LFB1 and LFB3 homeoproteins are sequentially expressed during kidney development.
LFB1 (HNF-1/HNF-1 alpha/APF) and LFB3 (vHNF-1/HNF-1 beta) are two homeoproteins involved in the transcriptional regulation of several liver-specific genes. Both genes are expressed in the polarized epithelia of a wide range of tissues, including liver, the digestive tract and kidney. We have analyzed the expression pattern of LFB1 and LFB3 in the developing rat kidney by in situ hybridization. Our results show that LFB3 transcripts can be detected in mesoderm-derived cells as soon as they are induced to differentiate into a polarized epithelium, while LFB1 transcripts appear only at a later stage when the three different segments of the nephron become apparent. LFB1 transcripts are restricted to the proximal and distal tubules, whereas LFB3 is also detected in the collecting ducts. Neither LFB1 nor LFB3 are expressed in the glomeruli or in the transition epithelia of the ureters and of the urinary bladder, none of which are involved in active transport mechanisms. The sequential activation of these two genes is also observed in transfilter organ cultures of nephrogenic mesenchyme at different stages after induction. This expression pattern suggests that LFB3 and LFB1 play a role in two critical stages of the developmentally regulated conversion of the nephric mesenchyme into a polarized epithelium: the early inductory phase (LFB3) and the postinductory phase (LFB1+LFB3).


Suicide Attempts and Childhood Maltreatment Among Street Youth: A Prospective Cohort Study.
Although suicide is a known leading cause of death among street youth, few prospective studies have explored childhood experiences as risk factors for future suicide attempt in this population. We examined the risk of attempted suicide in relation to childhood maltreatment among street youth. From September 2005 to November 2013, data were collected from the At Risk Youth Study (ARYS), a prospective cohort of street youth in Vancouver, Canada. Inclusion criteria were age 14 to 26 years, past-month illicit drug use, and street involvement. Participants completed the Childhood Trauma Questionnaire, an instrument measuring self-reported sexual, physical, and emotional abuse and physical and emotional neglect. Suicide attempts were assessed semiannually. Using Cox regression, we examined the association between the 5 types of maltreatment and suicide attempts. Of 660 participants, 68.2% were male and 24.6% were Aboriginal. Median age was 21.5 years. The prevalence of moderate to extreme childhood maltreatment ranged from 16.8% (sexual abuse) to 45.2% (emotional abuse). Participants contributed 1841 person-years, with suicide attempts reported by 35 (5.3%) individuals (crude incidence density: 1.9 per 100 person-years; 95% confidence interval [CI]: 1.4-2.6 per 100 person-years). In adjusted analyses, types of maltreatment associated with suicide attempts included physical abuse (adjusted hazard ratio [HR]: 4.47; 95% CI: 2.12-9.42), emotional abuse (adjusted HR: 4.92; 95% CI: 2.11-11.5), and emotional neglect (adjusted HR: 3.08; 95% CI: 1.05-9.03). Childhood maltreatment is associated with subsequent risk of suicidal behavior among street youth. Suicide prevention efforts should be targeted toward this marginalized population and delivered from a trauma-informed perspective.


Family participation during intensive care unit rounds: attitudes and experiences of parents and healthcare providers in a tertiary pediatric intensive care unit.
To compare the experiences and attitudes of healthcare providers and parents regarding parental participation in morning rounds, in particular to evaluate for differences in perception of parental comprehension of rounds content and parental comfort with attendance, and to identify subgroups of parents who are more likely to report comfort with attending rounds. Cross-sectional survey of 100 parents and 131 healthcare providers in a tertiary care pediatric medical/surgical intensive care unit. Descriptive statistics were used to analyze survey responses; univariate and multivariate analyses were performed to compare parent and healthcare provider responses. Of parents, 92% reported a desire to attend rounds, and 54% of healthcare providers reported a preference for parental presence. There were significant discrepancies in perception of understanding between the 2 groups, with healthcare providers much less likely to perceive that parents understood both the format (30% vs 73%, P < .001) and content (21% vs 84%, P < .001) of rounds compared with parents. Analysis of parent surveys did not reveal characteristics correlated with increased comfort or desire to attend rounds. A majority of parents wish to participate in morning rounds, whereas healthcare provider opinions are mixed. Important discrepancies exist between parent and healthcare provider perceptions of parental comfort and comprehension on rounds, which may be important in facilitating parental presence.


AMPK agonist AICAR improves cognition and motor coordination in young and aged mice.
Normal aging can result in a decline of memory and muscle function. Exercise may prevent or delay these changes. However, aging-associated frailty can preclude physical activity. In young sedentary animals, pharmacological activation of AMP-activated protein kinase (AMPK), a transcriptional regulator important for muscle physiology, enhanced spatial memory function, and endurance. In the present study we investigated effects of AMPK agonist 5-aminoimidazole-4-carboxamide riboside (AICAR) on memory and motor function in young (5- to 7-wk-old) and aged (23-mo-old) female C57Bl/6 mice, and in young (4- to 6-wk-old) transgenic mice with muscle-specific mutated AMPK α2-subunit (AMPK-DN). Mice were injected with AICAR (500 mg/kg) for 3-14 d. Two weeks thereafter animals were tested in the Morris water maze, rotarod, and open field. Improved water maze performance and motor function were observed, albeit at longer duration of administration, in aged (14-d AICAR) than in young (3-d AICAR) mice. In the AMPK-DN mice, the compound did not enhance behavior, providing support for a muscle-mediated mechanism. In addition, microarray analysis of muscle and hippocampal tissue derived from aged mice treated with AICAR revealed changes in gene expression in both tissues, which correlated with behavioral effects in a dose-dependent manner. Pronounced up-regulation of mitochondrial genes in muscle was observed. In the hippocampus, genes relevant to neuronal development and plasticity were enriched. Altogether, endurance-related factors may mediate both muscle and brain health in aging, and could play a role in new therapeutic interventions.


Astrocyte-derived retinoic acid: a novel regulator of blood-brain barrier function in multiple sclerosis.
Multiple sclerosis (MS) lesions are characterized by the presence of activated astrocytes, which are thought to actively take part in propagating lesion progression by secreting pro-inflammatory mediators. Conversely, reactive astrocytes may exert disease-dampening effects through the production of trophic factors and anti-inflammatory mediators. Astrocytic control of the blood-brain barrier (BBB) is crucial for normal brain homeostasis and BBB disruption is a well-established early event in MS lesion development. Here, we set out to unravel potential protective effects of reactive astrocytes on BBB function under neuroinflammatory conditions as seen in MS, where we focus on the role of the brain morphogen retinoic acid (RA). Immunohistochemical analysis revealed that retinaldehyde dehydrogenase 2 (RALDH2), a key enzyme for RA synthesis, is highly expressed by reactive astrocytes throughout white matter lesions compared to control and normal appearing white matter. In vitro modeling of reactive astrocytes resulted in increased expression of RALDH2, enhanced RA synthesis, and a protective role for astrocyte-derived RA on BBB function during inflammation-induced barrier loss. Furthermore, RA induces endothelial immune quiescence and decreases monocyte adhesion under inflammatory conditions. Finally, we demonstrated that RA attenuated oxidative stress in inflamed endothelial cells, through activation of the antioxidant transcription factor nuclear factor E2 related factor 2. In summary, RA synthesis by reactive astrocytes represents an endogenous protective response to neuroinflammation, possibly aimed at protecting the BBB against inflammatory insult. A better understanding of RA signaling in MS pathophysiology may lead to the discovery of novel targets to halt disease progression.


Near ultraviolet InGaN/AlGaN-based light-emitting diodes with highly reflective tin-doped indium oxide/Al-based reflectors.
The enhanced light output power of a InGaN/AlGaN-based light-emitting diodes (LEDs) using three different types of highly reflective Sn-doped indium oxide (ITO)/Al-based p-type reflectors, namely, ITO/Al, Cu-doped indium oxide (CIO)/s-ITO(sputtered)/Al, and Ag nano-dots(n-Ag)/CIO/s-ITO/Al, is presented. The ITO/Al-based reflectors exhibit lower reflectance (76 - 84% at 365 nm) than Al only reflector (91.1%). However, unlike Al only n-type contact, the ITO/Al-based contacts to p-GaN show good ohmic characteristics. Near-UV (365 nm) InGaN/AlGaN-based LEDs with ITO/Al, CIO/s-ITO/Al, and n-Ag/CIO/s-ITO/Al reflectors exhibit forward-bias voltages of 3.55, 3.48, and 3.34 V at 20 mA, respectively. The LEDs with the ITO/Al and CIO/s-ITO/Al reflectors exhibit 9.5% and 13.5% higher light output power (at 20 mA), respectively, than the LEDs with the n-Ag/CIO/s-ITO/Al reflector. The improved performance of near UV LEDs is attributed to the high reflectance and low contact resistivity of the ITO/Al-based reflectors, which are better than those of conventional Al-based reflectors.


Silica uptake and release in live and decaying biomass in a northern hardwood forest.
In terrestrial ecosystems, a large portion (20-80%) of the dissolved Si (DSi) in soil solution has passed through vegetation. While the importance of this "terrestrial Si filter" is generally accepted, few data exist on the pools and fluxes of Si in forest vegetation and the rate of release of Si from decomposing plant tissues. We quantified the pools and fluxes of Si through vegetation and coarse woody debris (CWD) in a northern hardwood forest ecosystem (Watershed 6, W6) at the Hubbard Brook Experimental Forest (HBEF) in New Hampshire, USA. Previous work suggested that the decomposition of CWD may have significantly contributed to an excess of DSi reported in stream-waters following experimental deforestation of Watershed 2 (W2) at the HBEF. We found that woody biomass (wood + bark) and foliage account for approximately 65% and 31%, respectively, of the total Si in biomass at the HBEF. During the decay of American beech (Fagus grandifolia) boles, Si loss tracked the whole-bole mass loss, while yellow birch (Betula alleghaniensis) and sugar maple (Acer saccharum) decomposition resulted in a preferential Si retention of up to 30% after 16 yr. A power-law model for the changes in wood and bark Si concentrations during decomposition, in combination with an exponential model for whole-bole mass loss, successfully reproduced Si dynamics in decaying boles. Our data suggest that a minimum of 50% of the DSi annually produced in the soil of a biogeochemical reference watershed (W6) derives from biogenic Si (BSi) dissolution. The major source is fresh litter, whereas only ~2% comes from the decay of CWD. Decay of tree boles could only account for 9% of the excess DSi release observed following the experimental deforestation of W2. Therefore, elevated DSi concentrations after forest disturbance are largely derived from other sources (e.g., dissolution of BSi from forest floor soils and/or mineral weathering).


Predicting the deforestation-trend under different carbon-prices.
Global carbon stocks in forest biomass are decreasing by 1.1 Gt of carbon annually, owing to continued deforestation and forest degradation. Deforestation emissions are partly offset by forest expansion and increases in growing stock primarily in the extra-tropical north. Innovative financial mechanisms would be required to help reducing deforestation. Using a spatially explicit integrated biophysical and socio-economic land use model we estimated the impact of carbon price incentive schemes and payment modalities on deforestation. One payment modality is adding costs for carbon emission, the other is to pay incentives for keeping the forest carbon stock intact. Baseline scenario calculations show that close to 200 mil ha or around 5% of today's forest area will be lost between 2006 and 2025, resulting in a release of additional 17.5 GtC. Today's forest cover will shrink by around 500 million hectares, which is 1/8 of the current forest cover, within the next 100 years. The accumulated carbon release during the next 100 years amounts to 45 GtC, which is 15% of the total carbon stored in forests today. Incentives of 6 US$/tC for vulnerable standing biomass payed every 5 year will bring deforestation down by 50%. This will cause costs of 34 billion US$/year. On the other hand a carbon tax of 12 $/tC harvested forest biomass will also cut deforestation by half. The tax income will, if enforced, decrease from 6 billion US$ in 2005 to 4.3 billion US$ in 2025 and 0.7 billion US$ in 2100 due to decreasing deforestation speed. Avoiding deforestation requires financial mechanisms that make retention of forests economically competitive with the currently often preferred option to seek profits from other land uses. Incentive payments need to be at a very high level to be effective against deforestation. Taxes on the other hand will extract budgetary revenues from the regions which are already poor. A combination of incentives and taxes could turn out to be a viable solution for this problem. Increasing the value of forest land and thereby make it less easily prone to deforestation would act as a strong incentive to increase productivity of agricultural and fuelwood production, which could be supported by revenues generated by the deforestation tax.


Effects of various denture cleansers on surface roughness of hard permanent reline resins.
The aim of this study was to investigate the influence of denture cleansers on surface roughness (Ra, µm) of two hard permanent reline resins and a conventional acrylic denture base resin. Fifty specimens of each material, measuring 10 mm×2 mm were randomly divided into 1 control and 4 experimental subgroups (n=10). Surface roughness values were measured using profilometer before and after immersion in distilled water and in 4 different denture cleansers for 8 h for 140 days. The Kruskal Wallis and Wilcoxon Signed Ranks tests were used for comparison among groups with a significance level of α=0.05. Immersion in denture cleansers significantly increased the surface roughness of reline resins and the difference among the cleansers was statistically significant (p=0.059). Denture cleansers can cause significant surface roughness alterations on hard permanent reline resins and denture base resin where their effect may differ according to the selected resin material.


Potassium phosphate and potassium carbonate administration by feed or drinking water improved broiler performance, bone strength, digestive phosphatase activity and phosphorus digestibility under induced heat stress conditions.
Potassium phosphate (K2HPO4) and potassium carbonate (K2CO3) administration by feed or water were evaluated on broiler performance, bone strength, alkaline phosphatase activity (ALP), and phosphorus digestibility under heat stress and high chloride condition. Experimental groups include control; 15 cc/kg K2HPO4; 30 cc/kg K2HPO4; 15 cc/l K2HPO4; and 3.7 g/kg K2CO3. Body weight (BW), feed and water consumption, plasma potassium, phosphorus, and calcium concentration along with plasma and digestive ALP and intestinal digesta pH were measured during the trial. Tibia ash, calcium and phosphorus content, and breaking strength were measured on days 21 and 42 and phosphorus digestibility on day 36 of age. As a result of this, study feed and water consumption was increased by supplementation of the feed or water with K2HPO4 (P ≤ 0.001). K2HPO4 increased body weight at 42 days of age (P ≤ 0.001). Tibia ash and phosphorus content was increased by K2HPO4 supplementation (P ≤ 0.004; P ≤ 0.003). K2CO3 did increased tibia ash but not changed tibia phosphorus content significantly. Tibia shear force, shear energy, extension, and length were improved by K2HPO4 administration at 42 days of age (P ≤ 0.001). Administration of either feed or water with K2HPO4 increased plasma potassium, phosphorus, and calcium concentration at 21 days of age, whereas K2CO3 reduced plasma potassium at 21 days of age (P ≤ 0.05). Plasma ALP reduced by addition of 15 cc K2HPO4 and K2CO3 to diets at 42 days of age, whereas digestive ALP was increased by inclusion of K2HPO4 and not by K2CO3. Supplementation of either feed or water with K2HPO4 increased phosphorus digestibility, whereas K2CO3 reduced phosphorus digestibility (P ≤ 0.003). Jejunum and ileum pH was reduced by K2HPO4 or by K2CO3 at 21 and 42 days of age (P ≤ 0.006; (P ≤ 0.05). Over all, results of current study revealed that K2HPO4 can be a suitable potassium salt choice instead of KCL in hot weather conditions especially when the water or diet contains high levels of chloride.


Separation of Benzene and Cyclohexane by Nonporous Adaptive Crystals of a Hybrid[3]arene.
The separation of benzene and cyclohexane is one of the most challenging tasks in the petrochemical field. However, conventional separation methods suffer from cumbersome operation, huge energy expenditure, or use of entrainers. Herein, we develop an environmentally friendly and energy saving adsorptive separation strategy using nonporous adaptive crystals of a hybrid[3]arene (1). Adaptive 1 crystals separate benzene from an equimolar benzene/cyclohexane mixture with a purity of 97.5%. The selectivity comes from the stability and variability of the new crystal structure upon capture of the preferred guest, benzene. Moreover, reversible transformations between the nonporous guest-free structure and the guest-containing structure make 1 highly recyclable.


Hazard of deceptive advertising of athletic footwear.
Athletic footwear are associated with frequent injury that are thought to result from repetitive impact. No scientific data suggest they protect well. Expensive athletic shoes are deceptively advertised to safeguard well through "cushioning impact", yet account for 123% greater injury frequency than the cheapest ones. This study tested the hypothesis that deceptive advertising creates a false sense of security with users of expensive athletic shoes, inducing attenuation of impact moderating behaviour, increased impact, and injury. Fifteen young healthy male volunteers confronted four surfaces: a bare force moment platform, and three with this platform covered by identical shoe sole material made to appear different and advertised divergently. Advertising messages suggested superior impact absorption and protection (deceptive message), poor impact absorption and high injury risk (warning message), and unknown impact absorption and safety (neutral message). Ground reaction forces were recorded for 10 barefoot footfalls, according to a protocol requiring stepping forward from perch to a surface 4.5 cm below. Impact varied as a function of advertising message (p < 0.001). Deceptive message equalled neutral message in eliciting higher impact than the warning message and the bare platform. Differences grew with repetitions (p < 0.001). These data provide a plausible mechanism explaining higher injury frequency in users of expensive athletic shoes. This is the first report to suggest: (1) deceptive advertising of protective devices may represent a public health hazard and may have to be eliminated presumably through regulation; (2) a tendency in humans to be less cautious when using new devices of unknown benefit because of overly positive attitudes associated with new technology and novel devices.


Reconstitution of recombinant chromatin establishes a requirement for histone-tail modifications during chromatin assembly and transcription.
The human ISWI-containing factor RSF (remodeling and spacing factor) was found to mediate nucleosome deposition and, in the presence of ATP, generate regularly spaced nucleosome arrays. Using this system, recombinant chromatin was reconstituted with bacterially produced histones. Acetylation of the histone tails was found to play an important role in establishing regularly spaced nucleosome arrays. Recombinant chromatin lacking histone acetylation was impaired in directing transcription. Histone-tail modifications were found to regulate transcription from the recombinant chromatin. Acetylation of the histone tails by p300 was found to increase transcription. Methylation of the histone H3 tail by Suv39H1 was found to repress transcription in an HP1-dependent manner. The effects of histone-tail modifications were observed in nuclear extracts. A highly reconstituted RNA polymerase II transcription system was refractory to the effect imposed by acetylation and methylation.


Effectiveness of statins in the reduction of the risk of myocardial infarction is modified by the GNB3 C825T variant.
The GNB3 C825T polymorphism has been shown to affect lipid parameters, atherosclerosis progression, and incidence of myocardial infarction (MI). Therefore, we assessed whether the effectiveness of statins in reducing the risk of MI was modified by the GNB3 C825T polymorphism. In a population-based registry of pharmacy records linked to hospital discharge records (PHARMO), we used a nested case-control design. We selected patients hospitalized for MI as cases if they used antihypertensive drugs and had a diagnosis of hypercholesterolemia before their first MI. Controls met the same eligibility criteria, but were not hospitalized for MI. Logistic regression analysis was used to calculate odds ratios (OR) and synergy index with corresponding 95% confidence intervals (CI), and to adjust for potential confounding factors. We included 459 cases and 1805 controls. The risk of MI was significantly lower among participants exposed to statins compared with participants not exposed to statins (adjusted OR: 0.37, 95% CI: 0.29-0.47). The GNB3T allele was associated with a reduced risk of MI (adjusted OR: 0.74, 95% CI: 0.60-0.92). Among homozygous wild-type (CC) individuals (n=1119), exposure to statins was associated with a lower risk of MI (OR: 0.48, 95% CI: 0.34-0.67). However, T allele carriers (CT and TT) who used statins had an even stronger reduced risk of MI (OR: 0.27, 95% CI: 0.19-0.39). Overall, the interaction between exposure to statins and the GNB3 C825T polymorphism was significantly increased on the multiplicative scale (synergy index: 1.67, 95% CI: 1.06-2.65). Our findings show that T allele carriers of the GNB3 C825T polymorphism have less risk of MI and are more likely to benefit from statin therapy in a hypercholesterolemic population of antihypertensive drug users.


Induction of hypothermia in patients with various types of neurologic injury with use of large volumes of ice-cold intravenous fluid.
Mounting evidence suggests that mild to moderate hypothermia can mitigate neurologic and myocardial injury. The speed of induction appears to be a key factor in determining its efficacy. However, even when the fastest currently available cooling techniques are used, reaching target temperatures takes at least 2 hrs and usually longer. We hypothesized that infusion of refrigerated fluids could be a safe accessory method to increase cooling speed. Prospective intervention study. University teaching hospital. One hundred thirty-four patients with various types of neurologic injury (postanoxic encephalopathy, subarachnoid hemorrhage, or traumatic brain injury). Hypothermia was induced in 134 patients with various types of neurologic injury, by means ice-water cooling blankets and infusion of refrigerated (4 degrees C) saline (110 patients) or saline and colloids (24 patients). An average volume of 2340 +/- 890 mL of refrigerated fluids was infused in 50 mins. Core temperatures decreased from 36.9 +/- 1.9 degrees C to 34.6 +/- 1.5 degrees C at t = 30 mins and to 32.9 +/- 0.9 degrees C at t = 60 mins (target temperature: 32 degrees C-33 degrees C). Monitoring of blood pressure, heart rhythm, central venous pressure, blood gasses, electrolyte and glucose levels, and platelet and white blood cell count revealed no additional adverse effects. Mean arterial pressure increased by 15 mm Hg, with larger increases in blood pressure occurring in hemodynamically unstable patients. No patient developed pulmonary edema. Induction of hypothermia by means of cold-fluid infusion combined with ice-water cooling blankets is safe, efficacious, and quick. Because the speed of cooling is important to increase its protective effects, we recommend that cold-fluid infusion be used in all patients treated with induced hypothermia. This should be combined with another method to safely and accurately maintain hypothermia once target temperatures have been reached.


Sedation After Cardiac Surgery: Is One Drug Better Than Another?
The classic high-dose narcotic-based cardiac anesthetic has been modified to facilitate a fast-track, rapid recovery in the intensive care unit (ICU). Postoperative sedation is consequently now an essential component in recovery of the patient undergoing cardiac surgery. It must facilitate the patient's unawareness of the environment as well as reduce the discomfort and anxiety caused by surgery, intubation, mechanical ventilation, suction, and physiotherapy. Benzodiazepines seem well suited for this role, but propofol, opioids, and dexmedetomidine are among other agents commonly used for sedation in the ICU. However, what is an ideal sedative for this application? When compared with benzodiazepine-based sedation regimens, nonbenzodiazepines have been associated with shorter duration of mechanical ventilation and ICU length of stay. Current sedation guidelines recommend avoiding benzodiazepine use in the ICU. However, there are no recommendations on which alternatives should be used. In postcardiac surgery patients, inotropes and vasoactive medications are often required because of the poor cardiac function. This makes sedation after cardiac surgery unique in comparison with the requirements for most other ICU patient populations. We reviewed the current literature to try to determine if 1 sedative regimen might be better than others; in particular, we compare outcomes of propofol and dexmedetomidine in postoperative sedation in the cardiac surgical ICU.


The loss of c-Jun N-terminal protein kinase activity prevents the amyloidogenic cleavage of amyloid precursor protein and the formation of amyloid plaques in vivo.
Phosphorylation plays a central role in the dynamic regulation of the processing of the amyloid precursor protein (APP) and the production of amyloid-β (Aβ), one of the clinically most important factors that determine the onset of Alzheimer's disease (AD). This has led to the hypothesis that aberrant Aβ production associated with AD results from regulatory defects in signal transduction. However, conflicting findings have raised a debate over the identity of the signaling pathway that controls APP metabolism. Here, we demonstrate that activation of the c-Jun N-terminal protein kinase (JNK) is essential for mediating the apoptotic response of neurons to Aβ. Furthermore, we discovered that the functional loss of JNK signaling in neurons significantly decreased the number of amyloid plaques present in the brain of mice carrying familial AD-linked mutant genes. This correlated with a reduction in Aβ production. Biochemical analyses indicate that the phosphorylation of APP at threonine 668 by JNK is required for γ-mediated cleavage of the C-terminal fragment of APP produced by β-secretase. Overall, this study provides genetic evidence that JNK signaling is required for the formation of amyloid plaques in vivo. Therefore, inhibition of increased JNK activity associated with aging or with a pathological condition constitutes a potential strategy for the treatment of AD.


Surgical approaches for antrochoanal polyp: a comparative analysis.
The aim of this study was to evaluate the clinical and histopathological characteristics of antrochoanal polyps (ACPs) and to perform a comparative analysis of surgical techniques in terms of recurrence. The clinical, radiological and histopathological features of 42 patients with a diagnosis of ACP who underwent surgery in a period of 6 years (January 2000 - January 2006) were investigated retrospectively. Histopathological examinations were present for all patients and were re-examined for histological analysis. Endoscopic sinus surgery (ESS) was performed in all patients. Transcanine sinoscopy (TS) and the Caldwell-Luc approach (CL) were used in addition to ESS in 14 and 13 patients respectively. The attachment site was detected in 21 patients (50%) and the most frequent site was found to be the lateral wall in 15 patients (71.4%). There was no relationship between the choice of surgery, the attachment site or accessory ostium, or any sinusitis with ACP. Histological examination showed prominent eosinophilia in 29 patients (69%). The follow-up time was a minimum of 12 months with a mean of 28.9 months. Three recurrences were seen after ESS. However, there was no recurrence after ESS+TS and ESS+CL. Our study showed that the most important factors affecting the choice of surgical approaches are the preference of the surgeon, the age of the patient and the presence of recurrent disease. Combined approaches with either TS or CL should be considered, particularly when the attachment site of the antral part of ACP is undetected, in order to prevent incomplete excision and recurrences.


Right-Sided Endocarditis involving Eustachian Valve Following the Use of a Central Venous Line.
BACKGROUND Right-sided endocarditis is a well-known condition that occurs predominantly in intravenous drug users and patients with cardiovascular implantable electronic devices, central venous lines, and congenital heart disease. Most cases involve the tricuspid valve apparatus. Eustachian valve endocarditis (EVE) is a very rare and underdiagnosed condition with only a few previously reported cases. CASE REPORT We present a rare case of 2-sided infective thromboembolism from Staphylococcus aureus endocarditis involving both the eustachian and mitral valves in a 27-year-old man with mitochondrial neurogastrointestinal encephalopathy disease, which is a rare mitochondrial disease. CONCLUSIONS Endocarditis involving the eustachian valve is rare and presents a significant dilemma in diagnosis and treatment. Late diagnosis can lead to missed thromboembolic events and can have a significant impact on treatment and prognosis. In cases with high suspicion, early use of transesophageal echocardiography and chest CT can greatly advance diagnosis. The international guidelines do not specifically address patients with EVE; therefore, we recommend that the endocarditis team should be involved in any case of EVE to customize a treatment strategy.


The PREMM(1,2,6) model predicts risk of MLH1, MSH2, and MSH6 germline mutations based on cancer history.
We developed and validated a model to estimate the risks of mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6 based on personal and family history of cancer. Data were analyzed from 4539 probands tested for mutations in MLH1, MSH2, and MSH6. A multivariable polytomous logistic regression model (PREMM(1,2,6)) was developed to predict the overall risk of MMR gene mutations and the risk of mutation in each of the 3 genes. The discriminative ability of the model was validated in 1827 population-based colorectal cancer (CRC) cases. Twelve percent of the original cohort carried pathogenic mutations (204 in MLH1, 250 in MSH2, and 71 in MSH6). The PREMM(1,2,6) model incorporated the following factors from the probands and first- and second-degree relatives (odds ratio; 95% confidence intervals [CIs]): male sex (1.9; 1.5-2.4), a CRC (4.3; 3.3-5.6), multiple CRCs (13.7; 8.5-22), endometrial cancer (6.1; 4.6-8.2), and extracolonic cancers (3.3; 2.4-4.6). The areas under the receiver operating characteristic curves were 0.86 (95% CI, 0.82-0.91) for MLH1 mutation carriers, 0.87 (95% CI, 0.83-0.92) for MSH2, and 0.81 (95% CI, 0.69-0.93) for MSH6; in validation, they were 0.88 for the overall cohort (95% CI, 0.86-0.90) and the population-based cases (95% CI, 0.83-0.92). We developed the PREMM(1,2,6) model, which incorporates information on cancer history from probands and their relatives to estimate an individual's risk of mutations in the MMR genes MLH1, MSH2, and MSH6. This Web-based decision making tool can be used to assess risk of hereditary CRC and guide clinical management.


Simultaneous extraction of phenolics and essential oil from peppermint by pressurized hot water extraction.
Phenolics and essential oil of peppermint were obtained by pressurized hot water extraction (PHWE). The best extraction conditions were found to be 130 °C for temperature, 10 min for extraction time, and 3 cycles for extraction number. There were no statistically significant differences between 130 and 160 °C in terms of essential oil content. Total phenolic contents (TPC) of the extracts were higher at 160 °C than that of 130 °C. However, further HPLC analysis of the extracts revealed that hydrolysis and/or decomposition of phenolics were observed in the extracts obtained at 160 °C. The main phenolic of peppermint was determined as eriocitrin by HPLC-DAD, while menthol was the dominant component in essential oil fraction of peppermint by GC-FID. The present study demonstrated that PHWE was a suitable technique for simultaneous extraction of phenolics and essential oil from peppermint. The technique might be used as an analytical extraction tool for determination of phenolics and essential oil. Moreover, the extracts of PHWE could directly be evaluated for the enrichment of liquid food formulations or be transformed into solid form by suitable techniques such as spray drying for easy storage and subsequent enrichment of food products.


A highly stable and hierarchical tetrathiafulvalene-based metal-organic framework with improved performance as a solid catalyst.
Herein we report the synthesis of a tetrathiafulvalene (TTF)-based MOF, namely MUV-2, which shows a non-interpenetrated hierarchical crystal structure with mesoporous one-dimensional channels of ca. 3 nm and orthogonal microporous channels of ca. 1 nm. This highly stable MOF (aqueous solution with pH values ranging from 2 to 11 and different organic solvents), which possesses the well-known [Fe3(μ3-O)(COO)6] secondary building unit, has proven to be an efficient catalyst for the aerobic oxidation of dibenzothiophenes.


Effects of exercise training on resting energy expenditure and lean mass during pediatric burn rehabilitation.
Severe burns cause profound hormonal and metabolic disturbances resulting in hypermetabolism, reflected in extreme elevation of resting energy expenditure (REE) and extensive skeletal muscle catabolism. Aerobic and resistive exercise programs during rehabilitation have shown substantial benefits, although whether such training potentially exacerbates basal metabolism is unknown. Therefore, the effects of exercise training on REE during the rehabilitation of severely burned pediatric patients were examined. Children with 40% total body surface area burns and greater were enrolled at admission to the burn intensive care unit to participate in a 12-week, hospital-based exercise program (EX) or a home-based standard of care program (SOC), commencing 6 months after injury. Twenty-one patients (aged 7-17 years) were enrolled and randomized to SOC (n = 10) or EX (n = 11). Age, sex, and total body surface area burned were similar. Mean change (+/-standard deviation) in REE, normalized to individual lean body mass, was almost negligible between SOC and EX group patients (SOC, 0.03 +/- 17.40% vs EX, 0.01 +/- 26.38%). A significant increase in lean body mass was found for EX patients (SOC, 2.06 +/- 3.17% vs EX, 8.75 +/- 5.65%; P = .004), which persisted when normalized to height (SOC, 0.70 +/- 2.39% vs EX, 6.14 +/- 6.46%; P = .02). Peak torque also improved significantly more in EX patients (SOC, 12.29 +/- 16.49% vs EX, 54.31 +/- 44.25%; P = .02), reflecting improved strength. Exercise training significantly enhanced lean mass and strength, without observed exacerbation of postburn hypermetabolism. Therefore, the use of exercise conditioning as a safe and effective component of pediatric burn rehabilitation is advocated.


Predation in High CO2 Waters: Prey Fish from High-Risk Environments are Less Susceptible to Ocean Acidification.
Most studies investigating the effects of anthropogenic environmental stressors do so in conditions that are often optimal for their test subjects, ignoring natural stressors such as competition or predation. As such, the quantitative results from such studies may often underestimate the lethality of certain toxic compounds. A well-known example of this concept is illustrated by the marked increase in the lethality of pesticides when larval amphibians are concurrently exposed to the odor of potential predators. Here, we investigated the interaction between background levels of environmental predation risk (high vs. low) and ocean acidification (ambient vs. elevated CO2) in 2 × 2 design. Wild-caught juvenile damselfish, Pomacentrus amboinensis, were exposed in the laboratory to the different risk and CO2 conditions for 4 days and released onto coral reef patches. Using a well-established field assay, we monitored the in situ behavior and mortality of the damselfish for 2 days. We predicted that juvenile fish exposed to elevated CO2 and high-risk conditions would display more severe behavioral impairments and increased mortality compared to fish exposed to elevated CO2 maintained under low-risk conditions. As expected, elevated CO2 exposure led to impaired antipredator responses and increased mortality in low-risk fish compared to ambient CO2 controls. However, we failed to find an effect of elevated CO2 on the behavior and survival of the high-risk fish. We hypothesized that the results may stem from either a behavioral compensation or a physiological response to high risk. Our results provide insights into the interactive nature of environmental and natural stressors and advance our understanding of the predicted effect of ocean acidification on aquatic ecosystems.


Diradical reaction mechanisms in [3 + 2]-cycloadditions of hetaryl thioketones with alkyl- or trimethylsilyl-substituted diazomethanes.
Reactions of dihetaryl and aryl/hetaryl thioketones with 2-diazopropane, diazoethane, and (trimethylsilyl)diazomethane were studied at variable temperature. The experiments showed that reactions with 2-diazopropane carried out at -75 °C occur mainly via the initially formed, relatively stable 1,3,4-thiadiazolines as products of the [3 + 2]-cycloaddition of the diazo dipole onto the C=S bond. The latter decompose only at higher temperature (ca. -40 °C) to generate thiocarbonyl S-isopropanide. In the absence of the starting thioketone, the corresponding thiiranes and/or ethene derivatives, formed from them via spontaneous desulfurization, are the main products. In contrast, reactions with diazoethane occurred predominantly via initially formed diradicals, which in cascade processes gave sterically crowded 4,4,5,5-tetrahetaryl-1,3-dithiolanes as major products. Finally, the reaction of dihetaryl thioketones with (trimethylsilyl)diazomethane occur smoothly at -75 °C leading to the corresponding 4,4,5,5-tetrahetaryl-1,3-dithiolanes as the exclusive [3 + 2]-cycloadducts formed via a cascade of postulated diradicals. The presence of S or Se atoms in the hetaryl rings is of importance for stabilizing diradical intermediates. Remarkably, in no single case, the 'head-to-head dimerization' of aryl/hetaryl and dihetaryl substituted thiocarbonyl ylides was observed.


Wound-Induced Proteinase Inhibitor in Plant Leaves: A Possible Defense Mechanism against Insects.
Wounding of the leaves of potato or tomato plants by adult Colorado potato beetles, or their larvae, induces a rapid accumulation of a proteinase inhibitor throughout the plants' tissues that are exposed to air. This effect of insect damage can be simulated by mechanically wounding the leaves. The transport of a factor out of damaged leaves takes place rapidly after the wound is inflicted and the levels of proteinase inhibitor, in both damaged and adjacent leaves, rises strikingly within a few hours. The rapid accumulation of a powerful inhibitor of major intestinal proteinases of animals in response to wounding of the leaves is probably a defense mechanism.


Risk model for severe postoperative complications after total pancreatectomy based on a nationwide clinical database.
Total pancreatectomy is required to completely clear tumours that are locally advanced or located in the centre of the pancreas. However, reports describing clinical outcomes after total pancreatectomy are rare. The aim of this retrospective observational study was to assess clinical outcomes following total pancreatectomy using a nationwide registry and to create a risk model for severe postoperative complications. Patients who underwent total pancreatectomy from 2013 to 2017, and who were recorded in the Japan Society of Gastroenterological Surgery and Japanese Society of Hepato-Biliary-Pancreatic Surgery database, were included. Severe complications at 30 days were defined as those with a Clavien-Dindo grade III needing reoperation, or grade IV-V. Occurrence of severe complications was modelled using data from patients treated from 2013 to 2016, and the accuracy of the model tested among patients from 2017 using c-statistics and a calibration plot. A total of 2167 patients undergoing total pancreatectomy were included. Postoperative 30-day and in-hospital mortality rates were 1·0 per cent (22 of 2167 patients) and 2·7 per cent (58 of 167) respectively, and severe complications developed in 6·0 per cent (131 of 2167). Factors showing a strong positive association with outcome in this risk model were the ASA performance status grade and combined arterial resection. In the test cohort, the c-statistic of the model was 0·70 (95 per cent c.i. 0·59 to 0·81). The risk model may be used to predict severe complications after total pancreatectomy.


Date seed extract ameliorates β-amyloid-induced impairments in hippocampus of male rats.
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder among the elderly. Because the existing treatments for Alzheimer's disease only offer limited symptomatic alleviation, more efficient therapeutic agents are urgently needed. Date seed is a hepatoprotective and neuroprotective agent. Date seed extract (DSE) has bioactive components like phenolics, flavonoids, and vitamins. In view of the ameliorative effects of DSE against an oxidative injury, the current study was designed to reveal whether DSE has a neuroprotective resource in the rat model of Alzheimer's disease. In the current study, 24 adult male Sprague-Dawely rats were divided into three groups (n=8) of: Sham (Distilled Water, 3μl intracerebroventricular (ICV) injection), β-Amyloid (β-amyloid, 3μl ICV injection), and DSE-treated groups (80mg/kg, Intraperitoneal (IP) injection), for 12days. Twelve days after Alzheimer induction, behavioral analysis, the Morris Water Maze (MWM), as well as western blot and histological studies were performed to reveal the neuroprotective potential of DSE in rats. Administration of DSE significantly restored memory and learning impairments induced by Aβ in the MWM test. DSE significantly decreased the caspase-3 expression level in the treated group. In addition, DSE reduced the number of degenerated neurons in the hippocampal CA1 subfield of the DSE treated rats. These results demonstrate that DSE may have beneficial effects in the prevention of Aβ-induced Alzheimer in a rat model. Date seed extract may have advantageous effects in preventing Alzheimer's disease in male rats.


Histology of specimens taken by prostatectomy and needle biopsy.
To determine the histology of the prostate in prostatectomy done for benign prostatic hypertrology (BPH), and prostate needle biopsy done for raised prostatic specific antigen (PSA). A retrospective study. Nairobi Hospital, Kenyatta National Hospital and Upper Hill Medical Centre. The records of all the patients who had prostatectomy for BPH or trans-rectal needle biopsy of the prostate for raised prostatic specific antigen by the author and whose histology was determined at the Nairobi Hospital between May 2004 and December 2006. A total of 108 specimens from 108 patients were sent to the laboratory. The ages of the patients ranged from 48 years to 83 years with a mean of 71.3 years. Of the 108 specimens submitted 82 were benign prostatic hypertrophy and 26 were carcinoma of the prostate. Out of 78 prostatectomy specimens ten (12.8%) had prostate cancer. In the needle biopsy group 16 out of 30 (53%) had prostate cancer. In total there were 82 (76%) patients with histology of benign prostate enlargement and 26 (24%) with histology of prostate cancer. Prostate cancer is a common disease in Kenya and a lot of it is important cancer as it will progress and cause death. In this poor resource setting it is possible to make diagnosis of prostate cancer even in the absence of transrectal ultrasound (TRUS) to help biopsy the prostate. The higher the prostatic specific antigen in asymptomatic patients the higher the yield of prostate cancer on biopsy of the prostate.


Diagnostic criteria for CADASIL in the International Classification of Headache Disorders (ICHD-II): are they appropriate?
We reviewed the characteristics of headache in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), to verify the appropriateness of the International Classification of Headache Disorders, second edition (ICHD-II) criteria. Available data were found through Medline/PubMed using the keyword "cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)". The search was restricted to studies published in English in the years between 1993 and 2008. We excluded studies that did not report original data on CADASIL and information regarding the presence of headache. We found 34 studies reporting data on 749 patients overall; 387 (51.7%) patients had headache. According to the authors' definition, 356 (92%) patients were reported as having migraine and 31 (8%) as having headache. Of the 356 patients who were defined as migraineurs, 125 (35.1%) had migraine with aura, 7 (2%) migraine without aura, 156 (43.8%) unspecified migraine and 68 (19.1%) had more than one type of migraine. Among the 31 patients reported as suffering from headache, the headache was not further detailed in 18 (58.1%) patients; it was defined as chronic in 6 (19.3%), as resembling migraine with aura in 4 (12.9%), as resembling migraine without aura in 2 (6.5%) and as tension type in 1 (3.2%) patient. In patients with CADASIL, the headache was usually referred to as migraine and mostly as migraine with aura. However, this referral is formally incorrect since the diagnostic criteria for any type of migraine in the ICHD-II require that the disturbance is not attributed to another disorder. For this reason, we suggest updating the ICHD-II in relation to CADASIL. Our suggestion is to insert a new category referred to as Headache attributed to genetic disorder including Headache attributed to CADASIL.


Examining the Effects of Sodium Ions on the Binding of Antagonists to Dopamine D2 and D3 Receptors.
Many G protein-coupled receptors have been shown to be sensitive to the presence of sodium ions (Na+). Using radioligand competition binding assays, we have examined and compared the effects of sodium ions on the binding affinities of a number of structurally diverse ligands at human dopamine D2 and dopamine D3 receptor subtypes, which are important therapeutic targets for the treatment of psychotic disorders. At both receptors, the binding affinities of the antagonists/inverse agonists SB-277011-A, L,741,626, GR 103691 and U 99194 were higher in the presence of sodium ions compared to those measured in the presence of the organic cation, N-methyl-D-glucamine, used to control for ionic strength. Conversely, the affinities of spiperone and (+)-butaclamol were unaffected by the presence of sodium ions. Interestingly, the binding of the antagonist/inverse agonist clozapine was affected by changes in ionic strength of the buffer used rather than the presence of specific cations. Similar sensitivities to sodium ions were seen at both receptors, suggesting parallel effects of sodium ion interactions on receptor conformation. However, no clear correlation between ligand characteristics, such as subtype selectivity, and sodium ion sensitivity were observed. Therefore, the properties which determine this sensitivity remain unclear. However these findings do highlight the importance of careful consideration of assay buffer composition for in vitro assays and when comparing data from different studies, and may indicate a further level of control for ligand binding in vivo.


Karst pools in subsurface environments: collectors of microbial diversity or temporary residence between habitat types.
We studied bacterial diversity and community composition in three shallow pools of a Swiss karst cave system with contrasting hydrological and hydrochemical properties. The microbial assemblages in the pools were remarkably different, and only one operational taxonomic unit of 16S rRNA genes (OTU, 97% similarity) was shared between the three of them (total OTU number in all pools: 150). Unexpectedly high microbial phylotype richness was found even in the two pools without groundwater contact and with low concentrations of organic carbon and total cell numbers (< 10(4) ml(-1)). One of these seepage water fed systems harboured 15 distinct OTUs from several deeply branching lineages of the candidate phylum OP3, whereas representatives of this group were not detected in the other two pools. A tentative phylogeographic analysis of available OP3-related sequences in the context of our data set revealed that there was generally little agreement between the habitats of origin of closely related sequence types. Two bacterial clades affiliated with the obligate methylamine utilizer Methylotenera mobilis were only found in the pool that was exposed to repeated flooding events. These bacteria formed relatively stable populations of up to 6% of total cell counts over periods of several months irrespective of inundation by groundwater. This suggests that karst water may provide a means of transport for these bacteria from terrestrial to freshwater habitats.


Security Assessment of Cyberphysical Digital Microfluidic Biochips.
A digital microfluidic biochip (DMFB) is an emerging technology that enables miniaturized analysis systems for point-of-care clinical diagnostics, DNA sequencing, and environmental monitoring. A DMFB reduces the rate of sample and reagent consumption, and automates the analysis of assays. In this paper, we provide the first assessment of the security vulnerabilities of DMFBs. We identify result-manipulation attacks on a DMFB that maliciously alter the assay outcomes. Two practical result-manipulation attacks are shown on a DMFB platform performing enzymatic glucose assay on serum. In the first attack, the attacker adjusts the concentration of the glucose sample and thereby modifies the final result. In the second attack, the attacker tampers with the calibration curve of the assay operation. We then identify denial-of-service attacks, where the attacker can disrupt the assay operation by tampering either with the droplet-routing algorithm or with the actuation sequence. We demonstrate these attacks using a digital microfluidic synthesis simulator. The results show that the attacks are easy to implement and hard to detect. Therefore, this work highlights the need for effective protections against malicious modifications in DMFBs.


Noninvasive Blood Pressure Monitoring and Prediction of Fluid Responsiveness to Passive Leg Raising.
Intravenous fluid boluses are administered to patients in shock to improve tissue hypoperfusion. However, fluid boluses result in clinically significant stroke volume increases in only about 50% of patients. Hemodynamic responses to passive leg raising measured with invasive and minimally invasive methods are accurate predictors of fluid responsiveness. However, few studies have used noninvasive blood pressure measurement to evaluate responses to passive leg raising. To determine if passive leg raising-induced increases in pulse pressure or systolic blood pressure can be used to predict clinically significant increases in stroke volume index in healthy volunteers. In a repeated-measures study, hemodynamic measurements were obtained in 30 healthy volunteers before, during, and after passive leg raising. Each participant underwent the procedure twice. In the first test, 20 participants (69%) were responders (stroke volume index increased by ≥ 15%); 9 (31%) were nonresponders. In the second test, 15 participants (50%) were responders and 15 (50%) were nonresponders. A passive leg raising-induced increase in pulse pressure of 9% or more predicted a 15% increase in stroke volume index (sensitivity, 50%; specificity, 44%). There was no association between passive leg raising-induced changes in systolic blood pressure and fluid responsiveness. A passive leg raising-induced change in stroke volume index measured by bioreactance differentiated fluid responders and nonresponders. Pulse pressure and systolic blood pressure measured by oscillometric noninvasive blood pressure monitoring were not sensitive or specific predictors of fluid responsiveness in healthy volunteers.


Predicting reading ability over the long term: The changing roles of letter naming, phonological awareness and orthographic processing.
A cohort of 92 children was followed through sixth grade to investigate the relationship of preschool skills and first grade phonological awareness to reading and spelling. In particular, the focus was on the changing roles of letter naming, orthographic awareness, and phonological processing in prediction, as reading experience increased. Preschool letter naming was a consistently significant predictor of reading vocabulary, reading comprehension, and spelling at each grade level, but the preschool orthographic task contributed most to reading comprehension and spelling at the higher grades. Conversely, the contribution of the first grade phonemic awareness measures to reading skills dropped sharply after third grade, although they continued to contribute to spelling prediction. When preschool precursors of phonological processing were examined, letter naming was found to be a predictor of first and third grade phonemic awareness. Findings confirm the importance of letter naming as a predictor and of the role of phonemic awareness in early reading acquisition, but also highlight the contribution of orthographic processing skills to later reading.


Minipigs as an animal model for dermal vaccine delivery.
Appropriate animal models for intradermal vaccine delivery are scarce. Given the high similarity of their skin anatomy to that of humans, minipigs may be a suitable model for dermal vaccine delivery. Here we describe the immunization of Göttingen minipigs by using intradermal and intramuscular delivery of hepatitis B surface antigen (HBsAg). Intradermal vaccine delivery by needle and syringe and by needle-free jet injection induced humoral antiHBsAg responses. Priming immunization by using the disposable syringe jet injector (DSJI) resulted in a higher antibody titer than did conventional intradermal immunization and a titer comparable to that after intramuscular vaccination with HBsAg and Al(OH)3 adjuvant. This study highlights the utility of the minipig model in vaccine studies assessing the efficacy of conventional and novel methods of dermal delivery. Moreover, we include suggestions regarding working with minipigs during dermal vaccine delivery studies, thereby fostering future work in this area of vaccinology.


The acute impact of polyphenols from Hibiscus sabdariffa in metabolic homeostasis: an approach combining metabolomics and gene-expression analyses.
We explored the acute multifunctional effects of polyphenols from Hibiscus sabdariffa in humans to assess possible consequences on the host's health. The expected dynamic response was studied using a combination of transcriptomics and metabolomics to integrate specific functional pathways through network-based methods and to generate hypotheses established by acute metabolic effects and/or modifications in the expression of relevant genes. Data were obtained from healthy male volunteers after 3 hours of ingestion of an aqueous Hibiscus sabdariffa extract. The data were compared with data obtained prior to the ingestion, and the overall findings suggest that these particular polyphenols had a simultaneous role in mitochondrial function, energy homeostasis and protection of the cardiovascular system. These findings suggest beneficial actions in inflammation, endothelial dysfunction, and oxidation, which are interrelated mechanisms. Among other effects, the activation of the heme oxygenase-biliverdin reductase axis, the systemic inhibition of the renin-angiotensin system, the inhibition of the angiotensin-converting enzyme, and several actions mirroring those of the peroxisome proliferator-activated receptor agonists further support this notion. We also found concordant findings in the serum of the participants, which include a decrease in cortisol levels and a significant increase in the active vasodilator metabolite of bradykinin (des-Arg(9)-bradykinin). Therefore, our data support the view that polyphenols from Hibiscus sabdariffa play a regulatory role in metabolic health and in the maintenance of blood pressure, thus implying a multi-faceted impact in metabolic and cardiovascular diseases.


Solar tomography adaptive optics.
Conventional solar adaptive optics uses one deformable mirror (DM) and one guide star for wave-front sensing, which seriously limits high-resolution imaging over a large field of view (FOV). Recent progress toward multiconjugate adaptive optics indicates that atmosphere turbulence induced wave-front distortion at different altitudes can be reconstructed by using multiple guide stars. To maximize the performance over a large FOV, we propose a solar tomography adaptive optics (TAO) system that uses tomographic wave-front information and uses one DM. We show that by fully taking advantage of the knowledge of three-dimensional wave-front distribution, a classical solar adaptive optics with one DM can provide an extra performance gain for high-resolution imaging over a large FOV in the near infrared. The TAO will allow existing one-deformable-mirror solar adaptive optics to deliver better performance over a large FOV for high-resolution magnetic field investigation, where solar activities occur in a two-dimensional field up to 60'', and where the near infrared is superior to the visible in terms of magnetic field sensitivity.


Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression.
Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 × 10-6). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.


Tumor angiogenesis is enforced by autocrine regulation of high-mobility group box 1.
The endothelium plays a pivotal role in the progression of solid tumors and is considered a highly relevant target for therapy. However, it emerges that current clinical angiogenesis inhibitors that act through inhibition of tumor-derived growth factors are prone to inducing drug resistance. Therefore, markers of tumor endothelial cells (ECs) themselves provide attractive novel therapeutic targets. In a screen for markers of tumor angiogenesis, we recently identified high-mobility group box 1 (HMGB1), known to act as proinflammatory cytokine and chromatin-binding molecule. Here we report on the role of HMGB1 in angiogenesis by showing that its overexpression is associated with an increased angiogenic potential of ECs. HMGB1 stimulates the expression of players in vascular endothelial growth factor and platelet-derived growth factor signaling, both in vitro and in vivo. Importantly, we show that HMGB1 triggers and helps to sustain this proangiogenic gene expression program in ECs, additionally characterized by increased activity of matrix metalloproteinases, integrins and nuclear factor-κB. Moreover, we found that HMGB1 is involved in several autocrine and/or paracrine feedback mechanisms resulting in positive enforcement of HMGB1 expression, and that of its receptors, RAGE (receptor for advanced glycation end products) and Toll-like receptor 4 (TLR4). Interference in HMGB1 expression and/or function using knockdown approaches and antibody-mediated targeting to break this vicious circle resulted in inhibited migration and sprouting of ECs. Using different in vivo models, therapeutic efficacy of HMGB1 targeting was confirmed. First, we demonstrated induction of HMGB1 expression in the chicken embryo chorioallantoic membrane (CAM) neovasculature following both photodynamic therapy and tumor challenge. We subsequently showed that anti-HMGB1 antibodies inhibited vessel density in both models, accompanied by a reduced vascular expression of angiogenic growth factor receptors. Collectively, these data identify HMGB1 as an important modulator of tumor angiogenesis and suggest the feasibility of targeting HMGB1 for multi-level cancer treatment.


Photoelectron spectra of Al2O2- and Al3O3-via slow electron velocity-map imaging.
High-resolution photoelectron spectra of cryogenically-cooled Al2O2- and Al3O3- cluster anions are obtained using slow electron velocity-map imaging. These spectra show vibrationally-resolved detachment from the (X[combining tilde]2B3u) ground state of Al2O2- to the X[combining tilde]1Ag and ã3B3u neutral electronic states, giving an electron affinity of 1.87904(4) eV for neutral Al2O2 and a term energy of 0.4938(4) eV for the triplet excited state. Additionally, there is evidence for autodetachment from photoexcited anions as well as influences from vibronic coupling between excited states of the neutral Al2O2 cluster. Detachment from both the "kite" and "book" isomers of Al3O3- is observed, yielding electron affinities of 2.0626(4) and 2.792(3) eV for the corresponding neutral isomers. Experiments carried out at different anion temperatures suggest that the two anionic isomers are nearly isoenergetic but clearly identify the kite isomer as the global minimum structure, in contrast to prior studies. This finding is supported by density functional theory calculations, which show that the relative ordering of the anion isomers is sensitive to basis set size; calculations for the anion isomers at the B3LYP/aug-cc-pVQZ level find the kite isomer to lie 0.011 eV below the book isomer.


Cucurbitacin E, a tetracyclic triterpenes compound from Chinese medicine, inhibits tumor angiogenesis through VEGFR2-mediated Jak2-STAT3 signaling pathway.
Cucurbitacin E (CuE, α-elaterin), a tetracyclic triterpenes compound from folk traditional Chinese medicine plants, has been shown to inhibit cancer cell growth, inflammatory response and bilirubin-albumin binding. However, the effects of CuE on tumor angiogenesis and its potential molecular mechanism are still unknown. Here, we demonstrated that CuE significantly inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, migration and tubulogenesis in vitro and blocked angiogenesis in chick embryo chorioallantoic membrane assay and mouse corneal angiogenesis model in vivo. Furthermore, we found that CuE remarkably induced HUVEC apoptosis, inhibited tumor angiogenesis and suppressed human prostate tumor growth in xenograft tumor model. Finally, we showed that CuE blocked vascular endothelial growth factor receptor (VEGFR) 2-mediated Janus kinase (Jak) 2-signal transducer and activator of transcription (STAT) 3 signaling pathway in endothelial cells and suppressed the downstream protein kinases, such as extracellular signal-regulated kinase and p38 mitogen-activated protein kinases. Therefore, our studies provided the first evidence that CuE inhibited tumor angiogenesis by inhibiting VEGFR2-mediated Jak-STAT3 and mitogen-activated protein kinases signaling pathways and CuE is a potential candidate in angiogenesis-related disease therapy.


Weighted Performance Metrics for Automatic Neonatal Seizure Detection Using Multiscored EEG Data.
In neonatal intensive care units, there is a need for around the clock monitoring of electroencephalogram (EEG), especially for recognizing seizures. An automated seizure detector with an acceptable performance can partly fill this need. In order to develop a detector, an extensive dataset labeled by experts is needed. However, accurately defining neonatal seizures on EEG is a challenge, especially when seizure discharges do not meet exact definitions of repetitiveness or evolution in amplitude and frequency. When several readers score seizures independently, disagreement can be high. Commonly used metrics such as good detection rate (GDR) and false alarm rate (FAR) derived from data scored by multiple raters have their limitations. Therefore, new metrics are needed to measure the performance with respect to the different labels. In this paper, instead of defining the labels by consensus or majority voting, popular metrics including GDR, FAR, positive predictive value, sensitivity, specificity, and selectivity are modified such that they can take different scores into account. To this end, 353 hours of EEG data containing seizures from 81 neonates were visually scored by a clinical neurophysiologist, and then processed by an automated seizure detector. The scored seizures were mixed with false detections of an automated seizure detector and were relabeled by three independent EEG readers. Then, all labels were used in the proposed performance metrics and the result was compared with the majority voting technique and showed higher accuracy and robustness for the proposed metrics. Results were confirmed using a bootstrapping test.


Epigenome mapping reveals distinct modes of gene regulation and widespread enhancer reprogramming by the oncogenic fusion protein EWS-FLI1.
Transcription factor fusion proteins can transform cells by inducing global changes of the transcriptome, often creating a state of oncogene addiction. Here, we investigate the role of epigenetic mechanisms in this process, focusing on Ewing sarcoma cells that are dependent on the EWS-FLI1 fusion protein. We established reference epigenome maps comprising DNA methylation, seven histone marks, open chromatin states, and RNA levels, and we analyzed the epigenome dynamics upon downregulation of the driving oncogene. Reduced EWS-FLI1 expression led to widespread epigenetic changes in promoters, enhancers, and super-enhancers, and we identified histone H3K27 acetylation as the most strongly affected mark. Clustering of epigenetic promoter signatures defined classes of EWS-FLI1-regulated genes that responded differently to low-dose treatment with histone deacetylase inhibitors. Furthermore, we observed strong and opposing enrichment patterns for E2F and AP-1 among EWS-FLI1-correlated and anticorrelated genes. Our data describe extensive genome-wide rewiring of epigenetic cell states driven by an oncogenic fusion protein.


Physiotherapy, and speech and language therapy intervention for patients with refractory chronic cough: a multicentre randomised control trial.
Physiotherapy, and speech and language therapy are emerging non-pharmacological treatments for refractory chronic cough. We aimed to investigate the efficacy of a physiotherapy, and speech and language therapy intervention (PSALTI) to improve health-related quality of life (HRQoL) and to reduce cough frequency in patients with refractory chronic cough. In this multicentre randomised controlled trial, patients with refractory chronic cough were randomised to four weekly 1:1 sessions of either PSALTI consisting of education, laryngeal hygiene and hydration, cough suppression techniques, breathing exercises and psychoeducational counselling or control intervention consisting of healthy lifestyle advice. We assessed the change in HRQoL at week 4 with the Leicester Cough Questionnaire (LCQ). Secondary efficacy outcomes included 24-hour objective cough frequency (Leicester Cough Monitor) and cough reflex sensitivity. The primary analysis used an analysis of covariance adjusted for baseline measurements with the intention-to-treat population. This study was registered at UK Clinical Research Network (UKCRN ID 10678). Between December 2011 and April 2014, we randomly assigned 75 participants who underwent baseline assessment (34 PSALTI and 41 controls). In the observed case analysis, HRQoL (LCQ) improved on average by 1.53 (95% CI 0.21 to 2.85) points more in PSALTI group than with control (p=0.024). Cough frequency decreased by 41% (95% CI 36% to 95%) in PSALTI group relative to control (p=0.030). The improvements within the PSALTI group were sustained up to 3 months. There was no significant difference between groups in the concentration of capsaicin causing five or more coughs. Greater improvements in HRQoL and cough frequency were observed with PSALTI intervention. Our findings support the use of PSALTI for patients with refractory chronic cough. UKCRN ID 10678 and ISRCTN 73039760; Results.


Patient satisfaction is rated higher by radiation oncology outpatients receiving nutrition intervention compared with usual care.
Satisfaction with services has been considered vital for the provision of quality health care, however, there are few published papers utilizing patient satisfaction with nutrition services as a measurable outcome. A randomized, controlled trial investigating the impact of nutrition intervention (NI) vs. usual care (UC) in 54 ambulatory oncology patients receiving radiotherapy to the gastrointestinal or head and neck area demonstrated beneficial impacts in terms of body weight, nutritional status, quality of life and bowel health. This study reports the changes in patient satisfaction that were associated with these improved outcomes for patients receiving NI compared with UC. The patient satisfaction with clinical nutrition services questionnaire was used to measure overall satisfaction and satisfaction with four components of nutrition services 12 weeks after patients commenced radiotherapy. Patients receiving NI rated satisfaction higher for staff interpersonal skills (P < 0.001), perceived health benefits (P = 0.008), staff presentation skills (P = 0.044) and for overall patient satisfaction with nutrition services (P = 0.002). There were no significant differences between those patients receiving NI or UC for the nutrition supplements factor (P = 0.191). These data suggest that patients receiving NI perceive nutrition as being beneficial and of higher importance to their health than those receiving UC. This may lead to increased compliance with the nutrition prescription and help explain the better outcomes observed in the NI group compared with the UC group. Patient satisfaction with nutrition services should be conducted regularly to act as a quality-control measure and target areas for improvement.


Sulfate-sulfur metabolism in the rat fetus as indicated by sulfur-35.
Twenty-four hours after the intraperitoneal injection of sodium sulfate-S(35) into pregnant rats, sulfur-35 was found in the embryos. The amount of the sulfur-35 retained by the embryos was directly related to their degree of development in utero. A large fraction of the sulfur-35 found in the embryos was insoluble in 5 per cent trichloroacetic acid. At the 9th to 10th day of development, about 40 per cent of the sulfur-35 was present in this fraction. In 20-day-old embryos this fraction accounted for nearly 90 per cent of the total. Radioautographs of sections of embryos fixed in a solution of formaldehyde revealed that the sulfur-35 was most highly concentrated in the cartilaginous portion of the skeleton. All other tissues gave much weaker autographic reactions, comparable with the over-all reaction obtained when sections from embryos fixed in a solution of formaldehyde saturated with barium hydroxide were used. By analysis for the sulfur-35 content of individual tissues the concentration of the sulfur-35 in humeri from 20-day-old embryos was found to be about 30 times that in the maternal sternum. The concentration of the isotope in the skeletal muscle, brain, heart, and skin of the same embryos was also higher than in the corresponding maternal tissues. On the other hand, the concentration of the sulfur-35 in the maternal gastrointestinal tract plus contents was higher than in the gastrointestinal tract and contents of the embryos.


Supramolecular activation of a molecular photocatalyst.
The effects of the planar aromatic organic molecules anthracene and pyrene on the catalytic performance of the intramolecular hydrogen evolving photocatalyst [Ru(tbbpy)2(tpphz)PdCl2](PF6)2 functioning as a photocatalytic dyad have been studied. (1)H-NMR studies on [Ru(tbbpy)2(tpphz)PdCl2](PF6)2 and [Ru(tbbpy)2(tpphz)](PF6)2 show a pronounced interaction of pyrene with the ruthenium complexes due to π-π-interactions. The solid state structure of [Ru(tbbpy)2(tpphz)PdCl2]2[Mo8O24] shows a pronounced π-π-stacking of the polyaromatic ligands. In addition, dimerization constants for the complexes and association constants between the complexes and pyrene were determined. Studies on the photocatalytic hydrogen production show a decreased induction phase and increased turn over frequencies during the initial phase of the catalysis in the presence of anthracene and pyrene utilising the catalyst [Ru(tbbpy)2(tpphz)PdCl2](PF6)2 irrespective of the nature of the polycyclic aromatic hydrocarbon.


Mathematical modeling of oncogenesis control in mature T-cell populations.
T-cell receptor (TCR) polyclonal mature T cells are surprisingly resistant to oncogenic transformation after retroviral insertion of T-cell oncogenes. In a mouse model, it has been shown that mature T-cell lymphoma/leukemia (MTCLL) is not induced upon transplantation of mature, TCR polyclonal wild-type (WT) T cells, transduced with gammaretroviral vectors encoding potent T-cell oncogenes, into RAG1-deficient recipients. However, further studies demonstrated that quasi-monoclonal T cells treated with the same protocol readily induced MTCLL in the recipient mice. It has been hypothesized that in the TCR polyclonal situation, outgrowth of preleukemic cells and subsequent conversion to overt malignancy is suppressed through regulation of clonal abundances on a per-clone basis due to interactions between TCRs and self-peptide-MHC-complexes (spMHCs), while these mechanisms fail in the quasi-monoclonal situation. To quantitatively study this hypothesis, we applied a mathematical modeling approach. In particular, we developed a novel ordinary differential equation model of T-cell homeostasis, in which T-cell fate depends on spMHC-TCR-interaction-triggered stimulatory signals from antigen-presenting cells (APCs). Based on our mathematical modeling approach, we identified parameter configurations of our model, which consistently explain the observed phenomena. Our results suggest that the preleukemic cells are less competent than healthy competitor cells in acquiring survival stimuli from APCs, but that proliferation of these preleukemic cells is less dependent on survival stimuli from APCs. These predictions now call for experimental validation.


Acute exposure to environmental tobacco smoke and heart rate variability.
Environmental tobacco smoke (ETS) has been associated with cardiovascular mortality. Pathophysiologic pathways leading from ETS exposure to cardiopulmonary disease are still being explored. Reduced cardiac autonomic function, as measured by heart rate variability (HRV), has been associated with cardiac vulnerability and may represent an important pathophysiologic mechanism linking ETS and risk of cardiac mortality. In this study we evaluated acute ETS exposure in a commercial airport with changes in HRV in 16 adult nonsmokers. We conducted ambulatory electrocardiographic (ECG) monitoring for 8-hr periods while participants alternated 2 hr in nonsmoking and smoking areas. Nicotine and respirable suspended particle concentrations and participants' blood oxygen saturation were also monitored. We calculated time and frequency domain measures of HRV for periods in and out of the smoking area, and we evaluated associations with ETS using comparative statistics and regression modeling. ETS exposure was negatively associated with all measures of HRV. During exposure periods, we observed an average decrement of approximately 12% in the standard deviation of all normal-to-normal heart beat intervals (an estimate of overall HRV). ETS exposures were not associated with mean heart rate or blood oxygen saturation. Altered cardiac autonomic function, assessed by decrements in HRV, is associated with acute exposure to ETS and may be part of the pathophysiologic mechanisms linking ETS exposure and increased cardiac vulnerability.


Management of AL amyloidosis in 2020.
In amyloid light chain (AL) amyloidosis, a small B-cell clone, most commonly a plasma cell clone, produces monoclonal light chains that exert organ toxicity and deposit in tissue in the form of amyloid fibrils. Organ involvement determines the clinical manifestations, but symptoms are usually recognized late. Patients with disease diagnosed at advanced stages, particularly when heart involvement is present, are at high risk of death within a few months. However, symptoms are always preceded by a detectable monoclonal gammopathy and by elevated biomarkers of organ involvement, and hematologists can screen subjects who have known monoclonal gammopathy for amyloid organ dysfunction and damage, allowing for a presymptomatic diagnosis. Discriminating patients with other forms of amyloidosis is difficult but necessary, and tissue typing with adequate technology available at referral centers, is mandatory to confirm AL amyloidosis. Treatment targets the underlying clone and should be risk adapted to rapidly administer the most effective therapy patients can safely tolerate. In approximately one-fifth of patients, autologous stem cell transplantation can be considered up front or after bortezomib-based conditioning. Bortezomib can improve the depth of response after transplantation and is the backbone of treatment of patients who are not eligible for transplantation. The daratumumab+bortezomib combination is emerging as a novel standard of care in AL amyloidosis. Treatment should be aimed at achieving early and profound hematologic response and organ response in the long term. Close monitoring of hematologic response is vital to shifting nonresponders to rescue treatments. Patients with relapsed/refractory disease are generally treated with immune-modulatory drugs, but daratumumab is also an effective option.


Thymus size in children with moderate malnutrition: a cohort study from Burkina Faso.
Moderate acute malnutrition (MAM) affects millions of children, increasing their risk of dying from infections. Thymus atrophy may be a marker of malnutrition-associated immunodeficiency, but factors associated with thymus size in children with MAM are unknown, as is the effect of nutritional interventions on thymus size. Thymus size was measured by ultrasound in 279 children in Burkina Faso with MAM, diagnosed by low mid-upper arm circumference (MUAC) and/or low weight-for-length z-score (WLZ), who received 12 weeks treatment with different food supplements as part of a randomized trial. Correlates of thymus size and of changes in thymus size after treatment, and after another 12 weeks of follow-up were identified. Thymus size correlated positively with age, anthropometry and blood haemoglobin, and was smaller in children with malaria. Children with malnutrition diagnosed using MUAC had a smaller thymus than children diagnosed based on WLZ. Thymus size increased during and after treatment, similarly across the different food supplement groups. In children with MAM, the thymus is smaller in children with anaemia or malaria, and grows with recovery. Assuming that thymus size reflects vulnerability, low MUAC seems to identify more vulnerable children than low WLZ in children with MAM. Thymus atrophy is known to be a marker of the immunodeficiency associated with malnutrition in children. In children with moderate malnutrition, we found the thymus to be smaller in children with anaemia or malaria. Assuming that thymus size reflects vulnerability, low MUAC seems to identify more vulnerable children than low weight for length. Thymus atrophy appears reversible with recovery from malnutrition, with similar growth seen in children randomized to treatment with different nutritional supplements.


Role of epidermal growth factor receptor transactivation in PPAR gamma-dependent suppression of Helicobacter pylori interference with gastric mucin synthesis.
Peroxisome-proliferator-activated receptor gamma (PPARgamma) is recognized for its role in regulation of genes associated with inflammation, and its activation of phosphatidylinositol 3-kinase (PI3K) has emerged recently as an important regulator of mucosal responses to bacterial infection. In this study, we report that PPARgamma activation leading to the impedance of Helicobacter pylori lipopolysaccharide (LPS) inhibitory effect on salivary mucin synthesis requires epidermal growth factor receptor (EGFR) participation. Using gastric mucosal cells in culture, we show that activation of PPARgamma with a specific agonist, ciglitazone, prevents the LPS-induced reduction in mucin synthesis, and the effect is reflected in a marked decrease in apoptosis, caspase-3 activity and NO generation. The impedance by ciglitazone of the LPS-induced reduction in mucin synthesis was blunted (up to 65.8%) in a concentration-dependent fashion by a specific inhibitor of EGFR kinase, PD153035, as well as the PPARgamma antagonist BADGE, and wortmannin, an inhibitor of PI3K. Moreover, the inhibitory effect of ciglitazone on the LPS-induced reduction in mucin synthesis and upregulation in apoptosis, caspase-3 activity and NO generation was countered by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR transactivation. These findings indicate that PPARgamma activation leading to the suppression of H. pylori LPS inhibition of gastric mucin synthesis involves Src kinase-dependent EGFR transactivation.


Development and validation of the Kilifi Epilepsy Beliefs and Attitude Scale.
Epilepsy remains misunderstood, particularly in resource poor countries (RPC). We developed and validated a tool to assess beliefs and attitudes about epilepsy among people with epilepsy (PWE) in Kilifi, Kenya. The 50-item scale was developed through a literature review and qualitative study findings, and its reliability and validity were assessed with 673 PWE. A final scale of 34 items had Cronbach's alpha scores for the five subscales: causes of epilepsy (α=0.71); biomedical treatment of epilepsy (α=0.70); cultural treatment of epilepsy (α=0.75); risk and safety concerns about epilepsy (α=0.56); and negative attitudes about epilepsy (α=0.76) and entire scale (α=0.70). Test-retest reliability was acceptable for all the subscales. The Kilifi Epilepsy Beliefs and Attitude Scale is a reliable and valid tool that measures beliefs and attitudes about epilepsy. It may be useful in other RPC or as a tool to assess the effectiveness of interventions to improve knowledge, beliefs, and attitudes about epilepsy.


Binding an event to its source at encoding improves children's source monitoring.
Children learn information from a variety of sources and often remember the content but forget the source. Whereas the majority of research has focused on retrieval mechanisms for such difficulties, the present investigation examines whether the way in which sources are encoded influences future source monitoring. In Study 1, 86 children aged 3 to 8 years participated in 2 photography sessions on different days. Children were randomly assigned to either the Difference condition (they were asked to pay attention to differences between the 2 events), the Memory control condition (asked to pay attention with no reference to differences), or the No-Instruction control (no special instructions were given). One week later, during a structured interview about the photography session, the 3- to 4-year-olds in the No-Instruction condition were less accurate and responded more often with 'do not know' than the 7- to 8-year-olds. However, the older children in the Difference condition made more source confusions than the younger children suggesting improved memory for content but not source. In Study 2, the Difference condition was replaced by a Difference-Tag condition where details were pointed out along with their source (i.e., tagging source to content). Ninety-four children aged 3 to 8 years participated. Children in the Difference-Tag condition made fewer source-monitoring errors than children in the Control condition. The results of these 2 studies together suggest that binding processes at encoding can lead to better source discrimination of experienced events at retrieval and may underlie the rapid development of source monitoring in this age range. (PsycINFO Database Record


Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial.
The purpose of this trial was to evaluate the role of radiation therapy with concurrent gemcitabine (GEM) compared with GEM alone in patients with localized unresectable pancreatic cancer. Patients with localized unresectable adenocarcinoma of the pancreas were randomly assigned to receive GEM alone (at 1,000 mg/m(2)/wk for weeks 1 to 6, followed by 1 week rest, then for 3 of 4 weeks) or GEM (600 mg/m(2)/wk for weeks 1 to 5, then 4 weeks later 1,000 mg/m(2) for 3 of 4 weeks) plus radiotherapy (starting on day 1, 1.8 Gy/Fx for total of 50.4 Gy). Measurement of quality of life using the Functional Assessment of Cancer Therapy-Hepatobiliary questionnaire was also performed. Of 74 patients entered on trial and randomly assigned to receive GEM alone (arm A; n = 37) or GEM plus radiation (arm B; n = 34), patients in arm B had greater incidence of grades 4 and 5 toxicities (41% v 9%), but grades 3 and 4 toxicities combined were similar (77% in A v 79% in B). No statistical differences were seen in quality of life measurements at 6, 15 to 16, and 36 weeks. The primary end point was survival, which was 9.2 months (95% CI, 7.9 to 11.4 months) and 11.1 months (95% CI, 7.6 to 15.5 months) for arms A and B, respectively (one-sided P = .017 by stratified log-rank test). This trial demonstrates improved overall survival with the addition of radiation therapy to GEM in patients with localized unresectable pancreatic cancer, with acceptable toxicity.


Co-administration of aspirin and allogeneic adipose-derived stromal cells attenuates bone loss in ovariectomized rats through the anti-inflammatory and chemotactic abilities of aspirin.
Osteoporosis is a syndrome of excessive skeletal fragility characterized by the loss of mass and deterioration of microarchitecture in bone. Single use of aspirin or adipose-derived stromal cells (ASCs) has been recognized recently to be effective against osteoporosis. The goal of the study was to evaluate the osteogenic effects of the co-administration of aspirin and allogeneic rat adipose-derived stromal cells (rASCs) on ovariectomized (OVX)-induced bone loss in rats. The underlying mechanisms were investigated in vitro and in vivo. Firstly, allogeneic rASCs were isolated and cultured, and the conditioned medium (CM) from the maintenance of rASCs was collected. Secondly, the OVX rats were administrated CM, rASCs, aspirin (ASP) or rASCs + ASP, respectively. Twelve weeks later, the anti-inflammatory and osteogenic effects were assessed by micro-CT, undecalcified histological sections, dynamic histomorphometric analyses and serologic assays for biochemical markers. Finally, a Transwell migration assay in vitro and cell-trafficking analyses in vivo were used to explore the effects of aspirin on rASC migration. Systemic administration of aspirin and rASCs attenuated OVX-induced bone loss better than single use of aspirin or ASCs (p < 0.05, respectively). Next, we analyzed the underlying mechanisms of the anti-inflammatory and chemotactic abilities of aspirin. Aspirin suppressed serum levels of the pro-inflammatory cytokines on tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), and the anti-inflammatory ability was positively associated with bone morphometry. Also, aspirin exhibited excellent chemotactic effects in vitro and accelerated the homing of allogeneic rASCs into bone marrow during early in vivo stages. Co-administered aspirin and allogeneic ASCs can partially reverse OVX-induced bone loss in rats. This effect appears to be mediated by the anti-inflammatory and chemotactic abilities of aspirin.


Macrophage inhibitory cytokine-1 (MIC-1/GDF15) and mortality in end-stage renal disease.
Elevated macrophage inhibitory cytokine-1 (MIC-1/GDF15) levels in serum mediate anorexia and weight loss in some cancer patients and similarly elevated levels occur in chronic kidney disease (CKD). Serum MIC-1/GDF15 is also elevated in chronic inflammatory diseases and predicts atherosclerotic events independently of traditional risk factors. The relationship between chronic inflammation, decreasing body mass index (BMI) and increased mortality in CKD is not well understood and is being actively investigated. MIC-1/GDF15 may link these features of CKD. Cohorts of incident dialysis patients from Sweden (n = 98) and prevalent hemodialysis patients from the USA (n = 381) had serum MIC-1/GDF15, C-reactive protein (CRP) levels and BMI measured at study entry. Additional surrogate markers of nutritional adequacy, body composition and inflammation were assessed in Swedish patients. Patients were followed for all-cause mortality. In the Swedish cohort, serum MIC-1/GDF15 was associated with decreasing BMI, measures of nutrition and markers of oxidative stress and inflammation. Additionally, high serum MIC-1/GDF15 levels identified patients with evidence of protein-energy wasting who died in the first 3 years of dialysis. The ability of serum MIC-1/GDF15 to predict mortality in the first 3 years of dialysis was confirmed in the USA cohort. In both cohorts, serum MIC-1/GDF15 level was an independent marker of mortality when adjusted for age, CRP, BMI, history of diabetes mellitus and/or cardiovascular disease and glomerular filtration rate or length of time on dialysis at study entry. MIC-1/GDF15 is a novel independent serum marker of mortality in CKD capable of significantly improving the mortality prediction of other established markers. MIC-1/GDF15 may mediate protein-energy wasting in CKD and represent a novel therapeutic target for this fatal complication.


Kv1.3 deletion biases T cells toward an immunoregulatory phenotype and renders mice resistant to autoimmune encephalomyelitis.
Increasing evidence suggests ion channels have critical functions in the differentiation and plasticity of T cells. Kv1.3, a voltage-gated K(+) channel, is a functional marker and a pharmacological target for activated effector memory T cells. Selective Kv1.3 blockers have been shown to inhibit proliferation and cytokine production by human and rat effector memory T cells. We used Kv1.3 knockout (KO) mice to investigate the mechanism by which Kv1.3 blockade affects CD4(+) T cell differentiation during an inflammatory immune-mediated disease. Kv1.3 KO animals displayed significantly lower incidence and severity of myelin oligodendrocyte glycoprotein (MOG) peptide-induced experimental autoimmune encephalomyelitis. Kv1.3 was the only K(V) channel expressed in MOG 35-55-specific CD4(+) T cell blasts, and no K(V) current was present in MOG-specific CD4(+) T cell-blasts from Kv1.3 KO mice. Fewer CD4(+) T cells migrated to the CNS in Kv1.3 KO mice following disease induction, and Ag-specific proliferation of CD4(+) T cells from these mice was impaired with a corresponding cell-cycle delay. Kv1.3 was required for optimal expression of IFN-γ and IL-17, whereas its absence led to increased IL-10 production. Dendritic cells from Kv1.3 KO mice fully activated wild-type CD4(+) T cells, indicating a T cell-intrinsic defect in Kv1.3 KO mice. The loss of Kv1.3 led to a suppressive phenotype, which may contribute to the mechanism by which deletion of Kv1.3 produces an immunotherapeutic effect. Skewing of CD4(+) T cell differentiation toward Ag-specific regulatory T cells by pharmacological blockade or genetic suppression of Kv1.3 might be beneficial for therapy of immune-mediated diseases such as multiple sclerosis.


The dominant Anopheles vectors of human malaria in the Americas: occurrence data, distribution maps and bionomic précis.
An increasing knowledge of the global risk of malaria shows that the nations of the Americas have the lowest levels of Plasmodium falciparum and P. vivax endemicity worldwide, sustained, in part, by substantive integrated vector control. To help maintain and better target these efforts, knowledge of the contemporary distribution of each of the dominant vector species (DVS) of human malaria is needed, alongside a comprehensive understanding of the ecology and behaviour of each species. A database of contemporary occurrence data for 41 of the DVS of human malaria was compiled from intensive searches of the formal and informal literature. The results for the nine DVS of the Americas are described in detail here. Nearly 6000 occurrence records were gathered from 25 countries in the region and were complemented by a synthesis of published expert opinion range maps, refined further by a technical advisory group of medical entomologists. A suite of environmental and climate variables of suspected relevance to anopheline ecology were also compiled from open access sources. These three sets of data were then combined to produce predictive species range maps using the Boosted Regression Tree method. The predicted geographic extent for each of the following species (or species complex*) are provided: Anopheles (Nyssorhynchus) albimanus Wiedemann, 1820, An. (Nys.) albitarsis*, An. (Nys.) aquasalis Curry, 1932, An. (Nys.) darlingi Root, 1926, An. (Anopheles) freeborni Aitken, 1939, An. (Nys.) marajoara Galvão & Damasceno, 1942, An. (Nys.) nuneztovari*, An. (Ano.) pseudopunctipennis* and An. (Ano.) quadrimaculatus Say, 1824. A bionomics review summarising ecology and behaviour relevant to the control of each of these species was also compiled. The distribution maps and bionomics review should both be considered as a starting point in an ongoing process of (i) describing the distributions of these DVS (since the opportunistic sample of occurrence data assembled can be substantially improved) and (ii) documenting their contemporary bionomics (since intervention and control pressures can act to modify behavioural traits). This is the first in a series of three articles describing the distribution of the 41 global DVS worldwide. The remaining two publications will describe those vectors found in (i) Africa, Europe and the Middle East and (ii) in Asia. All geographic distribution maps are being made available in the public domain according to the open access principles of the Malaria Atlas Project.


Cold atmospheric pressure plasma: simple and efficient strategy for preparation of poly(2-oxazoline)-based coatings designed for biomedical applications.
Poly(2-oxazolines) (POx) are an attractive material of choice for biocompatible and bioactive coatings in medical applications. To prepare POx coatings, the plasma polymerization represents a fast and facile approach that is surface-independent. However, unfavorable factors of this method such as using the low-pressure regimes and noble gases, or poor control over the resulting surface chemistry limit its utilization. Here, we propose to overcome these drawbacks by using well-defined POx-based copolymers prepared by living cationic polymerization as a starting material. Chemically inert polytetrafluoroethylene (PTFE) is selected as a substrate due to its beneficial features for medical applications. The deposited POx layer is additionally post-treated by non-equilibrium plasma generated at atmospheric pressure. For this purpose, diffuse coplanar surface barrier discharge (DCSBD) is used as a source of "cold" homogeneous plasma, as it is operating at atmospheric pressure even in ambient air. Prepared POx coatings possess hydrophilic nature with an achieved water contact angle of 60°, which is noticeably lower in comparison to the initial value of 106° for raw PTFE. Moreover, the increased fibroblasts adhesion in comparison to raw PTFE is achieved, and the physical and biological properties of the POx-modified surfaces remain stable for 30 days.