Sleep transitions in hypocretin-deficient narcolepsy.
Narcolepsy is characterized by instability of sleep-wake, tonus, and rapid eye movement (REM) sleep regulation. It is associated with severe hypothalamic hypocretin deficiency, especially in patients with cataplexy (loss of tonus). As the hypocretin neurons coordinate and stabilize the brain's sleep-wake pattern, tonus, and REM flip-flop neuronal centers in animal models, we set out to determine whether hypocretin deficiency and/or cataplexy predicts the unstable sleep-wake and REM sleep pattern of the human phenotype. We measured the frequency of transitions in patients with narcolepsy between sleep-wake states and to/from REM and NREM sleep stages. Patients were subdivided by the presence of +/- cataplexy and +/- hypocretin-1 deficiency. Sleep laboratory studies conducted from 2001-2011. In total 63 narcolepsy patients were included in the study. Cataplexy was present in 43 of 63 patients and hypocretin-1 deficiency was present in 37 of 57 patients. Hypocretin-deficient patients with narcolepsy had a significantly higher frequency of sleep-wake transitions (P = 0.014) and of transitions to/from REM sleep (P = 0.044) than patients with normal levels of hypocretin-1. Patients with cataplexy had a significantly higher frequency of sleep-wake transitions (P = 0.002) than those without cataplexy. A multivariate analysis showed that transitions to/from REM sleep were predicted mainly by hypocretin-1 deficiency (P = 0.011), whereas sleep-wake transitions were predicted mainly by cataplexy (P = 0.001). In human narcolepsy, hypocretin deficiency and cataplexy are both associated with signs of destabilized sleep-wake and REM sleep control, indicating that the disorder may serve as a human model for the sleep-wake and REM sleep flip-flop switches.


No change of body mass, fat mass, and skeletal muscle mass in ultraendurance swimmers after 12 hours of swimming.
We evaluated whether ultraendurance swimmers suffer a change of body mass, fat mass, skeletal muscle mass, total body water and specific gravity of urine during a 12-hr swim in 12 male Caucasian ultraswimmers. Proton nuclear magnetic resonance of urine samples before and after the race was performed to detect alanine, lactate, and 3-hydroxybutyrate. The 12 swimmers achieved an average distance of 29.4 km (SD = 5.1). No statistically significant changes in body mass, fat mass, skeletal muscle mass, and total body water could be determined (p > .05), but urine gravity decreased significantly (p < .001). Two participants showed increased signals of ketone bodies after the race. In these samples, the hydroxybutyrate-creatinine ratio increased more than tenfold.


Assessment and management of periodontal infections: a medical-surgical approach.
Over the last 30 years, significant advances have been achieved in elucidating the etiology, pathogenesis, and treatment of periodontal diseases. A new paradigm has emerged that includes the initiation of disease by specific bacteria within a biofilm that stimulate an immunoinflammatory host response, resulting in host tissue destruction. Disease modifiers, which may be of genetic, environmental, or acquired origin, have been recognized as major determinants of disease severity and progression. Current treatment protocols include an assessment of risk factors to identify an individual's degree of susceptibility and therapeutic responsiveness. Basic and clinical research has resulted in the development of several strategies to identify specific bacteria and host-derived markers associated with disease progression. Preventive and therapeutic antimicrobial therapies, which use various delivery systems, have been devised to target drug placement to the infection site. More recently, host modulatory therapies have been created that inhibit disease progression through the reduction of inflammatory mediators. Finally, biological mediators, including growth and differentiation factors, have been used to enhance an individual's healing potential to achieve periodontal and bone regeneration. A combined medical-surgical approach is indicated for these new methods of diagnosis, prevention, and treatment of periodontal diseases, which will allow for earlier treatment interventions and improved patient outcomes.


Nutrient availability induces community shifts in seagrass meadows grazed by turtles.
In the Caribbean, green turtles graze seagrass meadows dominated by Thalassia testudinum through rotational grazing, resulting in the creation of grazed and recovering (abandoned) patches surrounded by ungrazed seagrasses. We evaluated the seagrass community and its environment along a turtle grazing gradient; with the duration of (simulated) grazing as a proxy for the level of grazing pressure. The grazing levels consisted of Short-term (4 months clipping), Medium-term (8 months clipping), Long-term grazing (8 months of clipping in previously grazed areas), 8-months recovery of previously grazed patches, and ungrazed or unclipped patches as controls. We measured biomass and density of the seagrasses and rhizophytic algae, and changes in sediment parameters. Medium- and Long-term grazing promoted a shift in community species composition. At increasing grazing pressure, the total biomass of T. testudinum declined, whereas that of early-successional increased. Ammonium concentrations were highest in the patches of Medium-term (9.2 + 0.8 μM) and Long-term grazing levels (11.0 + 2.2 μM) and were lowest in the control areas (4.6 + 1.5 μM). T. testudinum is a late-successional species that maintains sediment nutrient concentrations at levels below the requirements of early-successional species when dominant. When the abundance of this species declines due to grazing, these resources become available, likely driving a shift in community composition toward a higher abundance of early-successional species.


Diagnosis, treatment and prevention of gonorrhoea.
Neisseria gonorrhoeae is a Gram-negative bacteria responsible for the sexually transmitted infection gonorrhoea, which is increasingly common in the UK. Drug-resistant strains of the bacteria have emerged, which is making gonorrhoea difficult to treat. Therefore, preventing infection is important. This article identifies people at increased risk of contracting the infection, and explores how nurses can offer testing and treatment as well as helping to prevent infection through education and health promotion.


Kinetic study of aggregation of milk protein and/or surfactant-stabilized oil-in-water emulsions by sedimentation field-flow fractionation.
Milk proteins are able to facilitate the formation and stabilization of oil droplets in food emulsions. This study employed Sedimentation Field-Flow Fractionation (SdFFF) to monitor changes in particle size distribution of freshly prepared emulsions with varying weight contributions of sodium caseinate (SC) and whey protein concentrate (WPC). The effect of the addition of Tween 80 (T) on the initial droplet size was also investigated. The results indicated that emulsifying ability follows the order Tween 80>WPC>SC, with corresponding weight average droplet diameter of 0.319, 0.487 and 0.531μm respectively, when each of the above emulsifiers was used solely. The stability of sodium caseinate emulsions was studied at 30.5 and 80.0°C by measuring the particle size distribution for a period of 70h. Emulsions withstood the temperatures and exhibited an initial increase in particle size distribution caused by heat-induced droplet aggregation, followed by a decrease to approximately the initial droplet size. The rate of droplet aggregation depends on the severity of thermal processing, as revealed by the kinetics of particle aggregation during aging at different temperatures. Comparison of the experimental rate constants found from SdFFF, with those determined theoretically gives invaluable information about the oil droplet stability and the aggregation mechanism. Based on the proposed mechanistic scheme various physicochemical quantities, which are very important in explaining the stability of oil-in-water emulsions, were determined. Finally, the advantages of SdFFF in studying the aggregation of the oil-in-water droplets, in comparison with other methods used for the same purpose, are discussed.


Emotional stress and tako-tsubo cardiomyopathy: observations on 2 distinct clinical phenotypes.
Tako-tsubo syndrome is a transient cardiomyopathy usually precipitated by an acute emotional or physiological stress. Our study objectives were to review and analyze the impact of emotional stress on clinical variables, echocardiographic characteristics, and short-term outcomes in patients with tako-tsubo syndrome. Retrospective chart review. Eleven patients presented with tako-tsubo syndrome (1 man and 10 women) during the 8-year period (January 2000 to January 2008). The patients were split into 2 groups, defined by presenting either after emotional stress (6/11, 54.5%) or after idiopathic/physical stress (5/11, 45.5%). The mean age was 53.8 (12.6) years. The mean peak troponin T level was 0.54 ng/mL (range, 0.03-2.06 ng/mL), and the mean left ventricular end-diastolic pressure was 15.8 (8.1) mm Hg. Emotional stress was associated with younger age (P = 0.024), a lower left ventricular end-diastolic pressure (P < 0.05), more ST segment changes on electrocardiogram (66.7% vs 40%), and a higher ejection fraction (P = 0.012). The patients in the idiopathic/physical stress group required more frequent hemodynamic support. We conclude that clinical, echocardiographic, and outcome characteristics can differentiate tako-tsubo patients presenting with emotional stress from those with idiopathic/physical stress into 2 distinct clinical phenotypes. Clinicians should monitor idiopathic/physically stressed tako-tsubo patients carefully for hemodynamic compromise.


[4 + 2] Cycloadditions of 1-phosphono-1,3-butadienes with nitroso heterodienophiles: a versatile synthetic route for polyfunctionalized aminophosphonic derivatives.
The hetero-Diels-Alder (HDA) reaction of 1-(diethoxyphosphonyl)-1,3-butadiene, 1-(dibenzyloxyphosphonyl)-1,3-butadiene, and 1-(diethoxyphosphonyl)-3-tert-butyldimethylsilyloxy-1,3-butadiene with various nitroso heterodienophiles has been investigated as a new synthetic route for aminophosphonic derivatives. The HDA cycloadditions regioselectively led to the proximal isomers, i.e., presenting the NR(3) group in the meta position regarding the phosphonate substituent. From the resulting 6-phosphono-3,6-dihydro-1,2-oxazine cycloadducts, a limited number of chemical steps were allowed to obtain a significant variety of aminophosphonic compounds of potential interest in medicinal chemistry. This has been illustrated through the synthesis of (Z)-4-(o-tolylamino)-1-hydroxybut-2-enylphosphonic acid, diethyl 3,4-dihydroxy-1-o-tolylpyrrolidin-2-yl-2-phosphonate, 4-(o-tolylamino)-1,2,3-trihydroxybutylphosphonic acid, diethyl 3-(2-(o-tolylamino)-1-hydroxyethyl)oxiran-2-yl-2-phosphonate, and diethyl 4,5-dihydroxymorpholin-6-yl-6-phosphonate.


Plastidic Isoprenoid Synthesis during Chloroplast Development : Change from Metabolic Autonomy to a Division-of-Labor Stage.
The chloroplast isoprenoid synthesis of very young leaves is supplied by the plastidic CO(2) --> pyruvate --> acetyl-coenzyme A (C(3) --> C(2)) metabolism (D Schulze-Siebert, G Schultz [1987] Plant Physiol 84: 1233-1237) and occurs via the plastidic mevalonate pathway. The plastidic C(3) --> C(2) metabolism and/or plastidic mevalonate pathway of barley (Hordeum vulgare L.) seedlings changes from maximal activity at the leaf base (containing developing chloroplasts with incomplete thylakoid stacking but a considerable rate of photosynthetic CO(2)-fixation) almost to ineffectivity at the leaf tip (containing mature chloroplasts with maximal photosynthetic activity). The ability to import isopentenyl diphosphate from the extraplastidic space gradually increases to substitute for the loss of endogenous intermediate supply for chloroplast isoprenoid synthesis (change from autonomic to division-of-labor stage). Fatty acid synthesis from NaH(14)CO(3) decreases in the same manner as shown for leaf sections and chloroplasts isolated from these. Evidence has been obtained for a drastic decrease of pyruvate decarboxylase-dehydrogenase activity during chloroplast development compared with other anabolic chloroplast pathways (synthesis of aromatic amino acid and branched chain amino acids). The noncompetition of pyruvate and acetate in isotopic dilution studies indicates that both a pyruvate-derived and an acetate-derived compound are simultaneously needed to form introductory intermediates of the mevalonate pathway, presumably acetoacetyl-coenzyme A.


Feline onychectomy: Current practices and perceptions of veterinarians in Ontario, Canada.
The objective of the study was to determine the proportion of practitioners from Ontario, Canada who perform onychectomy, identify the techniques utilized, and obtain practitioners views on the procedure. An anonymous survey was distributed to Ontario Veterinary Medical Association members. Mann-Whitney U-tests were used to compare responses of opinion questions related to declawing between respondents who indicated they perform declawing procedures and those who do not. Of 500 respondents, 75.8% reported performing onychectomy, with 60.1% of those reporting performing the procedure less than monthly and 73.3% only performing the procedure after recommending alternatives. Statistically significant differences were found between those who do and those who do not perform onychectomy for perception of procedural pain, concept of mutilation, perception of procedural necessity for behavior modification or prevention of euthanasia, and support of province-wide procedural bans.


White matter integrity and key structures affected in Alzheimer's disease characterized by diffusion tensor imaging.
White matter (WM) degeneration is suggested to predict the early signs of Alzheimer's disease (AD). The exact structural regions of brain circuitry involved are not known. This study aims to examine the associations between WM tract integrity, represented by the diffusion tensor imaging (DTI) measures, and AD diagnosis and to denote the key substrates in predicting AD. It included DTI measures of mean diffusivity (MD), fractional anisotropy, radial diffusivity and axial diffusivity of 18 main WM tracts in 84 non-Hispanic white participants from the Alzheimer's Disease Neuroimaging Initiative dataset. The multivariable general linear model was used to examine the association of AD diagnosis with each DTI measure adjusting for age, gender and education. The corpus callosum, fornix, cingulum hippocampus, uncinate fasciculus, sagittal striatum, left posterior thalamic radiation and fornix-stria terminalis showed significant increases in MD, radial and axial diffusivity, whereas the splenium of corpus callosum and the fornix showed significant decreases in fractional anisotropy among AD patients. Variable cluster analysis identified that hippocampus volume, mini-mental state examination (MMSE), cingulate gyrus/hippocampus, inferior fronto-occipital fasciculus and uncinate fasciculus are highly correlated in one cluster with MD measures. In conclusion, there were significant differences in DTI measures between the brain WM of AD patients and controls. Age is the risk factor associated with AD, not gender or education. Right cingulum gyrus and right uncinate fasciculus are particularly affected, correlating well with a cognitive test MMSE and MD measures for dementia in AD patients and could be a region of focus for AD staging.


Effects of Daily Melatonin Supplementation on Visual Loss, Circadian Rhythms, and Hepatic Oxidative Damage in a Rodent Model of Retinitis Pigmentosa.
Retinitis pigmentosa (RP) is a group of inherited neurodegenerative diseases characterized by a progressive loss of visual function that primarily affect photoreceptors, resulting in the complete disorganization and remodeling of the retina. Progression of the disease is enhanced by increased oxidative stress in the retina, aqueous humor, plasma, and liver of RP animal models and patients. Melatonin has beneficial effects against age-related macular degeneration, glaucoma, and diabetic retinopathy, in which oxidative stress plays a key role. In the present study, we used the P23HxLE rat as an animal model of RP. Melatonin treatment (10 mg/kg b.w. daily in drinking water for 6 months) improved the parameters of visual function and decreased the rate of desynchronization of the circadian rhythm, both in P23HxLE and wild-type rats. Melatonin reduced oxidative stress and increased antioxidant defenses in P23HxLE animals. In wild-type animals, melatonin did not modify any of the oxidative stress markers analyzed and reduced the levels of total antioxidant defenses. Treatment with melatonin improved visual function, circadian synchronization, and hepatic oxidative stress in P23HxLE rats, an RP model, and had beneficial effects against age-related visual damage in wild-type rats.


A unipolar compact nanosecond pulsed power supply with high power factor for dielectric barrier discharge applications.
A high voltage with a very short duration and fast rising time is beneficial to generate uniform and diffuse plasma in dielectric barrier discharge (DBD) loads, and a power supply with a high power factor (PF) can reduce the impact on the power grid. According to two requirements, a unipolar high voltage pulsed power supply with power factor correction (PFC) is proposed in this paper. The power supply consists of a unipolar pulse high voltage generating unit, a PFC unit, and a driving circuit. By introducing a feedback clamping diode and a reverse current blocking diode in a flyback converter, repetitive nanosecond pulses are generated in the unipolar pulse high voltage generating unit. Because a discontinuous current mode strategy is adopted in the PFC unit and the driving signal is shared by the two units, a compact structure of the power supply is achieved, and a high PF is obtained. To validate the proposed pulsed power supply, an experimental setup is built for a DBD excimer lamp. The results show that the proposed power supply has the capability of not only providing a unipolar nanosecond pulse high voltage for the DBD excimer lamp but also achieving PF close to 1 and total harmonic distortion of less than 24%.


Enhancing plant resistance at the seed stage: low concentrations of methyl jasmonate reduce the performance of the leaf miner Tuta absoluta but do not alter the behavior of its predator Chrysoperla externa.
Plants express inducible direct and indirect defenses in response to herbivory. The plant hormone jasmonic acid (JA) and related signaling compounds referred to as jasmonates play a central role in regulating defense responses to a wide range of herbivores.We assessed whether treating tomato seeds with 0.8 mM of methyl jasmonate (MeJA) affected the performance of the leaf miner Tuta absoluta, and whether possible changes in volatile profiles altered the behavior of its predator Chrysoperla externa. MeJA-treatment significantly lengthened larval development and decreased the pupal weight of T. absoluta. Herbivory alone increased the emissions of α-pinene, 6-methyl 5-hepten-2-one, β-myrcene, (E)-β-ocimene, isoterpinolene, TMTT, (Z)-3-hexenyl butyrate, and hexyl salicylate. MeJA seed treatment significantly decreased the emissions of α-cubebene from undamaged and herbivore-infested plants. In addition, the emissions of several compounds were lower in the absence of herbivory. Chrysoperla. externa preferred odors from herbivore-infested plants over those from control plants, regardless of the MeJA-treatment, and they did not show any preference for herbivore-infested plants for any of the MeJA-treatments. Our results show preliminary evidence that the treatment of tomato seeds with MeJA can reduce the performance of Tuta absoluta, and that the chemical differences observed in plant VOC profiles do not alter the behavior of the model predator.


Association Between Delays in Radiography and Surgery With Hip Fracture Outcomes in Elderly Patients.
Appropriate waiting time for hip fracture surgery is disputed. The American Academy of Orthopaedic Surgeons recommends surgery within 48 hours of presentation, although evidence suggests that earlier surgery (within 24 hours) reduces the risks of complications and death. The authors asked: (1) Do patients who receive earlier radiographic evaluation of hip fracture undergo surgery earlier? and (2) Is "surgery delay" (time from presentation to surgery) associated with postoperative opioid use, duration of hospital stay, and 30-day and 1-year mortality rates? The authors identified 511 adults 60 years or older who were admitted to their emergency department with hip fractures from 2015 through 2017. Patients were divided into 6 cohorts according to length of surgery delay and 3 cohorts according to length of radiography delay (time from presentation to first hip radiograph). The authors found that medium radiography delay (>2 to 4 hours) was associated with an additional 11 hours of surgery delay compared with short radiography delay (≤2 hours; P=.026). Longer surgery delay (>12 hours) was associated with use of 9.6 more morphine equivalents (95% confidence interval, 0.7 to 8.6) during the first 24 hours postoperatively compared with shorter surgery delay (≤12 hours). Surgery delay of greater than 36 hours was an independent risk factor for longer hospital stay (odds ratio, 2.8; 95% confidence interval, 1.7 to 4.8). Thirty-day and 1-year mortality rates were significantly higher among patients who experienced a surgery delay of greater than 36 hours compared with those who experienced a surgery delay of 36 hours or less. [Orthopedics. 2020;43(6):e609-e615.].


Anisotropic nano-column arrays of bismuth and its conductivity.
Anisotropic nanostructures are becoming more and more attractive due to their unique properties different from isotropic nanostructures. However, previous most of studies are limited to high melting point materials with poor crystalline, which has confined their extended applications. In this work, we successfully prepared the anisotropic nano-column arrays of bismuth (melting point: 271.3 degrees C) with improved crystallinity by glancing angle deposition. The anisotropic conductivity of the products is investigated, and its origin is ascribed to the anisotropic scattering of the carriers in the boundary layer. Our work is not only helpful to understand the anisotropic nanostructures fabricated by glancing angle deposition on both their growth and properties, as well as provides an approachable route for constructing functional devices based on Bi and its anisotropic nanostructures.


Glycogen synthase kinase-3 beta inhibitors as novel cancer treatments and modulators of antitumor immune responses.
As a kinase at the crossroads of numerous metabolic and cell growth signaling pathways, glycogen synthase kinase-3 beta (GSK-3β) is a highly desirable therapeutic target in cancer. Despite its involvement in pathways associated with the pathogenesis of several malignancies, no selective GSK-3β inhibitor has been approved for the treatment of cancer. The regulatory role of GSK-3β in apoptosis, cell cycle, DNA repair, tumor growth, invasion, and metastasis reflects the therapeutic relevance of this target and provides the rationale for drug combinations. Emerging data on GSK-3β as a mediator of anticancer immune response also highlight the potential clinical applications of novel selective GSK-3β inhibitors that are entering clinical studies. This manuscript reviews the preclinical and early clinical results with GSK-3β inhibitors and delineates the developmental therapeutics landscape for this potentially important target in cancer therapy.


BLT humanized mice as model to study HIV vaginal transmission.
The majority of human immunodeficiency virus type 1 (HIV-1) infections occur by sexual exposure, and vaginal transmission accounts for more than half of all newly acquired infections. Studies of vaginal transmission of simian immunodeficiency virus to nonhuman primates (NHPs) have suggested an important role for immune cell trafficking in the establishment of infection as well is in the process of viral dissemination. However, NHP models do not permit the study of HIV transmission and dissemination. The improvement of humanized mouse models with robust human immune cell reconstitution of the female genital tract renders these mice susceptible to intravaginal HIV infection. Thus humanized mouse models of HIV vaginal infection will allow the study of the mechanisms involved in HIV transmission and dissemination in vivo.


Ki-67 and bromodeoxyuridine labeling of human choroidal melanoma cells.
Understanding tumor growth patterns has implications for prognosis as well as for response and susceptibility to treatment. The antibody Ki-67 was used as a marker of cycling cells and bromodeoxyuridine (BrdUrd) was used as a marker of proliferating cells to characterize the cycling and proliferative rates of cells from human choroidal melanoma. The BrdUrd labeling indices varied from 0-1.1% and the Ki-67 labeling indices ranged from 0-3.0.3%. Linear regression modeling showed good correlation defined by the equation: Ki-67 index = 0.237 + 1.63 x BrdUrd labeling index with r = 0.919. Correlations between these indices and clinical and histologic parameters were not significant.


Severe anaphylactic reaction to ibuprofen in a child with recurrent urticaria.
An acute anaphylactic reaction after a conventional antipyretic dose of ibuprofen was diagnosed in a child with allergic rhinitis, recurrent idiopathic urticaria, and nonimmunologic cross-reactive hypersensitivity to nonsteroidal antiinflammatory drugs and acetaminophen. The patient reported several previous, mild (isolated cutaneous) hypersensitivity reactions after exposure to acetaminophen or ibuprofen. There was no evidence of an underlying inflammatory disease except as described above. Patients with chronic or recurrent idiopathic urticaria and those with atopic disease represent groups at increased risk of nonsteroidal antiinflammatory drug hypersensitivity. Mild hypersensitivity reactions to acetaminophen and/or ibuprofen may precede subsequent, more-severe adverse reactions. Risks and benefits of continued use of nonsteroidal antiinflammatory drugs in these children should be carefully considered.


Photodynamic Therapy Targeting Macrophages Using IRDye700DX-Liposomes Decreases Experimental Arthritis Development.
Macrophages play a crucial role in the initiation and progression of rheumatoid arthritis (RA). Liposomes can be used to deliver therapeutics to macrophages by exploiting their phagocytic ability. However, since macrophages serve as the immune system's first responders, it is inadvisable to systemically deplete these cells. By loading the liposomes with the photosensitizer IRDye700DX, we have developed and tested a novel way to perform photodynamic therapy (PDT) on macrophages in inflamed joints. PEGylated liposomes were created using the film method and post-inserted with micelles containing IRDye700DX. For radiolabeling, a chelator was also incorporated. RAW 264.7 cells were incubated with liposomes with or without IRDye700DX and exposed to 689 nm light. Viability was determined using CellTiterGlo. Subsequently, biodistribution and PDT studies were performed on mice with collagen-induced arthritis (CIA). PDT using IRDye700DX-loaded liposomes efficiently induced cell death in vitro, whilst no cell death was observed using the control liposomes. Biodistribution of the two compounds in CIA mice was comparable with excellent correlation of the uptake with macroscopic and microscopic arthritis scores. Treatment with 700DX-loaded liposomes significantly delayed arthritis development. Here we have shown the proof-of-principle of performing PDT in arthritic joints using IRDye700DX-loaded liposomes, allowing locoregional treatment of arthritis.


Chemical profiling with modeling differentiates wild and farm-raised salmon.
Classifications of fish production methods, wild or farm-raised salmon, by elemental profiles or C and N stable isotope ratios combined with various modeling approaches were determined. Elemental analysis (As, Ba, Be, Ca, Co, Cd, Cr, Cu, Fe, K, Mg, Mn, Na, Ni, P, Pb, Sr, Ti, and Zn) of wild and farm-raised salmon samples was performed using an inductively coupled plasma atomic emission spectroscopy. Isotopic and compositional analyses of carbon and nitrogen were performed using mass spectrometry as an alternative fingerprinting technique. Each salmon (king salmon, Oncorhynchus tshawytscha ; coho salmon, Oncorhynchus kisutch ; Atlantic salmon, Salmo salar ) was analyzed from two food production practices, wild and farm raised. Principal component analysis (PCA) and canonical discriminant analysis (CDA) were used for data exploration and visualization. Five classification modeling approaches were investigated: linear discriminate function, quadratic discriminant function, neural network, probabilistic neural network, and neural network bagging. Methods for evaluating model reliability included four strategies: resubstitution, cross-validation, and two very different test set scenarios. Generally speaking, the models performed well, with the percentage of samples classified correctly depending on the particular choice of model and evaluation method used.


Atypical hemodynamic manifestations of cardiac tamponade.
Clinical examination and transthoracic echocardiography play a vital role in the management of patients with pericardial effusion and cardiac tamponade physiology. We report patients in advanced phase 3 cardiac tamponade with variant clinical and hemodynamic presentations. These atypical cardiac tamponade cases include: A patient with severe aortic valve regurgitation who lacked pulsus paradoxus; a patient with systemic sclerosis without hypotension; and a patient with pulmonary hypertension lacking right heart collapse on echocardiography. Recognition of these atypical clinical and hemodynamic manifestations of cardiac tamponade will avoid undue delay in the treatment.


Variants in the APOA5 gene region and the response to combination therapy with statins and fenofibric acid in a randomized clinical trial of individuals with mixed dyslipidemia.
Atherogenic dyslipidemia is highly associated with coronary heart disease and is characterized by elevated triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C), and elevated low-density lipoprotein cholesterol (LDL-C). The combination of statins and fibrates is a common modality to treat individuals with atherogenic dyslipidemia. We sought to identify single nucleotide polymorphisms (SNPs) associated with HDL-C, TG, and apolipoprotein A1 (ApoA-I) response to combination therapy with statins and fenofibric acid (FA) in individuals with atherogenic dyslipidemia. 2228 individuals with mixed dyslipidemia who were participating in a multicenter, randomized, double-blind, active-controlled study comparing FA alone, in combination with a statin, or statin alone for a 12-week period, were genotyped for 304 candidate SNPs. A multivariate linear regression analysis for percent change in HDL-C, ApoA-I and TG levels was performed. SNPs in the apolipoprotein (APO) A5-ZNF259 region rs3741298 (P = 1.8 × 10(-7)), rs964184 (P = 3.6 × 10(-6)), rs651821 (P = 4.5 × 10(-5)), and rs10750097 (P = 1 × 10(-4)), were significantly associated with HDL-C response to combination therapy with statins and FA, with a similar association identified for ApoA-I. A haplotype composed of the minor alleles of SNPs rs3741298, rs964184, and rs10750097, was associated with a positive response to statins and FA (P = 8.7 × 10(-7)) and had a frequency of 18% in the study population. In a population with atherogenic dyslipidemia, common SNPs and haplotypes within the APOA5-ZNF259 region are highly associated with HDL-C and ApoA-I response to combination therapy with statins and FA.


Is it useful to measure supratentorial ICP in the presence of a posterior fossa lesion? Absence of transtentorial pressure gradients in an animal model.
Previous studies with animal models of supratentorial ICP elevation have demonstrated a pressure gradient between the supratentorial and the infratentorial compartments. The present study was designed to investigate the possible presence of such a gradient in the case of infratentorial ICP elevation. An inflatable infratentorial balloon catheter was implanted in seven domestic pigs. The infratentorial ICP (ICPi) was measured in the left cerebellar hemisphere, and the supratentorial ICP (ICPs) was measured in the left cerebral hemisphere. The corresponding pulse amplitudes (ICPi-PA, ICPs-PA) were recorded in both compartments, and the cerebral perfusion pressure (CPP) was calculated. ICPi and ICPs values prior to balloon inflation were 4.4 (SD 2.2) and 4.1 (SD 2.3) mm Hg, respectively, and increased to 63.1 (SD 32.6) and 62.3 (SD 28.1) mmHg after balloon inflation. ICPi-PA rose from 3.1 (SD 0.43) to 12.8 (SD 8.0) mmHg, and ICPs-PA rose from 3.2 (SD 0.63) to 13.0 (SD 7.1) mmHg. CPP decreased from 86.1 (SD 12.0) to 55.4 (SD 14.6) mm Hg. The paired difference between ICPi and ICPs values was 0.44 (SD 1.96) mmHg, and the paired difference of ICP amplitudes was 0.03 (SD 1.19) mmHg. All these differences in infratentorial and supratentorial values were statistically not significant. In conclusion, infratentorial ICP elevation in the presented pig model leads to a uniform ICP elevation in the intracranial space without development of a considerable pressure gradient below and above the tentorium. In the low pressure part of the ICP curve, cerebrospinal fluid connects the compartments and contributes to the pressure equilibrium. The early obstruction of the foramen magnum by intruding cerebellar tissue seems to isolate the infratentorial from the spinal compartment. In the high-pressure part of the curve, the upwards cerebellar transtentorial herniation takes over the pressure transfer, and the whole intracranial space can be considered as a single compartment in the pig.


Shoulder movements during quadrupedal locomotion in arboreal primates.
The kinematics of scapula and shoulder joint movements were analyzed in three species of arboreal quadrupedal primates using cineradiography. Our findings indicate that scapular movement is highly important for forelimb movement in primates with this ancestral mode of locomotion. Retroversion of the scapula (syn. caudal rotation or extension) during the stance phase contributes more than 40% to the stride length of the forelimb. Lateral forelimb excursions, a general feature for arboreal primates, are based on complex three-dimensional scapular movements guided by the clavicle. Humeral abduction is achieved by scapular abduction and transversal rotation of the scapula about its longitudinal axis, and is therefore strikingly different from humeral abduction in humans. At the same time, the movements of the shoulder joint are limited to flexion and extension only.


Molecular cloning and tissue distribution of keratocan. Bovine corneal keratan sulfate proteoglycan 37A.
Previous studies showed that the keratan sulfate-containing proteoglycans of bovine corneal stroma contain three unique core proteins designated 37A, 37B, and 25 (Funderburgh, J. L., Funderburgh, M. L., Mann, M. M., and Conrad, G. W. (1991) J. Biol. Chem. 266, 14226-14231). Degenerate oligonucleotides designed from amino acid sequences of the 37A protein were used to screen a cDNA expression library from cultured bovine keratocytes. A cDNA clone coding for keratocan, a 37A protein, was isolated and sequenced. The deduced keratocan amino acid sequence is unique but related to two other keratan sulfate-containing proteins, lumican (the 37B core protein) and fibromodulin. These three proteins share approximately 35% amino acid identity and a number of conserved structural features. Northern hybridization and immunoblotting of tissue extracts found keratocan distribution to be more limited than that of lumican or fibromodulin. Keratocan is abundant in cornea and sclera and detected in much lesser amounts in skin, ligament, cartilage, artery, and striated muscles. Only in cornea was keratocan found to contain large, sulfated keratan sulfate chains. Keratocan, like lumican, is a core protein of a major corneal proteoglycan but is present in non-corneal tissues primarily as a nonsulfated glycoprotein.


Inequalities in reported cancer patient experience by socio-demographic characteristic and cancer site: evidence from respondents to the English Cancer Patient Experience Survey.
Patient experience is a critical dimension of cancer care quality. Understanding variation in experience among patients with different cancers and characteristics is an important first step for designing targeted improvement interventions. We analysed data from the 2011/2012 English Cancer Patient Experience Survey (n = 69,086) using logistic regression to explore inequalities in care experience across 64 survey questions. We additionally calculated a summary measure of variation in patient experience by cancer, and explored inequalities between patients with cancers treated by the same specialist teams. We found that younger and very old, ethnic minority patients and women consistently reported worse experiences across questions. Patients with small intestine/rarer lower gastrointestinal, multiple myeloma and hepatobiliary cancers were most likely to report negative experiences whereas patients with breast, melanoma and testicular cancer were least likely (top-to-bottom odds ratio = 1.91, P < 0.0001). There were also inequalities in experience among patients with cancers treated by the same specialty for five of nine services (P < 0.0001). Specifically, patients with ovarian, multiple myeloma, anal, hepatobiliary and renal cancer reported notably worse experiences than patients with other gynaecological, haematological, gastrointestinal and urological malignancies respectively. Initiatives to improve cancer patient experience across oncology services may be suitably targeted on patients at higher risk of poorer experience.


Global cerebral dysplasia due to dysplasia and hyperplasia of periventricular germinal cells.
Complete obliteration of the cerebral ventricular cavities has not been previously described as an entity among central nervous system malformations. Markedly disorganized maldevelopment of the deep cerebral nuclei and moderately disorganized maldevelopment of the cerebral cortex were observed in the brains of two cases, a 3-year-old female and a male newborn infant. One showed complete and the other partial obliteration of the lateral and third ventricles. Both showed severe maldevelopment of the basal ganglia, which were represented by a large central mass consisting of randomly distributed multiple nodules of gray matter without any discernible differentiation into lenticulostriate nuclei, thalamus, or hypothalamus. Minor malformations involved the cerebral cortex, cerebellum, and mesencephalon to varying degrees. Each of the above two cases was thought to be unique and different until the brain of a fetus of 155 days' gestation was studied. This fetal brain showed exuberant and disorganized periventricular proliferation and migration of germinal matrix cells, with obliteration of the lateral and third ventricles. It was concluded that hyperplasia and disorganized migration of the periventricular germinal matrix early in gestation of whatever cause itself can result in severe maldevelopment of the deep cerebral nuclei and obliteration of the ventricular cavities.


[Treatment of Crohn disease].
Crohn's disease is a chronic inflammatory disease of the bowel for which there is no curative treatment. The purpose of treatment is to reduce mortality to the absolute minimum and to give the patients a normal quality of life. Acute episodes of low severity are treated with sulfasalazine and its most recent derivatives such as 5-aminosalicylate. More severe episodes require oral corticosteroid therapy which, when prescribed in adequate doses, results in clinical remission in over 90% of the cases. To this must be added parenteral nutrition in patients with very severe symptoms or when a major nutritional deficit is present. During remissions, a maintenance treatment with 5-aminosalicylate or azathioprine is justified when the acute episodes are frequent and/or severe. These continuous chronic forms require prolonged low-dose corticosteroid therapy or azathioprine. Artificial nutrition is the best way of treating corticosteroid-resistant episodes. In children, corticosteroids must be avoided as much as possible, and low-flow rate enteral nutrition is often used as primary treatment of salicylate-resistant episodes. The surgical treatment of Crohn's disease consists of resection of the lesions with anastomosis or ileostomy in case of total proctocolectomy. Following resection-anastomosis, the cumulative relapse rate is about 50% ten years after surgery; it is lower after colostomy and proctocolectomy. Surgery is indicated in case of complications (abscesses, stenosis, fistulae, perforation) and when the disease does not respond to a well-conducted medical treatment. Specialized teams including physicians, surgeons, proctologists and specialists in nutrition are essential to a correct treatment of Crohn's disease.


Development and randomized trial evaluation of a novel computer-delivered anxiety sensitivity intervention.
Anxiety disorders contribute substantially to the overall public health burden of psychopathology. Anxiety sensitivity (AS), a fear of anxiety related sensations, is one of the few known malleable risk factors for anxiety pathology. Previous AS reduction treatments have utilized highly trained clinicians. A completely-computerized AS treatment would reduce costs and increase dissemination possibilities. Cognitive bias modification for interpretation biases (CBM-I) interventions have shown clinically significant reductions in anxiety symptoms. Another emerging literature focused on learning has shown context-shifting tasks can greatly increase learning without adding logistical burden to an intervention. The current study evaluated a CBM-I for AS that utilized a context-shifting task to deliver twice the treatment dose of extant interventions. Single-site randomized controlled trial. Participants completed an intervention appointment, as well as one-week and one-month follow-up assessments. Individuals with elevated levels of AS. Single-session computer-delivered CBM-I for AS. Results indicate that the CBM-I for AS was successful in reducing overall AS (62% post-intervention) and these reductions were maintained through one-month post-intervention (64%). Results also revealed that individuals in the active condition reported significantly less incidents of panic responding to a physiological straw-breathing challenge and that change in interpretation bias significantly mediated the relationship between treatment condition and post-treatment AS reductions. Taken together, the results show that the current CBM-I intervention was strong in terms of immediate and one-month AS reductions. Given its brevity, low cost, low stigma and portability, this intervention could have substantial impact on reducing the burden of anxiety disorders.


Intracellular pH of Cotton Embryos and Seed Coats during Fruit Development Determined by P Nuclear Magnetic Resonance Spectroscopy.
The pH of the phosphate-containing compartments of developing cotton seed coat and embryo tissues was determined by means of (31)P nuclear magnetic resonance spectroscopy. The pH values of these tissues varied as a function of developmental age. From 27 to approximately 38 days postanthesis, a strong pH differential existed between the two tissues; the seed coat was up to 1.4 pH units more acid than developing cotton embryos. The pattern of pH values found with this technique agrees with pH values of tissue homogenates in distilled water. The results confirm an earlier suggestion that seed coat cells are more acidic than embryo cells during key developmental stages of the seed. The pH differential between these two tissues causes abscisic acid to diffuse from seed coats to embryos against its apparent concentration gradient to prevent viviparous germination, despite a higher abscisic acid concentration in the embryo.


Mixed-phenotypic acute leukemia series from tertiary care center.
Mixed-phenotype acute leukemias (MPALs) are a heterogeneous group of rare leukemias constituting approximately 2%-5% of all leukemias, in which assigning a single lineage of origin is not possible. They are diagnosed by either the presence of antigens of more than one lineage or by the presence of dual population of blasts belonging to two or more lineages. We highlight the clinicopathological, immunophenotype, and genetic data of a cohort (n = 14) of patients diagnosed and treated at our center. We retrospectively analyzed consecutive cases of MPAL diagnosed in our flow cytometry laboratory from May 2012 to August 2015. These cases were diagnosed based on immunophenotyping of peripheral blood/bone marrow aspirates and morphology/genetics wherever available as per the World Health Organization (WHO) 2008 guideline. Among 628 consecutive acute leukemia (AL) cases diagnosed and evaluated during this period, we identified 14 (2.2%) patients with MPAL fulfilling WHO 2008/EGIL criteria for immunological characterizing of AL criteria. Majority of these were males (n = 8, male:female ratio 1.3:1) and adults (n = 11, 78.5%). The median age of this cohort was 41 years (range 2-80). These cases were further classified as: B/myeloid (n = 9), T/myeloid (n = 4), and B/T MPAL (n = 1). Cytogenetics was available in 12 out of 14 cases, out of which, three cases had normal karyotype, three with t(9;22)(q34;q11), and two cases with complex karyotype. We also came across a rare case of B + T lymphoid MPAL who had mixed-lineage leukemia gene t(v; 11q23) rearrangement. MPAL is a complex entity with heterogeneous clinical, immunophenotypic, cytogenetic, and molecular features. Multiparametric flowcytometry by using comprehensive antibody panels is a valuable tool for diagnosis. Subsequent cytogenetic and molecular analysis for further prognostic stratification and treatment modalities are important.


Enantioselective Aryl-Iodide-Catalyzed Wagner-Meerwein Rearrangements.
We report a strategy for effecting catalytic, enantioselective carbocationic rearrangements through the intermediacy of alkyl iodanes as stereodefined carbocation equivalents. Asymmetric Wagner-Meerwein rearrangements of β-substituted styrenes are catalyzed by the C2-symmetric aryl iodide 1 to provide access to enantioenriched 1,3-difluorinated molecules possessing interesting and well-defined conformational properties. Hammett and kinetic isotope effect studies, in combination with computational investigations, reveal that two different mechanisms are operative in these rearrangement reactions, with the pathway depending on the identity of the migrating group. In reactions involving alkyl-group migration, intermolecular fluoride attack is product- and enantio-determining. In contrast, reactions in which aryl rearrangement occurs proceed through an enantiodetermining intramolecular 1,2-migration prior to fluorination. The fact that both pathways are promoted by the same chiral aryl iodide catalyst with high enantioselectivity provides a compelling illustration of generality across reaction mechanisms in asymmetric catalysis.


A Non-Linear Association of Triglyceride Glycemic Index With Cardiovascular and All-Cause Mortality Among Patients With Hypertension.
To investigate the association between insulin resistance (IR), quantified by triglyceride glycemic index (TyG index), cardiovascular mortality (CVM), and all-cause mortality (ACM) in hypertension patients. We included 8,554 patients with hypertension aged ≥18 years old from the 1999-2014 National Health and Nutrition Examination Surveys (NHANES). The status of CVM and ACM of participants were followed through December 31, 2015. Cox proportional hazards models and Kaplan-Meier survival curves were used to evaluate the relationship between TyG index, CVM, and ACM. During a median of 82 months follow-up, 1,882 mortality cases had occurred, 434 of which were due to cardiovascular disease. The patients with hypertension with TyG ≥ 10 were older, had a higher chance of being smokers, were obese, had higher blood pressure, and had risk or had cardiovascular disease. In Cox proportional hazards models, compared with the patients with TyG <8, those with TyG ≥ 10 had 56% increased risk for ACM. On the other hand, no significant difference for CVM between the four groups were observed. In the restricted cubic spline regression models, the relationship between TyG index and ACM was non-linear. Subgroup analysis showed non-linear relationship between TyG index and ACM in elderly patients aged ≥60 years. The cut-off value of TyG for ACM was 9.45, and those with higher or lower than 9.45 had more risk of ACM. When TyG index was more than 9.52, the risk for CVM would increase among the whole group. Kaplan-Meier survival curves showed patients with TyG ≥ 10 had higher risk of ACM and CVM (Log rank P < 0.05). We demonstrated that the association between ACM and TyG index in elderly patients with hypertension aged ≥60 years was non-linear. However, TyG index was only more than 9.52, hence, the risk for CVM would increase among the whole hypertension group.


[Vulnerability to schizophrenia: neuropsychological performance and schizotypal personality traits].
Although some neuropsychological deficits and a high rate of schizotypal personality disorders have been found in the first-degree relatives of patients with schizophrenia, few studies have looked for a link between those two types of potential marker of vulnerability to this disease. The aims of this study were: 1) to confirm some executive/attentional deficits in a group of first-degree relatives including not only siblings but also parents; 2) to evaluate the schizotypal traits using the French version of 4 self-reporting scales proposed by Chapman and his colleagues; 3) to look for a dependence or independence between the neuropsychological performance and the scores on the scales of schizotypy. Twenty four patients with schizophrenia, 48 of their first-degree relatives and 31 controls were included in the study. Both attentional tests (a Digit Symbol Substitution Test and a Degraded Stimulus-Continuous Performance Test) confirmed a worse performance in the patient and in the first-degree relative groups than in the control group. On the opposite side, the executive performance assessed by the Wisconsin Sorting Card Test, was poorer in the patient group only. Scores of the first-degree relative group on the social anhedonia, physical anhedonia and perceptual aberrations scales were at an intermediate level between those of the patient and control groups; moreover, only scores on the social anhedonia scale tended to be significantly higher in the first-degree relative group than in the control group. Among the first-degree relative group, the only significant correlation found was between the number of perseverative errors on the WCST and the scores on the physical anhedonia scale.


S224 Presents a Catalytic Trade-off in PLP-Dependent l-Lanthionine Synthase from Fusobacterium nucleatum.
Lanthionine synthase from the oral bacterium Fusobacterium nucleatum is a fold type II pyridoxal-5'-phosphate (PLP)-dependent enzyme that catalyzes the β-replacement of l-cysteine by a second molecule of l-cysteine to form H2S and l-lanthionine. The meso-isomer of the latter product is incorporated into the F. nucleatum peptidoglycan layer. Herein, we investigated the catalytic role of S224, which engages in hydrogen-bond contact with the terminal carboxylate of l-lanthionine in the closed conformation of the enzyme. Unexpectedly, the S224A variant elicited a 7-fold increase in the turnover rate for H2S and lanthionine formation and a 70-fold faster rate constant for the formation of the α-aminoacrylate intermediate compared to the wild-type enzyme. Presteady state kinetic analysis further showed that the reaction between S224A and l-cysteine leads to the formation of the more reactive ketoenamine tautomer of the α-aminoacrylate. The α-aminoacrylate with the protonated Schiff base is not an observable intermediate in the analogous reaction with the wild type, which may account for its attenuated kinetic properties. However, the S224A substitution is detrimental to other aspects of the catalytic cycle; it facilitates the α,β-elimination of l-lanthionine, and it weakens the enzyme's catalytic preference for the formation of l-lanthionine over that of l-cystathionine.


Congenital Afibrinogenemia and Hypofibrinogenemia: Laboratory and Genetic Testing in Rare Bleeding Disorders with Life-Threatening Clinical Manifestations and Challenging Management.
Congenital fibrinogen disorders are rare pathologies of the hemostasis, comprising quantitative (afibrinogenemia, hypofibrinogenemia) and qualitative (dysfibrinogenemia and hypodysfibrinogenemia) disorders. The clinical phenotype is highly heterogeneous, being associated with bleeding, thrombosis, or absence of symptoms. Afibrinogenemia and hypofibrinogenemia are the consequence of mutations in the homozygous, heterozygous, or compound heterozygous state in one of three genes encoding the fibrinogen chains, which can affect the synthesis, assembly, intracellular processing, stability, or secretion of fibrinogen. In addition to standard coagulation tests depending on the formation of fibrin, diagnostics also includes global coagulation assays, which are effective in monitoring the management of replacement therapy. Genetic testing is a key point for confirming the clinical diagnosis. The identification of the precise genetic mutations of congenital fibrinogen disorders is of value to permit early testing of other at risk persons and better understand the correlation between clinical phenotype and genotype. Management of patients with afibrinogenemia is particularly challenging since there are no data from evidence-based medicine studies. Fibrinogen concentrate is used to treat bleeding, whereas for the treatment of thrombotic complications, administered low-molecular-weight heparin is most often. This review deals with updated information about afibrinogenemia and hypofibrinogenemia, contributing to the early diagnosis and effective treatment of these disorders.


Influence of Gating System Parameters of Die-Cast Molds on Properties of Al-Si Castings.
The resulting quality of castings indicates the correlation of the design of the mold inlet system and the setting of technological parameters of casting. In this study, the influence of design solutions of the inlet system in a pressure mold on the properties of Al-Si castings was analyzed by computer modelling and subsequently verified experimentally. In the process of computer simulation, the design solutions of the inlet system, the mode of filling the mold depending on the formation of the casting and the homogeneity of the casting represented by the formation of shrinkages were assessed. In the experimental part, homogeneity was monitored by X-ray analysis by evaluating the integrity of the casting and the presence of pores. Mechanical properties such as permanent deformation and surface hardness of castings were determined experimentally, depending on the height of the inlet notch. The height of the inlet notch has been shown to be a key factor, significantly influencing the properties of the die-cast parts and influencing the speed and filling mode of the mold cavity. At the same time, a significant correlation between porosity and mechanical properties of castings is demonstrated. With the increasing share of porosity, the values of permanent deformation of castings increased. It is shown that the surface hardness of castings does not depend on the integrity of the castings but on the degree of subcooling of the melt in contact with the mold and the formation of a fine-grained structure in the peripheral zones of the casting.


Using Gene Expression to Study Specialized Metabolism-A Practical Guide.
Plants produce a vast array of chemical compounds that we use as medicines and flavors, but these compounds' biosynthetic pathways are still poorly understood. This paucity precludes us from modifying, improving, and mass-producing these specialized metabolites in suitable bioreactors. Many of the specialized metabolites are expressed in a narrow range of organs, tissues, and cell types, suggesting a tight regulation of the responsible biosynthetic pathways. Fortunately, with unprecedented ease of generating gene expression data and with >200,000 publicly available RNA sequencing samples, we are now able to study the expression of genes from hundreds of plant species. This review demonstrates how gene expression can elucidate the biosynthetic pathways by mining organ-specific genes, gene expression clusters, and applying various types of co-expression analyses. To empower biologists to perform these analyses, we showcase these analyses using recently published, user-friendly tools. Finally, we analyze the performance of co-expression networks and show that they are a valuable addition to elucidating multiple the biosynthetic pathways of specialized metabolism.


Controversies in the treatment of pediatric immune thrombocytopenias.
Although pediatric immune thrombocytopenia (ITP) is common, there is no consensus on the optimal approach to therapy. Childhood ITP differs in its clinical course and trigger from adult immune thrombocytopenic purpura. There appear to be two clinical phenotypes among children with ITP: children with polyclonal autoantibody production triggered by an external exposure such as infection, and children with coexistent immune deficiency or dysregulation on a congenital or acquired basis. Treatment implications exist for each group. The first may be best managed by observation and conservative measures; for the latter, treatment could include normal intravenous gammaglobulin concentrate, anti-blood group D antigen (anti-Rh factor), or steroids. Early recognition of the thrombocytopenic child with immune dysfunction versus the normal child with a polyclonal response to a particular environmental antigen will result in better prognosis for both by selecting the appropriate therapy and minimizing long-term side effects.


Synthetic Optimization and MAPK Pathway Activation Anticancer Mechanism of Polyisoprenylated Cysteinyl Amide Inhibitors.
Abnormalities of the MAPK pathway play vital roles in cancer initiation and progression. RAS GTPases that are key upstream mediators of the pathway are mutated in 30% of human cancers. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) were designed as potential targeted therapies against the RAS-driven cancers. The current study reports on the optimization of the PCAIs and the determination of their mechanisms of action in KRAS-mutant cancer cells. They display ClogP values ranging from 3.01 to 6.35, suppressing the viabilities of KRAS-mutant MDA-MB-231, A549, MIA PaCa-2, and NCI-H1299 cells in 2D and 3D cultures with EC50 values of 2.2 to 6.8, 2.2 to 7.6, 2.3 to 6.5 and 5.0 to 14 µM, respectively. When A549 cells were treated with the PCAIs, NSL-YHJ-2-27, for 48 h, no significant difference was observed in the levels of total or phosphorylated B- and C-Raf proteins. However, at 5 µM, it stimulated the phosphorylation of MEK1/2, ERK1/2, and p90RSK by 84%, 59%, and 160%, respectively, relative to controls. A non-farnesylated analog, NSL-YHJ-2-62, did not elicit similar effects. These data reveal that effects on the RAS-MAPK signaling axis most likely contribute to the anticancer effects of the PCAIs, possibly through the proapoptotic isoforms of p90RSK. The PCAIs may thus have the potential to serve the unmet therapeutic needs of patients with aberrant hyperactive G-protein signaling.


Plasmonic imaging and detection of single DNA molecules.
The capability of imaging and detecting single DNA molecules is critical in the study, analysis, and applications of DNA. Fluorescence imaging is a widely used method, but it suffers from blinking and photobleaching, and fluorescence tags may block or affect binding sites on DNA. We report on label-free imaging of single DNA molecules with a differential plasmonic imaging technique. The technique produces high contrast images due to the scattering of surface plasmonic waves by the molecules and the removal of background noises and interference patterns, allowing for quantitative analysis of individual DNA molecules. Simulation of the images based on a scattering model shows good agreement with the experiment. We further demonstrate optical mapping of single DNA molecules.


Modification of a mechanical twist drill trephine for craniostomy in trauma patients.
A commercially available mechanical twist drill system was modified and evaluated in 35 craniotomies for frontal ventriculostomy in 31 trauma patients. The modified mechanical twist drill enabled faster and seemingly easier and safer craniotomy. It can be used as a safer alternative to common mechanical twist drill trephines, and is particularly recommended in difficult emergency conditions.


Thyroid function and survival following breast cancer.
Thyroid function has been associated with breast cancer risk, and breast cancer cell growth and proliferation. It is not clear whether thyroid function affects prognosis following breast cancer but, if so, this could have an important clinical impact. The present study analysed prospectively collected measurements of free tri-iodothyronine (T3), free thyroxine (T4), thyroid-stimulating hormone (TSH) and thyroid peroxidase antibodies (TPO-Ab) in relation to breast cancer survival. The Malmö Diet and Cancer Study is a prospective cohort study of 17 035 women in Sweden. Study enrolment was conducted between 1991 and 1996. Patients with incident breast cancer were identified through record linkage with cancer registries until 31 December 2006. Information on vital status was collected from the Swedish Cause of Death Registry, with the endpoint breast cancer mortality (31 December 2013). Hazard ratios (HRs) with 95 per cent confidence intervals (c.i.) were obtained by Cox proportional hazards analysis. Some 766 patients with incident breast cancer were identified, of whom 551 were eligible for analysis. Compared with patients in the first free T4 tertile, breast cancer mortality was lower among those in the second tertile (HR 0·49, 95 per cent c.i. 0·28 to 0·84). There was an indication, although non-significant, of lower breast cancer mortality among patients in the second TSH tertile (HR 0·63, 0·37 to 1·09) and in those with positive TPO-Ab status (HR 0·61, 0·30 to 1·23). Free T3 showed no clear association with mortality. In the present study, there was a positive association between free T4 levels and improved breast cancer survival.


Electrochemical DNA Sensor Based on Acridine Yellow Adsorbed on Glassy Carbon Electrode.
Electrochemical DNA sensors offer unique opportunities for the sensitive detection of specific DNA interactions. In this work, a voltametric DNA sensor is proposed on the base of glassy carbon electrode modified with carbon black, adsorbed acridine yellow and DNA for highly sensitive determination of doxorubicin antitumor drug. The signal recorded by cyclic voltammetry was attributed to irreversible oxidation of the dye. Its value was altered by aggregation of the hydrophobic dye molecules on the carbon black particles. DNA molecules promote disaggregation of the dye and increased the signal. This effect was partially suppressed by doxorubicin compensate for the charge of DNA in the intercalation. Sensitivity of the signal toward DNA and doxorubicin was additionally increased by treatment of the layer with dimethylformamide. In optimal conditions, the linear range of doxorubicin concentrations determined was 0.1 pM-1.0 nM, and the detection limit was 0.07 pM. No influence of sulfonamide medicines and plasma electrolytes on the doxorubicin determination was shown. The DNA sensor was tested on two medications (doxorubicin-TEVA and doxorubicin-LANS) and showed recoveries of 102-105%. The DNA sensor developed can find applications in the determination of drug residues in blood and for the pharmacokinetics studies.


Induction of reduced photorespiratory activity in submersed and amphibious aquatic macrophytes.
Incubation under water in a 30 C/14-hour or 12 C/10-hour photoperiod caused the CO(2) compensation points of 10 aquatic macrophytes to decrease below 25 or increase above 50 microliters CO(2) per liter, respectively. Submerged and aerial leaves of two amphibious angiosperms (Myriophyllum brasiliense and Proserpinaca palustris) maintained high compensation points when incubated in air but, when the submerged or aerial leaves of Proserpinaca were incubated under water, the compensation points dropped as low as 10. This suggests that, in addition to temperature and photoperiod, some factor associated with submergence regulates the compensation point of aquatic plants. In the high-compensation point plants, photorespiration, as a percentage of net photosynthesis, was equivalent to that in terrestrial C(3) plants. For Hydrilla verticillata, the decreasing CO(2) compensation points (110, 40, and 10) were associated with reduced photorespiration, as indicated by decreased O(2) inhibition, decreased rates of CO(2) evolution into CO(2)-free air, and increased net photosynthetic rates.The decrease in the CO(2) compensation points of Hydrilla, Egeria densa, and Cabomba caroliniana was accompanied by an increase in the activity of phosphoenolpyruvate, but not of ribulose bisphosphate, carboxylase. In Hydrilla, several C(4) enzymes also increased in activity to the following levels (micromoles per gram fresh weight per hour): pyruvate Pi dikinase (35), pyrophosphatase (716), adenylate kinase (525), NAD and NADP malate dehydrogenase (6565 and 30), NAD and NADP malic enzymes (239 and 44), and aspartate and alanine aminotransferases (357 and 85), whereas glycolate oxidase (6) and phosphoglycolate and phosphoglycerate phosphatases (76 and 32) showed no change. Glycolate dehydrogenase and phosphoenolpyruvate carboxykinase were undetectable. The reduced photorespiration in these plants may be due to increased CO(2) fixation via a C(4) acid pathway. However, for three Myriophyllum species, some other mechanism appears operative, as phosphoenolpyruvate carboxylase was not increased in the low compensation point state, and ribulose bisphosphate carboxylase remained the predominant carboxylation enzyme.


The role of interleukin-18 in the diagnosis and monitoring of hemophagocytic lymphohistiocytosis/macrophage activation syndrome - a systematic review.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, hyperinflammatory disorder, characterized by multiorgan failure, fever and cytopenias. The diagnosis of HLH and its subtype Macrophage Activation Syndrome (MAS) remains a challenge. Interleukin 18 (IL-18) is emerging as a potential biomarker for HLH/MAS but is currently not a part of diagnostic criteria. This systematic review aimed to assess the potential role of IL-18 in the diagnosis and monitoring of HLH and MAS, and was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed and Embase were searched on 30 January 2020. Studies included all subtypes of HLH and a range of underlying disorders in both children and adults. A total of 14 studies were included. Generally, serum IL-18 was elevated in both primary and secondary HLH (> 1000 pg/ml) compared with other inflammatory conditions and with healthy individuals; thus, serum IL-18 may be able to discriminate between HLH and other inflammatory conditions. Significantly increased IL-18 (> 10 000 pg/ml) was also consistently described in MAS compared with other subtypes of HLH. The ability of IL-18 to distinguish MAS from systemic juvenile idiopathic arthritis (JIA) is less unambiguous, as IL-18 levels > 100 000 pg/ml were described in sJIA patients both with and without MAS. IL-18 may help to differentiate between HLH subtypes and other inflammatory conditions. As HLH and MAS are rare disorders, only few and relatively small studies exist on the subject. Larger, prospective multi-center studies are called for to assess the diagnostic precision of IL-18 for HLH and MAS.


The FAM171A2 gene is a key regulator of progranulin expression and modifies the risk of multiple neurodegenerative diseases.
Progranulin (PGRN) is a secreted pleiotropic glycoprotein associated with the development of common neurodegenerative diseases. Understanding the pathophysiological role of PGRN may help uncover biological underpinnings. We performed a genome-wide association study to determine the genetic regulators of cerebrospinal fluid (CSF) PGRN levels. Common variants in region of FAM171A2 were associated with lower CSF PGRN levels (rs708384, P = 3.95 × 10-12). This was replicated in another independent cohort. The rs708384 was associated with increased risk of Alzheimer's disease, Parkinson's disease, and frontotemporal dementia and could modify the expression of the FAM171A2 gene. FAM171A2 was considerably expressed in the vascular endothelium and microglia, which are rich in PGRN. The in vitro study further confirmed that the rs708384 mutation up-regulated the expression of FAM171A2, which caused a decrease in the PGRN level. Collectively, genetic, molecular, and bioinformatic findings suggested that FAM171A2 is a key player in regulating PGRN production.


Diagnosing periprosthetic joint infections : a comparison of infection definitions: EBJIS 2021, ICM 2018, and IDSA 2013.
This study evaluated the definitions developed by the European Bone and Joint Infection Society (EBJIS) 2021, the International Consensus Meeting (ICM) 2018, and the Infectious Diseases Society of America (IDSA) 2013, for the diagnosis of periprosthetic joint infection (PJI). In this single-centre, retrospective analysis of prospectively collected data, patients with an indicated revision surgery after a total hip or knee arthroplasty were included between 2015 and 2020. A standardized diagnostic workup was performed, identifying the components of the EBJIS, ICM, and IDSA criteria in each patient. Of 206 included patients, 101 (49%) were diagnosed with PJI with the EBJIS definition. IDSA and ICM diagnosed 99 (48%) and 86 (42%) as infected, respectively. A total of 84 cases (41%) had an infection based on all three criteria. In 15 cases (n = 15/206; 7%), PJI was present when applying only the IDSA and EBJIS criteria. No infection was detected by one definition alone. Inconclusive diagnoses occurred more frequently with the ICM criteria (n = 30/206; 15%) compared to EBJIS (likely infections: n = 16/206; 8%) (p = 0.029). A better preoperative performance of the EBJIS definition was seen compared with the ICM and IDSA definitions (p < 0.001). The novel EBJIS definition identified all PJIs diagnosed by any other criteria. Use of the EBJIS definition significantly reduced the number of uncertain diagnoses, allowing easier clinical decision-making.Cite this article: Bone Joint Res 2022;11(9):608-618.


TOFI phenotype - its effect on the occurrence of diabetes.
Recent studies have reported a significant increase in the incidence of type 2 diabetes in the past 30 years. They also predict that this trend will continue. This is related to a change in lifestyle, which results in a parallel increase in the incidence of overweight and obesity. However, symptoms of the metabolic syndrome, so far closely related to abdominal obesity, are relatively common among people with normal body mass index (BMI) and waist circumference. The aim of the study is to present the TOFI phenotype (thin outside, fat inside) as an important factor in pathogenesis of type 2 diabetes. In the 1980s, the first study of the MONW (metabolic obese normal weight), a phenotype that is characterized by metabolic diseases in people with normal body weight. Since then, no uniform criteria have been established for MONW deployment, which has created difficulties in identifying affected individuals. Recent work has appeared describing the TOFI phenotype, which seems to lead to the appearance of MONW. People affected by this problem, in spite of undersized fatty tissue, have an increased amount of adipose tissue surrounding the internal organs, which increases the risk of insulin resistance and type 2 diabetes. In the diagnostics of the TOFI phenotype, magnetic resonance imaging is of paramount importance. Previous studies did not provide clear answers about the pathogenesis of TOFI nor which factors stimulate its development. Prophylaxis and treatment of the syndrome include increased physical activity, the promotion of correct eating habits, and a use of metformin.


The clinical spectrum of osteoarticular tuberculosis in non-human immunodeficiency virus patients in a defined area of northwestern Spain (1988-1997).
To examine the frequency and clinical manifestations of osteoarticular tuberculosis in non-human immunodeficiency virus (HIV) patients during the past 10 years in a northwestern area of Spain. The charts of all patients older than 14 years of age, not HIV-infected, and diagnosed as having osteoarticular tuberculosis at the Xeral-Calde Hospital from 1988 through 1997 were reviewed. All patients were residents of the region of Lugo. The diagnosis of osteoarticular tuberculosis was made on the basis of a positive culture for Mycobacterium tuberculosis from synovial fluid, joint tissue or paravertebral abscess or by histological findings of caseating granulomas in biopsied tissue. Thirty-two HIV-negative patients (20 men and 12 women) were diagnosed with osteoarticular tuberculosis. The average annual incidence rate of osteoarticular tuberculosis in the combined (male and female) non-HIV population > or = 15 years of age was 15.68/million (95% CI: 10.25; 21.11); males 20.02/million (95% CI: 11.25; 28.79); females 11.52/million (95% CI: 5.00; 18.03). The age at the time of diagnosis was 60.8 +/- 17.5 years. Peripheral monoarthritis was observed in 16 of the 32 cases. The knee was the most frequent site of peripheral tuberculous arthritis (31%), but involvement of the non-weight-bearing joints (50%) was also common. Spondylitis involving the lower thoracic and upper lumbar vertebrae (31%) and unilateral sacroiliitis (19%) were less commonly observed. In general, patients with osteoarticular tuberculosis had a long duration of symptoms of the disease prior to the diagnosis (median: 5.5 months). The tuberculin skin test was negative in 3 cases. Chest radiograph was abnormal in only 6 of 32 patients (19%). The ESR (mean +/- SD) at the time of diagnosis was 55.7 +/- 29.0 mm/hr. Computed tomography was very useful in detecting early involvement of the sacroiliac joints and in defining the extent of the abscesses and the severity of the involvement in patients with spondylitis. All patients received chemotherapy for tuberculosis. None of them suffered relapses of tuberculosis. Tuberculosis is a major source of osteoarticular complications in northwestern Spain. The prevailing low level of clinical suspicion may explain the long delay to the diagnosis in most patients. A greater awareness of the possibility of this severe complication, especially in the elderly people or in high-risk populations, would be advisable.


Functionalized Concave Cube Gold Nanoparticles as Potent Antimicrobial Agents against Pathogenic Bacteria.
Gold (Au) is an inert metal in a bulk state; however, it can be used for the preparation of Au nanoparticles (i.e., AuNPs) for multidimensional applications in the field of nanomedicine and nanobiotechnology. Herein, monodisperse concave cube AuNPs (CCAuNPs) were synthesized and functionalized with a natural antioxidant lipoic acid (LA) and a tripeptide glutathione (GSH) because different crystal facets of AuNPs provide binding sites for distinct ligands. There was an ∼10 nm bathochromic shift of the UV-vis spectrum when CCAuNPs were functionalized with LA, and the size of the as-synthesized monodisperse CCAu nanoparticles was 76 nm. The LA-functionalized CCAu nanoparticles (i.e., CCAuLA) showed the highest antibacterial activity against Bacillus subtilis. Both fluorescence images and scanning electron microscopy images confirm the damage of the bacterial cell wall as the mode of antibacterial activity of CCAuNPs. CCAuNPs also cause the oxidation of bacterial cell membrane fatty acids to produce reactive oxygen species, which pave the way for the death of bacteria. Both CCAu nanoparticles and their functionalized derivatives showed excellent hemocompatibility (i.e., percentage of hemolysis is <5% at 80 μg of AuNPs) to human red blood cells and very high biocompatibility to HeLa, L929, and Chinese hamster ovary-green fluorescent protein (CHO-GFP) cells. Taken together, LA and GSH enhance the antibacterial activity and biocompatibility, respectively, of CCAu nanoparticles that interact with the bacteria through Coulomb as well as hydrophobic interactions before demonstrating antibacterial propensity.


Sirtuins at the crossroads of stemness, aging, and cancer.
Sirtuins are stress-responsive proteins that direct various post-translational modifications (PTMs) and as a result, are considered to be master regulators of several cellular processes. They are known to both extend lifespan and regulate spontaneous tumor development. As both aging and cancer are associated with altered stem cell function, the possibility that the involvement of sirtuins in these events is mediated by their roles in stem cells is worthy of investigation. Research to date suggests that the individual sirtuin family members can differentially regulate embryonic, hematopoietic as well as other adult stem cells in a tissue- and cell type-specific context. Sirtuin-driven regulation of both cell differentiation and signaling pathways previously involved in stem cell maintenance has been described where downstream effectors involved determine the biological outcome. Similarly, diverse roles have been reported in cancer stem cells (CSCs), depending on the tissue of origin. This review highlights the current knowledge which places sirtuins at the intersection of stem cells, aging, and cancer. By outlining the plethora of stem cell-related roles for individual sirtuins in various contexts, our purpose was to provide an indication of their significance in relation to cancer and aging, as well as to generate a clearer picture of their therapeutic potential. Finally, we propose future directions which will contribute to the better understanding of sirtuins, thereby further unraveling the full repertoire of sirtuin functions in both normal stem cells and CSCs.


Anxiety and depression are common in rheumatoid arthritis and correlate with poor quality of life in Indian patients.
We planned this study to assess the prevalence of anxiety and depression in rheumatoid arthritis (RA) patients and its correlation with quality of life (QOL) in these patients. Eighty-eight patients (76 females) were included in this cross-sectional study. The Hospital Anxiety and Depression Scale (HADS) was used to assess anxiety and depression. Quality of life was measured using the World Health Organization WHOQOL-BREF. The severity of pain was measured by 100-millimetre-long Visual Analogue Scale (VAS), and functional disability was measured by using the Indian version of the Health Assessment Questionnaire (HAQ). The disease activity was measured by Disease Activity Score for 28 joints with 3 variables. Probable anxiety and depression were seen in 61 (69%) and 68 (77%) of the patients, respectively. Patients with anxiety had more severe pain (VAS 53.8 ±26.4 vs. 39.7 ±26.1, p < 0.05), and significantly lower scores in all the 4 domains of the WHOQOL-BREF. Patients with depression had more pain (VAS 54.2 ±25.2 vs. 33.5 ±27.3, p < 0.01), higher HAQ scores (1.0 ±0.7 vs. 0.5 ±0.7, p < 0.01), and lower QOL scores. Both anxiety and depression scores had a negative correlation with all the 4 domains of the WHOQOL-BREF. Anxiety had a significant negative effect on psychological (β = -0.58, p < 0.001) and environmental domains (β = -0.39, p < 0.001), while depression had a significant negative effect on psychological (β = -0.57, p < 0.001) and environmental domains (β = -0.53, p < 0.001). Both anxiety and depression predicted more pain in RA patients (β = 0.24, p < 0.001 and β = 0.44, p < 0.001, respectively). Anxiety and depression correlated with poor QOL in all 4 domains of the WHOQOL-BREF. Higher HADS scores had a negative effect on all the domains of the WHOQOL-BREF and predicted more severe pain in RA patients. Thus, patients with RA need to be screened and treated for underlying anxiety and depression to improve their QOL, pain, and functional status.


Systematic optimization of targeted and multiplexed MS-based screening workflows for protein biomarkers.
Background: The capability of targeted MS-based methods to simultaneously measure multiple analytes with high selectivity and sensitivity greatly facilitates the discovery and quantitation of novel biomarkers. However, the complexity of biological samples is a major bottleneck that requires extensive sample preparation. Results: This paper reports a generic workflow to optimize surrogate peptide-based protein biomarker screening for seven human proteins in a multiplexed manner without the need for any specific affinity reagents. Each step of the sample processing and LC-MS methods is systematically assessed and optimized for better analytical performance. Conclusion: The established method is used for the screening of multiple myeloma patient samples to determine which proteins could be robustly measured and serve as potential biomarkers of the disease.


Molecular characterization of the protein encoded by the Hermansky-Pudlak syndrome type 1 gene.
Hermansky-Pudlak syndrome (HPS) comprises a group of genetic disorders characterized by defective lysosome-related organelles. The most common form of HPS (HPS type 1) is caused by mutations in a gene encoding a protein with no homology to any other known protein. Here we report the identification and biochemical characterization of this gene product, termed HPS1p. Endogenous HPS1p was detected in a wide variety of human cell lines and exhibited an electrophoretic mobility corresponding to a protein of approximately 80 kDa. In contrast to previous theoretical analysis predicting that HPS1p is an integral membrane protein, we found that this protein was predominantly cytosolic, with a small amount being peripherally associated with membranes. The sedimentation coefficient of the soluble form of HPS1p was approximately 6 S as inferred from ultracentrifugation on sucrose gradients. HPS1p-deficient cells derived from patients with HPS type 1 displayed normal distribution and trafficking of the lysosomal membrane proteins, CD63 and Lamp-1. This was in contrast to cells from HPS type 2 patients, having mutations in the beta3A subunit of the AP-3 adaptor complex, which exhibited increased routing of these lysosomal proteins through the plasma membrane. Similar analyses performed on fibroblasts from 10 different mouse models of HPS revealed that only the AP-3 mutants pearl and mocha display increased trafficking of Lamp-1 through the plasma membrane. Taken together, these observations suggest that the product of the HPS1 gene is a cytosolic protein capable of associating with membranes and involved in the biogenesis and/or function of lysosome-related organelles by a mechanism distinct from that dependent on the AP-3 complex.


Complete recovery after an intraoral approach for Eagle syndrome.
Eagle syndrome is considered a rare disease. It is an aggregation of symptoms that includes neck, throat, and hemifacial pain; sensation of foreign body in the throat; dysphagia; otalgia; and change in voice as a direct result of an elongated styloid process or calcified stylohyoid ligament.The clinical diagnosis is generally difficult and must be confirmed by radiologic imaging. Our patient was a 37-year-old woman who had a 3 years' history of dysphagia and foreign body sensation. Computed tomographic scan showed a long left styloid process and calcification in the upper part of the stylohyoid ligament suggestive of Eagle syndrome. The patient underwent surgical removal of the elongated styloid process through an intraoral approach. The patient became symptom-free at 9 months after the surgery.


Long-term sampling of airborne cadmium dust in an alkaline battery factory.
Concentrations of cadmium in workroom air in a Swedish battery factory were estimated for the time period 1946 to 1976. A sampling strategy was chosen before 389 stationary and 190 mobile measurements took place between December 1974 and February 1976. The studies showed that observations made by the company can be used together with data collected in the present study, the dust in the factory consistE mainly of respirable particles, cyclic variation over time is absent, and type ol work affects the concentration of airborne cadmium dust. Based on these findings earlier measurements in the factory were critically evaluated. It was found that, due to actions taken by the company, the average level of cadmium in workroom air decreased from about 5000 microg Cd/m3 air in 1946 to about 10 microg Cd/m3 air in 1976.


Laser-polarized (129)Xe NMR and MRI at ultralow magnetic fields.
Laser-polarized (129)Xe and a high-T(c)superconducting quantum interference device (SQUID) are used to obtain magnetic resonance images in porous materials at a magnetic field of 2.3 mT, corresponding to a Larmor frequency of 27 kHz. Image resolution of 1 mm is obtained with gradients of only 1 mT/m. The resolution of xenon chemical shifts in different physicochemical environments at ultralow fields is also demonstrated. Details of the circulating flow optical pumping apparatus and the SQUID spectrometer are presented.


Gene, brain, and behavior relationships in fragile X syndrome: evidence from neuroimaging studies.
Fragile X syndrome (FraX) remains the most common inherited cause of intellectual disability and provides a valuable model for studying gene-brain-behavior relationships. Over the past 15 years, structural and functional magnetic resonance imaging studies have emerged with the goal of better understanding the neural pathways contributing to the cognitive and behavioral outcomes seen in individuals with FraX. Specifically, structural MRI studies have established and begun to refine the specific topography of neuroanatomical variation associated with FraX. In addition, functional neuroimaging studies have begun to elucidate the neural underpinnings of many of the unique characteristics of FraX including difficulties with eye gaze, executive functioning, and behavioral inhibition. This review highlights studies with a focus on the relevant gene-brain-behavior connections observed in FraX. The relationship of brain regions and activation patterns to FMRP are discussed as well as the clinical cognitive and behavioral correlates of these neuroimaging findings.


DNA sequence specificity of antitumor agents. Oncogenes as possible targets for cancer therapy.
An examination of the DNA sequence specificity of guanine-N7 alkylation for nitrogen mustards and chlorethylnitrosoureas revealed that large variations in alkylation intensities existed among different guanines in the DNA sequence. The most striking finding was that most agents reacted preferentially at runs of G's, the degree of preference being much greater than would be expected from the number of G's alone. This correlated with the molecular electrostatic potential induced at the guanine-N7 position by the nearest neighbor base pairs. Uracil and quinacrine mustards, however, showed distinctly different reaction patterns from other mustards and a detailed examination has led to structural hypotheses to account for the differences. Certain regions of the genome including regions in some oncogenes and the Epstein-Barr virus have unusually high GC contents (greater than 80% GC) which suggests that the antitumor effectiveness of alkylating agents may in part be due to selective reaction at certain regions in the genome. In fact certain mustards have been shown to exhibit enhanced reactivities with such regions in DNA fragments derived from the c-H-ras oncogene. The above findings point to the possibility of design of alkylating agents to optimise the selectivity of reaction with critical DNA regions. An alternative approach presently under investigation has emerged from an understanding of the characteristics of the sequence specific interaction of the natural oligopeptide antibiotics netropsin and distamycin in the minor groove of DNA. This has led to the synthesis of novel agents (lexitropsins) in which the binding specificity can be shifted from (AT)n in (GC)n in a predictable fashion. Thus the rational design of DNA sequence specific vectors linked to DNA reactive groups, such as alkylating or cleaving agents, could enable DNA damage to be delivered selectively to predetermined critical sites on the genome.


Synergistic Inhibition of Human Carcinoma Cell Growth via Co-Delivery of p53 Plasmid DNA and bcl-2 Antisense Oligodeoxyribonucleotide by Cholic Acid-modified Polyethylenimine.
This study investigated the co-delivery of plasmid DNA and antisense oligodeoxyribonucleotide (AS ODN) into carcinoma cells by cholic acid-modified polyethylenimine (PEI-CA). PEI-CA/plasmid DNA and AS ODN complexes were formulated and evaluated for delivery of plasmid DNA and AS ODN in HeLa cells. The efficiency of co-delivery of plasmid DNA and AS ODN was evaluated by cell growth inhibition using p53 and bcl-2 AS ODN. AS ODN intracellular delivery and green fluorescent protein expression upon cellular transfection were greater than in cells treated with uncomplexed nucleic acids. Treatment of the cells with PEI-CA/p53 plasmid DNA and bcl-2 AS ODN complexes resulted in cell growth inhibition that was greater than that of either PEI-CA/p53 plasmid DNA complexes or PEI-CA/bcl-2 AS ODN complexes alone. The co-delivery of p53 plasmid DNA and bcl-2 AS ODN in PEI-CA complexes enhanced therapeutic activities of both p53 plasmid DNA and bcl-2 AS ODN.


Association Between the miR-146a Rs2910164 Polymorphism and Childhood Acute Lymphoblastic Leukemia Susceptibility in an Asian Population.
Background: miR-146a has been demonstrated to be involved in normal hematopoiesis and the pathogenesis of many hematological malignancies by inhibiting the expression of its targets. Rs2910164(G>C) may modify the expression of the miR-146a gene, which might influence an individual's predisposition to childhood acute lymphoblastic leukemia (ALL). However, inconsistent findings have been reported on the association between the rs2910164(G>C) polymorphism and the risk of childhood ALL. Methods: A comprehensive meta-analysis was performed to accurately estimate the association between the miR-146a rs2910164 polymorphism and childhood ALL among four different genetic models. Results: This meta-analysis included Asian studies with a total of 1,543 patients and 1,816 controls. We observed a significant difference between patients and controls for the additive model (CC vs. GG: OR = 1.598, 95% CI: 1.003-2.545, P = 0.049) using a random effects model. Meanwhile, there was a trend of increased childhood ALL risk in the dominant model (CC + CG vs. GG: OR = 1.501, 95% CI: 0.976-2.307, P = 0.065), recessive model (CC vs. GG + CG: OR = 1.142, 95% CI: 0.946-1.380, P = 0.168) and allele model (C vs. G: OR = 1.217, 95% CI: 0.987-1.500, P = 0.066) between patients and controls. Conclusions: Our findings suggest that the miR-146a rs2910164 CC genotype was significantly associated with childhood ALL susceptibility.


[Application and reliability of balloon occlusion test in treatment of cerebrovascular diseases].
To study the reliability of applying balloon occlusion test (BOT) to evaluate the compensation capacity of cerebral collateral circulation, and investigate the validity of different criterion about BOT and techniques to improve the security of BOT. A retrospective analysis was conducted on the results of 86 patients, 39 males and 47 females, aged 49.8 (13 - 72), 67 suffering from intracranial aneurysm and 19 from traumatic carotid cavernous fistula, who received BOT, and on the results of 38 of the 66 patients who accepted artery occlusion after the BOT. The positive rate of diagnosis was 10.47% and the negative rate was 89.53% by conventional BOT; whereas the positive rate of diagnosis was 36.05% and the negative rate was 63.95% with combined cross circulation and conventional test. The brain ischemia rate after cerebral artery occlusion therapy was 8.33%. The BOT-related complication rate was 3.49%. (1) The current BOT technique can basically provide reliable results. (2) The cross circulation test and hypotensive provocative test can effectively improve the specificity of BOT. (3) More perfect BOT criterion for the prediction of cerebral tolerance is still to be worked out. Combination of the conventional method and advanced imaging technique and search for an objective and quantificational criterion would be of reward.


Myelin/oligodendrocyte glycoprotein-specific T-cells induce severe optic neuritis in the C57BL/6 mouse.
The optic nerve is a common site of tissue damage in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). To determine the relationship between optic neuritis (ON) and EAE, we examined the incidence of ON in C57BL/6 (B6) mice immunized with a myelin oligodendrocyte/glycoprotein (MOG)-derived peptide or injected with MOG-specific T cells, which are known to induce EAE. Mice were immunized with MOG35-55 or MOG40-54 peptides emulsified in complete Freund's adjuvant (CFA). Pertussis toxin (PTX) was injected intraperitoneally 1 day before and after immunization. For disease induction by adoptive transfer of primed cells, donor C57BL/6 mice were received with T-cell blasts (1-6 x 10(6)/mouse). Both EAE and ON were observed by either clinical signs or histology. ON developed in a high proportion of B6 mice treated with either protocol. The most severe inflammation was observed in the adoptively transferred mice. The induced ON was most frequently bilateral. In either actively or adoptively transferred diseases, both association and dissociation of EAE and ON was observed. Different MOG-specific T-cell subsets might be involved in the pathogenesis of EAE and ON. A better understanding of the pathogenesis of ON after induction by MOG may have important diagnostic and therapeutic implications.


Mind the gap: the delayed recovery of a population of the biological control agent Megamelus scutellaris Berg. (Hemiptera: Delphacidae) on water hyacinth after winter.
Cold winter temperatures significantly affect the biological control effort against water hyacinth, Pontederia ( = Eichhornia) crassipes Mart. (Pontederiaceae), in more temperate regions around the world. The population dynamics of the planthopper Megamelus scutellaris Berg. (Hemiptera: Delphacidae), a newly released biological control agent of water hyacinth, were recorded on the Kubusi River in the Eastern Cape Province (South Africa) over 15 months to determine the population recovery post-winter. Megamelus scutellaris incurred a severe population decline at the onset of winter when the water hyacinth plants became frost damaged. The combined effect of a population bottleneck and low minimum winter temperatures (6.12°C) below the agent's lower developmental threshold (11.46°C) caused a post-winter lag in agent density increase. Subsequently, the maximum agent population density was only reached at the end of the following summer growing season which allowed the water hyacinth population to recover in the absence of any significant biological control immediately post-winter. Supplementary releases of agents from mass-reared cultures at the beginning of the growing season (spring) is suggested as a potential method of reducing the lag-period in field populations in colder areas where natural population recovery of agents is slower.


Differentiation of Neospora hughesi from Neospora caninum based on their immunodominant surface antigen, SAG1 and SRS2.
Neospora hughesi is a newly recognised parasite that is closely related to Neospora caninum, and is a cause of equine protozoal myeloencephalitis. We have characterised two N. hughesi immunodominant tachyzoite antigens which exhibit antigenic and molecular differences from the homologous tachyzoite antigens on N. caninum. These antigens on N. hughesi are referred to as NhSAG1 and NhSRS2, using the same mnemonics as used for the N. caninum antigens (NcSAG1 and NcSRS2), and are homologous to Toxoplasma gondii surface antigen 1 (SAG1) and SAG1-related sequence 2 (SRS2). The NcSAG1 and NcSRS2 were antigenically conserved in six different N. caninum isolates from cattle and dogs. The two equine-derived Neospora isolates, one designated as N. hughesi, were similar to each other but different from N. caninum. There was 6% difference in amino acid identity between NcSAG1 and NhSAG1, whereas there was a 9% difference when NcSRS2 and NhSRS2 were compared. The polymorphism of these genes and their corresponding proteins provide additional markers which can be used to distinguish N. caninum from N. hughesi.