Exciton size and binding energy limitations in one-dimensional organic materials.

In current organic photovoltaic devices, the loss in energy caused by the charge transfer step necessary for exciton dissociation leads to a low open circuit voltage, being one of the main reasons for rather low power conversion efficiencies. A possible approach to avoid these losses is to tune the exciton binding energy to a value of the order of thermal energy, which would lead to free charges upon absorption of a photon, and therefore increase the power conversion efficiency towards the Shockley-Queisser limit. We determine the size of the excitons for different organic molecules and polymers by time dependent density functional theory calculations. For optically relevant transitions, the exciton size saturates around 0.7 nm for one-dimensional molecules with a size longer than about 4 nm. For the ladder-type polymer poly(benzimidazobenzophenanthroline), we obtain an exciton binding energy of about 0.3 eV, serving as a lower limit of the exciton binding energy for the organic materials investigated. Furthermore, we show that charge transfer transitions increase the exciton size and thus identify possible routes towards a further decrease of the exciton binding energy.

MicroRNA-206 functions as a pleiotropic modulator of cell proliferation, invasion and lymphangiogenesis in pancreatic adenocarcinoma by targeting ANXA2 and KRAS genes.

Recent advances in cancer biology have emerged important roles for microRNAs (miRNAs) in regulating tumor responses. However, their function in mediating intercellular communication within the tumor microenvironment is thus far poorly explored. Here, we found miR-206 to be abrogated in human pancreatic ductal adenocarcinoma (PDAC) specimens and cell lines. We show that miR-206 directly targets the oncogenes KRAS and annexin a2 (ANXA2), thereby acting as tumor suppressor in PDAC cells by blocking cell cycle progression, cell proliferation, migration and invasion. Importantly, we identified miR-206 as a negative regulator of oncogenic KRAS-induced nuclear factor-κB transcriptional activity, resulting in a concomitant reduction of the expression and secretion of pro-angiogenic and pro-inflammatory factors including the cytokine interleukin-8, the chemokines (C-X-C motif) ligand 1 and (C-C motif) ligand 2, and the granulocyte macrophage colony-stimulating factor. We further show that miR-206 abrogates the expression and secretion of the potent pro-lymphangiogenic factor vascular endothelial growth factor C in pancreatic cancer cells through an NF-κB-independent mechanism. By using in vitro and in vivo approaches, we reveal that re-expression of miR-206 in PDAC cells is sufficient to inhibit tumor blood and lymphatic vessel formation, thus leading to a significant delay of tumor growth and progression. Taken together, our study sheds light onto the role of miR-206 as a pleiotropic modulator of different hallmarks of cancer, and as such raising the intriguing possibility that miR-206 may be an attractive candidate for miRNA-based anticancer therapies.

MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting NF-κB and TGF-ß signaling pathways.

MicroRNAs (miRNAs) as modulators of gene expression have been described to display both tumor-promoting and tumor-suppressive functions. Although their role has been studied in different tumor types, little is known about how they regulate nuclear factor κB (NF-κB) signaling in breast cancer. Here, we performed an unbiased whole genome miRNA (miRome) screen to identify novel modulators of NF-κB pathway in breast cancer. The screen identified 13 miRNA families whose members induced consistent effects on NF-κB activity. Among those, the miR-520/373 family inhibited NF-κB signaling through direct targeting of RELA and thus strongly reduced expression and secretion of the pro-inflammatory cytokines interleukin (IL)-6 and IL-8. With a combination of in vitro and in vivo approaches, we propose a metastasis-suppressive role of miR-520/373 family. miR-520c and miR-373 abrogated both in vitro cell invasion and in vivo intravasation of highly invasive MDA-MB-231 cells. However, knockdown of RELA did not affect their metastatic ability. mRNA profiling of MDA-MB-231 cells on overexpression of miR-520/373 members revealed a strong downregulation of transforming growth factor-ß (TGF-ß) signaling. Mechanistically, the metastasis-suppressive role of miR-520/373 can be attributed to direct suppression of TGFBR2, as the silencing of TGFBR2 phenocopied the effects of miR-520/373 overexpression on suppression of Smad-dependent expression of the metastasis-promoting genes parathyroid hormone-related protein, plasminogen activator inhibitor-1 and angiopoietin-like 4 as well as tumor cell invasion, in vitro and in vivo. A negative correlation between miR-520c and TGFBR2 expression was observed in estrogen receptor negative (ER(-)) breast cancer patients but not in the ER positive (ER(+)) subtype. Remarkably, decreased expression of miR-520c correlated with lymph node metastasis specifically in ER(-) tumors. Taken together, our findings reveal that miR-520/373 family has a tumor-suppressive role in ER(-) breast cancer by acting as a link between the NF-κB and TGF-ß pathways and may thus contribute to the interplay of tumor progression, metastasis and inflammation.

Introduction of sapropterin dihydrochloride as standard of care in patients with phenylketonuria.

Sapropterin dihydrochloride, a synthetic, stable form of the tetrahydrobiopterin cofactor of phenylalanine hydroxylase, has been shown to reduce plasma phenylalanine (Phe) levels in a significant portion of patients with phenylketonuria (PKU). When we undertook introducing this medication to our PKU clinic population, the challenges of recalling and reconnecting with a variably treated and variably compliant patient population became apparent. We offered a trial of sapropterin to all of our clinic patients with PKU. In order to determine responsiveness, we used a two tier dose escalation protocol. After diet records were taken, and baseline plasma Phe levels were established, a 7-day trial of sapropterin at 10mg/kg/day was started. At day 8, plasma phenylalanine levels were measured. Patients were considered to be responders if they had a 30% reduction in plasma Phe. If they did not respond, the dose of sapropterin was increased to 20 mg/kg/day, and levels were rechecked again in 8 days. Patients who were not responders at this time continued sapropterin for a total of 30 days and had Phe levels checked one last time. Patients who were responders and who were on a Phe-restricted diet underwent gradual liberalization of their diet to the maximum tolerated natural protein intake while still maintaining plasma levels in the acceptable treatment range of 120-360 micromol/L. In our population, 36/39 patients with hyperphenylalaninemia (HPA) who were offered a trial of sapropterin elected to start sapropterin. Five of 36 patients were non-adherent with diet records and/or medication doses and we were unable to determine if they were responders. We were unable to categorize 2 of 31 of the patients who completed the trial as responders due to dietary issues, though they were probably responders. Of the 29 patients who completed the sapropterin trial and we could categorize, 18/29 (62%) were determined to be responders. Patients were classified based on their off-diet diagnostic plasma phenylalanine levels as classical PKU (>1200 micromol/L) and variant PKU (>400 and <1200 micromol/L). The group with variant PKU had a 100% response rate, and patients with classical PKU had a 27% response rate. For the patients in the responder group who were on Phe-restricted diet, we were able to liberalize most diets, in two cases to unrestricted protein intake. We also had unexpected beneficial findings in our clinic experience, including positive behavioral improvements in an adult severely affected by untreated PKU. Even in patients who were not considered to be responders, the introduction of sapropterin provided a tool to reconnect with patients and re-introduce beneficial dietary measures.

Lenticular lesions: not always an epidural hematoma.

Ewing's sarcoma is a tumor of the bone, which occurs most often in the diaphysis of long and flat bone. The most common sites of metastasis are the lungs and bones. Less frequently, the primary site is an intracranial or pelvic lesion (either as a soft tissue or a bone lesion). We report a case of a 16-year-old female with an extraosseous intracranial lesion, who presented with a history of minor trauma, unilateral facial swelling, and head pain. Though head computed tomography scan showed a lesion consistent with an epidural hematoma, further exploration revealed Ewing's sarcoma.

Hypoallergenicity and efficacy of an amino acid-based formula in children with cow's milk and multiple food hypersensitivities.

OBJECTIVE: To determine the hypoallergenicity and efficacy of a pediatric amino acid-based formula (AAF), EleCare, for children with cow's milk allergy (CMA) and multiple food allergies (MFA). STUDY DESIGN: Hypoallergenicity was determined by performing blinded oral food challenges in 31 consecutive children with documented CMA. Growth, tolerance, and biochemical response were evaluated during a nonrandomized feeding study with each child serving as his or her own control. RESULTS: Thirty-one children (median age, 23.3 months; range, 6 months to 17.5 years) were recruited; 29 had MFA, 17 had acute reactions and cow's milk-specific IgE antibody, and 14 had allergic eosinophilic gastroenteritis. At study entry, 23 were receiving another AAF; 13 had not tolerated extensively hydrolyzed formula. Eighteen subjects with allergic eosinophilic gastroenteritis and/or MFA were followed up while receiving AAF for a median of 21 months (range, 7 to 40 months), with biochemical analysis performed at 4 months. No statistically significant differences were observed in the change in weight or height National Center for Health Statistics z scores from entry; the percent of expected growth exceeded 90%. There was a small decline in percent eosinophils and increase in hemoglobin, hematocrit, and serum ferritin level (P < .05). Except for small increases in plasma leucine and valine levels (P < or = .006), the remaining biochemical markers were unchanged. CONCLUSIONS: The AAF was hypoallergenic and effective in maintaining normal growth for children with CMA and MFA.

The natural history of peanut allergy.

BACKGROUND: It has traditionally been assumed that peanut allergy is rarely outgrown. OBJECTIVE: The goal of this study was to determine the number of children with peanut allergy who become tolerant of peanut. METHODS: Patients aged 4 to 20 years with a diagnosis of peanut allergy were evaluated by questionnaire, skin testing, and a quantitative antibody fluorescent-enzyme immunoassay. Patients who had been reaction free in the past year and had a peanut IgE (PN-IgE) level less than 20 kilounits of antibody per liter (kU(A)/L) were offered an open or double-blind, placebo-controlled peanut challenge. RESULTS: A total of 223 patients were evaluated, and of those, 85 (PN-IgE < 0.35-20.4 kU(A)/L [median 1.42 kU(A)/L]) participated in an oral peanut challenge. Forty-eight (21.5%) patients had negative challenge results and were believed to have outgrown their peanut allergy (aged 4-17.5 years [median 6 years]; PN-IgE < 0.35-20.4 kU(A)/L [median 0.69 kU(A)/L]). Thirty-seven failed the challenge (aged 4-13 years [median 6.5 years]; RAST < 0.35-18.2 kU(A)/L [median 2.06 kU(A)/L]). Forty-one patients with PN-IgE levels less than 20 kU(A)/L declined to undergo challenge, and 97 were not eligible for challenge because their PN-IgE levels were greater than 20 kU(A)/L or they had had a recent reaction. Sixty-seven percent of patients with PN-IgE levels less than 2 kU(A)/L and 61% with levels less than 5 kU(A)/L had negative challenge results. Of those who underwent challenge, PN-IgE levels for those who passed versus those who failed were different at the time of challenge (P = .009), but not at the time of diagnosis (P = .25). CONCLUSION: This study demonstrates that peanut allergy is outgrown in about 21.5% of patients. Patients with low PN-IgE levels should be offered a peanut challenge in a medical setting to demonstrate whether they can now tolerate peanuts.

Oropharyngeal dysphagia and aspiration in patients with ataxia-telangiectasia.

OBJECTIVES: To determine whether patients with ataxia-telangiectasia exhibit oropharyngeal dysphagia with concomitant aspiration and to examine the relationships among swallowing function, age, and nutritional status. STUDY DESIGN: Seventy patients (mean age, 10.7 years; range, 1.8 to 30 years) had feeding/swallowing and nutritional evaluations. Fifty-one patients, in whom there were concerns about swallowing safety, were examined with a standardized videofluoroscopic swallow study. RESULTS: Fourteen of the 51 patients (27%) with histories suggestive of dysphagia demonstrated aspiration. Of these, silent aspiration (aspiration without a cough) occurred in 10 (71%) patients. Aspirators were significantly older than non-aspirators (mean age, 16.9 vs 10.8 years; P =.002). Advancing age was the strongest factor associated with aspiration during continuous drinking (P =.01). In patients with ataxia-telangiectasia, weight and weight/height were abnormally low at all ages and most compromised in older patients. Patients who aspirated had significantly lower mean weight (P <.002) and weight/height z scores (P <.001) than did patients who did not aspirate. CONCLUSIONS: Oropharyngeal dysphagia is common and appears to be progressive in patients with ataxia-telangiectasia. Older patients also have a higher incidence of poorer nutritional status. The relationship between dysphagia and nutritional status deserves further investigation.

Thalamic NMDA transmission in a genetic model of absence epilepsy in rats.

In the selected strain of GAERS Wistar rats (Genétic Absence Epilepsy Rats from Strasbourg), all animals present spontaneously recurrent absence seizures characterized by bilateral and synchronous generalized spike-and-wave discharges (SWD) accompanied by behavioural arrest. SWD depend on a thalamo-cortical network connecting the reticular and relay nuclei of the thalamus and their cortical projection areas. This loop involves both GABAergic and glutamatergic synapses. In the present study, we investigated the implication of NMDA transmission in the genesis of absence seizures in GAERS. Intra-peritoneal or intra-cerebroventricular injections of NMDA, the competitive NMDA antagonist CGP 40116, the non-competitive NMDA antagonist (+)-MK 801 and the antagonist of the glycine modulatory site 5,7-dichlorokynurenic acid dose-dependently suppressed SWD. Bilateral infusions of the same drugs in the lateral relay nuclei of the thalamus had similar suppressive effects. Intra-cerebroventricular or intrathalamic administration of D-serine, an agonist of the glycine modulatory site, had no effect on SWD. These data show that NMDA neurotransmission, especially within the thalamus, plays a major role in the control of absence seizures in GAERs. Disregulation of NMDA-mediated transmission by NMDA or antagonists, interacting with various sites of the receptor complex, may suppress the thalamo-cortical oscillatory activity which underlies SWD.

Evaluation of pulmonary function and polysomnography in obese children and adolescents.

Obese adults have an increased prevalence of pulmonary disorders. Although childhood obesity is a common problem, few studies have evaluated the pulmonary complications of obesity in the pediatric population. We, therefore, performed pulmonary function tests (PFTs), polysomnography, and multiple sleep latency tests (MSLTs) in 22 obese children and adolescents [mean age, 10 +/- 5 (SD) years; 73 percent female; 184 +/- 36 percent ideal body weight], none of whom presented because of sleep or respiratory complaints. PFTs were normal in all but two subjects. Ten (46 percent) subjects had abnormal polysomnograms. There was a positive correlation between the degree of obesity and the apnea index (r = 0.47, P < 0.05), and an inverse correlation between the degree of obesity and the Sa0(2) nadir (r = -0.60, P < 0.01). The degree of sleepiness on MSLT correlated with the degree of obesity (r = -0.50, P < 0.05). We conclude that obese children and adolescents have a high prevalence of sleep-disordered breathing, although in many cases it is mild. Obstructive sleep apnea syndrome (OSAS) improved following tonsillectomy and adenoidectomy. We recommend that pediatricians have a high index of suspicion for OSAS when evaluating obese patients, and that polysomnography be considered for these patients.

Determinants of growth in children with the obstructive sleep apnea syndrome.

Failure to thrive is a common complication of childhood obstructive sleep apnea syndrome (OSAS). To further evaluate its cause, we obtained 3-day dietary records, anthropometric measurements, polysomnography, and measurements of energy expenditure during sleep (SEE) in children with OSAS before and after tonsillectomy and adenoidectomy. Fourteen children were studied (mean age, 4 +/- 1 (SD) years). During initial polysomnography, patients had 6 +/- 3 episodes of obstructive apnea/hr, an arterial oxygen saturation nadir of 85% +/- 8%, and peak end-tidal carbon dioxide tension of 52 +/- 6 mm Hg. After surgery, OSAS resolved in all patients. The standard deviation score (z score) for weight increased from -0.30 +/- 1.47 to 0.04 +/- 1.34 (p < 0.005), despite unaltered caloric intake (91 +/- 30 vs 90 +/- 27 kcal/kg per day; not significant). The initial SEE (averaged over all sleep states) was 51 +/- 6 kcal/kg per day; postoperatively, it decreased to 46 +/- 7 kcal/kg per day (p < 0.005). Although SEE decreased during all sleep stages, the greatest decrease occurred during rapid eye movement sleep. The patients with the highest SEE on initial study had the lowest z scores (r = -0.62; p < 0.05). We conclude that SEE decreases and weight improves after resolution of OSAS. We speculate that the poor growth seen in some children with OSAS is secondary to increased caloric expenditure caused by increased work of breathing during sleep.

Control of prostanoid synthesis: role of reincorporation of released precursor fatty acids.

Prostanoid synthesis is limited by the availability of free arachidonic acid. This polyunsaturated fatty acid is liberated by phospholipases and usually is an intermediate of the deacylation-reacylation cycle of membrane phospholipids. In rat peritoneal macrophages, ethylmercurisalicylate (merthiolate) or N-ethylmaleimide (NEM) dose dependently inhibited the incorporation of arachidonic acid into cellular phospholipids, at lower concentrations specifically into phosphatidylcholine. Furthermore, merthiolate could be shown to be a rather selective inhibitor of lysophosphatidylcholine acyltransferase. In contrast, phospholipase A2 activity was not affected over a wide dose range. Consequently, macrophages showed a large increase in prostanoid synthesis (prostaglandin E, prostacyclin and thromboxane) in the presence of both lysophosphatide acyltransferase inhibiting agents. Similar results were obtained with human platelets, in which merthiolate increased the release of thromboxane. Addition of free arachidonic acid also enhanced prostanoid synthesis in macrophages. At optimal concentrations, merthiolate had no further augmenting effect. It is concluded that the rate of prostanoid synthesis is not only controlled by phospholipase A2 activity, but rather by the activity of the reacylating enzymes, mainly lysophosphatide acyltransferase.