Differential excretion of leucocyte granule components in inflammatory bowel disease: implications for pathogenesis.
1. Faecal excretion of the leucocyte primary granule component, myeloperoxidase, and of the secondary granule component, lactoferrin, were compared in inflammatory bowel disease and infective diarrhoea. 2. Faecal lactoferrin correlated with faecal myeloperoxidase in both inflammatory bowel disease (P = 0.0018; n = 32) and infective diarrhoea (P = 0.00013; n = 37), but inflammatory bowel disease was associated with a much higher faecal excretion of lactoferrin but lower excretion of myeloperoxidase than infective diarrhoea. As a consequence, the median ratio of lactoferrin/myeloperoxidase excretion (both expressed as ng/mg of protein) for inflammatory bowel disease was 7.5 (range 3.5-21.3) with similar values for ulcerative colitis (n = 18) and Crohn's disease (n = 14) compared with only 0.9 (range 0.4-2.3; P < 0.0001) for infective diarrhoea. In inflammatory bowel disease faecal lactoferrin and myeloperoxidase excretion remained increased even in clinical remission. 3. In subsequent immunohistochemical studies to assess the possible explanation for these findings, lactoferrin and myeloperoxidase were demonstrated within crypt abscesses and surface mucus, both in inflammatory bowel and in infective diarrhoea mucosal samples. There was a slight increase in the number of lactoferrin-containing cells in the mucosal samples from ulcerative colitis and in the submucosa of samples from Crohn's disease compared with infective diarrhoea, but these changes were not sufficient to account for the marked increase in faecal lactoferrin excretion in inflammatory bowel disease. 4. In all mucosal samples, including those from normal mucosa, lactoferrin was also shown to be contained within mast cells. 5. These results could best be explained by a different mechanism for leucocyte activation in inflammatory bowel disease compared with infective diarrhoea, and are compatible with selective secretion of secondary granule components, which include lactoferrin but not myeloperoxidase, as a result of leucocyte activation by N-formylated bacterial peptides in inflammatory bowel disease.


Prepectoral Implant-Based Breast Reconstruction: Rationale, Indications, and Preliminary Results.
Implant-based breast reconstruction is currently performed with placement of the implant in a subpectoral pocket beneath the pectoralis major muscle, by means of the dual-plane approach. Although the safety and breast aesthetics of this approach are well recognized, it is not without concerns. Animation deformities and accompanying patient discomfort, which are direct consequences of muscle elevation, can be severe in some patients. Moving the implant prepectorally may eliminate these concerns. For a successful prepectoral approach, the authors advocate use of their bioengineered breast concept, which was detailed in a previous publication. In this report, the authors discuss the rationale for prepectoral implant reconstruction, its indications/contraindications, and preliminary results from over 350 reconstructions. Therapeutic, IV.


[Capacitative Ca²⁺ entry is involved in ACh-induced distal colon smooth muscle contraction in rats].
Contraction of smooth muscle cells is triggered by an increase in cytosolic Ca(2+) upon agonist stimulation. Ca(2+) influx across the plasma membrane constitutes a major component of the agonist-induced response in smooth muscle cells. Traditionally, voltage-operated Ca(2+) channel (VOCC) is considered as the channel mediating the Ca(2+) entry. However, this view has been challenged by recent discoveries, which demonstrated that other types of ion channels, such as store-operated and/or receptor-operated Ca(2+) channels (SOCC and/or ROCC), also participate in Ca(2+) response induced by agonists in smooth muscle cells. SOCC is defined as the channel activated in response to the depletion of the internal Ca(2+) stores, an event secondary to G protein coupled receptor or receptor tyrosine kinase stimulation. The Ca(2+) flow mediated by SOCC is termed as capacitative Ca(2+) entry (CCE). Previous study from other group has demonstrated that VOCC played a predominant role in ACh-induced contraction of distal colon smooth muscle in guinea pig. However, whether SOCC participates in the agonist-induced contractile response in this particular tissue is unknown. The present study was performed to investigate the role of CCE in ACh-induced mechanical activity of distal colon smooth muscle in rats. The contractile function of the smooth muscle was assessed by measuring isometric force of isolated rat distal colon rings. We showed that both high extracellular K(+) (40 mmol/L) and ACh (5 mumol/L) evoked striking contraction of the smooth muscle. The contractile responses were almost abolished by removal of extracellular Ca(2+) with ethylene glycol-bis(2-aminoethylether)-N,N,N',N' tetraacetic acid (EGTA), suggesting a critical contribution of extracellular source of Ca(2+) to the contraction. Verapamil (5 mumol/L), an L-type VOCC blocker, significantly attenuated, but didn't completely eliminate the high K(+)- and ACh-induced contraction (74% and 41% for high K(+) and ACh, respectively), indicating that additional channels might be involved in the contractile mechanism. Furthermore, ACh only induced transient contractions in the absence of extracellular Ca(2+). Readmission of Ca(2+) into the extracellular compartment resulted in a significant and sustained increase in the tension of the smooth muscle. This response was not affected by verapamil (5 mumol/L) and Cd(2+) (5 mumol/L), both of which efficiently block VOCC at the doses. However, La(3+), a known inhibitor of SOCC, significantly suppressed the Ca(2+) readdition-induced contraction in a dose-dependent manner. On the basis of these results, we conclude that contraction of smooth muscle in the distal colon is regulated by multiple Ca(2+) channels. In addition to VOCC-mediated Ca(2+) influx, SOCC-mediated CCE participates in agonist-induced contractile response of distal colon smooth muscle in rats.


Hormonal changes during non-climacteric ripening in strawberry.
In contrast to climacteric fruits, where ethylene is known to be pivotal, the regulation of ripening in non-climacteric fruits is not well understood. In the non-climacteric strawberry (Fragaria anannassa), auxin and abscisic acid (ABA) are thought to be important, but the roles of other hormones suggested to be involved in fruit development and ripening are not clear. Here changes in the levels of indole-3-acetic acid (IAA), ABA, GA1, and castasterone from anthesis to fully ripened fruit are reported. The levels of IAA and GA1 rise early in fruit development before dropping to low levels prior to colour accumulation. Castasterone levels are highest at anthesis and drop to very low levels well before ripening commences, suggesting that brassinosteroids do not play an important role in ripening in strawberry. ABA levels are low at anthesis and gradually rise through development and ripening. The synthetic auxin, 1-naphthaleneacetic acid (NAA), can delay ripening, but the application of GA3, the gibberellin biosythesis inhibitor paclobutrazol, and ABA had no significant effect. IAA and ABA levels are higher in the developing achenes than in the receptacle tissue and may be important for receptacle enlargement and ripening, and seed maturation, respectively. Contrary to a recent report, the biologically active GA4 was not detected. The pattern of changes in the levels of the hormones are different from those reported in another well studied non-climateric fruit, grape, suggesting that a single consistent pattern of hormone changes does not occur in this group of fruit during ripening.


Simultaneous masking interactions between chromatic and luminance gratings.
Simultaneous masking using test and mask gratings composed of isochromatic luminance variations and isoluminant chromatic variations was studied. Masking of chromatic gratings by chromatic gratings shows less spatial-frequency specificity than does masking of luminance gratings by luminance gratings. Luminance gratings mask chromatic gratings of identical space-average luminance and chromaticity little and only when the spatial frequencies of the test and mask gratings are similar. Chromatic gratings, however, profoundly mask luminance gratings with a degree of spatial-frequency specificity akin to that of luminance-luminance masking. The insensitivity of the luminance-color masking results to the relative phase of the chromatic and luminance gratings indicates that the observed asymmetry is not due to local interactions.


Dietary fat intake promotes the development of hepatic steatosis independently from excess caloric consumption in a murine model.
Nonalcoholic fatty liver disease results from overconsumption and is a significant and increasing cause of liver failure. The type of diet that is conducive to the development of this disease has not been established, and evidence-based treatment options are currently lacking. We hypothesized that the onset of hepatic steatosis is linked to the consumption of a diet with a high fat content, rather than related to excess caloric intake. In addition, we also hypothesized that fully manifested hepatic steatosis could be reversed by reducing the fat percentage in the diet of obese mice. C57BL/6J male mice were fed either a purified rodent diet containing 10% fat or a diet with 60% of calories derived from fat. A pair-feeding design was used to distinguish the effects of dietary fat content and caloric intake on dietary-induced hepatic lipid accumulation and associated injury. Livers were analyzed by quantitative reverse transcriptase polymerase chain reaction for lipid metabolism-related gene expression. After 9 weeks, mice on the 60%-fat diet exhibited more weight gain, insulin resistance, and hepatic steatosis compared with mice on a 10%-fat diet with equal caloric intake. Furthermore, mice with established metabolic syndrome at 9 weeks showed reversal of hepatic steatosis, insulin resistance, and obesity when switched to a 10%-fat diet for an additional 9 weeks, independent of caloric intake. Quantitative reverse transcriptase polymerase chain reaction revealed that transcripts related to both de novo lipogenesis and increased uptake of free fatty acids were significantly up-regulated in mice pair-fed a 60%-fat diet compared with 10%-fat-fed animals. Dietary fat content, independent from caloric intake, is a crucial factor in the development of hepatic steatosis, obesity, and insulin resistance in the C57BL/6J diet-induced obesity model caused by increased uptake of free fatty acids and de novo lipogenesis. In addition, once established, all these features of the metabolic syndrome can be successfully reversed after switching obese mice to a diet low in fat. Low-fat diets deserve attention in the investigation of a potential treatment of patients with nonalcoholic fatty liver disease.


Control of IP(3)-mediated Ca2+ puffs in Xenopus laevis oocytes by the Ca2+-binding protein parvalbumin.
1. Elementary events of Ca2+ release (Ca2+ puffs) can be elicited from discrete clusters of inositol 1,4,5 trisphosphate receptors (IP(3)Rs) at low concentrations of IP(3). Ca(2+) puffs have rarely been observed unless elicited by either hormone treatment or introduction of IP(3) into the cell. However, cells appear to have sufficient concentrations of IP(3) (0.1-3.0 microM) to induce Ca2+ release under resting conditions. 2. Here, we investigated Ca2+ puff activity in non-stimulated Xenopus oocytes using confocal microscopy. The fluorescent Ca2+ dye indicators Calcium Green 1 and Oregon Green 488 BAPTA-2 were injected into oocytes to monitor basal Ca2+ activity. 3. In this preparation, injection or overexpression of parvalbumin, an EF-hand Ca(2+)-binding protein (CaBP), induced Ca2+ puffs in resting Xenopus oocytes. This activity was inhibited by heparin, an IP(3)R channel blocker, and by mutation of the Ca(2+)-binding sites in parvalbumin. 4. Ca2+ puff activity was also evoked by injection of low concentrations of the Ca2+ chelator EGTA, but not by calbindin D(28k), another member of the EF-hand CaBP superfamily. 5. BAPTA and the Ca2+ indicator dye Oregon Green 488 BAPTA-1 evoked Ca2+ puff activity, while the dextran conjugate of Oregon Green 488 BAPTA-1 did not. These data indicate that a Ca(2+) buffer must be mobile in order to increase Ca2+ puff activity. 6. Together, the data indicate that some IP(3)Rs spontaneously release Ca2+ under resting concentrations of IP(3). These elementary Ca2+ events appear to be below the level of detection of current imaging techniques. We suggest that parvalbumin evokes Ca2+ puffs by coordinating the activity of elementary IP(3)R channel openings. 7. We conclude that Ca2+ release can be evoked not only by hormone-induced increases in IP(3), but also by expression of mobile cytosolic CaBPs under resting concentrations of IP(3).


A streamlined search technology for identification of synergistic drug combinations.
A major key to improvement of cancer therapy is the combination of drugs. Mixing drugs that already exist on the market may offer an attractive alternative. Here we report on a new model-based streamlined feedback system control (s-FSC) method, based on a design of experiment approach, for rapidly finding optimal drug mixtures with minimal experimental effort. We tested combinations in an in vitro assay for the viability of a renal cell adenocarcinoma (RCC) cell line, 786-O. An iterative cycle of in vitro testing and s-FSC analysis was repeated a few times until an optimal low dose combination was reached. Starting with ten drugs that target parallel pathways known to play a role in the development and progression of RCC, we identified the best overall drug combination, being a mixture of four drugs (axitinib, erlotinib, dasatinib and AZD4547) at low doses, inhibiting 90% of cell viability. The removal of AZD4547 from the optimized drug combination resulted in 80% of cell viability inhibition, while still maintaining the synergistic interaction. These optimized drug combinations were significantly more potent than monotherapies of all individual drugs (p < 0.001, CI < 0.3).


Selection of a management strategy for pediatric brainstem tumors.
Brainstem tumors arise in portions of the rhombencephalon and mesencephalon. Some authorities include diencephalic tumors in this group. We have reviewed our clinical experience of 69 children (less than 21 years of age) with brainstem tumors evaluated and treated at Duke University Medical Center (DUMC) from 1960 to 1986. There were 19 patients with group 1 tumors (thalamus, third ventricle region, or midbrain) and 50 with group II tumors (pons, medulla oblongata). The common presenting signs and symptoms were ataxia, headache, motor loss, and cranial nerve palsies. The most commonly employed diagnostic imaging studies were air examinations and CT. Preradiotherapy confirmation of malignancy was obtained in five group I patients (astrocytoma, 4; germinoma, 1) and 8 group II patients (astrocytoma, 3; anaplastic astrocytoma, 2; glioblastoma multiforme, 3). All patients received radiotherapy. The 5-year survival rate for the entire population was 40%. The survival rate for group I patients was significantly better than that observed for group II patients. In the 50 group II patients neither patient sex nor age nor presence of cranial nerve palsies nor pretreatment CT scan findings nor field size influenced survival. A long duration of symptoms positively influenced survival. The vast majority of tumor recurrences were within the radiation field. Half of the patients had either stable or improved Karnofsky status 6 months following completion of irradiation. The management strategy for childhood brainstem tumors is discussed.


A drug-eluting contact lens.
To formulate and characterize a drug-eluting contact lens designed to provide extended, controlled release of a drug. Prototype contact lenses were created by coating PLGA (poly[lactic-co-glycolic acid]) films containing test compounds with pHEMA (poly[hydroxyethyl methacrylate]) by ultraviolet light polymerization. The films, containing encapsulated fluorescein or ciprofloxacin, were characterized by scanning electron microscopy. Release studies were conducted in phosphate-buffered saline at 37 degrees C with continuous shaking. Ciprofloxacin eluted from the contact lens was studied in an antimicrobial assay to verify antimicrobial effectiveness. After a brief and minimal initial burst, the prototype contact lenses demonstrated controlled release of the molecules studied, with zero-order release kinetics under infinite sink conditions for over 4 weeks. The rate of drug release was controlled by changing either the ratio of drug to PLGA or the molecular mass of the PLGA used. Both the PLGA and the pHEMA affected release kinetics. Ciprofloxacin released from the contact lenses inhibited ciprofloxacin-sensitive Staphylococcus aureus at all time-points tested. A prototype contact lens for sustained drug release consisting of a thin drug-PLGA film coated with pHEMA could be used as a platform for ocular drug delivery with widespread therapeutic applications.


The influence of size, shape and vessel geometry on nanoparticle distribution.
Nanoparticles (NPs) are emerging as promising carrier platforms for targeted drug delivery and imaging probes. To evaluate the delivery efficiency, it is important to predict the distribution of NPs within blood vessels. NP size, shape and vessel geometry are believed to influence its biodistribution in circulation. Whereas, the effect of size on nanoparticle distribution has been extensively studied, little is known about the shape and vessel geometry effect. This paper describes a computational model for NP transport and distribution in a mimetic branched blood vessel using combined NP Brownian dynamics and continuum fluid mechanics approaches. The simulation results indicate that NPs with smaller size and rod shape have higher binding capabilities as a result of smaller drag force and larger contact area. The binding dynamics of rod-shaped NPs is found to be dependent on their initial contact points and orientations to the wall. Higher concentration of NPs is observed in the bifurcation area compared to the straight section of the branched vessel. Moreover, it is found that Péclet number plays an important role in determining the fraction of NPs deposited in the branched region and the straight section. Simulation results also indicate that NP binding decreases with increased shear rate. Dynamic NP re-distribution from low to high shear rates is observed due to the non-uniform shear stress distribution over the branched channel. This study would provide valuable information for NP distribution in a complex vascular network.


Cannabinoids and the gut: new developments and emerging concepts.
Cannabis has been used to treat gastrointestinal (GI) conditions that range from enteric infections and inflammatory conditions to disorders of motility, emesis and abdominal pain. The mechanistic basis of these treatments emerged after the discovery of Delta(9)-tetrahydrocannabinol as the major constituent of Cannabis. Further progress was made when the receptors for Delta(9)-tetrahydrocannabinol were identified as part of an endocannabinoid system, that consists of specific cannabinoid receptors, endogenous ligands and their biosynthetic and degradative enzymes. Anatomical, physiological and pharmacological studies have shown that the endocannabinoid system is widely distributed throughout the gut, with regional variation and organ-specific actions. It is involved in the regulation of food intake, nausea and emesis, gastric secretion and gastroprotection, GI motility, ion transport, visceral sensation, intestinal inflammation and cell proliferation in the gut. Cellular targets have been defined that include the enteric nervous system, epithelial and immune cells. Molecular targets of the endocannabinoid system include, in addition to the cannabinoid receptors, transient receptor potential vanilloid 1 receptors, peroxisome proliferator-activated receptor alpha receptors and the orphan G-protein coupled receptors, GPR55 and GPR119. Pharmacological agents that act on these targets have been shown in preclinical models to have therapeutic potential. Here, we discuss cannabinoid receptors and their localization in the gut, the proteins involved in endocannabinoid synthesis and degradation and the presence of endocannabinoids in the gut in health and disease. We focus on the pharmacological actions of cannabinoids in relation to GI disorders, highlighting recent data on genetic mutations in the endocannabinoid system in GI disease.


Precipitated abstinence in orally dosed benzodiazepine-dependent dogs.
The ability of graded doses of flumazenil (2, 6, 18, 36 and 72 mg/kg) and a lactose placebo to precipitate abstinence was studied in dogs treated chronically with diazepam, nordiazepam, flunitrazepam, alprazolam, oxazepam, halazepam and lorazepam by oral dosing. A scale comprised of 10 precipitated abstinence signs, the Benzodiazepine Precipitated Abstinence Scale, was developed, which yielded linear flumazenil log-dose response lines with significant slopes in dogs dependent on diazepam, nordiazepam and flunitrazepam. The effects of 18, 36 and 72 mg/kg of flumazenil in otherwise drug naive dogs were studied. In naive dogs, the most prominent effect of flumazenil was to reduce activity. All benzodiazepines studied produced dependence that was characterized by signs of precipitated abstinence; however, the intensity and quality of abstinence varied from one benzodiazepine to another. Precipitated abstinence in dogs treated chronically with diazepam and flunitrazepam was characterized by a dose-related increase in clonic convulsions and Benzodiazepine Precipitated Abstinence Scale scores. This pattern differed from that seen in nordiazepam- and alprazolam-dependent dogs, which showed a comparable flumazenil dose-related increase in clonic convulsion but only a modest increase in Benzodiazepine Precipitated Abstinence Scale scores. Oxazepam and lorazepam produced dependence that was less intense than that seen with the other benzodiazepines. Plasma levels of the benzodiazepines and their metabolites were repeatedly determined after single doses and during addiction cycles. Nordiazepam accumulated in diazepam- and nordiazepam-dependent dogs and alpha-OH alprazolam accumulated in alprazolam-dependent dogs. Other drugs and metabolites did not. These observations suggest that: 1) different benzodiazepines or their metabolites produce different types of physical dependence, suggesting that they or their metabolites have different mechanisms and sites of action; 2) plasma cumulation of the benzodiazepines or their active metabolites is an important factor in the genesis of physical dependence; and 3) metabolism of benzodiazepines plays an important role in their dependence-producing capacity, and because of differences in the way species metabolize benzodiazepines, the type of dependence produced in different species may differ.


Fluoxetine for depression in diabetes: a randomized double-blind placebo-controlled trial.
Depression is prevalent in patients with diabetes. It is associated with poor glycemic control and is linked to an increased risk for diabetic complications. In this study, we assessed the efficacy of fluoxetine for depression in patients with diabetes. Sixty patients with diabetes (type 1, n = 26; type 2, n = 34) and major depressive disorder entered an 8-week randomized placebo-controlled double-blind trial. Patients were given daily doses of fluoxetine (up to 40 mg/day). The Beck Depression Inventory (BDI) and Hamilton Rating Scale for Depression (HAMD) were used to measure the severity of depression and to determine the percentage of patients who achieved substantial improvement or complete remission. GHb levels were obtained to monitor glycemic control. Reduction in depression symptoms was significantly greater in patients treated with fluoxetine compared with those receiving placebo (BDI, -14.0 vs. -8.8, P = 0.03; HAMD, -10.7 vs. -5.2, P = 0.01). The percentage of patients achieving a significant improvement in depression per the BDI was also higher in the fluoxetine group (66.7 vs. 37.0%, P = 0.03). Additionally, trends toward a greater rate of depression remission (48.1 vs. 25.9%, P = 0.09 per the HAMD) and greater reduction in GHb (-0.40 vs. -0.07%, P = 0.13) were observed in the fluoxetine group. Fluoxetine effectively reduces the severity of depression in diabetic patients. Our study demonstrated that after only 8 weeks, this treatment also produced a trend toward better glycemic control.


Altered EEG Signal Complexity Induced by Hand Proximity: A Multiscale Entropy Approach.
Visual short-term memory (VSTM) is an important cognitive function that acts as a temporary storage for visual information. Previous studies have shown that VSTM capacity can be modulated by the location of one's hands, where hand proximity enhances neural processing and memory of nearby visual stimuli. The present study used traditional event-related potentials (ERP) along with multiscale entropy (MSE) analysis to shed light on the neural mechanism(s) behind such near-hand effect. Participants' electroencephalogram (EEG) data were recorded as they performed a VSTM task with their hands either proximal or distal to the display. ERP analysis showed altered memory processing in the 400-700 ms time window during memory retrieval period. Importantly, MSE analysis also showed significant EEG difference between hand proximal and distal conditions between scales 10 to 20, and such difference is clustered around the right parietal cortex - a region that is involved in VSTM processing and bimodal hand-eye integration. The implications of higher MSE time scale in the parietal cortex are discussed in the context of signal complexity and its possible relation to cognitive processing. To our knowledge, this study provides the first investigation using MSE to characterize the temporal characteristics and signal complexity behind the effect of hand proximity.


5-(Hydroxyphenyl)-γ-Valerolactone-Sulfate, a Key Microbial Metabolite of Flavan-3-ols, Is Able to Reach the Brain: Evidence from Different in Silico, In Vitro and In Vivo Experimental Models.
Phenolic compounds have been recognized as promising compounds for the prevention of chronic diseases, including neurodegenerative ones. However, phenolics like flavan-3-ols (F3O) are poorly absorbed along the gastrointestinal tract and structurally rearranged by gut microbiota, yielding smaller and more polar metabolites like phenyl-γ-valerolactones, phenylvaleric acids and their conjugates. The present work investigated the ability of F3O-derived metabolites to cross the blood-brain barrier (BBB), by linking five experimental models with increasing realism. First, an in silico study examined the physical-chemical characteristics of F3O metabolites to predict those most likely to cross the BBB. Some of these metabolites were then tested at physiological concentrations to cross the luminal and abluminal membranes of brain microvascular endothelial cells, cultured in vitro. Finally, three different in vivo studies in rats injected with pure 5-(3',4'-dihydroxyphenyl)-γ-valerolactone, and rats and pigs fed grapes or a F3O-rich cocoa extract, respectively, confirmed the presence of 5-(hydroxyphenyl)-γ-valerolactone-sulfate (3',4' isomer) in the brain. This work highlighted, with different experimental models, the BBB permeability of one of the main F3O-derived metabolites. It may support the neuroprotective effects of phenolic-rich foods in the frame of the "gut-brain axis".


Noncanonical splicing junctions between exons and transposable elements represent a source of immunogenic recurrent neo-antigens in patients with lung cancer.
Although most characterized tumor antigens are encoded by canonical transcripts (such as differentiation or tumor-testis antigens) or mutations (both driver and passenger mutations), recent results have shown that noncanonical transcripts including long noncoding RNAs and transposable elements (TEs) can also encode tumor-specific neo-antigens. Here, we investigate the presentation and immunogenicity of tumor antigens derived from noncanonical mRNA splicing events between coding exons and TEs. Comparing human non-small cell lung cancer (NSCLC) and diverse healthy tissues, we identified a subset of splicing junctions that is both tumor specific and shared across patients. We used HLA-I peptidomics to identify peptides encoded by tumor-specific junctions in primary NSCLC samples and lung tumor cell lines. Recurrent junction-encoded peptides were immunogenic in vitro, and CD8+ T cells specific for junction-encoded epitopes were present in tumors and tumor-draining lymph nodes from patients with NSCLC. We conclude that noncanonical splicing junctions between exons and TEs represent a source of recurrent, immunogenic tumor-specific antigens in patients with NSCLC.


Proton pump inhibitors exert anti-inflammatory effects and decrease human microglial and monocytic THP-1 cell neurotoxicity.
To explore whether proton pump inhibitors (PPIs) possess anti-inflammatory effects on microglia, we investigated the effect of lansoprazole (LPZ) and omeprazole (OPZ) on the toxic action towards SH-SY5Y neuroblastoma cells of supernatants from human microglia and THP-1 cells stimulated by lipopolysaccharide combined with interferon-gamma. In addition, we studied the effect of LPZ and OPZ on the THP-1 cell production of the pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 using enzyme-linked immunosorbent assays. We found that both PPIs had a protective effect on the toxicity of supernatants and that there was a synergism of this effect with S-ibuprofen (IBP), a typical non-steroidal anti-inflammatory drug (NSAID). A similar protective effect of LPZ was observed with supernatants from stimulated human microglia. We also found that both PPIs significantly reduced the TNF-alpha secretion from stimulated THP-1 cells in a concentration dependent manner and that there was a trend towards such reduction of IL-6. These results indicate that PPIs possess anti-inflammatory effects and can decrease human microglial and monocytic neurotoxicity. They suggest that PPIs combined with NSAIDs may be effective in the treatment of a broad spectrum of neurodegenerative diseases associated with activated microglia.


How expensive is a cardioprotective diet? Analysis from the CRESSIDA study.
To determine whether a cardioprotective dietary intervention based on UK dietary guidelines was more expensive than a conventional UK diet. Cost analysis of food records collected at baseline and after a 12-week dietary intervention of a cardioprotective diet v. conventional UK diet. A randomized controlled dietary intervention study (CRESSIDA; ISRCTN 92382106) investigating the impact of following a diet consistent with UK dietary guidelines on CVD risk. Participants were healthy UK residents aged 40-70 years. A sub-sample of participants was randomly selected from those who completed the cardioprotective dietary intervention (n 20) or the conventional UK dietary intervention (n 20). Baseline diet costs did not differ between groups; mean daily food cost for all participants was £6·12 (sd £1·83). The intervention diets were not more expensive: at end point the mean daily cost of the cardioprotective diet was £6·43 (sd £2·05) v. the control diet which was £6·53 (sd £1·53; P=0·86). There was no evidence that consumption of a cardioprotective diet was more expensive than a conventional dietary pattern. Despite the perception that healthier foods are less affordable, these results suggest that cost may not be a barrier when modifying habitual intake and under tightly controlled trial conditions. The identification of specific food groups that may be a cost concern for individuals may be useful for tailoring interventions for CVD prevention for individuals and populations.


Non-response bias and hazardous alcohol use in relation to previous alcohol-related hospitalization: comparing survey responses with population data.
This study examines whether alcohol-related hospitalization predicts survey non-response, and evaluates whether this missing data result in biased estimates of the prevalence of hazardous alcohol use and abstinence. Registry data on alcohol-related hospitalizations during the preceding ten years were linked to two representative surveys. Population data corresponding to the surveys were derived from the Stockholm County registry. The alcohol-related hospitalization rates for survey responders were compared with the population data, and corresponding rates for non-responders were based on the differences between the two estimates. The proportions with hazardous alcohol use and abstinence were calculated separately for previously hospitalized and non-hospitalized responders, and non-responders were assumed to be similar to responders in this respect. Persons with previous alcohol-related admissions were more likely currently to abstain from alcohol (RR=1.58, p<.001) or to have hazardous alcohol use (RR=2.06, p<.001). Alternatively, they were more than twice as likely to have become non-responders. Adjusting for this skewed non-response, i.e., the underrepresentation of hazardous users and abstainers among the hospitalized, made little difference to the estimated rates of hazardous use and abstinence in total. During the ten-year period 1.7% of the population were hospitalized. Few people receive alcohol-related hospital care and it remains unclear whether this group's underrepresentation in surveys is generalizable to other groups, such as hazardous users. While people with severe alcohol problems--i.e. a history of alcohol-related hospitalizations--are less likely to respond to population surveys, this particular bias is not likely to alter prevalence estimates of hazardous use.


A systematic review of cervical artificial disc replacement wear characteristics and durability.
Systematic review.Clinical questions: (1) What evidence is available from studies of cervical total disc arthroplasty (C-ADR) failure and retrieval regarding durability, wear, and reasons for failure of C-ADR? (2) What evidence is available from experimental models regarding the durability of C-ADR beyond 5 years? We searched electronic databases to identify published reports of explanted cervical artificial discs and biomechanical simulations of disc wear. Nine articles were identified describing 17 devices explanted from human patients and four articles describing 23 devices explanted from non-human subjects. Wear properties were not consistently reported across studies, so summaries for specific variables are based on few cases. No device had been implanted longer than 4 years. In both human and non-human subjects, devices showed evidence of metallic and polymeric (for discs with polymer components) debris. Inflammatory cells were frequently present in surrounding soft tissues. Signs of infection were uncommon.Four patients had reactions interpreted as hypersensitivity to metal. We identified three articles on biomechanical wear simulations. Devices were tested between 10 and 20 million cycles in axial loading, flexion/extension, and lateral bending. No device failures were reported. One study suggests such simulations may represent 50 or more years of wear in actual patients. Cervical disc implants consistently produced polymeric and metallic debris, which was typically accompanied by inflammation. Hypersensitivity to metal may increase risk for device failure. Biomechanical simulations indicate that cervical disc implants may be durable beyond the currently reported length of clinical follow-up.


Selective separation of the major whey proteins using ion exchange membranes.
Synthetic microporous membranes with functional groups covalently attached were used to selectively separate beta-lactoglobulin, BSA, and alpha-lactalbumin from rennet whey. The selectivity and membrane performance of strong (quaternary ammonium) and weak (diethylamine) ion-exchange membranes were studied using breakthrough curves, measurement of binding capacity, and protein composition of the elution fraction to determine the binding behavior of each membrane. When the weak and strong anion exchange membranes were saturated with whey, they were both selective primarily for beta-lactoglobulin with less than 1% of the eluate consisting of alpha-lactalbumin or BSA. The binding capacity of a pure beta-lactoglobulin solution was in excess of 1.5 mg/cm2 of membrane. This binding capacity was reduced to approximately 1.2 mg/cm2 when using a rennet whey solution (pH 6.4). This reduction in protein binding capacity can be explained by both the competitive effects of other whey proteins and the effect of ions present in whey. Using binary solution breakthrough curves and rennet whey breakthrough curves, it was shown that alpha-lactalbumin and BSA were displaced from the strong and weak anion exchange membranes by beta-lactoglobulin. Finally, the effect of ionic strength on the binding capacity of individual proteins for each membrane was determined by comparing model protein solutions in milk permeate (pH 6.4) and a 10 mM sodium phosphate buffer (pH 6.4). Binding capacities of beta-lactoglobulin, alpha-lactalbumin, and BSA in milk permeate were reduced by as much as 50%. This reduction in capacity coupled with the low binding capacity of current ion exchange membranes are 2 serious considerations for selectively separating complex and concentrated protein solutions.


Oligodendroglia metabolically support axons and contribute to neurodegeneration.
Oligodendroglia support axon survival and function through mechanisms independent of myelination, and their dysfunction leads to axon degeneration in several diseases. The cause of this degeneration has not been determined, but lack of energy metabolites such as glucose or lactate has been proposed. Lactate is transported exclusively by monocarboxylate transporters, and changes to these transporters alter lactate production and use. Here we show that the most abundant lactate transporter in the central nervous system, monocarboxylate transporter 1 (MCT1, also known as SLC16A1), is highly enriched within oligodendroglia and that disruption of this transporter produces axon damage and neuron loss in animal and cell culture models. In addition, this same transporter is reduced in patients with, and in mouse models of, amyotrophic lateral sclerosis, suggesting a role for oligodendroglial MCT1 in pathogenesis. The role of oligodendroglia in axon function and neuron survival has been elusive; this study defines a new fundamental mechanism by which oligodendroglia support neurons and axons.


Protective Effects of Ammannia baccifera Against CCl4-Induced Oxidative Stress in Rats.
Ammannia baccifera Linn. is commonly used as a traditional medicine in India and China. The antioxidant potential of an ethanolic extract of A. baccifera (EEAB; 250 mg/kg and 500 mg/kg) was evaluated against CCL4-induced toxicity in rats. Antioxidant activity was assessed by measuring the enzymatic and non-enzymatic antioxidants. Phytochemical constituents of EEAB were also analyzed by using UHPLC-QTOF-MS. EEAB treatment markedly reduced CCl4 effects on lipid peroxidation, cholesterol, triacylglycerides, and protein carbonyls. It increased the levels of phospholipids, total sulfhydryl, and antioxidant enzymes, which were reduced by CCl4 intoxication. Treatment with EEAB significantly alleviated the CCl4 effect on non-enzymatic antioxidants. Isoenzyme pattern analyses revealed that significant alterations in superoxide dismutase (SOD1), glutathione peroxidase (GPx2, GPx3), and catalase (CAT) occurred in rats that were exposed to CCl4 and restored post EEAB treatment. Moreover, CCl4-induced down regulation of SOD, CAT, and GPx gene expression was conversely counteracted by EEAB. Its bioactivity may be due to its incorporation of major compounds, such as chlorogenic acid, quercetin, protocatechuic acid, lamioside, crocetin, and khayasin C. These results suggest that EEAB may be used as a potent antioxidant and hepatoprotective agent since it is a rich source of flavonoids and phenolic compounds.


Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members.
Mutations in the progranulin gene (GRN) are an important cause of frontotemporal lobar degeneration (FTLD) with ubiquitin and TAR DNA-binding protein 43 (TDP43)-positive pathology. The clinical presentation associated with GRN mutations is heterogeneous and may include clinical probable Alzheimer's disease. All GRN mutations identified thus far cause disease through a uniform disease mechanism, i.e. the loss of functional GRN or haploinsufficiency. To determine if expression of GRN in plasma could predict GRN mutation status and could be used as a biological marker, we optimized a GRN ELISA and studied plasma samples of a consecutive clinical FTLD series of 219 patients, 70 control individuals, 72 early-onset probable Alzheimer's disease patients and nine symptomatic and 18 asymptomatic relatives of GRN mutation families. All FTLD patients with GRN loss-of-function mutations showed significantly reduced levels of GRN in plasma to about one third of the levels observed in non-GRN carriers and control individuals (P < 0.001). No overlap in distributions of GRN levels was observed between the eight GRN loss-of-function mutation carriers (range: 53-94 ng/ml) and 191 non-GRN mutation carriers (range: 115-386 ng/ml). Similar low levels of GRN were identified in asymptomatic GRN mutation carriers. Importantly, ELISA analyses also identified one probable Alzheimer's disease patient (1.4%) carrying a loss-of-function mutation in GRN. Biochemical analyses further showed that the GRN ELISA only detects full-length GRN, no intermediate granulin fragments. This study demonstrates that using a GRN ELISA in plasma, pathogenic GRN mutations can be accurately detected in symptomatic and asymptomatic carriers. The approximately 75% reduction in full-length GRN, suggests an unbalanced GRN metabolism in loss-of-function mutation carriers whereby more GRN is processed into granulins. We propose that plasma GRN levels could be used as a reliable and inexpensive tool to identify all GRN mutation carriers in early-onset dementia populations and asymptomatic at-risk individuals.


The potential role of 'non-rheumatic' therapies in rheumatic disease.
The relationship between inflammation and insulin resistance is complex and not fully understood. Patients with rheumatoid arthritis are at increased risk of mortality from cardiovascular disease, which is known to be associated with insulin resistance. In the previous issue of Arthritis Research & Therapy, Ormseth and colleagues report the results of an 8-week trial of pioglitazone, an agent commonly used to treat type 2 diabetes mellitus, upon the DAS-28 (disease activity score using 28 joint counts). Modest improvements in the DAS-28 CRP (DAS-28 C-reactive protein) were shown, with no effect on DAS-28 ESR (DAS-28 erythrocyte sedimentation rate). Other variables that improved with pioglitazone were the CRP, IL-6, and patient-reported assessment of global health. The authors discuss the contribution of insulin resistance to the inflammation noted in rheumatoid arthritis.


Sleep-wake rhythm disruption is associated with cancer-related fatigue in pediatric acute lymphoblastic leukemia.
To compare sleep-wake rhythms, melatonin, and cancer-related fatigue in pediatric patients with acute lymphoblastic leukemia (ALL) to healthy children and to assess the association between sleep-wake outcomes and cancer-related fatigue. A national cohort of ALL patients (2-18 years) was included. Sleep-wake rhythms were measured using actigraphy and generated the following variables: Interdaily stability (IS): higher IS reflects higher stability; intradaily variability (IV): lower IV indicates less fragmentation; L5 and M10 counts: activity counts during the five least and 10 most active hours, respectively; and relative amplitude (RA): the ratio of L5 and M10 counts (higher RA reflects a more robust rhythm). The melatonin metabolite, 6-sulfatoxymelatonin (aMT6s), was assessed in urine. Cancer-related fatigue was assessed with the PedsQL Multidimensional Fatigue Scale. Using regression models sleep-wake rhythms, aMT6s, and cancer-related fatigue were compared to healthy children and associations between sleep-wake outcomes and cancer-related fatigue were assessed in ALL patients. In total, 126 patients participated (response rate: 67%). IS, RA, and M10 counts were lower in patients compared to healthy children (p < 0.001). aMT6s levels were comparable to healthy children (p = 0.425). Patients with ALL were more fatigued compared to healthy children (p < 0.001). Lower IS, RA and M10 counts and higher IV were significantly associated with more parent-reported cancer-related fatigue. Associations between sleep-wake rhythms and self-reported cancer-related fatigue were not statistically significant. Sleep-wake rhythm impairment is associated with more cancer-related fatigue in pediatric ALL patients. Interventions aimed to improve sleep hygiene and encourage physical activity may reduce cancer-related fatigue.


The Ethics of Precision Rationing: Human Genetics and the Need for Debate on Stratifying Access to Medication.
Rising prices for new, transformative therapies are challenging health systems around the world, leading many payers and providers to begin rationing access to treatments, even in the countries that have been most resistant to doing so. This is the case for direct-acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV). However, little attention has been paid to the increasing role that human genetics might play in rationing decisions. Researchers have already proposed that genetic markers associated with spontaneous HCV clearance could be used to restrict DAA access for some patients, although treatment would be medically beneficial for those patients. Would such forms of rationing present a form of genetic discrimination? And what of the public health implications of these approaches? Here we present an ethical analysis of such proposals for "precision rationing" and raise 4 key areas of concern. We argue that ethical issues arising in this area are not substantively different from the pressing ethical issues regarding rationing and discrimination more broadly, but provide important impetus for motivating broad public debate to find ethically sound ways of managing genomics and new expensive medications.


High-dose vitamin K supplementation reduces fracture incidence in postmenopausal women: a review of the literature.
Although systematic review and meta-analysis of randomized controlled trials (RCTs) have concluded that vitamin K is effective in preventing fractures, the effect of vitamin K on the skeleton remains a matter of controversy. The objective of the present review of the literature was to evaluate the effect of vitamin K supplementation on the skeleton of postmenopausal women. PubMed was used to search the reliable literature for RCTs by using the search terms "vitamin K(1) or vitamin K(2)," "bone," and "postmenopausal women" and the following inclusion criteria: approximately 50 or more subjects per group and study period of 2 years or longer. Seven RCTs met the inclusion criteria. The results of these RCTs showed that vitamin K(1) and vitamin K(2) supplementation reduced serum undercarboxylated osteocalcin levels regardless of dose but that it had inconsistent effects on serum total osteocalcin levels and no effect on bone resorption. Despite the lack of a significant change or the occurrence of only a modest increase in bone mineral density, high-dose vitamin K(1) and vitamin K(2) supplementation improved indices of bone strength in the femoral neck and reduced the incidence of clinical fractures. The review of the reliable literature confirmed the effect of vitamin K(1) and vitamin K(2) supplementation on the skeleton of postmenopausal women mediated by mechanisms other than bone mineral density and bone turnover.


Semi-automatic delineation using weighted CT-MRI registered images for radiotherapy of nasopharyngeal cancer.
To develop a delineation tool that refines physician-drawn contours of the gross tumor volume (GTV) in nasopharynx cancer, using combined pixel value information from x-ray computed tomography (CT) and magnetic resonance imaging (MRI) during delineation. Operator-guided delineation assisted by a so-called "snake" algorithm was applied on weighted CT-MRI registered images. The physician delineates a rough tumor contour that is continuously adjusted by the snake algorithm using the underlying image characteristics. The algorithm was evaluated on five nasopharyngeal cancer patients. Different linear weightings CT and MRI were tested as input for the snake algorithm and compared according to contrast and tumor to noise ratio (TNR). The semi-automatic delineation was compared with manual contouring by seven experienced radiation oncologists. A good compromise for TNR and contrast was obtained by weighing CT twice as strong as MRI. The new algorithm did not notably reduce interobserver variability, it did however, reduce the average delineation time by 6 min per case. The authors developed a user-driven tool for delineation and correction based a snake algorithm and registered weighted CT image and MRI. The algorithm adds morphological information from CT during the delineation on MRI and accelerates the delineation task.


Post-translational regulation and trafficking of the granulin-containing protease RD21 of Arabidopsis thaliana.
RD21-like proteases are ubiquitous, plant-specific papain-like proteases typified by carrying a C-terminal granulin domain. RD21-like proteases are involved in immunity and associated with senescence and various types of biotic and abiotic stresses. Here, we interrogated Arabidopsis RD21 regulation and trafficking by site-directed mutagenesis, agroinfiltration, western blotting, protease activity profiling and protein degradation. Using an introduced N-glycan sensor, deglycosylation experiments and glyco-engineered N. benthamiana plants, we show that RD21 passes through the Golgi where it becomes fucosylated. Our studies demonstrate that RD21 is regulated at three post-translational levels. Prodomain removal is not blocked in the catalytic Cys mutant, indicating that RD21 is activated by a proteolytic cascade. However, RD21 activation in Arabidopsis does not require vacuolar processing enzymes (VPEs) or aleurain-like protease AALP. In contrast, granulin domain removal requires the catalytic Cys and His residues and is therefore autocatalytic. Furthermore, SDS can (re-)activate latent RD21 in Arabidopsis leaf extracts, indicating the existence of a third layer of post-translational regulation, possibly mediated by endogenous inhibitors. RD21 causes a dominant protease activity in Arabidopsis leaf extracts, responsible for SDS-induced proteome degradation.


The surface chemistry of metal-organic frameworks.
Metal-organic frameworks (MOFs) have received particular attention over the last 20 years as a result of their attractive properties offering potential applications in a number of areas. Typically, these characteristics are tuned by functionalisation of the bulk of the MOF material itself. This Feature Article focuses instead on modification of MOF particles at their surfaces only, which can also offer control over the bulk properties of the material. The differing surface modification techniques available to the synthetic chemist will be discussed, with a focus on the effect of surface modification of MOFs on their fundamental properties and application in adsorption, catalysis, drug delivery and other areas.


Low income countries have the highest percentages of open access publication: A systematic computational analysis of the biomedical literature.
Open access publication rates have been steadily increasing over time. In spite of this growth, academics in low income settings struggle to gain access to the full canon of research literature. While the vast majority of open access repositories and funding organizations with open access policies are based in high income countries, the geographic patterns of open access publication itself are not well characterized. In this study, we developed a computational approach to better understand the topical and geographical landscape of open access publications in the biomedical research literature. Surprisingly, we found a strong negative correlation between country per capita income and the percentage of open access publication. Open access publication rates were particularly high in sub-Saharan Africa, but vastly lower in the Middle East and North Africa, South Asia, and East Asia and the Pacific. These effects persisted when considering papers only bearing authors from within each region and income group. However, papers resulting from international collaborations did have a higher percentage of OA than single-country papers, and inter-regional collaboration increased OA publication for all world regions. There was no clear relationship between the number of open access policies in a region and the percentage of open access publications in that region. To understand the distribution of open access across topics of biomedical research, we examined keywords that were most enriched and depleted in open access papers. Keywords related to genomics, computational biology, animal models, and infectious disease were enriched in open access publications, while keywords related to the environment, nursing, and surgery were depleted in open access publications. This work identifies geographic regions and fields of research that could be priority areas for open access advocacy. The finding that open access publication rates are highest in sub-Saharan Africa and low income countries suggests that factors other than open access policy strongly influence authors' decisions to make their work openly accessible. The high proportion of OA resulting from international collaborations indicates yet another benefit of collaborative research. Certain applied fields of medical research, notably nursing, surgery, and environmental fields, appear to have a greater proportion of fee-for-access publications, which presumably creates barriers that prevent researchers and practitioners in low income settings from accessing the literature in those fields.


SU-E-T-139: Feasibility Study of Glass Dosimeter for in Vivo Measurement: Dosimetric Characterization and Clinical Application in Proton Beams.
To evaluate the suitability of the GD-301 glass dosimeter for use in in vivo dose verification in proton therapy. The glass dosimeter was analyzed for its dosimetric characteristic in proton beam. Dosimeters were calibrated in a water phantom using a stair-like holder specially designed for this study. To determine the accuracy of the glass dosimeter in proton dose measurements, we compared the glass dosimeter and TLD dose measurements of plan delivery using a cylindrical phantom. We investigated the feasibility of the glass dosimeter for the measurement of dose distributions near the superficial region for proton therapy plans with a varying separation between the target volume and the surface of 6 patients. Uniformity was within 1.5%. The dose-response has a good linear. Dose-rate, fading, and energy dependence were found to be within 3%. The beam profile measured using the glass dosimeter was in good agreement with the profile obtained from the ionization chamber. Depth-dose distributions in non-modulated and modulated proton beams obtained with the glass dosimeter were estimated to be within 3%, which was lower than those with the ionization chamber. In the phantom study, the difference of isocenter dose between the delivery dose calculated by the Eclipse and that of the measured by the glass dosimeter was within 5%. In vivo dosimetry of patients, given the results of the glass dosimeter and TLD measurements, calculated doses on the surface of the patient are typically overestimated between 4% and 16%. As such, it is recommended that bolus be added for these clinical cases. We also believe that the glass dosimeter has considerable potential to be used for in vivo patient proton dosimetry.


Intraventricular metastases from small cell carcinoma of the lung.
Small cell lung carcinoma (SCLC) represents 15-20% of all lung cancers. It is characterised by rapid growth and early metastatic dissemination. Generally, the prognosis of these patients is poor. When brain metastases develop, the prognosis is even poorer. Most of these cases present parenchymal metastases; however, intraventricular dissemination may also occur although it is very uncommon. To our knowledge the case reported here is the first showing multiple synchronic intraventricular dissemination from SCLC.


Characteristics of chicken nuggets as affected by added fat and variable salt contents.
Several studies have been conducted in many countries on how to increase the per capita consumption of poultry meat. With the growing demand for poultry meat, the development of value added product, such as chicken nuggets has been identified as the best way to increase poultry meat consumption. Apart from this allowing for the flourishing growth of fast food industries; chicken nuggets needs to be produced in higher quantity and to reduce cost, there is increasing interest in using of various meat additives. Though, chicken fat are edible, it is important to evolve production processes for gainful utilization of this part. So the main objective of this work was to study the effect of the addition of chicken fat and various salt contents on the physicochemical, proximate composition and sensory characteristics of chicken nuggets. Based on the results it is concluded that, even up to 5% level of chicken fat with 1.5-2% added salt there is no adverse effect in terms of physico-chemical, proximate composition and sensory qualities of cooked chicken nuggets. Even, at this fat and salt level product was more preferred by panellist than no fat-no salt chicken nuggets.


Quantitation of ischemia during total coronary occlusion with computer-assisted high resolution ST-segment monitoring: effect of collateral flow.
The effect of increasing grades of collateral flow to the distal target vessel on the clinical and electrocardiographic manifestations of ischemia was evaluated in 118 patients undergoing transluminal coronary angioplasty (TCA). A qualitative scoring system for collateralization was defined as follows: 0--no visible collaterals; 1--visualization of collateral vessels only with no filling of the distal TCA vessel; 2--partial filling of the distal TCA vessel, and; 3--complete filling of the distal TCA vessel. All patients underwent computerized ST-segment monitoring using 3-channel Holter recorders. Criteria for an ischemic ST-segment response was 1.0 mm ST-segment deviation from ST baseline measured 60 msec after the J-point. Episodes of chest pain during and after the procedure were noted. Patients with collateral filling (collateral scores 2 and 3) of the distal TCA vessel had a significantly decreased incidence of angina and diagnostic ischemic ST-segment changes (42% and 15% respectively) as compared to patients without collateral filling (collateral scores 0 and 1) (83% and 74%) (p less than .001). Fifty-eight percent of patients without collateral filling had ischemic ST-segment responses on every balloon inflation as opposed to only 9% with collateral filling (p less than .0001). After TCA, the incidence of angina and ischemic ST-segment changes was similar in both groups (20% and 17% without collateral filling vs. 9% and 9%). We conclude that: 1. increasing qualitative collateralization protects against the development of myocardial ischemia during TCA, but; 2. the similar incidence of late episodes of ischemia after successful TCA suggests that collateral flow may no longer be adequate.


Optomechanical dark mode.
Thermal mechanical motion hinders the use of a mechanical system in applications such as quantum information processing. Whereas the thermal motion can be overcome by cooling a mechanical oscillator to its motional ground state, an alternative approach is to exploit the use of a mechanically dark mode that can protect the system from mechanical dissipation. We have realized such a dark mode by coupling two optical modes in a silica resonator to one of its mechanical breathing modes in the regime of weak optomechanical coupling. The dark mode, which is a superposition of the two optical modes and is decoupled from the mechanical oscillator, can still mediate an effective optomechanical coupling between the two optical modes. We show that the formation of the dark mode enables the transfer of optical fields between the two optical modes. Optomechanical dark mode opens the possibility of using mechanically mediated coupling in quantum applications without cooling the mechanical oscillator to its motional ground state.


Environmental context influences both the intensity of seed predation and plant demographic sensitivity to attack.
Variation in mutualistic and antagonistic interactions are important sources of variation in population dynamics and natural selection. Environmental heterogeneity can influence the outcome of interactions by affecting the intensity of interactions, but also by affecting the demography of the populations involved. However, little is known about the relative importance of environmental effects on interaction intensities and demographic sensitivity for variation in population growth rates. We investigated how soil depth, soil moisture, soil nutrient composition, and vegetation height influenced the intensity of seed predation as well as host plant demography and sensitivity to seed predation in the perennial herb Primula farinosa. Intensity of seed predation ranged from 0% to 80% of seeds damaged among the 24 study populations and was related to soil moisture in two of four years. The effect of seed predation on plant population growth rate (lambda) ranged from negligible to a reduction in lambda by 0.70. Sensitivity of population growth rate to predation explained as much of the variation in the reductions in population growth rate due to seed predation as did predation intensity. Plant population growth rate in the absence of seed predation and sensitivity to predation were negatively related to soil depth and soil moisture. Both intensity of predation and sensitivity to predation were positively correlated with potential population growth rate and, as a result, there was no significant relationship between predation intensity and realized population growth rate. We conclude that in our study system environmental context influences the effects of seed predation on plant fitness and population dynamics in two important ways: through variation in interaction intensity and through sensitivity to the effects of this interaction. Moreover, our results show that a given abiotic factor can influence population growth rate in different directions through effects on potential growth rate, intensity of biotic interactions, and the sensitivity of population growth rate to interactions.


X-ray absorption spectroscopy studies of the adducts formed between cytotoxic gold compounds and two major serum proteins.
Gold metallodrugs form a class of promising antiproliferative agents showing a high propensity to react with proteins. We exploit here X-ray absorption spectroscopy (XAS) methods [both X-ray absorption near-edge spectroscopy (XANES) and extended X-ray absorption fine structure (EXAFS)] to gain insight into the nature of the adducts formed between three representative gold(I, III) metallodrugs (i.e., auranofin, [Au(2,2'-bipyridine)(OH)(2)](PF(6)), Aubipy, and dinuclear [Au(2)(6,6'-dimethyl-2,2'-bipyridine)(2)(μ-O)(2)](PF(6))(2), Auoxo6) and two major plasma proteins, namely, bovine serum albumin (BSA) and human serum apotransferrin (apoTf). The following metallodrug-protein systems were investigated in depth: auranofin/apoTf, Aubipy/BSA, and Auoxo6/apoTf. XANES spectra revealed that auranofin, upon protein binding, conserves its gold(I) oxidation state. Protein binding most probably takes place through release of the thiosugar ligand and its subsequent replacement by a thiol (or a thioether) from the protein. This hypothesis is independently supported by EXAFS results. In contrast, the reactions of Aubipy with serum albumin and of Auoxo6 with serum apoTf invariantly result in gold(III) to gold(I) reduction. Gold(III) reduction, clearly documented by XANES, is accompanied, in both cases, by release of the bipyridyl ligands; for Auoxo6 cleavage of the gold-gold dioxo bridge is also observed. Gold(III) reduction leads to formation of protein-bound gold(I) species, with deeply modified metal coordination environments, as evidenced by EXAFS. In these adducts, the gold(I) centers are probably anchored to the protein through nitrogen donors. In general, these two XAS methods, i.e., XANES and EXAFS, used here jointly, allowed us to gain independent structural information on metallodrug/protein systems; detailed insight into the gold oxidation state and the local environment of protein-bound metal atoms was achieved in the various cases.


Epidermal growth factor inhibits intestinal NHE8 expression via reducing its basal transcription.
Sodium/hydrogen exchangers (NHEs) play a major role in Na(+) absorption, cell volume regulation, and intracellular pH regulation. Of the nine identified mammalian NHEs, three (NHE2, NHE3, and NHE8) are localized on the apical membrane of epithelial cells in the small intestine and the kidney. Although the regulation of NHE2 and NHE3 expression has been extensively studied in the past decade, little is known about the regulation of NHE8 gene expression under physiological conditions. The current studies were performed to explore the role of epidermal growth factor (EGF) on NHE8 expression during intestinal maturation. Brush-border membrane vesicles (BBMV) were isolated from intestinal epithelia, and Western blot analysis was performed to determine NHE8 protein expression of sucking male rats treated with EGF. Real-time PCR was used to quantitate NHE8 mRNA expression in rats and Caco-2 cells. Human NHE8 promoter activity was characterized through transfection of Caco-2 cells. Gel mobility shift assays (GMSAs) were used to identify the promoter sequences and the transcriptional factors involved in EGF-mediated regulation. Our results showed that intestinal NHE8 mRNA expression was decreased in EGF-treated rats and Caco-2 cells, and NHE8 protein abundance was also decreased in EGF-treated rats. The activity of the human NHE8 gene promoter transfected in Caco-2 cells was also reduced by EGF treatment. This could be explained by reduced binding of transcription factor Sp3 on the NHE8 basal promoter region in the presence of EGF. Pretreatment with MEK1/2 inhibitor UO-126 could prevent EGF-mediated inhibition of NHE8 gene expression. In conclusion, this study showed that EGF inhibits NHE8 gene expression through reducing its basal transcription, suggesting an important role of EGF in regulating NHE expression during intestinal maturation.


Expression of 17 alpha-hydroxylase and 3 beta-hydroxysteroid dehydrogenase in fetal human adrenocortical cells transfected with SV40 T antigen.
Primary fetal human adrenocortical cells of definitive zone origin were transfected by electroporation with pSV3neo, a plasmid coding for SV40 T antigen and neo, which confers resistance to the antibiotic G418. The clones obtained proliferated for 30 to 40 population doublings after isolation when grown under standard medium conditions, and then entered 'crisis'. When early-passage clones were incubated with cyclic AMP (1:1 N6-monobutyryl and 8-bromo analogues), cell rounding was observed, as in primary cultures of human adrenocortical cells. As previously shown in bovine adrenocortical cells, rounding was inhibited with a monoclonal antibody against urokinase plasminogen activator but not with a monoclonal antibody against tissue plasminogen activator. The regulation of the steroidogenic pathway in clones was investigated. The effects of cyclic AMP and activation of protein kinase C were examined in cells maintained in defined medium or in the presence of serum. 17 alpha-Hydroxylase was strongly induced by cyclic AMP, as evidenced by Northern blotting and by the conversion of progesterone or 25-hydroxy-[1,2-3H]cholesterol, this induction being blocked by low concentrations of 12-O-tetradecanoylphorbol-13-acetate (TPA). Cholesterol side-chain cleavage enzyme was strongly induced by cyclic AMP, and clones also showed low activities of 21-hydroxylase and 11 beta-hydroxylase. Under all circumstances levels of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), as assessed by Northern blotting or by conversion of 25-hydroxycholesterol, were very low. 3 beta-HSD was not induced by cyclic AMP or TPA alone, but was induced by the combination of the two agents. The regulation of 17 alpha-hydroxylase and 3 beta-HSD resembles that previously described in primary cultures of human fetal adrenocortical cells. Thus, transfection with SV40 T antigen resulted in the production of clones which preserve the unique characteristics of the human adrenal cortex.


Worse prognosis of KRAS c.35 G > A mutant metastatic colorectal cancer (MCRC) patients treated with intensive triplet chemotherapy plus bevacizumab (FIr-B/FOx).
Prognosis of KRAS wild-type and mutant metastatic colorectal cancer (MCRC) patients (pts) treated with bevacizumab (BEV)-containing chemotherapy is not significantly different. Since specific KRAS mutations confer different aggressive behaviors, the prognostic role of prevalent KRAS mutations was retrospectively evaluated in MCRC pts treated with first line FIr-B/FOx, associating BEV to triplet chemotherapy. Tumor samples were screened for KRAS codon 12, 13 and BRAF V600E mutations by SNaPshot and/or direct sequencing. MCRC pts <75-years-old were consecutively treated with FIr-B/FOx: weekly 12 hour-timed-flat-infusion/5-fluorouracil (900 mg/m(2) on days 1,2, 8, 9, 15, 16,22, 23), irinotecan plus BEV (160 mg/m(2) and 5 mg/kg, respectively, on days 1,15); and oxaliplatin (80 mg/m(2), on days 8,22). Pts were classified as liver-limited (L-L) and other/multiple metastatic (O/MM). Progression-free survival (PFS) and overall survival (OS) were compared using the log-rank test. Fifty-nine pts were evaluated at a median follow-up of 21.5 months. KRAS mutant pts: c.35 G > A, 15 (25.4%); c.35 G > T, 7 (11.8%); c.38 G > A, 3 (5%); other, 3 (5%). KRAS wild-type, 31 pts (52.7%). The objective response rate (ORR), PFS and OS were, respectively: c.35 G > A mutant, 71%, 9 months, 14 months; other than c.35 G > A mutants, 61%, 12 months, 39 months. OS was significantly worse in c.35 G > A pts compared to KRAS wild-type (P = 0.002), KRAS/BRAF wild-type (P = 0.03), other MCRC patients (P = 0.002), other than c.35 G > A (P = 0.05), other codon 12 (P = 0.03) mutant pts. OS was not significantly different compared to c.35 G > T KRAS mutant (P = 0.142). KRAS c.35 G > A mutant status may be significantly associated with a worse prognosis of MCRC pts treated with first line FIr-B/FOx intensive regimen compared to KRAS/BRAF wild type and other than c.35 G > A mutant pts.


Zampanolide and dactylolide: cytotoxic tubulin-assembly agents and promising anticancer leads.
Zampanolide is a marine natural macrolide and a recent addition to the family of microtubule-stabilizing cytotoxic agents. Zampanolide exhibits unique effects on tubulin assembly and is more potent than paclitaxel against several multi-drug resistant cancer cell lines. A high-resolution crystal structure of αβ-tubulin in complex with zampanolide explains how taxane-site microtubule-stabilizing agents promote microtubule assemble and stability. This review provides an overview of current developments of zampanolide and its related but less potent analogue dactylolide, covering their natural sources and isolation, structure and conformation, cytotoxic potential, structure-activity studies, mechanism of action, and syntheses.


Metabolic Syndrome in Fasting and Non-Fasting Participants: The UAE Healthy Future Study.
Metabolic syndrome (MetS) is a multiplex of risk factors that predispose people to the development of diabetes and cardiovascular disease (CVD), two of the major non-communicable diseases that contribute to mortality in the United Arab Emirates (UAE). MetS guidelines require the testing of fasting samples, but there are evidence-based suggestions that non-fasting samples are also reliable for CVD-related screening measures. In this study, we aimed to estimate MetS and its components in a sample of young Emiratis using HbA1c as another glycemic marker. We also aimed to estimate the associations of some known CVD risk factors with MetS in our population. The study was based on a cross-sectional analysis of baseline data of 5161 participants from the UAE Healthy Future Study (UAEHFS). MetS was identified using the NCEP ATP III criteria, with the addition of HbA1c as another glycemic indicator. Fasting blood glucose (FBG) and HbA1c were used either individually or combined to identify the glycemic component of MetS, based on the fasting status. Multivariate regression analysis was used to test for associations of selected social and behavioral factors with MetS. Our sample included 3196 men and 1965 women below the age of 40 years. Only about 21% of the sample were fasting at the time of recruitment. The age-adjusted prevalence of MetS was estimated as 22.7% in males and 12.5% in females. MetS prevalence was not statistically different after substituting FBG by HbA1c in the fasting groups (p > 0.05). Age, increased body mass index (BMI), and family history of any metabolic abnormality and/or heart disease were consistently strongly associated with MetS. MetS is highly prevalent in our sample of young Emirati adults. Our data showed that HbA1c may be an acceptable tool to test for the glycemic component of MetS in non-fasting samples. We found that the most relevant risk factors for predicting the prevalence of MetS were age, BMI, and family history.


Structural and Functional Impact of Parkinson Disease-Associated Mutations in the E3 Ubiquitin Ligase Parkin.
Mutations in the PARKIN/PARK2 gene that result in loss-of-function of the encoded, neuroprotective E3 ubiquitin ligase Parkin cause recessive, familial early-onset Parkinson disease. As an increasing number of rare Parkin sequence variants with unclear pathogenicity are identified, structure-function analyses will be critical to determine their disease relevance. Depending on the specific amino acids affected, several distinct pathomechanisms can result in loss of Parkin function. These include disruption of overall Parkin folding, decreased solubility, and protein aggregation. However pathogenic effects can also result from misregulation of Parkin autoinhibition and of its enzymatic functions. In addition, interference of binding to coenzymes, substrates, and adaptor proteins can affect its catalytic activity too. Herein, we have performed a comprehensive structural and functional analysis of 21 PARK2 missense mutations distributed across the individual protein domains. Using this combined approach, we were able to pinpoint some of the pathogenic mechanisms of individual sequence variants. Similar analyses will be critical in gaining a complete understanding of the complex regulations and enzymatic functions of Parkin. These studies will not only highlight the important residues, but will also help to develop novel therapeutics aimed at activating and preserving an active, neuroprotective form of Parkin.


Closed-loop double-vasopressor automated system vs manual bolus vasopressor to treat hypotension during spinal anaesthesia for caesarean section: a randomised controlled trial.
Hypotension necessitating vasopressor administration occurs commonly during caesarean section under spinal anaesthesia. We developed a novel vasopressor delivery system that automatically administers phenylephrine or ephedrine based on continuous non-invasive arterial pressure monitoring. A phenylephrine bolus of 50 μg was given at 30-s intervals when systolic blood pressure fell < 90% of baseline; an ephedrine bolus of 4 mg was given instead if systolic pressure fell < 90% of baseline together with a heart rate < 60 beats.min(-1). The control group used manual boluses of either phenylephrine 100 μg or ephedrine 8 mg, administered at 1-min intervals based on the same thresholds for systolic pressure and heart rate. This randomised, controlled, double-blinded trial involved 213 healthy women who underwent elective caesarean delivery under spinal anaesthesia using 11 mg hyperbaric bupivacaine with 15 μg fentanyl and 100 μg morphine. The automated vasopressor group had better systolic pressure control, with 37/106 (34.9%) having any beat-to-beat systolic pressure reading < 80% of baseline compared with 63/107 (58.9%) in the control group (p < 0.001). There was no difference in the incidence of reactive hypertension, defined as systolic pressure > 120% of baseline, with 8/106 (7.5%) in the automated vasopressor group vs 14/107 (13.1%) in the control group, or total dose of vasopressors. The automated vasopressor group had lower median absolute performance error of 8.5% vs control of 9.8% (p = 0.013), and reduced incidence of nausea (1/106 (0.9%) vs 11/107 (10.3%), p = 0.005). Neonatal umbilical cord pH, umbilical lactate and Apgar scores were similar. Hence, our system afforded better control of maternal blood pressure and reduced nausea with no increase in reactive hypertension when compared with manual boluses.


Dual-acting peptide with prolonged glucagon-like peptide-1 receptor agonist and glucagon receptor antagonist activity for the treatment of type 2 diabetes.
Type 2 diabetes is characterized by reduced insulin secretion from the pancreas and overproduction of glucose by the liver. Glucagon-like peptide-1 (GLP-1) promotes glucose-dependent insulin secretion from the pancreas, while glucagon promotes glucose output from the liver. Taking advantage of the homology between GLP-1 and glucagon, a GLP-1/glucagon hybrid peptide, dual-acting peptide for diabetes (DAPD), was identified with combined GLP-1 receptor agonist and glucagon receptor antagonist activity. To overcome its short plasma half-life DAPD was PEGylated, resulting in dramatically prolonged activity in vivo. PEGylated DAPD (PEG-DAPD) increases insulin and decreases glucose in a glucose tolerance test, evidence of GLP-1 receptor agonism. It also reduces blood glucose following a glucagon challenge and elevates fasting glucagon levels in mice, evidence of glucagon receptor antagonism. The PEG-DAPD effects on glucose tolerance are also observed in the presence of the GLP-1 antagonist peptide, exendin(9-39). An antidiabetic effect of PEG-DAPD is observed in db/db mice. Furthermore, PEGylation of DAPD eliminates the inhibition of gastrointestinal motility observed with GLP-1 and its analogues. Thus, PEG-DAPD has the potential to be developed as a novel dual-acting peptide to treat type 2 diabetes, with prolonged in vivo activity, and without the GI side-effects.


Comparison of Effects of Oral Melatonin with Oral Alprazolam used as a Premedicant in Adult Patients Undergoing Various Surgical Procedures under General Anesthesia: A Prospective Randomized Placebo-Controlled Study.
Preoperative anxiety is a major concern in patients undergoing any surgical procedure. Various drugs have been used to alleviate it. This study aims to compare the effects of oral melatonin versus oral alprazolam on preoperative anxiety, sedation, orientation, and cognitive function. A total of 90 adult patients were randomly allocated into three groups. Group M (n = 30) received oral melatonin 3 mg (2 tablets); Group A (n = 30) received oral alprazolam 0.25 mg (2 tablets), and Group P (n = 30) received placebo, multivitamin tablet (2 tablets) as premedication. The objectives of our study were to compare anxiety, sedation, orientation, and cognitive function using visual analog scale (VAS) anxiety score, Ramsay Sedation Score (RSS), orientation score, and Digit symbol substitution test (DSST) score before and after 120 min of giving premedication. For statistical analysis, paired t-test, Chi-square test, analysis of variance, and post hoc bonferroni test were used. Mean VAS scores for anxiety (after 120 min) were significantly reduced in Group M (3.9 ± 1.53) and Group A (4.43 ± 1.67) when compared to Group P (4.73 ± 0.82) (P < 0.05). RSS was higher in Group A as compared to Group M and Group P (P < 0.05). No significant difference in orientation score was observed in all the three groups before and after premedication (P > 0.05). DSST score (cognitive function) was better in Group M when compared to both Group A and Group P (P < 0.05). Oral melatonin (6 mg) when used as a premedicant is an effective alternative to alprazolam regarding providing better anxiolysis, lesser sedation along with maintenance of cognitive, and psychomotor function.


The influence of the interfacial layer on the stability of all-solution-processed organic light-emitting diodes.
Improving the stability of large-area organic light-emitting diodes is very important for practical applications. The interfacial layer plays a crucial role to improve the electron injection characteristic. In this work, devices prepared by various solution-processed interfacial materials and thermal-evaporated CsF were compared. In the devices with active area of 2.25 mm × 2.25 mm, we found that the performance and lifetime of the device with solution-processed Liq interfacial layer was comparable with the device with thermal-evaporated CsF. However, for the devices with active area of 2.4 cm × 3.7 cm, the device based on thermal-evaporated CsF was the champion in both performance and lifetime. The influence of the thickness of CsF on the stability was investigated. The most stable blue fluorescent devices can be achieved when the thickness of CsF is about 0.1 nm, while the most stable green phosphorescent devices can be obtained by depositing 0.2 nm CsF. The best current efficiency for the blue fluorescent device is 4 cd A-1, while the best one for the green phosphorescent device is 22 cd A-1. Furthermore, burning points causing the failure of the devices were investigated by scanning electron microscopy, atomic force microscopy, thermography and secondary ion mass spectrometry. We demonstrated that burning points are defects, which can be observed after long-time operation, showing higher local temperature and fragmentary electrode.


Pathophysiology and prognosis in vietnamese adults with tuberculous meningitis.
The pathogenesis of tuberculous meningitis remains unclear, and there are few data describing the kinetics of the immune response during the course of its treatment. We measured concentrations of pro- and anti-inflammatory cytokines in serial blood and cerebrospinal fluid (CSF) samples from 21 adults who were being treated for tuberculous meningitis. CSF concentrations of soluble tumor necrosis factor-alpha receptors and of matrix metalloprotein-9 and its tissue inhibitor were also measured, and blood-brain barrier permeability was assessed by the albumin and IgG partition indices. CSF concentrations of lactate, interleukin-8, and interferon-gamma were high before treatment and then decreased rapidly with antituberculosis chemotherapy. However, significant immune activation and blood-brain barrier dysfunction were still apparent after 60 days of treatment. Death was associated with high initial CSF concentrations of lactate, low numbers of white blood cells, in particular neutrophils, and low CSF glucose levels.


Photodynamic therapy for the treatment of atherosclerotic plaque: Lost in translation?
Acute coronary syndrome is a life-threatening condition of utmost clinical importance, which, despite recent progress in the field, is still associated with high morbidity and mortality. Acute coronary syndrome results from a rupture or erosion of vulnerable atherosclerotic plaque with secondary platelet activation and thrombus formation, which leads to partial or complete luminal obstruction of a coronary artery. During the last decade, scientific evidence demonstrated that when an acute coronary event occurs, several nonculprit plaques are in a "vulnerable" state. Among the promising approaches, several investigations provided evidence of photodynamic therapy (PDT)-induced stabilization and regression of atherosclerotic plaque. Significant development of PDT strategies improved its therapeutic outcome. This review addresses PDT's pertinence and major problems/challenges toward its translation to a clinical reality.


MiRNA in melanoma-derived exosomes.
Proteins, RNAs and viruses can be spread through exosomes, therefore transport utilizing these nanovesicles is of the great interest. MiRNAs are common exosomal constituents capable of influencing expression of a variety of target genes. MiRNA signatures of exosomes are unique in cancer patients and differ from those in normal controls. The knowledge about miRNA profiles of tumor-derived exosomes may contribute to better diagnosis, determination of tumor progression and response to treatment, as well as to the development of targeted therapies. We summarize the current knowledge with regard to miRNAs that are found in exosomes derived from tumors, particularly from melanoma.


Multiple sevoflurane exposures in infant monkeys do not impact the mother-infant bond.
Exposure to general anesthesia during the postnatal period is associated with death of brain cells as well as long-term impairments in cognitive and emotional behavior in animal models. These models are critical for investigating mechanisms of pediatric anesthetic neurotoxicity as well as for testing potential strategies for preventing or mitigating this toxicity. Control conditions for anesthesia exposure involve separation of conscious infants from their mothers for variable periods of time, which could have its own effect on subsequent behavior because of stress to the mother and/or infant as a consequence of separation.We are conducting a long-term study of infant rhesus monkeys exposed three times for 4h each to sevoflurane anesthesia during the first six postnatal weeks, with a comparison condition of control infant monkeys that undergo brief maternal separations on the same schedule, to equate the period of time each infant is conscious and separated from its mother. Because mothers are separated from their infants longer for infants in the anesthesia condition, this could modify maternal behavior toward the infant, which may influence subsequent socioemotional behavior in the infants. In this study, we analyzed maternal behavior immediately after the first post-anesthesia (or control) reunion, as well as during reintroduction of the mother-infant pair to the larger social group 24 hpost-anesthesia or control separation, and found no differences between the conditions with mothers spending most of their time in contact with infants in all conditions analyzed. This indicates that the different durations of maternal separation in this study design do not impact the mother-infant bond, strengthening conclusions that subsequent differences in behavior between monkeys exposed to anesthesia compared to controls are a consequence of anesthesia exposure and not differential maternal behavior in the two conditions.


Autonomy and interdependence: beliefs of Brazilian mothers from state capitals and small towns.
This study aimed to investigate characteristics of Brazilian mothers' beliefs system, in the dimensions of autonomy and interdependence. A group of 600 women, half from state capitals and half from small towns, participated in the study. They were individually interviewed with Scales of Allocentrism, Beliefs about Parental Practices and Socialization Goals. Paired and Independent samples t tests and Multivariate GLM were performed. The results indicate that although mothers from both contexts value autonomy, mothers inhabiting small towns considered the relational dimension as the most important; whereas mothers inhabiting capitals valued equally both dimensions, either in their beliefs about practices or in the socialization goals for their children. Mothers from small towns have a higher mean score for allocentrism than mothers living in capitals. Thus, place of residence proved to be a relevant variable in the modulation of maternal beliefs. Educational level was not a significant factor in the variables considered and with this group of mothers. The study results are discussed in terms of their contribution to the understanding of the complex relationship between dimensions of autonomy and interdependence in mothers' beliefs system.


Interactive effects of physical activity and APOE-ε4 on BOLD semantic memory activation in healthy elders.
Evidence suggests that physical activity (PA) is associated with the maintenance of cognitive function across the lifespan. In contrast, the apolipoproteinE-ε4 (APOE-ε4) allele, a genetic risk factor for Alzheimer's disease (AD), is associated with impaired cognitive function. The objective of this study was to examine the interactive effects of PA and APOE-ε4 on brain activation during memory processing in older (ages 65-85) cognitively intact adults. A cross-sectional design was used with four groups (n=17 each): (1) Low Risk/Low PA; (2) Low Risk/High PA; (3) High Risk/Low PA; and (4) High Risk/High PA. PA level was based on self-reported frequency and intensity. AD risk was based on presence or absence of an APOE-ε4 allele. Brain activation was measured using event-related functional magnetic resonance imaging (fMRI) while participants performed a famous name discrimination task. Brain activation subserving semantic memory processing occurred in 15 functional regions of interest. High PA and High Risk were associated with significantly greater semantic memory activation (famous>unfamiliar) in 6 and 3 of the 15 regions, respectively. Significant interactions of PA and Risk were evident in 9 of 15 brain regions, with the High PA/High Risk group demonstrating greater semantic memory activation than the remaining three groups. These findings suggest that PA selectively increases memory-related brain activation in cognitively intact but genetically at-risk elders. Longitudinal studies are required to determine whether increased semantic memory processing in physically active at-risk individuals is protective against future cognitive decline.


Impact of a Ketogenic Diet on Metabolic Parameters in Patients with Obesity or Overweight and with or without Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials.
The aim of this meta-analysis was to explore the efficacy of a ketogenic diet in metabolic control in patients with overweight or obesity and with or without type 2 diabetes. Embase, PubMed, and Cochrane Library were searched for randomized controlled trials that enrolled patients with overweight or obesity on a ketogenic diet for metabolic control. Fourteen studies were included in meta-analysis. The effects of ketogenic diets on glycemic control were greater for diabetic patients relative to those of low-fat diets, indicated by lower glycated hemoglobin (SMD, -0.62; p < 0.001) and homeostatic model assessment index (SMD, -0.29; p = 0.02), while comparable effects were observed for nondiabetic patients. Ketogenic diets led to substantial weight reduction (SMD, -0.46; p = 0.04) irrespective of patients' diabetes status at baseline and improved lipid profiles in terms of lower triglyceride (SMD, -0.45; p = 0.01) and greater high-density lipoprotein (SMD, 0.31; p = 0.005) for diabetic patients. Other risk markers showed no substantial between-group difference post intervention. Our study findings confirmed that ketogenic diets were more effective in improving metabolic parameters associated with glycemic, weight, and lipid controls in patients with overweight or obesity, especially those with preexisting diabetes, as compared to low-fat diets. This effect may contribute to improvements in metabolic dysfunction-related morbidity and mortality in these patient populations.


The depths of virus exaptation.
Viruses are ubiquitous parasites of cellular life forms and the most abundant biological entities on earth. The relationships between viruses and their hosts involve the continuous arms race but are by no account limited to it. Growing evidence shows that, in the course of evolution, viruses and their components are repeatedly recruited (exapted) for host functions. The functions of exapted viruses typically involve either defense from other viruses or cellular competitors or transfer of nucleic acids between cells, or storage functions. Virus exaptation can reach different depths, from recruitment of a fully functional virus to exploitation of defective, partially degraded viruses, to utilization of individual virus proteins.


Comparison of gross body fat-water magnetic resonance imaging at 3 Tesla to dual-energy X-ray absorptiometry in obese women.
Improved understanding of how depot-specific adipose tissue mass predisposes to obesity-related comorbidities could yield new insights into the pathogenesis and treatment of obesity as well as metabolic benefits of weight loss. We hypothesized that three-dimensional (3D) contiguous "fat-water" MR imaging (FWMRI) covering the majority of a whole-body field of view (FOV) acquired at 3 Tesla (3T) and coupled with automated segmentation and quantification of amount, type, and distribution of adipose and lean soft tissue would show great promise in body composition methodology. Precision of adipose and lean soft tissue measurements in body and trunk regions were assessed for 3T FWMRI and compared to dual-energy X-ray absorptiometry (DXA). Anthropometric, FWMRI, and DXA measurements were obtained in 12 women with BMI 30-39.9 kg/m(2) . Test-retest results found coefficients of variation (CV) for FWMRI that were all under 3%: gross body adipose tissue (GBAT) 0.80%, total trunk adipose tissue (TTAT) 2.08%, visceral adipose tissue (VAT) 2.62%, subcutaneous adipose tissue (SAT) 2.11%, gross body lean soft tissue (GBLST) 0.60%, and total trunk lean soft tissue (TTLST) 2.43%. Concordance correlation coefficients between FWMRI and DXA were 0.978, 0.802, 0.629, and 0.400 for GBAT, TTAT, GBLST, and TTLST, respectively. While Bland-Altman plots demonstrated agreement between FWMRI and DXA for GBAT and TTAT, a negative bias existed for GBLST and TTLST measurements. Differences may be explained by the FWMRI FOV length and potential for DXA to overestimate lean soft tissue. While more development is necessary, the described 3T FWMRI method combined with fully-automated segmentation is fast (<30-min total scan and post-processing time), noninvasive, repeatable, and cost-effective.


Glycans Function as Anchors for Antibodies and Help Drive HIV Broadly Neutralizing Antibody Development.
Apex broadly neutralizing HIV antibodies (bnAbs) recognize glycans and protein surface close to the 3-fold axis of the envelope (Env) trimer and are among the most potent and broad Abs described. The evolution of apex bnAbs from one donor (CAP256) has been studied in detail and many Abs at different stages of maturation have been described. Using diverse engineering tools, we investigated the involvement of glycan recognition in the development of the CAP256.VRC26 Ab lineage. We found that sialic acid-bearing glycans were recognized by germline-encoded and somatically mutated residues on the Ab heavy chain. This recognition provided an "anchor" for the Abs as the core protein epitope varies, prevented complete neutralization escape, and eventually led to broadening of the response. These findings illustrate how glycan-specific maturation enables a human Ab to cope with pathogen escape mechanisms and will aid in optimization of immunization strategies to induce V2 apex bnAb responses.


Characterizing post-extubation negative pressure pulmonary edema in the operating room-a retrospective matched case-control study.
Post-extubation negative pressure pulmonary edema (NPPE) is an uncommon but important anesthesia-related emergency presenting with acute respiratory distress and hypoxemia after removal of airway devices. This study investigated the incidence and associated risk factors for post-extubation NPPE during emergence. This retrospective, matched case-control study was conducted by reviewing the post-anesthesia records in Tzu Chi General Hospital, Taiwan. Patients reported of having acute hypoxemia (SpO2 < 92%) shortly after the removal of the endotracheal tube or supraglottic airway, associating with radiographic evidence of pulmonary edema and/or pink frothy sputum, were identified as definite NPPE cases. The potential risk factors were compared with the matched controls, who were randomly selected from the same database. A total of 85,561 patients received general anesthesia with airway instrumentation during the 8.5-year study period. A total of 16 patients were identified as definite cases of NPPE. Compared with the matched controls (n = 131), males, active smokers, emergency operation, endotracheal intubation, use of desflurane, and prolonged operation time carried significantly higher risks of developing NPPE (P < 0.05). Multivariate logistic regression analysis illustrated that active smoking (AOR 7.66, 95% CI 1.67-35.3; P = 0.009) and endotracheal intubation (AOR 10.87, 95% CI 1.23-100; P = 0.03) were the two most significant independent variables of post-extubation NPPE. We present the first clinical comparative study demonstrating that the overall incidence of NPPE immediately after extubation in the operating room is 0.019%. Our results highlight that active smokers and patients receiving endotracheal intubation general anesthesia are associated with significantly higher risks of developing NPPE following extubation in the operating room.