomized split mouth clinical trial was performed involving 30 patients (120 teeth) diagnosed with DH after scaling and root planning. Two teeth of the experimental side were treated with the laser and 2 teeth of the control side were treated without activating the laser. The laser treatment parameters for each tooth were 660nm, 200mW, CW, illuminated area 1.15cm2, 173mW/cm2, 60 seconds, 12 J, 10.4J/cm2. Age, gender, smoking, plaque index, gingival recession, probing and VAS (for tactile and thermal stimulation) were registered before the laser treatment, immediate post treatment (after 2 minutes), 2 weeks, 1 month and 2 months after treatment. There was significant difference (p<0.01) in discomfort to thermal and mechanical stimulation between the control and diode laser treatment sites at all evaluation periods. The level of discomfort decreased immediately following diode laser therapy, and continued to demonstrate a decrease for the duration of the study. All teeth remained vital after laser treatment, without adverse reactions or complications. The PBM can be used to reduce DH without detrimental pulpal effects. Key words:Dental hypersensitivity, laser, diode laser, photobiomodulation.


Beverages and Non-alcoholic fatty liver disease (NAFLD): Think before you drink.
Beverages and Non-alcoholic fatty liver disease (NAFLD) both the terms are associated with westernized diet and sedentary lifestyle. Throughout recent decades, dietary changes have boosted demand of beverages to meet the liquid consumption needs, among which rising consumption of several calorie-rich beverages have increased the risk of fatty liver disease. Meanwhile, certain beverages have capacity to deliver many unanticipated health benefits thereby reducing the burden of NAFLD and metabolic diseases. The present review therefore addresses the increasing interconnections between beverages intake among population, dietary patterns and the overall effect of these beverage on the development and prevention of NAFLD. Methods In the present review, some frequently consumed beverage groups have been analyzed in light of their role in the advancement and prevention of NAFLD, including sugar sweetened, hot and alcoholic beverages. The nutritional composition of different beverages makes the progression of NAFLD distinctive. The ingestion of sugar-rich beverages has demonstrated the metabolic burden and in all cases, raises the risk of NAFLD, while intake of coffee and tea has decreased this risk without any significant adverse effects. In some cases, low to moderate alcohol intake has been shown to minimize the risk of advanced fibrosis and NAFLD-mortality. Together, this review discusses and supports work on new dietary approaches and clinical studies to accomplish nutrition-oriented NAFLD care by improving the drinking habits.


Delayed sleep phase syndrome response to melatonin.
The actions of melatonin on the sleep-wake cycle were investigated by means of a randomised, double-blind, placebo-controlled trial in 8 subjects with a delayed sleep phase syndrome attending a sleep disorders clinic. In randomised order the subjects received placebo or melatonin 5 mg daily for 4 weeks with a 1 week washout period between the treatments. Drug or placebo was given at 2200 h, 5 h before the mean time of sleep onset determined by pretrial sleep logs. In all 8 subjects sleep onset time (mean advance 82 [range 19-124] min; p less than 0.01) and wake time (117 [10-187] min; p less than 0.01) were significantly earlier during melatonin treatment than during placebo. Mean total sleep time was slightly less on melatonin (8 h 12 min) than on placebo (8 h 46 min). Alertness acrophase calculated from the subjects' ratings of alertness made every 2 h while awake was unaltered. Melatonin may act as a phase-setter for sleep-wake cycles in subjects with a delayed sleep phase syndrome.


Rhesus monkeys (Macaca mulatta) hear rising frequency sounds as looming.
Rising sound intensity provides an important cue for the detection of looming objects. Studies with humans indirectly suggest that rising pitch can also signal a looming object. This link between rising intensity and rising frequency is puzzling because no physical rise in frequency occurs when a sound source approaches. Putative explanations include (a) the idea that the loudness of sound depends on its frequency, (b) the frequent co-occurrence of rising intensity with rising frequency in vocalizations generates an association between the 2 features, and (c) auditory neurons process amplitude- and frequency-modulated sounds similarly. If these hypotheses are valid, then rhesus monkeys (Macaca mulatta)--which share some homologies in the vocal production apparatus and auditory system--should also associate rising frequency with rising intensity, and thus should perceive rising frequency as a looming sound source. A head-turning assay and a preferential-looking paradigm revealed that monkeys show an attentional bias toward rising versus falling frequency sounds and link the former to visual looming signals. This suggests that monkeys hear a rising frequency sound as a looming sound source even though, in the real world, no such link exists.


Effects of glycemic control on prevalence of diabetic frozen shoulder.
There is controversy regarding the influence of glycemic control in diabetic patients with frozen shoulder. To determine the relationship between glycemic control and the prevalence of frozen shoulder in diabetic patients, we hypothesized that increased glycosylated hemoglobin A1c (HbA1c) levels would correlate with an increased prevalence of frozen shoulder. A retrospective analysis with statistical review of 201,513 diabetic patients enrolled in a regional health maintenance organization in 2007 was performed. Analysis included determining the relationship between the prevalence of frozen shoulder and the following factors: HbA1c level, type of diabetes treatment, duration of diabetes treatment, and presence of end-stage diabetic manifestations. There were 1150 diabetic patients with a diagnosis of frozen shoulder. There was no significant relationship between HbA1c level and the prevalence of frozen shoulder. Insulin-dependent patients who used or did not use oral hypoglycemics were 1.93 times more likely than non-insulin-dependent diabetic patients to have frozen shoulder, and that rate increased to 1.96 times more likely when the results were adjusted for HbA1c level. Patients who were taking oral hypoglycemic drugs were 1.5 times more likely to develop frozen shoulder than those who did not use insulin or take oral hypoglycemic drugs. Duration of diabetes was also associated with the development of frozen shoulder, after controlling for insulin use (odds ratio: 1.85 for duration of more than ten years of use compared with less than five years of use). The prevalence of end-stage diabetic manifestations was increased in patients with frozen shoulder as compared with those without frozen shoulder (p < 0.0001). There was no association found between HbA1c level and the prevalence of frozen shoulder in this diabetic population.


Impacts of different land management histories on forest change.
Many western North American forest types have experienced considerable changes in ecosystem structure, composition, and function as a result of both fire exclusion and timber harvesting. These two influences co-occurred over a large portion of dry forests, making it difficult to know the strength of either one on its own or the potential for an interaction between the two. In this study, we used contemporary remeasurements of a systematic historical forest inventory to investigate forest change in the Sierra Nevada. The historical data opportunistically spanned a significant land management agency boundary, which protected part of the inventory area from timber harvesting. This allowed for a robust comparison of forest change between logged and unlogged areas. In addition, we assessed the effects of recent management activities aimed at forest restoration relative to the same areas historically, and to other areas without recent management. Based on analyses of 22,007 trees (historical, 9,573; contemporary, 12,434), live basal area and tree density significantly increased from 1911 to the early 2000s in both logged and unlogged areas. Both shrub cover and the proportion of live basal area occupied by pine species declined from 1911 to the early 2000s in both areas, but statistical significance was inconsistent. The most notable difference between logged and unlogged areas was in the density of large trees, which declined significantly in logged areas, but was unchanged in unlogged areas. Recent management activities had a varied impact on the forest structure and composition variables analyzed. In general, areas with no recent management activities experienced the greatest change from 1911 to the early 2000s. If approximating historical forest conditions is a land management goal the documented changes in forest structure and composition from 1911 to the early 2000s indicate that active restoration, including fire use and mechanical thinning, is needed in many areas.


A parallel algorithm for reverse engineering of biological networks.
Dynamic biological systems, such as gene regulatory networks (GRNs) and protein signaling networks, are often represented as systems of ordinary differential equations. Such equations can be utilized in reverse engineering these biological networks, specifically since identifying these networks is challenging due to the cost of the necessary experiments growing with at least the square of the size of the system. Moreover, the number of possible models, proportional to the number of directed graphs connecting nodes representing the variables in the system, suffers from combinatorial explosion as the size of the system grows. Therefore, exhaustive searches for systems of nontrivial complexity are not feasible. Here we describe a practical and scalable algorithm for determining candidate network interactions based on decomposing an N-dimensional system into N one-dimensional problems. The algorithm was tested on in silico networks based on known biological GRNs. The computational complexity of the network identification is shown to increase as N(2) while a parallel implementation achieves essentially linear speedup with the increasing number of processing cores. For each in silico network tested, the algorithm successfully predicts a candidate network that reproduces the network dynamics. This approach dramatically reduces the computational demand required for reverse engineering GRNs and produces a wealth of exploitable information in the process. Moreover, the candidate network topologies returned by the algorithm can be used to design future experiments aimed at gathering informative data capable of further resolving the true network topology.


Binge ethanol in adulthood exacerbates negative outcomes following juvenile traumatic brain injury.
Traumatic brain injuries (TBI) are a major public health problem with enormous costs in terms of health care dollars, lost productivity, and reduced quality of life. Alcohol is bidirectionally linked to TBI as many TBI patients are intoxicated at the time of their injury and we recently reported that, in accordance with human epidemiological data, animals injured during juvenile development self-administered significantly more alcohol as adults than did sham injured mice. There are also clinical data that drinking after TBI significantly reduces the efficacy of rehabilitation and leads to poorer long-term outcomes. In order to determine whether juvenile traumatic brain injury also increased the vulnerability of the brain to the toxic effects of high dose alcohol, mice were injured at 21days of age and then seven weeks later treated daily with binge-like levels of alcohol 5g/kg (by oral gavage) for ten days. Binge-like alcohol produced a greater degree of neuronal damage and neuroinflammation in mice that sustained a TBI. Further, mice that sustained a juvenile TBI exhibited mild learning and memory impairments in adulthood following binge alcohol and express a significant increase in hippocampal ectopic localization of newborn neurons. Taken together, these data provide strong evidence that a mild brain injury occurring early in life renders the brain highly vulnerable to the consequences of binge-like alcohol consumption.


The gut microbiota drives the impact of bile acids and fat source in diet on mouse metabolism.
As the gut microbiota contributes to metabolic health, it is important to determine specific diet-microbiota interactions that influence host metabolism. Bile acids and dietary fat source can alter phenotypes of diet-induced obesity, but the interplay with intestinal microorganisms is unclear. Here, we investigated metabolic consequences of diets enriched in primary bile acids with or without addition of lard or palm oil, and studied gut microbiota structure and functions in mice. In combination with bile acids, dietary lard fed to male C57BL/6N mice for a period of 8 weeks enhanced fat mass accumulation in colonized, but not in germ-free mice when compared to palm oil. This was associated with impaired glucose tolerance, lower fasting insulin levels, lower counts of enteroendocrine cells, fatty liver, and elevated amounts of hepatic triglycerides, cholesteryl esters, and monounsaturated fatty acids. Lard- and bile acid-fed mice were characterized by shifts in dominant gut bacterial communities, including decreased relative abundances of Lachnospiraceae and increased occurrence of Desulfovibrionaceae and the species Clostridium lactatifermentans and Flintibacter butyricus. Metatranscriptomic analysis revealed shifts in microbial functions, including lipid and amino acid metabolism. Caution is required when interpreting data from diet-induced obesity models due to varying effects of dietary fat source. Detrimental metabolic consequences of a diet enriched with lard and primary bile acids were dependent on microbial colonization of the host and were linked to hepatic lipid rearrangements and to alterations of dominant bacterial communities in the cecum.


Uncoupled surface spin induced exchange bias in α-MnO2 nanowires.
We have studied the microstructure, surface states, valence fluctuations, magnetic properties, and exchange bias effect in MnO2 nanowires. High purity α-MnO2 rectangular nanowires were synthesized by a facile hydrothermal method with microwave-assisted procedures. The microstructure analysis indicates that the nanowires grow in the [0 0 1] direction with the (2 1 0) plane as the surface. Mn(3+) and Mn(2+) ions are not found in the system by X-ray photoelectron spectroscopy. The effective magnetic moment of the manganese ions fits in with the theoretical and experimental values of Mn(4+) very well. The uncoupled spins in 3d(3) orbitals of the Mn(4+) ions in MnO6 octahedra on the rough surface are responsible for the net magnetic moment. Spin glass behavior is observed through magnetic measurements. Furthermore, the exchange bias effect is observed for the first time in pure α-MnO2 phase due to the coupling of the surface spin glass with the antiferromagnetic α-MnO2 matrix. These α-MnO2 nanowires, with a spin-glass-like behavior and with an exchange bias effect excited by the uncoupled surface spins, should therefore inspire further study concerning the origin, theory, and applicability of surface structure induced magnetism in nanostructures.


Efficient transduction of neural cells in vitro and in vivo by a baculovirus-derived vector.
Gene delivery to the central nervous system is central to the development of gene therapy for neurological diseases. We developed a baculovirus-derived vector, the Bac-CMV-GFP vector, containing a reporter gene encoding for the green fluorescent protein (GFP) under the control of the cytomegalovirus (CMV) promoter. Two neuroblastomal cell lines and three human primary neural cultures could be efficiently transduced. In all cases, addition of butyrate, an inhibitor of histone deacetylase, increased the level of expression in terms of the number of GFP-expressing cells and the intensity of fluorescence. The level of expression in a human telencephalic culture was over 50% of transduced cells with a multiplicity of infection of 25. GFP expression was demonstrated to be genuine expression and not pseudotransduction of the reporter protein. Most interestingly, Bac-CMV-GFP could transduce neural cells in vivo when directly injected into the brain of rodents and was not inactivated by the complement system. Thus, baculovirus is a promising tool for gene transfer into the central nervous system both for studies of the function of foreign genes and the development of gene therapy strategies.


[Health surveillance: foundations, interfaces and tendencies].
The present article rescues initially the forms, content and operational projection of the epidemiological surveillance as indispensable tool for the knowledge field and public health practices. After that, we verify that the health surveillance model establishes an enlargement of this operational concept of surveillance by integrating the collectives and individuals practices in different health necessities dimensions, which includes beyond of the risks and damages control also the eco-socials determinants. In the sequence, we search to dimension the distinct levels of actuation of this sanitary practice articulated to the interventions of promotion, protection and recovery under a located and integrated logic of the unique system of Brazilian health. Finally, we argue that all the conceptual-operational model framework of public health surveillance itself constitutes as a politics and sanitary base for the consolidation of the health promotion paradigm in the collective health field.


Self-monitoring and self-management of oral anticoagulation.
The introduction of point-of-care devices for the management of patients on oral anticoagulation allows self-testing by the patient at home. Patients who self-test can either adjust their medication according to a pre-determined dose-INR (international normalized ratio) schedule (self-management), or they can call a clinic to be told the appropriate dose adjustment (self-monitoring). Increasing evidence suggests self-testing of oral anticoagulant therapy is equal to or better than standard monitoring. This is an updated version of the original review published in 2010. To evaluate the effects on thrombotic events, major haemorrhages, and all-cause mortality of self-monitoring or self-management of oral anticoagulant therapy compared to standard monitoring. For this review update, we re-ran the searches of the Cochrane Central Register of Controlled Trials (CENTRAL), 2015, Issue 6, the Cochrane Library, MEDLINE (Ovid, 1946 to June week 4 2015), Embase (Ovid, 1980 to 2015 week 27) on 1 July 2015. We checked bibliographies and contacted manufacturers and authors of relevant studies. We did not apply any language restrictions . Outcomes analysed were thromboembolic events, mortality, major haemorrhage, minor haemorrhage, tests in therapeutic range, frequency of testing, and feasibility of self-monitoring and self-management. Review authors independently extracted data and we used a fixed-effect model with the Mantzel-Haenzel method to calculate the pooled risk ratio (RR) and Peto's method to verify the results for uncommon outcomes. We examined heterogeneity amongst studies with the Chi(2) and I(2) statistics and used GRADE methodology to assess the quality of evidence. We identified 28 randomised trials including 8950 participants (newly incorporated in this update: 10 trials including 4227 participants). The overall quality of the evidence was generally low to moderate. Pooled estimates showed a reduction in thromboembolic events (RR 0.58, 95% CI 0.45 to 0.75; participants = 7594; studies = 18; moderate quality of evidence). Both, trials of self-management or self-monitoring showed reductions in thromboembolic events (RR 0.47, 95% CI 0.31 to 0.70; participants = 3497; studies = 11) and (RR 0.69, 95% CI 0.49 to 0.97; participants = 4097; studies = 7), respectively; the quality of evidence for both interventions was moderate. No reduction in all-cause mortality was found (RR 0.85, 95% CI 0.71 to 1.01; participants = 6358; studies = 11; moderate quality of evidence). While self-management caused a reduction in all-cause mortality (RR 0.55, 95% CI 0.36 to 0.84; participants = 3058; studies = 8); self-monitoring did not (RR 0.94, 95% CI 0.78 to 1.15; participants = 3300; studies = 3); the quality of evidence for both interventions was moderate. In 20 trials (8018 participants) self-monitoring or self-management did not reduce major haemorrhage (RR 0.95, 95% CI, 0.80 to 1.12; moderate quality of evidence). There was no significant difference found for minor haemorrhage (RR 0.97, 95% CI 0.67 to 1.41; participants = 5365; studies = 13). The quality of evidence was graded as low because of serious risk of bias and substantial heterogeneity (I(2) = 82%). Participants who self-monitor or self-manage can improve the quality of their oral anticoagulation therapy. Thromboembolic events were reduced, for both those self-monitoring or self-managing oral anticoagulation therapy. A reduction in all-cause mortality was observed in trials of self-management but not in self-monitoring, with no effects on major haemorrhage.


Delayed presentation following accidental inhalation of a pushpin.
A previously fit and well 18-year-old woman presented to the accident and emergency department following referral by her general practitioner with a provisional diagnosis of appendicitis. The history obtained from the patient revealed the presence of a bitemporal headache with associated neck stiffness, photophobia and vomiting for approximately 1.5 weeks. The patient complained of abdominal pain localised to her right iliac fossa and anorexia for approximately 1 week. She also noted the presence of a cough productive of green sputum for 3 weeks. A chest radiograph was obtained which showed a large area of consolidation in the right lower lobe consistent with infection and a linear density in keeping with a metallic foreign body. Following review of the chest radiograph, the patient was interviewed further and recalled having inhaled a pushpin approximately 1 year before her presentation. Aspiration of foreign bodies is relatively common in children and is often associated with delayed diagnosis and high morbidity. To prevent delayed diagnosis, characteristic symptoms and clinical and radiological signs of foreign body aspiration should be checked in all suspected cases and a low index of suspicion for ordering additional imaging or using bronchoscopy for diagnostic purposes should be employed.


SU-E-J-113: A New Quantification Measure of the Difference Between Two Organ Contours.
To develop a measuring method between two contours, which can be used for validating a PTV during IGRT, organ motion and/or deformation studies. Quantifying the geometric difference between two organ/target surfaces is essential for Radiation therapy planning and delivery. Point-to-surface distance measures have been utilized to evaluate and visualize the local surface differences. However, previously well-known distance measures have critical shortfalls. Normal distance (ND) measure suffers when the reference surface is strongly curved. Minimum distance (MD) measure (a.k.a. Hausdorff distance) suffers when the test surface is strongly curved. Our new distance measure named Error-Proof Distance (EPD) can deal with both difficult cases.EPD measure calculates the maximum value between the Forward Minimum Distance (FMinD) and the Backward Maximum Distance (BMaxD) at each point. The FMinD denotes the minimum distance to the test surface from a point on the reference surface. The BMaxD means the maximum value among the minimum distances from all points of the test surface to the point on the reference surface. We tested EPD using three 2-D contour examples including a 20mm shifted contour, and two 3-D clinical cases. In case of 2-D contour examples, ND and MD measure failed in strongly curved areas, but EPD measure outperformed the others. The maximum distance measured between a reference and a 20mm shifted test contour should be equal to 20mm, but ND erroneously measured 24mm. Furthermore, ND reported erroneous distances where the reference surface is strongly curved in 3-D clinical cases. We succeeded to prove that a new EPD is arobust and accurate distance measure to compare two 2D or 3D surfaces. EPD measure can be used to evaluate and visualize the surface difference of organ contours. It is also helpful for proving PTV margin during IGRT, and organ motion and/or deformation studies. This project is partially supported by the Agency for Healthcare Research and Quality (AHRQ) grant 1R18HS017424-01A2.


Therapeutic drug monitoring of vancomycin.
Vancomycin, a glycopeptide antibiotic, was developed-and released in the 1950's for the treatment of aerobic gram-positive infections and has been widely used mainly in the treatment of methicillin-resistant Staphylococcus aureus infections. Early reports regarding the possibility of nephrotoxicity and ototoxicity led to concern about the use of vancomycin and the need to monitor serum concentrations. In Mexico, the National Institute of Cardiology measures serum level of some drugs, such as vancomycin on a routine basis. Nevertheless, although a large number of measurements are made, the quantification of drug in serum is only used by physicians as a empiric parameter for dose adjustment. The aim of this work was to know whether dosing was appropriate taking the therapeutic interval as a commonly accepted baseline and to propose viable alternatives in the case dosing was inadequate. Peak and through vancomycin levels were analyzed retrospectively (n=295), in patients from 18 to 65 yr old with diagnosis of sepsis. The relationship between administered dose and measured blood levels was established. The equation that characterizes the study population was obtained based on a single compartment model considering the proportional relationship between vancomycin and creatinine clearance. The analysis shows that only 44% of C(trough) and 47% of C(peak) values represented therapeutic levels, with the remainder either toxic or ineffective.


Coffee consumption and risk of endometrial cancer: a pooled analysis of individual participant data in the Epidemiology of Endometrial Cancer Consortium (E2C2).
Epidemiologic studies suggest that coffee consumption may be inversely associated with risk of endometrial cancer (EC), the most common gynecological malignancy in developed countries. Furthermore, coffee consumption may lower circulating concentrations of estrogen and insulin, hormones implicated in endometrial carcinogenesis. Antioxidants and other chemopreventive compounds in coffee may have anticarcinogenic effects. Based on available meta-analyses, the World Cancer Research Fund (WCRF) concluded that consumption of coffee probably protects against EC. Our main aim was to examine the association between coffee consumption and EC risk by combining individual-level data in a pooled analysis. We also sought to evaluate potential effect modification by other risk factors for EC. We combined individual-level data from 19 epidemiologic studies (6 cohort, 13 case-control) of 12,159 EC cases and 27,479 controls from the Epidemiology of Endometrial Cancer Consortium (E2C2). Logistic regression was used to calculate ORs and their corresponding 95% CIs. All models were adjusted for potential confounders including age, race, BMI, smoking status, diabetes status, study design, and study site. Coffee drinkers had a lower risk of EC than non-coffee drinkers (multiadjusted OR: 0.87; 95% CI: 0.79, 0.95). There was a dose-response relation between higher coffee consumption and lower risk of EC: compared with non-coffee drinkers, the adjusted pooled ORs for those who drank 1, 2-3, and >4 cups/d were 0.90 (95% CI: 0.82, 1.00), 0.86 (95% CI: 0.78, 0.95), and 0.76 (95% CI: 0.66, 0.87), respectively (P-trend < 0.001). The inverse association between coffee consumption and EC risk was stronger in participants with BMI > 25 kg/m2. The results of the largest analysis to date pooling individual-level data further support the potentially beneficial health effects of coffee consumption in relation to EC, especially among females with higher BMI.


Emergent Field-Driven Robot Swarm States.
We present an ecology-inspired form of active matter consisting of a robot swarm. Each robot moves over a planar dynamic resource environment represented by a large light-emitting diode array in search of maximum light intensity; the robots deplete (dim) locally by their presence the local light intensity and seek maximum light intensity. Their movement is directed along the steepest local light intensity gradient; we call this emergent symmetry breaking motion "field drive." We show there emerge dynamic and spatial transitions similar to gas, crystalline, liquid, glass, and jammed states as a function of robot density, resource consumption rates, and resource recovery rates. Paradoxically the nongas states emerge from smooth, flat resource landscapes, not rough ones, and each state can directly move to a glassy state if the resource recovery rate is slow enough, at any robot density.


Automated method for optimization of electric field distributions and optical parameters in thin-film polarizers.
An efficient method based on the modified needle optimization technique is proposed to design high-power laser thin-film polarizers. In order to minimize the influence of the standing-wave electric field on the laser-induced damage threshold of the polarizers, a crucial optimization parameter, the maximum electric field intensity in the high-refractive-index layers, is included in the proposed merit function. The electric field distribution and optical performance obtained by the proposed method are studied. Improved electric field and identical optical characteristics are observed in comparison with those of the designs obtained by optimizing the traditional merit function without a standing-wave electric field term and by the analytical synthesis method.


Is it time to reassess alpha lipoic acid and niacinamide therapy in schizophrenia?
As sulfur containing thiols, alpha lipoic acid (ALA) and its reduced form dihydrolipoic acid (DHLA) are powerful antioxidants and free radical scavengers capable of performing many of the same functions as glutathione (GSH). ALA supplementation may help protect mitochondria from oxidative stress, a possible mechanism contributing to certain forms of brain diseases called schizophrenia. Shortly before the advent of antipsychotic medications, two small studies found ALA relieved psychiatric symptoms in schizophrenia. More recently, animal studies have shown ALA augmentation improves mitochondrial function. At pharmaceutical levels, niacinamide helps preserve mitochondrial membrane integrity and acts as an antioxidant. ALA is a precursor for lipoamide, an essential mitochondrial coenzyme and niacinamide is a component of niacinamide adenine dinucleotide (NAD). NADH, the reduced form of NAD, is involved in the reduction of ALA to DHLA within the mitochondria. This is relevant to contemporary research because DHLA increases GSH and low GSH levels contribute to mitochondrial dysfunction and oxidative stress which have been implicated in the pathophysiology of schizophrenia.


Activation and epigenetic regulation of DNA transposon nDart1 in rice.
A large part of the rice genome is composed of transposons. Since active excision/reintegration of these mobile elements may result in harmful genetic changes, many transposons are maintained in a genetically or epigenetically inactivated state. However, some non-autonomous DNA transposons of the nDart1-3 subgroup, including nDart1-0, actively transpose in specific rice lines, such as pyl-v which carries an active autonomous element, aDart1-27, on chromosome 6. Although nDart1-3 subgroup elements show considerable sequence identity, they display different excision frequencies. The most active element, nDart1-0, had a low cytosine methylation status. The aDart1-27 sequence showed conservation between pyl-stb (pyl-v derivative line) and Nipponbare, which both lack autonomous activity for transposition of nDart1-3 subgroup elements. In pyl-v plants, the promoter region of the aDart1-27 transposase gene was more hypomethylated than in other rice lines. Treatment with the methylation inhibitor 5-azacytidine (5-azaC) induced transposition of nDart1-3 subgroup elements in both pyl-stb and Nipponbare plants; the new insertion sites were frequently located in genic regions. 5-AzaC treatment principally induced expression of Dart1-34 transposase rather than the other 38 aDart1-related elements in both pyl-stb and Nipponbare treatment groups. Our observations show that transposition of nDart1-3 subgroup elements in the nDart1/aDart1 tagging system is correlated with the level of DNA methylation. Our system does not cause somaclonal variation due to an absence of transformed plants, offers the possibility of large-scale screening in the field and can identify dominant mutants. We therefore propose that this tagging system provides a valuable addition to the tools available for rice functional genomics.


Pseudomonas aeruginosa detachment from surfaces via a self-made small molecule.
Pseudomonas aeruginosa is a significant threat in both healthcare and industrial biofouling. Surface attachment of P. aeruginosa is particularly problematic as surface association induces virulence and is necessary for the ensuing process of biofilm formation, which hampers antibiotic treatments. Previous efforts have searched for dispersal agents of mature biofilm collectives, but there are no known factors that specifically disperse individual surface-attached P. aeruginosa. In this study, we develop a quantitative single-cell surface-dispersal assay and use it to show that P. aeruginosa itself produces factors that can stimulate its dispersal. Through bioactivity-guided fractionation, mass spectrometry, and nuclear magnetic resonance, we elucidated the structure of one such factor, 2-methyl-4-hydroxyquinoline (MHQ). MHQ is an alkyl quinolone with a previously unknown activity and is synthesized by the PqsABC enzymes. Pure MHQ is sufficient to disperse P. aeruginosa, but the dispersal activity of natural P. aeruginosa conditioned media requires additional factors. Whereas other alkyl quinolones have been shown to act as antibiotics or membrane depolarizers, MHQ lacks these activities and known antibiotics do not induce dispersal. In contrast, we show that MHQ inhibits the activity of Type IV Pili (TFP) and that TFP targeting can explain its dispersal activity. Our work thus identifies single-cell surface dispersal as a new activity of P. aeruginosa-produced small molecules, characterizes MHQ as a promising dispersal agent, and establishes TFP inhibition as a viable mechanism for P. aeruginosa dispersal.


Potential value of phosphate compounds in enhancing immobilization and reducing bioavailability of mixed heavy metal contaminants in shooting range soil.
Shooting range soils contain mixed heavy metal contaminants including lead (Pb), cadmium (Cd), and zinc (Zn). Phosphate (P) compounds have been used to immobilize these metals, particularly Pb, thereby reducing their bioavailability. However, research on immobilization of Pb's co-contaminants showed the relative importance of soluble and insoluble P compounds, which is critical in evaluating the overall success of in situ stabilization practice in the sustainable remediation of mixed heavy metal contaminated soils. Soluble synthetic P fertilizer (diammonium phosphate; DAP) and reactive (Sechura; SPR) and unreactive (Christmas Island; CPR) natural phosphate rocks (PR) were tested for Cd, Pb and Zn immobilization and later their mobility and bioavailability in a shooting range soil. The addition of P compounds resulted in the immobilization of Cd, Pb and Zn by 1.56-76.2%, 3.21-83.56%, and 2.31-74.6%, respectively. The reactive SPR significantly reduced Cd, Pb and Zn leaching while soluble DAP increased their leachate concentrations. The SPR reduced the bioaccumulation of Cd, Pb and Zn in earthworms by 7.13-23.4% and 14.3-54.6% in comparison with earthworms in the DAP and control treatment, respectively. Bioaccessible Cd, Pb and Zn concentrations as determined using a simplified bioaccessibility extraction test showed higher long-term stability of P-immobilized Pb and Zn than Cd. The differential effect of P-induced immobilization between P compounds and metals is due to the variation in the solubility characteristics of P compounds and nature of metal phosphate compounds formed. Therefore, Pb and Zn immobilization by P compounds is an effective long-term remediation strategy for mixed heavy metal contaminated soils.


Efficacy of a Tobacco Quitline in Active Duty Military and TRICARE Beneficiaries: A Randomized Trial.
A higher proportion of military personnel than civilians smoke cigarettes. Few randomized trials of tobacco use interventions have been conducted in the U.S. military. We evaluated the efficacy of a tobacco quitline (QL) in 1298 active duty military personnel, their dependents, reservists, and retirees who smoke cigarettes. Participants were randomized to either a proactive (counselor-initiated) or reactive (participant-initiated) QL intervention for 8 weeks. The proactive condition included up to an 8-week supply of free nicotine replacement therapy, and the reactive condition included a 2-week supply. The primary outcome was 12-month smoking abstinence. The enrolled population was predominantly affiliated with the Air Force and Army. At the end of treatment, proactive treatment was associated with a greater odds of both prolonged (44.22% vs. 24.96%; odds ratio [OR] = 2.4, P < 0.0001) and 7-day point prevalence (49.92% vs. 28.20%; OR = 2.5, P < 0.0001) smoking abstinence, a difference that was maintained for prolonged smoking abstinence at 12 months (22.03% vs. 13.41%; OR = 1.8, P < 0.0001). Our findings provide evidence that a proactive QL with nicotine replacement therapy is highly efficacious among Air Force and Army active duty and TRICARE beneficiaries and would provide an effective telephonic treatment option for this population of smokers.


Blinding in Physical Therapy Trials and Its Association with Treatment Effects: A Meta-epidemiological Study.
The aim of this study was to examine whether blinding of participants, assessors, health providers, and statisticians have an effect on treatment effect estimates in physical therapy (PT) trials. This was a meta-epidemiological study. Randomized controlled trials in PT were identified by searching the Cochrane Database of Systematic Reviews for meta-analyses of PT interventions. Assessments of blinding in PT trials were conducted independently following established guidelines. Three hundred ninety-three trials and 43 meta-analyses that included 44,622 patients contributed to this study. Only a quarter of the trials were adequately blinded (n = 80; 20%). Most individual components of blinding as well as what they were blinded to were also poorly reported. Although trials with inappropriate blinding of assessors and participants tended to underestimate treatment effects when compared with trials with appropriate blinding of assessors and participants, the difference was not statistically significant (effect size, -0.07; 95% confidence interval, -0.22 to 0.08; effect size, -0.12; 95% confidence interval, -0.30 to 0.06, respectively). The lack of statistical significance between blinding and effect sizes should not be interpreted as meaning that an impact of blinding on effect size is not present in PT. More empirical evidence in a larger sample is needed to determine which biases are likely to influence reported effect sizes of PT trials and under which conditions.


Yeast RSP5 and its human homolog hRPF1 potentiate hormone-dependent activation of transcription by human progesterone and glucocorticoid receptors.
We have developed a system in Saccharomyces cerevisiae in which agonist-dependent transcriptional activity of the human progesterone receptor (hPR) is elevated to the point that it compromises cell growth. Screens for suppressors of this phenotype led to the demonstration that RSP5 is involved in hPR transactivation. Expression of RSP5 in yeast cells potentiated hPR and human glucocorticoid receptor (hGR) transcriptional activity and increased the efficacy of weak agonists of these receptors. Remarkably, expression of this yeast protein in mammalian cells had a similar effect on PR and GR transcriptional activity. Importantly, a human homolog of RSP5, hRPF1, functioned identically in mammalian cells. Previously, it has been demonstrated that RSP5 overexpression in yeast cells suppressed mutations within SPT3, a protein which interacts with the TATA-box-binding protein (TBP), suggesting that RSP5 and SPT3 operate in the same regulatory pathway. In support of this observation, we have shown that SPT3 enhances the activity of RSP5 on GR and PR when tested in yeast or mammalian cells. We conclude from these experiments that the regulatory pathways in which RSP5 and SPT3 operate in yeast cells are conserved in higher eukaryotes. Additionally, since SPT3 has been shown to contact yeast TBP directly and is the likely homolog of human TBP-associated factor TAFII18, we propose that RSP5/hRPF1 and SPT3 establish a functional link between activated PR and GR and the general transcription apparatus.


Effect of ACASI on Reporting of Abortion and Other Pregnancy Outcomes in the US National Survey of Family Growth.
Abortion is a behavior that is stigmatized and difficult to measure. To improve reporting of abortion and other sensitive behaviors in the United States, the National Survey of Family Growth (NSFG) supplements the interviewer administered face-to-face (FTF) interview with audio computer-assisted self-interviewing (ACASI). This paper estimates differential reporting of abortion and other pregnancy outcomes (miscarriage, live birth) in the NSFG (2002, 2006-2010, 2011-2015) between women's ACASI and FTF interviews. Examining reporting of less stigmatized pregnancy outcomes can help understand the relative contributions of stigma and survey-level factors in reporting of abortions. More women reported abortions, miscarriages and births in the ACASI than the FTF interview. Differences in reporting were moderated by the length of recall. The ACASI elicited relatively more reporting of abortions and miscarriages among non-white and low-income women. Reporting ratios increased over time. ACASI is a tool that may work differently across time, for different measures, and with varying survey contexts.


Mammalian gene expression variability is explained by underlying cell state.
Gene expression variability in mammalian systems plays an important role in physiological and pathophysiological conditions. This variability can come from differential regulation related to cell state (extrinsic) and allele-specific transcriptional bursting (intrinsic). Yet, the relative contribution of these two distinct sources is unknown. Here, we exploit the qualitative difference in the patterns of covariance between these two sources to quantify their relative contributions to expression variance in mammalian cells. Using multiplexed error robust RNA fluorescent in situ hybridization (MERFISH), we measured the multivariate gene expression distribution of 150 genes related to Ca2+ signaling coupled with the dynamic Ca2+ response of live cells to ATP. We show that after controlling for cellular phenotypic states such as size, cell cycle stage, and Ca2+ response to ATP, the remaining variability is effectively at the Poisson limit for most genes. These findings demonstrate that the majority of expression variability results from cell state differences and that the contribution of transcriptional bursting is relatively minimal.


Impact of an early childhood intervention on the home environment, and subsequent effects on child cognitive and emotional development: A secondary analysis.
The objective of this study was to use secondary data from the Preparing for Life (PFL) trial to test (1) the impact of a prenatal-to-age-five intervention targeting women from a disadvantaged Irish community on the quality of the home environment; (2) whether any identified changes in the home environment explain the positive effects of the PFL program on children's cognitive and emotional development at school entry which have been identified in previous reports of the PFL trial (ES = .72 and .50, respectively). Pregnant women were randomized into a treatment (home visits, baby massage, and parenting program, n = 115) or control (n = 118) group (trial registration: ISRCTN04631728). The home environment was assessed at 6 months, 1½, and 3 years using the Home Observation for Measurement of the Environment (responsiveness, acceptance, organization, learning material, involvement, variety). Cognitive skills were assessed at 5 years using the British Ability Scales. Emotional problems were teacher-reported at 5 years using the Short Early Development Inventory. Latent growth modeling was used to model changes in the home environment, and mediation analyses to test whether those changes explained children outcomes. Compared to controls, treatment children were exposed to more stimulating environments in terms of learning material (B = -1.62, p = 0.036) and environmental variety (B = -1.58, p = 0.009) at 6 months, but these differences faded at 3 years. Treatment families were also more likely to accept suboptimal child behaviors without using punishment (acceptance score, B = 1.49, p = 0.048) and were more organized at 3 years (B = 1.08, p = 0.033). None of the changes mediated children's outcomes. In conclusion, we found that the program positively impacted different home environment dimensions, but these changes did not account for improvements in children's outcomes. Exploratory analyses suggest that the impact of improvements in the home environment on child outcomes may be limited to specific groups of children. Limitations of the study include the potential lack of generalizability to other populations, the inability to assess the individual treatment components, and sample size restrictions which precluded a moderated mediation analysis.


Partnering urban academic medical centers and rural primary care clinicians to provide complex chronic disease care.
Many of the estimated thirty-two million Americans expected to gain coverage under the Affordable Care Act are likely to have high levels of unmet need because of various chronic illnesses and to live in areas that are already underserved. In New Mexico an innovative new model of health care education and delivery known as Project ECHO (Extension for Community Healthcare Outcomes) provides high-quality primary and specialty care to a comparable population. Using state-of-the-art telehealth technology and case-based learning, Project ECHO enables specialists at the University of New Mexico Health Sciences Center to partner with primary care clinicians in underserved areas to deliver complex specialty care to patients with hepatitis C, asthma, diabetes, HIV/AIDS, pediatric obesity, chronic pain, substance use disorders, rheumatoid arthritis, cardiovascular conditions, and mental illness. As of March 2011, 298 Project ECHO teams across New Mexico have collaborated on more than 10,000 specialty care consultations for hepatitis C and other chronic diseases.


Pharmacologic relevance of dihydropyridine binding sites in membranes from rat aorta: kinetic and equilibrium studies.
The kinetic features of the interaction of dihydropyridines with rat aortic smooth muscle were investigated in parallel mechanical and binding studies. The inhibitory action of (+)-PN200-110 and nisoldipine on contractions evoked by potassium chloride depolarization was characterized by a pronounced time dependency, in which the inhibition increased slowly after depolarization to attain a steady-state value, while with (-)-PN200-110 and (+)-Bay K8644 the inhibition was almost instantaneous. To explain these observations, specific binding sites for dihydropyridines were studied in membranes isolated from rat aorta, using [3H](+)-PN200-110 as a radioligand. We found that the time course of the development of inhibition of potassium chloride-evoked contractions by various concentrations of (+)-PN200-110 paralleled the time course of [3H](+)-PN200-110 binding to isolated membranes and that the level of inhibition was predictable from the level of occupation of these binding sites. These results indicate that depolarization increases the affinity of calcium channels for dihydropyridines in vascular smooth muscle and that the time course of the inhibitory effect on contraction is determined by the time course of association with the high-affinity state of the channel.


Understanding Marketing Responses to a Tax on Sugary Drinks: A Qualitative Interview Study in the United Kingdom, 2019.
The World Health Organization (WHO) recommends that countries implement fiscal policies to reduce the health impacts of sugary drinks. Few studies have fully examined the responses of industry to these policies, and whether they support or undermine health benefits of sugary drinks taxes. We aimed to explore the changes that sugary drinks companies may make to their marketing, and underlying decision-making processes, in response to such a tax. Following introduction of the UK Soft Drinks Industry Levy (SDIL) in 2018, we undertook one-to-one semi-structured interviews with UK stakeholders with experience of the strategic decision-making or marketing of soft drinks companies. We purposively recruited interviewees using seed and snowball sampling. We conducted telephone interviews with 6 representatives from each of industry, academia and civil society (total n=18), which were transcribed verbatim and thematically analysed. Four transcripts were double-coded, three were excluded from initial coding to allow comparison; and findings were checked by interviewees. Themes were organised into a theoretical framework that reveals a cyclical, iterative and ongoing process of soft drinks company marketing decision-making, which was accelerated by the SDIL. Decisions about marketing affect a product's position, or niche, in the market and were primarily intended to maintain profits. A product's position is enacted through various marketing activities including reformulation and price variation, and non-marketing activities like lobbying. A soft drinks company's selection of marketing activities appeared to be influenced by their internal context, such as brand strength, and external context, such as consumer trends and policy. For example, a company with low brand strength and an awareness of trends for reducing sugar consumption may be more likely to reformulate to lower-sugar alternatives. The theoretical framework suggests that marketing responses following the SDIL were coordinated and context-dependent, potentially explaining observed heterogeneity in responses across the industry.


Endocrine-disrupting chemicals: implications for human health.
Since reports published in 2015 and 2016 identified 15 probable exposure-outcome associations, there has been an increase in studies in humans of exposure to endocrine-disrupting chemicals (EDCs) and a deepened understanding of their effects on human health. In this Series paper, we have reviewed subsequent additions to the literature and identified new exposure-outcome associations with substantial human evidence. Evidence is particularly strong for relations between perfluoroalkyl substances and child and adult obesity, impaired glucose tolerance, gestational diabetes, reduced birthweight, reduced semen quality, polycystic ovarian syndrome, endometriosis, and breast cancer. Evidence also exists for relations between bisphenols and adult diabetes, reduced semen quality, and polycystic ovarian syndrome; phthalates and prematurity, reduced anogenital distance in boys, childhood obesity, and impaired glucose tolerance; organophosphate pesticides and reduced semen quality; and occupational exposure to pesticides and prostate cancer. Greater evidence has accumulated than was previously identified for cognitive deficits and attention-deficit disorder in children following prenatal exposure to bisphenol A, organophosphate pesticides, and polybrominated flame retardants. Although systematic evaluation is needed of the probability and strength of these exposure-outcome relations, the growing evidence supports urgent action to reduce exposure to EDCs.


Valproate prescription to women of childbearing age in English primary care: repeated cross-sectional analyses and retrospective cohort study.
Valproate is a teratogenic drug that should be avoided during the preconception period and pregnancy. The aim was to explore general practitioners' (GPs) prescription patterns over time, describe trends, and explore inter-practice variation within primary care. We identified women of childbearing age (12-46 years old) in the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) sentinel network. We performed repeated cross-sectional analyses from 2004 to 2018 to determine rates of prescription and a retrospective cohort estimated the prevalence of use of valproate during pregnancy. In 2004, 0.31% (95% Confidence Interval (95%CI):0.18 to 0.44%) women were prescribed valproate, decreasing to 0.16% (95%CI:0.07 to 0.24%) by 2018. Among women with epilepsy, the rate fell from 15.2% (95%CI:14.4 to 16.0%) to 8.8% (95% CI:8.2 to 9.7%) over the same period. In 2018, almost two thirds (62.2%) of women who were prescribed valproate had epilepsy only, whereas bipolar disorder and migraine accounted for 15.8% and 7.4% respectively. Contraceptive prescriptions did not increase over time, and only in 2018 was there greater odds of being prescribed contraception (OR 1.41, 95%CI:1.08 to 1.45). Just under a fifth (19.7%) of women were prescribed valproate during their pregnancy; two out of three of these pregnancies were preceded by folic acid prescription (5 mg). While some practices reduced their rate of valproate prescription, others did not. Regulatory guidelines have changed GPs' prescription patterns in women of childbearing potential for valproate but not for contraception. Further research is needed to identify the barriers of GPs and women of childbearing potential to undertaking contraception.


Two new prediction rules for spontaneous pregnancy leading to live birth among subfertile couples, based on the synthesis of three previous models.
Several models have been published for the prediction of spontaneous pregnancy among subfertile patients. The aim of this study was to broaden the empirical basis for these predictions by making a synthesis of three previously published models. We used the original data from the studies of Eimers et al. (1994), Collins et al. (1995) and Snick et al. (1997) on couples consulting for various forms of subfertility. We developed a so-called three-sample synthesis model for predicting spontaneous conception leading to live birth within 1 year after intake based on the three data sets. The predictors used are duration of subfertility, women's age, primary or secondary infertility, percentage of motile sperm, and whether the couple was referred by a general practitioner or by a gynaecologist (referral status). The performance of this model was assessed according to a 'jack-knife' analysis. Because the post-coital test (PCT) was not assessed in one of the samples, a synthesis model including the PCT was based on two samples only. The ability of the synthesis models to distinguish between women who became pregnant and those who did not was comparable to the ability of the one-sample models when applied in the other samples. The reliability of the predictions by the three-sample synthesis model was somewhat better. Predictions improved considerably by including the PCT. The synthesis models performed better and had a broader empirical basis than the original models. They are therefore better suitable for application in other centres.


Psychophysical and neural evidence for emotion-enhanced perceptual vividness.
Highly emotional events are associated with vivid "flashbulb" memories. Here we examine whether the flashbulb metaphor characterizes a previously unknown emotion-enhanced vividness (EEV) during initial perceptual experience. Using a magnitude estimation procedure, human observers estimated the relative magnitude of visual noise overlaid on scenes. After controlling for computational metrics of objective visual salience, emotional salience was associated with decreased noise, or heightened perceptual vividness, demonstrating EEV, which predicted later memory vividness. Event-related potentials revealed a posterior P2 component at ∼200 ms that was associated with both increased emotional salience and decreased objective noise levels, consistent with EEV. Blood oxygenation level-dependent response in the lateral occipital complex (LOC), insula, and amygdala predicted online EEV. The LOC and insula represented complimentary influences on EEV, with the amygdala statistically mediating both. These findings indicate that the metaphorical vivid light surrounding emotional memories is embodied directly in perceptual cortices during initial experience, supported by cortico-limbic interactions.


Brain Malignancy Steering Committee clinical trials planning workshop: report from the Targeted Therapies Working Group.
Glioblastoma is the most common primary brain malignancy and is associated with poor prognosis despite aggressive local and systemic therapy, which is related to a paucity of viable treatment options in both the newly diagnosed and recurrent settings. Even so, the rapidly increasing number of targeted therapies being evaluated in oncology clinical trials offers hope for the future. Given the broad range of possibilities for future trials, the Brain Malignancy Steering Committee convened a clinical trials planning meeting that was held at the Udvar-Hazy Center in Chantilly, Virginia, on September 19 and 20, 2013. This manuscript reports the deliberations leading up to the event from the Targeted Therapies Working Group and the results of the meeting.


Unraveling interrelationships among psychopathology symptoms, cognitive domains and insight dimensions in chronic schizophrenia.
Insight in schizophrenia is long known to have a complex relationship with psychopathology symptoms and cognition. However, very few studies have examined models that explain these interrelationships. In a large sample derived from the NIMH Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial (N=1391), we interrogated these interrelationships for potential causal pathways using structural equation modeling. Using the NIMH consensus model, latent variables were constructed for psychopathology symptom dimensions, including positive, negative, disorganized, excited and depressed from the Positive and Negative Syndrome Scale (PANSS) items. Neurocognitive variables were created from five predefined domains of working memory, verbal memory, reasoning, vigilance and processing speed. Illness insight and treatment insight were tested using latent variables constructed from the Illness and Treatment Attitude Questionnaire (ITAQ). Disorganized symptoms had the strongest effect on insight. Illness insight mediated the relationship of positive, depressed, and disorganized symptoms with treatment insight. Neurocognition mediated the relationship between disorganized and treatment insight and depressed symptoms and treatment insight. There was no effect of negative symptoms on either illness insight or treatment insight. Taken together, our results indicate overlapping and unique relational paths for illness and treatment insight dimensions, which could suggest differences in causal mechanisms and potential interventions to improve insight.


Plasminogen activator inhibitor: a risk factor for myocardial infarction in diabetic patients.
To determine whether diabetic patients admitted with acute myocardial infarction have impaired fibrinolytic activity due to raised plasminogen activator inhibitor compared with non-diabetic patients. A district general hospital. 90 non-diabetic and 38 diabetic patients admitted with acute myocardial infarction. Both plasminogen activator inhibitor activity and antigen were significantly higher in diabetic than in non-diabetic patients (24.7 (6.8) v 18.5 (6.8) AU/ml; p = 0.0001 and 64.2 (range 13.1 to 328.8) v 38.5 (range 10.9 to 173.7 ng/ml; z = 3.3; p = 0.0008) with a positive correlation between activity and antigen (rs = 0.51; p = 0.0001). In both groups, activity and antigen concentrations were significantly higher than in diabetic and non-diabetic subjects without coronary artery disease (p = 0.002 to 0.0001 for each comparison). Plasminogen activator inhibitor activity correlated significantly with admission plasma glucose (r = 0.32; p = 0.0001), glycated haemoglobin (r = 0.32; p = 0.0001), admission plasma insulin (rs = 0.48; p = 0.001), and Killip grade of heart failure both on admission (rs = 0.27; p = 0.001) and on discharge (rs = 0.22; p = 0.006), but not with cumulative creatine kinase MB isoenzyme release (rs = -0.08). There were similar but weaker correlations between tissue plasminogen activator antigen and admission plasma glucose, glycated haemoglobin, and insulin. In 18 patients (12 non-diabetic and six diabetic) plasminogen activator inhibitor activity was measured between six and 12 months (8.3 (1.6)) after the acute infarct and remained similar to activity on admission (24.8 (1.9) AU/ml (NS) for diabetic and 17.9 (6.9) AU/ml (NS) for non-diabetic patients) and was still significantly higher in diabetic than in non-diabetic patients (p = 0.007). These results show that diabetic patients have higher plasminogen activator inhibitor activity than non-diabetic patients both on admission with acute myocardial infarction and at follow up six to 12 months later. Raised plasminogen activator inhibitor activity may predispose diabetic patients to myocardial infarction and may also impair pharmacological and spontaneous reperfusion after acute myocardial infarction thus contributing to the poor outcome in these subjects.


The three steps of the carbonate biogenic dissolution process by microborers in coral reefs (New Caledonia).
Biogenic dissolution of carbonates by microborers is one of the main destructive forces in coral reefs and is predicted to be enhanced by eutrophication and ocean acidification by 2100. The chlorophyte Ostreobium sp., the main agent of this process, has been reported to be one of the most responsive of all microboring species to those environmental factors. However, very little is known about its recruitment, how it develops over successions of microboring communities, and how that influences rates of biogenic dissolution. Thus, an experiment with dead coral blocks exposed to colonization by microborers was carried out on a reef in New Caledonia over a year period. Each month, a few blocks were collected to study microboring communities and the associated rates of biogenic dissolution. Our results showed a drastic shift in community species composition between the 4th and 5th months of exposure, i.e., pioneer communities dominated by large chlorophytes such as Phaeophila sp. were replaced by mature communities dominated by Ostreobium sp. Prior the 4th month of exposure, large chlorophytes were responsible for low rates of biogenic dissolution while during the community shift, rates increased exponentially (×10). After 6 months of exposure, rates slowed down and reached a "plateau" with a mean of 0.93 kg of CaCO3 dissolved per m(2) of reef after 12 months of exposure. Here, we show that (a) Ostreobium sp. settled down in new dead substrates as soon as the 3rd month of exposure but dominated communities only after 5 months of exposure and (b) microbioerosion dynamics comprise three distinct steps which fully depend on community development stage and grazing pressure.


Platelet rich plasma in xeno-free stem cell culture: the impact of platelet count and processing method.
Stem cell culture for regenerative medicine needs platelet rich plasma (PRP) as fetal bovine/calf serum (FBS/FCS) substitute. However, the various studies used various protocols in preparing and processing the PRP. This study aimed to compare and conclude the most effective and efficient protocol. we searched in vitro studies that used human PRP as FBS/FCS substitute to culture human cells, and compared the various available protocols to identify the easiest and effective protocols for the preparation of PRP and the release of the growth factors (GFs) to support the highest cell growth in stem cell culture. ten studies fulfilled the selection criteria and were included in the analysis. Almost all studies on bone marrow mesenchymal stem cell (BM-MSC) and adipose stem cell (AT-SC) showed that platelet lysate and/or activated platelet releasate were superior or at least the same as either FBS or FCS, except for one study that got different results on human AT-SC. Several studies showed that either 5% activated PRP (aPRP) or platelet lysate (PL) was sufficient to support cell growth, or even better when they were compared to 10% FBS, while higher concentrations were counterproductive. However, some studies showed that 10% aPRP or PL was needed. The difference between studies was due to the difference in either the PRP preparation from blood and in the PRP processing to release the GFs, which yield various GF concentrations. In conclusion, studies are needed to reveal the optimal final platelet counts for the various PRP processing methods for various kinds of cells. The easiest PRP processing is freezing to -20°C followed by thawing, or thrombin activation using a final concentration of 100U/mL.


Perceptions of nursing students regarding responsible use of social media in the Eastern Cape.
Social media have become a popular communication system that has transformed communication from the traditional to the Web-based model. Because social media use has no limitations to place and time, it is now used extensively at clinical facilities. Social media useis becoming a popular activity amongst students at Nursing Education Institutions (NEI) in South Africa. However, lack of accountability and unethical use of social media by nursing students in South Africa has been reported. The aim of the study was to explore and describe the perceptions of nursing students regarding responsible use of social media. A qualitative, descriptive, explorative and contextual research design was used to explore and describe the perceptions of nursing students regarding the responsible use of social media. Twelve nursing students registered for the undergraduate nursing degree were purposely selected and interviewed individually using a semi-structured interview method. The results of this research study demonstrate that nursing students use socialmedia irresponsibly. Nursing students experience blurred boundaries between personal and professional lines and lack accountability when using social media. The extensive use of social media in the clinical environment, by healthcare students, requires a joint effort by Nursing Education Institutions and healthcare facilities to ensure that social media are used in an ethically acceptable manner. The implementation of the recommendations of this research study could positively influence legally and ethically acceptable use of social media at healthcare facilities.


Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis.
Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large EAC exome sequencing efforts to date have found recurrent loss-of-function mutations, oncogenic driving events have been underrepresented. Here we use a combination of whole-genome sequencing (WGS) and single-nucleotide polymorphism-array profiling to show that genomic catastrophes are frequent in EAC, with almost a third (32%, n=40/123) undergoing chromothriptic events. WGS of 22 EAC cases show that catastrophes may lead to oncogene amplification through chromothripsis-derived double-minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Telomere shortening is more prominent in EACs bearing localized complex rearrangements. Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations. These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC.


How to explain the unusually late age at skill competence among humans.
Humans stand out among primates and other mammals in reaching adult-level foraging skills very late in development, well after the onset of reproduction. The aim of this paper is to place this unusual human skill development into a broader comparative context. Among birds and mammals in general, duration of immaturity, indexed by age at first reproduction (AFR), and adult brain size have undergone correlated evolution. This pattern is consistent with two causal processes: AFR is either limited by the time needed to learn adult-level skills (needing to learn) or by the energy needed to grow brain and body to full size (energetic constraints). We tested predictions arising from these two hypotheses with data retrieved from the published literature for 57 mammal and bird species. First, most mammals reach adult-level foraging skills well before the developmental period is completed, implying that energy constraints determine the age at first reproduction, whereas most birds reach adult-level foraging skills around the time of maturity, suggesting time needed for skill acquisition determines the onset of reproduction. Second, within mammals we found that with increasing niche complexity, the age of adult-level skill competence moves closer to the age at first reproduction. Third, when looking at how adult-level skills can be reached later, we found that gregariousness, slow conservative development and post-weaning provisioning allow mammals to reach their skills later. Finally, in species with intense sharing of resources (such as cooperative hunters) competence in foraging skills may even reach peak values after age of first reproduction. We conclude that the human pattern of skill acquisition could arise because our hominin ancestors added cooperative breeding and hunting to the slow development they had as great apes with increasingly complex niches. This result provides a broad biological foundation for the embodied capital model.


Emotion Regulation through Movement: Unique Sets of Movement Characteristics are Associated with and Enhance Basic Emotions.
We have recently demonstrated that motor execution, observation, and imagery of movements expressing certain emotions can enhance corresponding affective states and therefore could be used for emotion regulation. But which specific movement(s) should one use in order to enhance each emotion? This study aimed to identify, using Laban Movement Analysis (LMA), the Laban motor elements (motor characteristics) that characterize movements whose execution enhances each of the basic emotions: anger, fear, happiness, and sadness. LMA provides a system of symbols describing its motor elements, which gives a written instruction (motif) for the execution of a movement or movement-sequence over time. Six senior LMA experts analyzed a validated set of video clips showing whole body dynamic expressions of anger, fear, happiness and sadness, and identified the motor elements that were common to (appeared in) all clips expressing the same emotion. For each emotion, we created motifs of different combinations of the motor elements common to all clips of the same emotion. Eighty subjects from around the world read and moved those motifs, to identify the emotion evoked when moving each motif and to rate the intensity of the evoked emotion. All subjects together moved and rated 1241 motifs, which were produced from 29 different motor elements. Using logistic regression, we found a set of motor elements associated with each emotion which, when moved, predicted the feeling of that emotion. Each emotion was predicted by a unique set of motor elements and each motor element predicted only one emotion. Knowledge of which specific motor elements enhance specific emotions can enable emotional self-regulation through adding some desired motor qualities to one's personal everyday movements (rather than mimicking others' specific movements) and through decreasing motor behaviors which include elements that enhance negative emotions.


Portal hypertension in acute liver failure.
Twenty five patients with acute liver failure were measured for hepatic venous pressure gradient as an index of portal pressure during the course of a transjugular liver biopsy. Hepatic venous pressure gradient ranged from 4 to 24.5 mm Hg with a mean of 12.8 (5.3) mm Hg (normal values less than 5 mm Hg). All patients but one had increased portal pressure gradient. Portal hypertension correlated with the degree of architectural distortion of the liver, as suggested by a direct correlation between hepatic venous pressure gradient and the area of reticulin collapse, evaluated by means of a morphometric analysis on Sirius red stained liver slides (r = 0.43, p less than 0.05). Hepatic venous pressure gradient was significantly higher in patients with ascites (15.1 (5) mm Hg, n = 15) or renal failure (14.4 (5.3) mm Hg, n = 16) than in those without (9.3 (3.4) mm Hg and 10.1 (4) mm Hg, respectively; p less than 0.05). Portal hypertension was associated with systemic vasodilation and a hyperkinetic circulatory state, with decreased arterial pressure, and peripheral resistance and increased cardiac output.


Work organization and its effects on the health of Chinese workers with English as a second language: a qualitative approach.
Work organization consists of three contexts: (a) the external context/factors, (b) the organizational context/practices, and, (c) the work context/process. The investigation of work organization may lead to more effective prevention and intervention for work-related injury and illness. Studies have suggested that workers with limited English proficiency may be more prone to work-related injury and illness. The purposes of this qualitative phenomenological study were to gain a better understanding of the meaning of work organization to Chinese workers with English as a second language (ESL) and to explore their lived experiences on how work organization affects their health. Ten in-depth face to face interviews were conducted with Chinese ESL workers (5 males and 5 females; ages ranged from 22 to 41 years) who were employed in English-speaking workplaces in the Greater Toronto Area, Ontario, Canada. Interviews were translated and transcribed before importing them into NUD*IST, a qualitative data management software program. The transcripts were then coded, and categories were developed based on the codes. Subsequently, eight themes were identified from the categories. Work organization was perceived by Chinese ESL workers to be at an impersonal and distant level. Workers also identified work organization related issues (i.e., employers' priority, communication, work culture, job autonomy, recognition, and individual characteristics) as factors affecting their health at workplaces. However, these workers commonly expressed resignation towards their own health. Workplaces, especially those with Chinese ESL workers, need to place greater emphasis on implementing effective health and safety approaches to maximize the health of these workers.


Drift in interference filters. Part 1.
Studies of narrow-band interference filters have shown that two mechanisms exist that cause drift to shorter wavelengths. One is dependent on the thermal history of the filter, and the other depends on the radiation history. The present paper presents experimental results on thermal effects; and it is shown that by a proper bake cycle, ZnS-cryolite filters are stable for years if stored at less than 38 degrees C.


Conservation of selection on matK following an ancient loss of its flanking intron.
The chloroplast gene trnK and its associated group II intron appear to be absent in a large and ancient clade that includes nearly 90% of fern species. However, the maturase protein encoded within the intron (matK) is still present and located on the boundary of a large-scale inversion. We surveyed the chloroplast genome sequence of clade-member Adiantum capillus-veneris for evidence of a still present but fragmented trnK intron. Lack of signature structural domains and sequence motifs in the genome indicate loss of the trnK intron through degradation in an ancestor of the clade. In plants, matK preferentially catalyzes splicing of the trnK intron, but may also have a generalist function, splicing other group II introns in the chloroplast genome. We therefore tested whether a shift in selective constraint has occurred after loss of the trnK intron. Using previously unavailable sequences for several ferns, we compared matK sequences of the intron-less fern clade to sequences from seed plants and ferns with the intron and found no significant differences in selection among lineages using multiple methods. We conclude that matK in ferns has maintained its apparently ancient and generalized function in chloroplasts, even after the loss of its co-evolved group II intron. Finally, we also present primers that will allow amplification and nucleotide sequencing of the phylogenetically useful matK gene in additional fern taxa.


Phosphorylation by Akt1 promotes cytoplasmic localization of Skp2 and impairs APCCdh1-mediated Skp2 destruction.
Deregulated Skp2 function promotes cell transformation, and this is consistent with observations of Skp2 overexpression in many human cancers. However, the mechanisms underlying elevated Skp2 expression are still unknown. Here we show that the serine/threonine protein kinase Akt1, but not Akt2, directly controls Skp2 stability by a mechanism that involves degradation by the APC-Cdh1 ubiquitin ligase complex. We show further that Akt1 phosphorylates Skp2 at Ser 72, which is required to disrupt the interaction between Cdh1 and Skp2. In addition, we show that Ser 72 is localized within a putative nuclear localization sequence and that phosphorylation of Ser 72 by Akt leads to cytoplasmic translocation of Skp2. This finding expands our knowledge of how specific signalling kinase cascades influence proteolysis governed by APC-Cdh1 complexes, and provides evidence that elevated Akt activity and cytoplasmic Skp2 expression may be causative for cancer progression.


[Autism: genetics].
Autism is a strongly genetic disorder, with an estimated heritability of greater than 90%. A combination of phenotypic heterogeneity and the likely involvement of multiple interacting loci have hampered efforts at gene discovery. As a consequence, the genetic etiology of the spectrum of autism related disorders remains largely unknown. Over the past several years, the convergence of rapidly advancing genomic technologies, the completion of the human genome project, and increasingly successful collaborative efforts to increase the number of patients available for study have led to the first solid clues to the biological origins of these disorders. This paper will review the literature to date summarizing the results of linkage, cytogenetic, and candidate gene studies with a focus on recent progress. In addition, promising avenues for future research are considered.


Long-Term Results of Deep Brain Stimulation of the Anterior Cingulate Cortex for Neuropathic Pain.
Deep brain stimulation (DBS) of the anterior cingulate cortex (ACC) is a recent technique that has shown some promising short-term results in patients with chronic refractory neuropathic pain. Three years after the first case series, we assessed its efficacy on a larger cohort, with longer follow-up. Twenty-four patients (19 males; average age, 49.1 years) with neuropathic pain underwent bilateral ACC DBS. Patient-reported outcome measures were collected before and after surgery, using the Numerical Rating Scale (NRS), Short-Form 36 quality of life (SF-36), McGill Pain Questionnaire (MPQ), and EuroQol 5-domain quality of life (EQ-5D) questionnaire. Twenty-two patients after a trial week were fully internalized and 12 had a mean follow-up of 38.9 months. Six months after surgery the mean NRS score decreased from 8.0 to 4.27 (P = 0.004). There was a significant improvement in the MPQ (mean, -36%; P = 0.021) and EQ-5D score significantly decreased (mean, -21%; P = 0.036). The physical functioning domain of SF-36 was significantly improved (mean, +54.2%; P = 0.01). Furthermore, in 83% of these patients, at 6 months, NRS score was improved by 60% (P < 0.001) and MPQ decreased by 47% (P < 0.01). After 1 year, NRS score decreased by 43% (P < 0.01), EQ-5D was significantly reduced (mean, -30.8; P = 0.05) and significant improvements were also observed for different domains of the SF-36. At longer follow-ups, efficacy was sustained up to 42 months in some patients, with an NRS score as low as 3. Follow-up results confirm that ACC DBS alleviates chronic neuropathic pain refractory to pharmacotherapy and improves quality of life in many patients.


Pparα deficiency inhibits the proliferation of neuronal and glial precursors in the zebrafish central nervous system.
Many molecules and signaling pathways involved in neural development play a role in neurodegenerative diseases and brain tumor progression. Peroxisome proliferator-activated receptor (PPAR) proteins regulate the differentiation of tissues and the progression of many diseases. However, the role of these proteins in neural development is unclear. We examined the function of Pparα in the neural development of zebrafish. Two duplicate paralogs for mammalian PPARA/Ppara, namely pparaa and pparab, are present in the zebrafish genome. Both pparaa and pparab are expressed in the developing central nervous system in zebrafish embryos. Inhibiting the function of Pparα by using either the PPARα/Pparα antagonist GW6471 or pparaa or pparab truncated constructs produced identical phenotypes, which were sufficient to reduce the proliferation of neuronal and glial precursor cells without affecting the formation of neural progenitors. We demonstrated that both Pparαa and Pparαb proteins are essential regulators of the proliferation of neuronal and glial precursors. This study provides a better understanding of the functions of PPARα/Pparα in neural development and further expands our knowledge of the potential role of PPARα/Pparα in neurological disorders and brain tumors. Developmental Dynamics 247:1264-1275, 2018. © 2018 Wiley Periodicals, Inc.


Impaired potassium-induced dilation in hypertensive rat cerebral arteries does not reflect altered Na+,K(+)-ATPase dilation.
We have recently demonstrated that K(+)-induced dilation of cerebral resistance-sized vessels has two independent components, only one of which seemed sodium pump dependent. In our current investigation, potassium-induced dilation of spontaneous tone was compared in cerebral arteries from normotensive Wistar-Kyoto rats and age-matched stroke-prone spontaneously hypertensive rats. Branches of the posterior cerebral artery were cannulated and pressurized, and these vessels developed spontaneous tone. After a 5-minute period in K(+)-free physiological saline solution, K+ was increased in 1-mM increments to a final concentration of 15 mM. In the normotensive arteries, K+ concentrations between 0 and 5 mM K+ resulted in dilations that had a transient (sodium pump-dependent) component, and K+ concentrations in excess of 7 mM produced dilations that lacked a transient (sodium pump-independent) component. Similar branches from the hypertensive rat also responded with transient dilations to K+ (less than 5 mM), and these were significantly greater at 3 mM K+. However, the maintained dilations to K+ (greater than 7 mM), noted in preparations from Wistar-Kyoto rats, were absent in seven of eight preparations. Thus, the impaired dilations, in the hypertensive vessels, to K+ described here is a consequence of altered function of some sodium pump-independent component rather than altered Na+,K(+)-ATPase activity.