The Garden of Eden: Implications for cardiovascular disease prevention.
Creationists and evolutionists acknowledge that the human diet has passed through at least four phases. The original plant food-based diet; a second phase of increasing meat consumption; a third phase of agricultural dependence on starchy foods; and, finally, the supermarket high-saturated fat, low-fibre phase with minimal energy expenditure. Our aim is to define the value of the original or 'Garden of Eden' diet and to speculate on which components should be retained in the modern supermarket diet. The original plant-based diet would have been high in vegetable proteins, plant sterols, dietary fibre and antioxidants, and low in saturated fats with no trans fatty acids. This diet would increase fecal cholesterol losses from the body as bile acids and neutral sterols, while providing little stimulus to cholesterol synthesis. To replace the bile acid losses we would have adapted to a relatively high capacity for cholesterol synthesis. Now, in the high-saturated fat, low-fibre supermarket age, this may be a disadvantage and predisposes consumers to high serum cholesterol and increased risk of cardiovascular disease. We believe part of the solution is a return to the plant-based 'Garden of Eden' diet combined with physical activity. A lipid-lowering portfolio containing vegetable proteins, especially soy, plant sterols and high fibre intakes combined with low saturated and trans fatty acids and cholesterol, would go a long way to reducing serum lipids and coronary heart disease risk seen in the modern Western diet.


[Prevalence of antiphospholipid antibodies in patients with primary Sjögren's syndrome].
The aim of this study was to determine prevalence of antiphospholipid antibodies (aPL) including anticardiolipin antibodies (aCL), and anti-beta2GP1 in a cohort of 32 patients with primary Sjogren's syndrome (pSS) diagnosed according to revised European criteria. aPL were found in 9/32 (28%) patients (IgG in 8 and IgM in one case). Anti-beta2GPI antibodies were detected only in two patients. Titres were usually low.


The current status of typhoid vaccine development and clinical trials with typhoid vaccines.
The killed whole cell typhoid vaccines, although protective, have limited usefulness because of the adverse reactions they evoke. In contrast, new typhoid vaccines protect without reactogenicity. Attenuated oral vaccine Ty2la has been evaluated in field trials of efficacy in Santiago, Chile. Three doses of Ty2la in an enteric-coated formulation given within one week provided 69% efficacy for at least four years. Ty2la has reached the stage of being a practical public health tool. Two double auxotrophic (Aro-, Pur-) mutant strains of S. typhi (541Ty and 543Ty) were well-tolerated and stimulated cell-mediated immune responses but evoked little serological response. Parenteral purified Vi polysaccharide of S. typhi (single 25 mcg dose) was safe and immunogenic and provided 64-72% protection (for at least 17-21 months) in controlled field trials in Nepal and South Africa.


Evaluating a self infusion device for children with haemophilia.
Although prophylactic treatment of boys with severe haemophilia has progressed significantly, there has been very little change in the way that coagulation factors are reconstituted and administered. Most boys with severe haemophilia can self infuse by the age of eight and most are totally self sufficient by the age of 14. This small study evaluated a product developed to improve the reconstitution and administration process by seeking the views of ten boys who self infuse recombinant coagulation factor. The boys completed a simple questionnaire related to the current method and after the introduction of new method of reconstitution using the ReFacto Rapid Reconstitution (R2) device. The R2 device was reported by most boys to be advantageous in terms of time and safety in reconstitution as well as being acceptable to all but one. Even relatively young children can be successfully included in research and their opinions about their health care should be sought before introduction of changes, especially when proposed changes could affect their ability to perform their own treatment.


Relationship of the Adherence to a Mediterranean Diet and Its Main Components with CRP Levels in the Spanish Population.
Background: Adherence to a Mediterranean diet seems to be inversely associated with C-reactive protein (CRP) concentration. A 14-point Mediterranean Diet Adherence Screener (MEDAS) has been developed to assess dietary compliance. Objective: The aim of this study was to assess whether each of the MEDAS questions as well as their final score were associated with the levels of CRP in general Spanish population. Cross-sectional analysis of 1411 subjects (mean age 61 years, 43.0% males) randomly selected from the general population. CRP levels were determined by a commercial ELISA kit. Adherence to the Mediterranean diet was measured by the 14-point MEDAS. Results: There was an inverse correlation between adherence to the Mediterranean diet and the CRP concentration, even after adjusting by age, gender, hypertension, metabolic syndrome, body mass index, statin treatment and hypertension treatment (p = 0.041). Subjects who consume ≥2 servings of vegetables per day (p = 0.003), ≥3 pieces of fruit per day (p = 0.003), ≥1 serving of butter, margarine, or cream per day (p = 0.041) or ≥3 servings of fish/seafood per week (p = 0.058) had significantly lower levels of CRP. Conclusions: Adherence to a Mediterranean-type diet measured by a simple questionnaire is associated with lower CRP concentration. However, this association seems to be particularly related to a higher consumption of vegetables, fruits, dairy products, and fish.


Neuroprotective effects of nonfeminizing estrogens in retinal photoreceptor neurons.
Retinal diseases such as macular degeneration and glaucoma are disorders that target specific retinal neurons that can ultimately lead to vision loss. Under these conditions and pathologies, retinal neurons can die via apoptosis that may be due to increased oxidative stress. The neuroprotective effects of 17β-estradiol (E2) and three synthetic nonfeminizing estrogen analogs (ZYC-26, ZYC-23, and ZYC-3) were investigated to examine their abilities to protect retinal neurons against glutamate toxicity. Using an in vitro model of glutamate-induced cell death in 661W cells, a mouse cone photoreceptor cell line, shown to express both estrogen receptors (ERs) via immunoblotting, was pretreated with E2 and its analogs and cell viability were assessed. It was observed that E2 and estrogen analogs, ZYC-26 and ZYC-3, were protective against a 5 mM glutamate insult in 661W cells. The neuroprotective abilities of ZYC-26 and ZYC-3 were autonomous of estrogen receptor-α (ERα) and ERβ demonstrated by their ability to protect in the presence of ICI 182780, a pan-ER antagonist with a high affinity for the estrogen receptor. Treatment with PPT and DPN, ERα- and ERβ-specific agonists, respectively, did not protect the 661W cells from the glutamate insult. Studying the membrane ER (mER) or GPR30 did show that activation of the receptor by G1 protected the retinal neuron from insult, whereas G15, an antagonist of the mER was not able to antagonize the protection previously seen. These data demonstrate that nonfeminizing estrogens may emerge as useful compounds for neuroprotection of retinal cells.


Assessment of Pulmonary Capillary Blood Volume, Membrane Diffusing Capacity, and Intrapulmonary Arteriovenous Anastomoses During Exercise.
Exercise is a stress to the pulmonary vasculature. With incremental exercise, the pulmonary diffusing capacity (DLCO) must increase to meet the increased oxygen demand; otherwise, a diffusion limitation may occur. The increase in DLCO with exercise is due to increased capillary blood volume (Vc) and membrane diffusing capacity (Dm). Vc and Dm increase secondary to the recruitment and distension of pulmonary capillaries, increasing the surface area for gas exchange and decreasing pulmonary vascular resistance, thereby attenuating the increase in pulmonary arterial pressure. At the same time, the recruitment of intrapulmonary arteriovenous anastomoses (IPAVA) during exercise may contribute to gas exchange impairment and/or prevent large increases in pulmonary artery pressure. We describe two techniques to evaluate pulmonary diffusion and circulation at rest and during exercise. The first technique uses multiple-fraction of inspired oxygen (FIO2) DLCO breath holds to determine Vc and Dm at rest and during exercise. Additionally, echocardiography with intravenous agitated saline contrast is used to assess IPAVAs recruitment. Representative data showed that the DLCO, Vc, and Dm increased with exercise intensity. Echocardiographic data showed no IPAVA recruitment at rest, while contrast bubbles were seen in the left ventricle with exercise, suggesting exercise-induced IPAVA recruitment. The evaluation of pulmonary capillary blood volume, membrane diffusing capacity, and IPAVA recruitment using echocardiographic methods is useful to characterize the ability of the lung vasculature to adapt to the stress of exercise in health as well as in diseased groups, such as those with pulmonary arterial hypertension and chronic obstructive pulmonary disease.


Developmental regulation of Ubc9 in the rat nervous system.
The SUMO-conjugating enzyme Ubc9 is an essential enzyme in the SUMO (small ubiquitin-related modifier) protein modification system. Although sumoylation, covalent modification of cellular proteins by SUMO, is considered to regulate various cellular processes, and many substrates for sumoylation have been identified recently, the regulation of Ubc9 expression has not been examined in detail. We analyzed the expression of Ubc9 during rat brain development at the mRNA and protein levels. Northern and Western blot analyses revealed that expression of Ubc9 and SUMO-1 was developmentally regulated, while that of the ubiquitin-conjugating enzyme UbcH7 did not change so dramatically. In situ hybridization analysis revealed that the expression of Ubc9 was high in neuronal stem cells and moderate in differentiated neurons at embryonic stages. In the adult brain, moderate expression was observed in subsets of neurons, such as the dentate granular neurons and pyramidal neurons in the hippocampal formation and the large pyramidal neurons in the cerebral cortex. These results suggest that the Ubc9-SUMO system might participate in the proliferation and differentiation of neuronal cells in the developing brain and in neuronal plasticity in the adult brain.


Functional role of the cysteine 451 thiol group in the M4 helix of the gamma subunit of Torpedo californica acetylcholine receptor.
Previous chemical modification studies of the acetylcholine receptor [Yee, A.S., Corey, D.E., & McNamee, M.G. (1986) Biochemistry 25, 2110-2119] were extended by using fluorescent N-pyrenylmaleimide to alkylate purified Torpedo californica nicotinic acetylcholine receptor (AChR). Peptide sequencing of the tryptic fragments of the labeled AChR gamma subunit identified cysteines 416, 420, and 451 as the modified residues. The functional role of Cys-451 in the M4 transmembrane domain of the AChR gamma subunit was further investigated by studying the functional consequences of the site-specific mutation of this cysteine to either serine or tryptophan by using AChR mRNAs injected into Xenopus laevis oocytes. Both mutants displayed about 50% reduction in the normalized channel activity of the receptor measured as the ACh-induced conductance per femtomole of surface alpha-bungarotoxin binding sites. However, the mutations did not change other AChR functional properties such as agonist binding ability, the slow phase of desensitization, and blockade by competitive and noncompetitive antagonists. The significant reduction in AChR ion channel activity associated with the above point mutations, especially the simple change of the -SH group on Cys-451 to the -OH group, suggests that this thiol group in the M4 helix of gamma subunit may play an important role in AChR ion channel function. Previous site-directed mutations of the Cys-416 and -420 residues showed a decreased response when both of these residues were changed to phenylalanine, but not when they were changed to serine [Pradier, L., Yee, A.S., & McNamee, M.G. (1989) Biochemistry 28, 6562-6571].(ABSTRACT TRUNCATED AT 250 WORDS)


Decreased Expression of SATB2 Associates with Tumor Growth and Predicts Worse Outcome in Patients with Clear Cell Renal Cell Carcinoma.
SATB2 (special AT-rich sequence-binding protein 2) is a DNA-binding protein that is involved in transcriptional regulation and chromatin remodeling. SATB2 protein has been described as a promising novel marker in several human cancers. This study compared SATB2 expression in tumor and matched unchanged renal tissues collected from 57 patients with clear cell renal cell carcinoma (ccRCC). SATB2 mRNA levels were determined by quantitative polymerase chain reaction, while SATB2 protein expression was estimated by immunohistochemistry. Moreover, the associations between SATB2 expression in ccRCC samples and clinicopathological and survival data of the patients were investigated. The mRNA level of SATB2 was lower in tumor tissues than in samples of corresponding unchanged kidney. Although the average immunoreactivity of SATB2 protein did not differ significantly between cancer cells and epithelial cells of proximal convoluted tubules, the decreased SATB2 expression in tumor specimens inversely correlated with the size of primary tumor and predicted worse patients' outcome. The results of the presented study suggest the tumor-suppressing function of SATB2 and that the expression level of this protein can be considered a potential prognostic factor in ccRCC.


ZNF518B gene up-regulation promotes dissemination of tumour cells and is governed by epigenetic mechanisms in colorectal cancer.
Most of colorectal cancer CRC-related death is due to metastasis and the finding of markers for prognosis of invasiveness, constitutes an appealing challenge. Here, after analysing cDNA array containing 43 tumour and 5 normal mucosa samples, we report that the expression of the ZNF518B gene as a whole and that of its two major splicing isoforms are significantly increased in tumours. The canonical isoform was also up-regulated in a patients' cohort containing 70 tumour and 69 adjacent tissue samples. The effects of silencing ZNF518B on the phenotype of CRC cell lines were then studied. The gene does not affect cell proliferation, but plays a significant role in cell migration and invasiveness and induces changes in the epithelial-to-mesenchymal transition markers, suggesting that ZNF518B favours tumour cell dissemination. To study the regulation of the gene, transcription-related changes in nucleosomal organisation and epigenetic marks around the transcriptional start site were analysed. The positioning of a nucleosome over the transcription start site and the differential presence of the epigenetic marks H3K9ac, H3K27ac, H3K4me3 and H3K9me3 correlate with gene expression. Inhibition of histone deacetylases increases the transcription of ZNF518B, which may be a candidate for invasiveness prognosis in CRC and a target for epigenetic drugs.


Tweaking the Molecular Geometry of a Tetraperylenediimide Acceptor.
Partial flattening of the spatially extended molecular scaffold has been employed as an effective tactic to improve the device performance of a perylenediimide (PDI)-based small-molecule acceptor because the less twisted yet not completely planar molecular geometry is anticipated to improve the molecular packing and thereby attain a more suitable balance between the carrier transport ability and phase domain size. A small-molecule acceptor BF-PDI comprising four α-substituted PDI units attached around a 9,9'-bifluorenylidene (BF) central moiety is designed and studied in polymer solar cells. The BF group is deemed a ring-fused analogue of the tetraphenylethylene (TPE) unit. Due to the less twisted and better conjugated BF skeleton, BF-PDI displays more delocalized lowest unoccupied molecular orbital. By virtue of both the electronic and steric effects, BF-PDI is suggested to bring about superior intermolecular stacking and donor-acceptor phase separation morphology in blend films. Indeed, the experimental results show that BF-PDI displays improved charge transport ability and a higher power-conversion efficiency of 8.05% than that of TPE-PDI. Grazing-incidence wide-angle X-ray diffraction and resonant soft X-ray scattering confirm the more compact and ordered molecular packing as well as smaller domain sizes in the P3TEA/BF-PDI blend.


Mastoscopic sentinel lymph node biopsy in breast cancer.
Previous studies have demonstrated that mastoscopic sentinel lymph node biopsy (MSLNB) has good identification rate (IR) and low false negative rate (FNR). However, few studies have directly compared the surgical performance and peri- and post-operative factors of MSLNB with conventional sentinel lymph node biopsy (SLNB). Sixty patients diagnosed with breast cancer were recruited and randomly assigned to one of the three groups: MSLNB, SLNB and SLNB with lipolysis injection. Peri- and post-operative parameters were compared using general linear models. To examine the effect of age on these parameters, we performed separate analysis stratified by age (≤50 years old vs. >50 years old). Patients in the MSLNB group experienced longer surgery and suffered higher surgical cost than patients who underwent conventional SLNB or SLNB with lipolysis injection (p<0.0001). Despite this, they had significantly less blood loss than those who underwent conventional SLNB (22.0±7.0 ml vs.73.5±39.6 ml; p<0.0001). Analysis by age group indicates a similar pattern of difference among the three groups. MSLNB and conventional SLNB have similar IR and FNR. As a minimally invasive technique, MSLNB can significantly reduce blood loss while providing similar IR and FNR, indicating that it can be a promising alternative to conventional SLNB. Variations in popliteal artery terminal branching pattern occurred in 7.4% to 17.6% of patients. Pre-surgical detection of these variations with MD CTA may help to reduce the risk of iatrogenic arterial injury by enabling a better surgical treatment plan.


[Native and trypsin-treated histone oligomers--tetramer (H3-H4)2 and dimer H2a-h2b].
The native oligomers of histones isolated from calf thymus nuclear chromatin were investigated. After mild treatment with trypsin, the tetramer, (H3-H4)2, has a molecular weight of 36 000, whereas Mr of the dimer, H2a-H2b, is equal to 25 000. Intact oligomers have Mr of 55 000 (tetramer) and 33 000 (dimer). Analysis of the fluorescence intensity changes indicates that the native tetramer can exist in three, while the dimer in two conformational states. The (H2a-H2b) dimer persists, but the (H3-H4)2 tetramer does not persist these transitions after proteolytic degradation. The trypsin-treated dimer H2a-H2b is highly labile and readily aggregates, while the tetramer (H3-H4)2 loses its aggregation capacity. It is assumed that the conformational features observed during the aggregation of histone oligomers may play a role in the assembly and structural transitions in nucleosomes and chromatin.


Performance of BioFire Blood Culture Identification 2 Panel (BCID2) for the detection of bloodstream pathogens and their associated resistance markers: a systematic review and meta-analysis of diagnostic test accuracy studies.
Early identification of bloodstream pathogens and their associated antimicrobial resistance may shorten time to optimal therapy in patients with sepsis. The BioFire Blood Culture Identification 2 Panel (BCID2) is a novel multiplex PCR detecting 43 targets directly from positive blood cultures, reducing turnaround times. We have performed a systematic review and meta-analysis of diagnostic test accuracy studies to assess the BCID2 performance for pathogen identification and resistance markers detection compared to gold standard culture-based methods (including phenotypic and/or genotypic characterization). Nine studies were identified reporting data to build 2 × 2 tables for each BCID2 target, including 2005 blood cultures. The pooled specificity of the assay was excellent (> 97%) across most subgroups of targets investigated, with a slightly broader confidence interval for S. epidermidis (98.1%, 95% CI 93.1 to 99.5). Pooled sensitivity was also high for the major determinants of bloodstream infection, including Enterobacterales (98.2%, 95% CI 96.3 to 99.1), S. aureus (96.0%, 95% CI 90.4 to 98.4), Streptococcus spp. (96.7%, 95% CI 92.8 to 98.5), P. aeruginosa (92.7%, 95% CI 83.1 to 97.0), E. faecalis (92.3%, 95% CI 83.5 to 96.6), as well as blaCTX-M (94.9, 95% CI 85.7 to 98.3), carbapenemases (94.9%, 95% CI 83.4 to 98.6) and mecA/C & MREJ (93.9%, 95% CI 83.0 to 98.0). Sensitivity for less common targets was slightly lower, possibly due to their under-representation in the included studies. BCID2 showed good performance for detecting major determinants of bloodstream infection and could support early antimicrobial treatment, especially for ESBL or carbapenemase-producing Gram-negative bacilli and methicillin-resistant S. aureus.


Homology, neocortex, and the evolution of developmental mechanisms.
The six-layered neocortex of the mammalian pallium has no clear homolog in birds or non-avian reptiles. Recent research indicates that although these extant amniotes possess a variety of divergent and nonhomologous pallial structures, they share a conserved set of neuronal cell types and circuitries. These findings suggest a principle of brain evolution: that natural selection preferentially preserves the integrity of information-processing pathways, whereas other levels of biological organization, such as the three-dimensional architectures of neuronal assemblies, are less constrained. We review the similarities of pallial neuronal cell types in amniotes, delineate candidate gene regulatory networks for their cellular identities, and propose a model of developmental evolution for the divergence of amniote pallial structures.


[The German Competence Analysis Questionnaire (KANN): Autism-spectrum-disorders and/or ADHD Compared].
The German Competence Analysis Questionnaire (KANN): Autism-spectrum-disorders and/or ADHD Compared. Due to the frequent comorbidity of autism spectrum disorders (ASD) and attention-deficit hyperactivity disorders (ADHD) the investigation of similarities and differences between these two syndromes has been the focus of research in recent years. The main objective of the present paper is to compare the three clinical groups "ASD", "ADHD" and "ASD+ADHD" as well as a control group on the basis of competencies relevant to everyday and social life by using the German Competence Analysis Questionnaire (Kompetenzanalyseverfahren, KANN). The KANN is an external assessment tool used to determine observable personal resources (competencies) in children and adolescents. A total of n = 205 children and adolescents under the care of child and youth welfare services are analyzed. The results show that the clinical group "ADHD" is superior to the groups "ASD" (in this case statistically significant) and "ASD+ADHD" at the KANN-scale "Leisure Behavior & Peer Groups" and "Independence in Everyday Life". The similar KANN-profiles of the two autistic groups do not support - contrary to the additionally collected data of behavior disorders (CBCL/4-18) - the hypothesis of an additive symptom effect within the meaning of the loss of competencies for the combined diagnoses group "ASD+ADHD". Furthermore, the ability of the KANN scales to differentiate between a clinical and a non-clinical child and youth welfare group underlines the validity of the KANN.


Normal changes in aging and nursing implications of drug therapy.
Safe and effective pharmacotherapy of the elderly goes far beyond the mechanical safeguards for administering the right drug to the right patient at the right time. A broad knowledge of cell membrane dynamics as reviewed here and how they are related to the processes of drug disposition provide baseline data used for monitoring drug action and drug-user responses. However, each period of the life span has its own particular characteristics that may qualify expected drug response unless standard drug regimens area adjusted and individualized. Normal changes in body structure and function imposed by the aging process require special attention, for while the patient may be in a steady state, age-related reduction in range of homeostatic processes leads to varied levels of drug response and changed susceptibility to drug reactions. Appreciation of these qualifiers of pharmacotherapy can help to reduce the high incidence of drug-related illnesses in the aged.


[In vitro activity of fusidic acid in combination with various antibiotics against Staphylococcus epidermidis].
In vitro antibacterial activity of fusidic acid (FUC) in combination with cefotaxime (CTX), imipenem (IMP), gentamicin (GEN), amikacin (AKN), rifampin (RIF), fosfomycin (FOS), vancomycin, pefloxacin (PEF) was studied against 19 presumably pathogen meti-R Staphylococcus epidermidis strains. The study was carried out by means of a microtiter checkerboard method (FICs index, 19 strains) and killing-curves (3 strains). FUC x GEN, FUC x AKN and FUC x IMP combinations were found synergistic with achievable therapeutic concentrations for IMP (MIC in the combination less than 1 microgram/ml) but with higher concentrations for AKN and GEN (greater than or equal to 8 micrograms/ml). FUC x PEF combinations were regularly antagonistic. FUC x RIF, and FUC x FOS combinations showed a modal FIC greater than or equal to 4 but were found respectively additive and synergistic with killing-curve method. Remaining FUC combinations results were variable. FUC resistant mutant frequency, studied for 3 S. epidermidis strains, was similar as S. aureus one's (0.5.10(-7) a 2.5.10(-8)).


Bile Acids in Polycystic Liver Diseases: Triggers of Disease Progression and Potential Solution for Treatment.
Polycystic liver diseases (PLDs) are a group of genetic hereditary cholangiopathies characterized by the development and progressive growth of cysts in the liver, which are the main cause of morbidity. Current therapies are based on surgical procedures and pharmacological strategies, which show short-term and modest beneficial effects. Therefore, the determination of the molecular mechanisms of pathogenesis appears to be crucial in order to find new potential targets for pharmacological therapy. Ductal plate malformation during embryogenesis and abnormal cystic cholangiocyte growth and secretion are some of the key mechanisms involved in the pathogenesis of PLDs. However, the discovery of the presence of bile acids in the fluid collected from human cysts and the intrahepatic accumulation of cytotoxic bile acids in an animal model of PLD (i.e. polycystic kidney (PCK) rat) suggest a potential role of impaired bile acid homeostasis in the pathogenesis of these diseases. On the other hand, ursodeoxycholic acid (UDCA) has emerged as a new potential therapeutic tool for PLDs by promoting the inhibition of cystic cholangiocyte growth in both PCK rats and highly symptomatic patients with autosomal dominant polycystic kidney disease (ADPKD: most common type of PLD), and improving symptoms. Chronic treatment with UDCA normalizes the decreased intracellular calcium levels in ADPKD human cholangiocytes in vitro, which results in the reduction of their baseline-stimulated proliferation. Moreover, UDCA decreases the liver concentration of cytotoxic bile acids in PCK rats and the bile acid-dependent enhanced proliferation of cystic cholangiocytes. Here, the role of bile acids in the pathogenesis of PLDs and the potential therapeutic value of UDCA for the treatment of these diseases are reviewed and future lines of investigation in this field are proposed.


Human T-cell leukemia virus type-1 Tax oncoprotein regulates G-protein signaling.
Human T-cell leukemia virus type-1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and neurological syndromes. HTLV-1 encodes the oncoprotein Tax-1, which modulates viral and cellular gene expression leading to T-cell transformation. Guanine nucleotide-binding proteins (G proteins) and G protein-coupled receptors (GPCRs) constitute the largest family of membrane proteins known and are involved in the regulation of most biological functions. Here, we report an interaction between HTLV-1 Tax oncoprotein and the G-protein beta subunit. Interestingly, though the G-protein beta subunit inhibits Tax-mediated viral transcription, Tax-1 perturbs G-protein beta subcellular localization. Functional evidence for these observations was obtained using conditional Tax-1-expressing transformed T-lymphocytes, where Tax expression correlated with activation of the SDF-1/CXCR4 axis. Our data indicated that HTLV-1 developed a strategy based on the activation of the SDF-1/CXCR4 axis in the infected cell; this could have tremendous implications for new therapeutic strategies.


Optimizing the Pharmacological Profile of New Bifunctional Antihyperlipidemic/Antioxidant Morpholine Derivatives.
Among the causal risk factors directly promoting the development of coronary and peripheral atherosclerosis are reactive oxygen species and elevated low-density lipoprotein plasma levels. We hereby designed new potent squalene synthase (SQS) inhibitors that may simultaneously tackle the oxidative stress induced by lipid peroxidation. Using previously developed morpholine derivatives as a starting point, we conducted extensive structural changes by either substituting or modifying the morpholine ring, aiming at an optimal SQS-antioxidant pharmacological profile. Compounds 2, 3, and 7 emerged as the most potent bifunctional analogues, displaying IC50 values for SQS inhibition of 0.014, 0.16, and 0.51 μΜ, respectively, and further significantly decreasing lipid peroxidation of hepatic microsomal membranes. The aforementioned activities were also confirmed in vivo since the most promising derivative 2 exhibited a remarkable antihyperlipidemic and antioxidant effect. In conclusion, rational drug design accompanied by structure-activity relationship studies led to compounds combining improved antioxidant and antihyperlipidemic activity that may serve as multifunctional agents against atherosclerosis.


Relationship between structure and function in distal tubule and collecting duct.
The relationship between structure and function in the distal tubule and collecting duct has been studied with morphologic and physiologic techniques, including morphometric analysis, to identify functionally distinct cell populations. The distal tubule, including the thick ascending limb (TAL) and the distal convoluted tubule (DCT), is involved in active reabsorption of sodium chloride. It is characterized by extensive invaginations of the basolateral plasma membrane, numerous mitochondria, and high Na-K-ATPase activity, features characteristic for an epithelium involved in active transport. Between the distal tubule and the collecting duct is a transition region, the connecting segment or the connecting tubule (CNT), which exhibits species differences with respect to both structure and function. The collecting duct includes the cortical (CCD), the outer medullary (OMCD), and the inner medullary (IMCD) collecting ducts. Principal cells are present throughout the collecting duct, whereas intercalated cells are located mainly in the CCD and OMCD. Morphometric analysis combined with micropuncture and microperfusion studies has provided evidence that the CNT and principal cells are responsible for potassium secretion in the connecting segment and the CCD. The OMCD is a main site of hydrogen ion secretion, and morphometric studies have provided evidence that the intercalated cells in this segment secrete hydrogen ion at least in the rat. Two configurations of intercalated cells exist in the CCD--a type A and a type B. The A cells are similar in ultrastructure to the intercalated cells in the OMCD and are believed to be involved in hydrogen ion secretion. The function of the B cells remains to be established. The inner two-thirds of the IMCD corresponds to the papillary collecting duct, which has a high permeability to urea. The relationship between structure and function in the IMCD has not been studied in detail. This review emphasizes the role of morphometric analysis in establishing the relationship between structure and function in the distal nephron.


Transcriptome Analysis Reveals Key Pathways and Candidate Genes Controlling Seed Development and Size in Ricebean (Vigna umbellata).
Ricebean (Vigna umbellata) is a lesser known pulse with well-recognized potential. Recently, it has emerged as a legume with endowed nutritional potential because of high concentration of quality protein and other vital nutrients in its seeds. However, the genes and pathways involved in regulating seed development and size are not understood in this crop. In our study, we analyzed the transcriptome of two genotypes with contrasting grain size (IC426787: large seeded and IC552985: small seeded) at two different time points, namely, 5 and 10 days post-anthesis (DPA). The bold seeded genotype across the time points (B5_B10) revealed 6,928 differentially expressed genes (DEGs), whereas the small seeded genotype across the time point (S5_S10) contributed to 14,544 DEGs. We have also identified several candidate genes for seed development-related traits like seed size and 100-seed weight. On the basis of similarity search and domain analysis, some candidate genes (PHO1, cytokinin dehydrogenase, A-type cytokinin, and ARR response negative regulator) related to 100-seed weight and seed size showed downregulation in the small seeded genotype. The MapMan and KEGG analysis confirmed that auxin and cytokinin pathways varied in both the contrasting genotypes and can therefore be the regulators of the seed size and other seed development-related traits in ricebeans. A total of 51 genes encoding SCF TIR1/AFB , Aux/IAA, ARFs, E3 ubiquitin transferase enzyme, and 26S proteasome showing distinct expression dynamics in bold and small genotypes were also identified. We have also validated randomly selected SSR markers in eight accessions of the Vigna species (V. umbellata: 6; Vigna radiata: 1; and Vigna mungo: 1). Cross-species transferability pattern of ricebean-derived SSR markers was higher in V. radiata (73.08%) than V. mungo (50%). To the best of our knowledge, this is the first transcriptomic study conducted in this crop to understand the molecular basis of any trait. It would provide us a comprehensive understanding of the complex transcriptome dynamics during the seed development and gene regulatory mechanism of the seed size determination in ricebeans.


[Diencephalic syndrome: An uncommon cause of malnutrition].
Diencephalic syndrome (DS) is a complex of signs and symptoms related to hypothalamic dysfunction. Its main features are emaciation despite normal energy intake and an alert appearance. This syndrome has been described in association with space-occupying lesions of the hypothalamic-optic chiasm region, mainly low-grade glioma, and less often with tumors in the proximity of the IV ventricle. Two patients with DS are reported. The first patient was an 8-month old boy with classical features of DS. Extensive investigation of malabsorption revealed no abnormalities and the first neurologic sign was a rotatory nystagmus. Magnetic resonance imaging (MRI) showed evidence of a hypothalamic tumor, which was identified after surgical resection as a pilocytic astrocytoma. The second patient was an adolescent boy who presented a 20-kg weight loss over a 6-month period and psychological disturbances. Gastrointestinal disease was ruled out as a cause of malnutrition. Because of a polydipsia-polyuria syndrome, manifest while the patient was hospitalized with a suspected diagnosis of anorexia nervosa, MRI of the brain was performed. Multiple intracranial lesions were revealed, mainly in the hypothalamus, and were identified as a disseminated disgerminoma. No neurologic signs or symptoms were present. The patients died 2 years and 1 year after diagnosis, respectively. Although DS is rare, it should be considered in severe failure to thrive or emaciation despite adequate food intake and normal absorptive function of the small bowel.


Optimal goals for statin use in patients with coronary artery disease.
Coronary artery disease is the largest cause of premature death in the Western world. Lipid-lowering therapy with statins has revolutionized the management of this condition over the past decade. Successive clinical trials have lowered the treatment bar for statin therapy in patients with coronary artery disease. In addition to traditional markers of efficacy such as low-density lipoprotein cholesterol, emerging targets such as C-reactive protein are becoming recognized as important therapeutic goals. This review focuses on the important contributions to the literature during the past year and provides an expert opinion of the therapeutic goals for statin therapy.


[Mesoptic vision in multi- and monofocal pseudophakia and in phakic control eyes].
The mesopic visual acuity (MVA) after intraocular lens (IOL) implantation is reduced compared to phakic patients of the same age. However, previous studies from our clinic have shown no significant MVA difference between multi- and monofocal IOLs. In the present study (with the patients matched exactly for age), this topic was reevaluated. We investigated three groups, each consisting of 28 persons, 51 to 60 years of age. Group I consisted of healthy phakic volunteers, group II of patients 3 months after cataract extraction and implantation of a monofocal posterior chamber IOL (Pharmacia 720A) and group III of patients 3 months after implantation of a diffractive multifocal posterior chamber IOL with biconvex optic configuration (3M 825X). The MVA was examined using the "Ocutrast," described by Nowak. The Ocutrast, a modification of the Mesoptometer II, provides a field luminance of 1 cd/m2 and a contrast of 1:23 between test optotype and background; the intensity of illumination under glare conditions amounts to 0.35 lx at the level of the pupil. The MVA without glare amounted to 0.50 +/- 0.12 (group I, healthy phakic eyes), 0.45 +/- 0.15 (group II, monofocal IOLs) and 0.32 +/- 0.11 (group III, multifocal IOLs). The MVA with glare amounted to 0.47 +/- 0.08 (group I), 0.35 +/- 0.12 (group II) and 0.24 +/- 0.10 (group III). Both for the MVA with and without glare there was a significant group difference (P < 0.05; two-factor analysis of covariance with repeated measurements). After implantation of diffractive multifocal IOLs of the presently used type (3M 825X), the mesopic vision--both with and without glare--is even more reduced than after monofocal IOL implantation. These findings are particularly relevant for aged pseudophakic car drivers, especially for driving at night.


Breast lipoma with central fat necrosis: case report.
Fat necrosis of the breast is a benign non-suppurative inflammatory process of adipose tissue that most commonly occurs as the result of minor breast trauma. We present a case of a 40-years-old female with fat necrosis in a breast lipoma. She presented with an overlapping mass on the lateral quadrants. Mammography showed Well delineated radiolucent mass with peripheral "egg-shell" calcifications, that appeared an hypoechoic mass with posterior shadowing on ultrasonography. A history of accidental trauma raises the suspicion of fat necrosis. Pathology is necessary when radiological findings simulate malignancy.


Comparison of methods for assessing abdominal adipose tissue from magnetic resonance images.
To compare the inter-rater and intra-rater reliability and analysis time of two methods for quantifying visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) volumes from magnetic resonance (MR) images. Ten subjects (BMI, 27.0 +/- 2.1 kg/m(2); 56 years of age +/- 4 years) underwent MR imaging of the abdomen. Ten transverse T1-weighted images were selected from each scan and analyzed using two software packages that differ in principle. The first method, ANALYZE version 5.0, represents the manual threshold method, and the second, HIPPO version 1.3, is based on the fuzzy clustering approach. Inter-rater reliability for each method was assessed by comparing the intra-class correlation coefficients (ICCs) for VAT and SAT results from two evaluators, and intra-rater reliability for each method was assessed by comparing ICCs for VAT and SAT analyses performed 1 week apart by the same evaluator. The total time for analysis also was compared between methods. The inter-rater reliability for VAT was greater with HIPPO than with ANALYZE (ICC = 0.996 vs. 0.828), whereas inter-rater reliability for SAT did not differ between methods (ICC = 0.975 and 0.987). The intra-rater reliability was equally high with HIPPO and ANALYZE for both VAT (ICC = 0.998 vs. 0.992) and SAT (ICC = 0.996 vs. 0.992). HIPPO required less than one-half as much analysis time as ANALYZE (15.9 +/- 4.4 vs. 36.5 +/- 8.2 minutes, p < 0.0001). HIPPO software appears advantageous for the quantification of VAT from multislice MR images because inter-rater results are more reliable, and it is more time-efficient than less automated methods.


Neuronal activity and amyloid plaque pathology: an update.
A breakthrough in Alzheimer's disease (AD) research came with the discovery of the link between activity-dependent release of amyloid-β (Aβ) from neurons and formation of amyloid plaques. Along with elucidating the cellular basis of behavioral-dependent fluctuations in Aβ levels in the brain, insights have been gained toward understanding the mechanisms that warrant selective vulnerability of various forebrain circuits to amyloid pathology. The notion of elevated activity as a source of excessive Aβ production and plaque formation is, however, in conflict with ample electrophysiological data, which demonstrate exceedingly intense activity (both intrinsic and synaptic) of neurons in several brain regions that are spared or marginally affected by amyloid plaques of AD. Thus, the link between the functional load of brain circuits and their vulnerability to amyloidosis, while evident, is also complex and remains poorly understood. Here, we discuss emerging data suggestive of a major role for super-intense synchronous activity of cortical and limbic networks in excessive Aβ production and plaque formation. It is proposed that dense recurrent wiring of associative areas prone to epileptic seizures might be of critical relevance to their higher susceptibility to plaque pathology and related functional impairments.


Shaping priorities in genetic medicine.
... Such moral problems raise the question whether society should make all or only some of the potential and existing genetic technologies widely available. Add to this the very real concern that the throng of products and services generated through this research has the potential to put significant further pressure on a health care system that already cannot provide adequate services to all persons. Given current restructuring of U.S. health services along the lines of managed health care, the need and desire of public and private parties to manage health resources aggressively by controlling costs and quality of care will call the question about what services to make available, to whom, on what basis. By what criteria should priorities be set? Should genetic services sought by only a few be made available? Should genetic screening and testing be offered for conditions for which there is no cure? Should specific groups be targeted for the distribution of genetic services? Are any genetic services more important than others? Where do genetic services fit relative to other health services? And -- the perennial question -- who should make these decisions? What does the newly emerging debate over the fair distribution of health resources mean for genetics?


Decreased production of interleukin-1 by monocytes from patients with lipoid nephrosis.
In order to further characterize monocyte function in patients with lipoid nephrosis (LN), we studied the production of interleukin-1 (IL-1). In this study we examined the ability of peripheral blood monocytes (PBM) from LN patients to produce this monokine in vitro under the stimulus of bacterial lipopolysaccharide (LPS). The levels of IL-1 were decreased in patients with LN compared with those in normal controls and lower in LN patients with nephrotic syndrome (NS) than in those without NS. In contrast, the values in IgA nephropathy (IgAN) patients with or without NS did not differ from normal subjects. The addition of indomethacin, an inhibitor of prostaglandin synthesis, partially restored this defect. These results suggest that the impaired IL-1 production of LN PBM is probably attributable, at least in part, to increased prostaglandin production and possibly influences the immune status of LN patients.


Intestinal metaplasia in the gastric remnant following resection for benign ulcer disease: a comparison between morphology and histochemistry.
A follow-up study including endoscopic examinations was performed on patients previously (23--27 years earlier) treated with partial gastrectomies for benign ulcer disease. From 106 patients satisfactory biopsy specimens were obtained. Intestinal metaplasia was diagnosed on pure morphologic findings and on histochemical findings (alcian blue at pH 2,5). The histochemical method was shown to be more sensitive. The significance of intestinal metaplasia in the carcinogenesis is briefly discussed.


Incidence, clinical characteristics and outcome of congestive heart failure as the initial presentation in patients with primary hyperthyroidism.
There are limited systematic data on the incidence, clinical characteristics and outcomes of congestive heart failure (CHF) in patients with hyperthyroidism. The aim of this study was to investigate the incidence, clinical characteristics and outcome of CHF as the initial presentation in patients with primary hyperthyroidism. The prevalence, clinical characteristics and outcome of CHF was studied in 591 consecutive patients (mean (SD) age 45 (1) years, 140 men) who presented with primary hyperthyroidism. CHF was the presenting condition in 34 patients (5.8%) with hyperthyroidism. The presence of atrial fibrillation at presentation (OR 37.4, 95% CI 9.72 to 144.0, p<0.001) was an independent predictor for the occurrence of CHF. Of the 34 patients with CHF, 16 (47%) had systolic left ventricular dysfunction with left ventricular ejection fraction (LVEF)<50%. They were predominantly male (OR 26.6, 95% CI 2.6 to 272.5, p = 0.006) and had a lower serum thyroxine level (OR 0.93, 95% CI 0.87 to 0.99, p = 0.044) than patients with preserved left ventricular systolic function. In these patients, LVEF (55 (4)% vs 30 (2)%, p<0.001) and New York Heart Association functional class (1.2 (0.1) vs 2.5 (0.2), p<0.001) improved significantly 3 months after achieving euthyroid status. Systolic left ventricular dysfunction (mean (SD) LVEF 38 (4)%) persisted on long-term follow-up in five no clinical parameter could be identified to predict the occurrence of this persistent cardiomyopathy (p>0.05). CHF was the initial clinical presentation in approximately 6% of patients with hyperthyroidism, and half of them had left ventricular systolic dysfunction. Symptoms of CHF subsided and LVEF improved after treatment for hyperthyroidism. Nonetheless, one-third of these patients developed persistent dilated cardiomyopathy.


Oocyte-specific expression of mouse Zp-2: developmental regulation of the zona pellucida genes.
The zona pellucida surrounds all mammalian oocytes and plays a vital role at fertilization and in early development. The genes that code for two of the mouse zona proteins (ZP2 and ZP3) represent a developmentally regulated set of genes whose expression serves as markers of mouse oocyte growth and differentiation. We previously characterized the single-copy Zp-3 gene and showed that its expression is oocyte specific and restricted to a narrow window of oocyte development. We now define the Zp-2 gene transcript and show that it is coordinately expressed with Zp-3 only during the 2-week growth phase of oogenesis that occurs prior to ovulation. Like Zp-3, the expression of Zp-2 is restricted to oocytes, and, although not detectable in resting oocytes, both ZP2 and ZP3 transcripts accumulate to become very abundant messengers in 50-microns-diameter oocytes. Ovulated eggs contain ZP2 and ZP3 transcripts which are 200 nucleotides shorter than those found in growing oocytes and have an abundance of less than 5% of the peak levels. In an attempt to understand the molecular details associated with the developmentally regulated, tissue-specific gene expression of the zona genes, the Zp-2 genetic locus has been characterized and its 5' flanking sequences have been compared with those of Zp-3. Both genes contain three short (8- to 12-base-pair) DNA sequences of 80 to 88% identity located within 250 base pairs of their transcription start sites.


Genome-Wide Identification and Analysis of Genes, Conserved between japonica and indica Rice Cultivars, that Respond to Low-Temperature Stress at the Vegetative Growth Stage.
Cold stress is very detrimental to crop production. However, only a few genes in rice have been identified with known functions related to cold tolerance. To meet this agronomic challenge more effectively, researchers must take global approaches to select useful candidate genes and find the major regulatory factors. We used five Gene expression omnibus series data series of Affymetrix array data, produced with cold stress-treated samples from the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/), and identified 502 cold-inducible genes common to both japonica and indica rice cultivars. From them, we confirmed that the expression of two randomly chosen genes was increased by cold stress in planta. In addition, overexpression of OsWRKY71 enhanced cold tolerance in 'Dongjin,' the tested japonica cultivar. Comparisons between japonica and indica rice, based on calculations of plant survival rates and chlorophyll fluorescence, confirmed that the japonica rice was more cold-tolerant. Gene Ontology enrichment analysis indicate that the 'L-phenylalanine catabolic process,' within the Biological Process category, was the most highly overrepresented under cold-stress conditions, implying its significance in that response in rice. MapMan analysis classified 'Major Metabolic' processes and 'Regulatory Gene Modules' as two other major determinants of the cold-stress response and suggested several key cis-regulatory elements. Based on these results, we proposed a model that includes a pathway for cold stress-responsive signaling. Results from our functional analysis of the main signal transduction and transcription regulation factors identified in that pathway will provide insight into novel regulatory metabolism(s), as well as a foundation by which we can develop crop plants with enhanced cold tolerance.


Distribution, diversity, and activities of sulfur dioxygenases in heterotrophic bacteria.
Sulfur oxidation by chemolithotrophic bacteria is well known; however, sulfur oxidation by heterotrophic bacteria is often ignored. Sulfur dioxygenases (SDOs) (EC 18.104.22.168) were originally found in the cell extracts of some chemolithotrophic bacteria as glutathione (GSH)-dependent sulfur dioxygenases. GSH spontaneously reacts with elemental sulfur to generate glutathione persulfide (GSSH), and SDOs oxidize GSSH to sulfite and GSH. However, SDOs have not been characterized for bacteria, including chemolithotrophs. The gene coding for human SDO (human ETHE1 [hETHE1]) in mitochondria was discovered because its mutations lead to a hereditary human disease, ethylmalonic encephalopathy. Using sequence analysis and activity assays, we discovered three subgroups of bacterial SDOs in the proteobacteria and cyanobacteria. Ten selected SDO genes were cloned and expressed in Escherichia coli, and the recombinant proteins were purified. The SDOs used Fe(2+) for catalysis and displayed considerable variations in specific activities. The wide distribution of SDO genes reveals the likely source of the hETHE1 gene and highlights the potential of sulfur oxidation by heterotrophic bacteria.


Two alternative promoters regulate the expression of lysinuric protein intolerance gene SLC7A7.
The human SLC7A7 gene encodes y(+)L amino acid transporter-1 (y(+)LAT-1). Mutations in the SLC7A7 coding region cause a rare recessive disorder, lysinuric protein intolerance (LPI). LPI is enriched in the Finnish population, where all patients carry the same homozygous founder mutation. Although the same LPI genotype is present in all patients, clinical symptoms vary greatly and thus show no genotype-phenotype correlation. In LPI, the transport of cationic amino acids is functionally affected at least at the basolateral membrane of the polarised epithelial cells in the kidney tubules and small intestine, although SLC7A7 is expressed much more widely. Interestingly, some LPI patients' tissues exhibit normal cationic amino acid transport despite the mutations leading to clinical phenotype. When studying the various manifestations of this monogenic disorder and the tissue specificity of the transport defect, it is crucial to know the transcriptional regulatory mechanisms of SLC7A7 gene. In this study, we have identified a novel alternative, TATA-box-containing promoter that plays a role in the tissue-specific regulation of the SLC7A7 gene expression. This newly found downstream promoter in front of exon 2 seems to be active in tissues with strong defects in the function of the transporter in patients with LPI.


Biochemical effects and growth inhibition in MCF-7 cells caused by novel sulphonamido oxa-polyamine derivatives.
The novel polyamine derivatives sulphonamido oxa-spermine (oxa-Spm) and sulphonamido oxa-spermidine (oxa-Spd) exhibited rapid cytotoxic action towards MCF-7 human breast cancer cells with IC50 values of 4.35 and 6.47 pM, respectively, after 24-h drug exposure. Neither compound is a substrate of serum amine oxidase. Both oxa-Spm and oxa-Spd caused cell shrinkage, as determined by phase-contrast microscopy. After incubation with 10 microM of either compound for 8 h, the cells underwent chromatin condensation and nuclear fragmentation. However, no clear DNA ladder was obtained by electrophoresis. The sulphonamido oxa-polyamine derivatives and especially oxa-Spd enhanced the activity of polyamine oxidase (PAO), an enzyme capable of oxidising N1-acetylated spermine and spermidine to spermidine and putrescine, respectively, generating cytotoxic H2O2 and 3-acetamidopropanal as by-products. The intracellular polyamine content was only marginally reduced in response to drug treatment. In conclusion, our data show that these novel sulphonamido oxa-polyamine derivatives possess high cytotoxic activity against MCF-7 cells and indicate that induction of PAO may mediate their cytotoxicity via apoptosis.


Phase reduction approach to elastohydrodynamic synchronization of beating flagella.
We formulate a theory for the phase reduction of a beating flagellum. The theory enables us to describe the dynamics of a beating flagellum in a systematic manner using a single variable called the phase. The theory can also be considered as a phase reduction method for the limit-cycle solutions in infinite-dimensional dynamical systems, namely, the limit-cycle solutions to partial differential equations representing beating flagella. We derive the phase sensitivity function, which quantifies the phase response of a beating flagellum to weak perturbations applied at each point and at each time. Using the phase sensitivity function, we analyze the phase synchronization between a pair of beating flagella through hydrodynamic interactions at a low Reynolds number.


Inhibition of hepatic apolipoprotein A-I gene expression by histamine.
In a recent high throughput analysis to identify drugs that alter hepatic apolipoprotein A-I (apo A-I) expression, histamine receptor one (H1) antagonists emerged as potential apo A-1 inducing drugs. Thus the present study was undertaken to identify some of the underlying molecular mechanisms of the effect of antihistaminic drugs on apo AI production. Apo A-I levels were measured by enzyme immunoassay and Western blots. Apo A-I mRNA levels were measured by reverse transcription real-time PCR using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA as the internal control. The effects of histamine and antihistamines on apo A-I gene were determined by transient transfection of plasmids containing the apo A-I gene promoter. Histamine repressed while (H1) receptor antagonist azelastine increased apo A-I protein and mRNA levels within 48 h in a dose-dependent manner. Azelastine and histamine increased and suppressed, respectively, apo A-I gene promoter activity through a peroxisome proliferator activated receptor α response element. Treatment of HepG2 cells with other H1 receptor antagonists including fexofenadine, cetirizine, and diphenhydramine increased apo A-I levels in a dose-dependent manner while treatment with H2 receptor antagonists including cimetidine, famotidine, and ranitidine had no effect. We conclude that H1 receptor signaling is a novel pathway of apo A1 gene expression and therefore could be an important therapeutic target for enhancing de-novo apo A-1 synthesis.


Effect of microbial fermentation on content of statin, GABA, and polyphenols in Pu-Erh tea.
Besides cancer prevention, the hypolipidemic effects of tea have been well studied in animals and humans. Recently, statin has been identified in Pu-erh tea extract. Clinical trials have confirmed that statin decreases the incidence of major coronary and cerebrovascular events and this may be due to its hypolipidemic and antiinflammatory effects. Since a good Pu-erh tea needs longer storage (10 years or more) of fermentation to enhance the flavor and fragrance, we screened microorganisms from two Pu-erh teas, 20 and 25 years old. Species of fungi and bacteria strains that contributed to a good taste of Pu-erh tea were isolated. The effect of fermentation was investigated by inoculating fresh tea leaves with individual strains of isolated microorganisms. Results showed that statin, total polyphenol content, and the scavenging activities of alpha,alpha-diphenyl-beta-picrylhydrazyl (DPPH) radicals increased during fermentation. Tea leaves inoculated with Streptomyces bacillaris strain R9 had the highest polyphenol content (3.3 mg/100 g) and scavenging ability to DPPH radicals (92%). Streptomyces cinereus strain Y11 was equally good for polyphenol content but yielded the highest amount of statin (1012 ng/g) after 42 days of fermentation. Interestingly, the statin content of fresh tea leaves fermented with strain R9 or Y11 after 180 days was much higher (4- and 8-fold, respectively) than that of the 25-year-old Pu-erh tea (513 ng/g) as measured by the HPLC method. Similarly, these two strains also increased the content of gamma-aminobutyric acid (GABA) 5.7- and 4.7-fold in tea fermented for 180 days as compared with the fresh leaves (1270 microg/g) and that were higher than that of the Pu-erh tea (4900 microg/g). Taken together, the present results indicate that tea short-term fermented with S. bacillaris or S. cinereus enhances the color and content of statin, GABA, and polyphenols.


Investigating the therapeutic role and molecular biology of curcumin as a treatment for glioblastoma.
Despite the aggressive standard of care for patients with glioblastoma multiforme, survival rates typically do not exceed 2 years. Therefore, current research is focusing on discovering new therapeutics or rediscovering older medications that may increase the overall survival of patients with glioblastoma. Curcumin, a component of the Indian natural spice, turmeric, also known for its antioxidant and anti-inflammatory properties, has been found to be an effective inhibitor of proliferation and inducer of apoptosis in many cancers. The goal of this study was to investigate the expanded utility of curcumin as an antiglioma agent. Using the PubMed MeSH database, we conducted a systematic review of the literature to include pertinent studies on the growth inhibitory effects of curcumin on glioblastoma cell lines based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 19 in vitro and five in vivo studies were analyzed. All of the studies indicated that curcumin decreased glioblastoma cell viability through various pathways (i.e. decrease in prosurvival proteins such as nuclear factor κB, activator protein 1, and phosphoinositide 3 kinase, and upregulation of apoptotic pathways like p21, p53, and executor caspase 3). Curcumin treatment also increased animal survival compared with control groups. Curcumin inhibits proliferation and induces apoptosis in certain subpopulations of glioblastoma tumors, and its ability to target multiple signaling pathways involved in cell death makes it an attractive therapeutic agent. As such, it should be considered as a potent anticancer treatment. Further experiments are warranted to elucidate the use of a bioavailable form of curcumin in clinical trials.


Isolation of Native Proanthocyanidins from Grapevine (Vitis vinifera) and Other Fruits in Aqueous Buffer.
Condensed tannins (also called proanthocyanidins) present in strategic tissues of fruits (outer pericarp and vascular bundles) were known as short polymers of flavan-3-ols. A pretreatment of the plant material (fruits from the grapevine, persimmon) with buffered ascorbic acid and Triton X-100 followed by acetone extraction provided native white fully depolymerizable tannins. Tannins are usually extracted with aqueous solvents and further purified, although artifactual oxidations occur, altering their physicochemical characteristics. Compared to artifactually oxidized tannins prepared according to standard protocols, white tannins (also called leukotannins) exhibit a higher degree of polymerization and a far lower polydispersity.


Another look at the molecular mechanism of the resistance of H5N1 influenza A virus neuraminidase (NA) to oseltamivir (OTV).
In the context of a recent pandemic threat by the worldwide spread of H5N1 avian influenza, the high resistance of H5N1 virus to the most widely used commercial drug, oseltamivir (Tamiflu), is currently an important research topic. Herein, molecular bases of the mechanism of H5N1 NA resistance to oseltamivir were elucidated using a computational approach in a systematic fashion. Using the crystal structure of the complex of H5N1 NA with OTV (PDB ID: 2hu0) as the starting point, the question, how mutations at His274 by both smaller side chain (Gly, Ser, Asn, Gln) and larger side chain (Phe, Tyr) residues influence the sensitivity of N1 to oseltamivir, was addressed and correlated with the experimental data. The smaller side chain residue mutations of His274 resulted in slightly enhanced or unchanged NA sensitivity to OTV, while His274Phe and His274Tyr reduced the susceptibility of OTV to N1. In contrast to the binding free energies, the net charges of Glu276 and Arg224, making charge-charge interactions with Glu276, were established to be more sensitive to detecting subtle conformational differences induced at the key residue Glu276 by the His274X mutations. This study provides deeper insights into the possibility of developing viable drug-resistant mutants.


The effects of resisted sled-pulling sprint training on acceleration and maximum speed performance.
The purpose of the present study was to examine the effects of resisted (RS) and un-resisted (US) sprint training programs on acceleration and maximum speed performance. Twenty-two male students (age 20.1+/-1.9 y, height 1.78+/-7 cm, and weight 73+/-2 kg) completed RS (n=11) or US (n=11) sprint training programs. The RS group followed a sprint-training program with 5 kg sled pulling and the US group followed a similar sprint-training program without sled pulling. The training program consisted of 4x20 m and 4x50 m maximal runs, and was applied 3 times/week for 8 weeks. Before and after the training programs the subjects performed a 50 m run and the running velocity of 0(-1)0 m, 10(-2)0 m, 20-40 m and 40-50 m was measured. In addition, stride length and stride frequency were evaluated at the 3(rd) stride in acceleration phase and between 42-47 m in maximum speed phase. The RS improved running velocity in the run sections 0(-1)0 m and 0(-2)0 m, while in US group the running velocity in all run sections in acceleration phase remained unchanged (p>0.05). In contrast, RS training had no effect on running velocity in maximum speed phase, whereas US improved running velocity in 20-40 m, 40-50 m, and 20-50 m run sections (p<0.05). Stride rate increased only after RS in acceleration phase (+7.1+/-2.9%; p<0.05), whereas stride length increased only after US in maximum speed phase (+5.5+/-2.5%; p<0.05). Sprint training with 5 kg sled pulling for 8 weeks improves acceleration performance (0(-2)0), while un-resisted sprint training improves performance in maximum speed phase (20-40) in non-elite athletes. It appears that each phase of sprint run demands a specific training approach.


Extracellular calcium triggers unique transcriptional programs and modulates staurosporine-induced cell death in Neurospora crassa.
Alterations in the intracellular levels of calcium are a common response to cell death stimuli in animals and fungi and, particularly, in the Neurospora crassa response to staurosporine. We highlight the importance of the extracellular availability of Ca2+ for this response. Limitation of the ion in the culture medium further sensitizes cells to the drug and results in increased accumulation of reactive oxygen species (ROS). Conversely, an approximately 30-fold excess of external Ca2+ leads to increased drug tolerance and lower ROS generation. In line with this, distinct staurosporine-induced cytosolic Ca2+ signaling profiles were observed in the absence or presence of excessive external Ca2+. High-throughput RNA sequencing revealed that different concentrations of extracellular Ca2+ define distinct transcriptional programs. Our transcriptional profiling also pointed to two putative novel Ca2+-binding proteins, encoded by the NCU08524 and NCU06607 genes, and provides a reference dataset for future investigations on the role of Ca2+ in fungal biology.


Brief report: glycemic control, quality of life, and school experiences among students with diabetes.
To investigate the relationships among perceived school experiences, diabetes control, and quality of life (QOL) in children with diabetes. Fifty-eight children with type 1 diabetes and their parents participated. The typical child was 12 years old, had diabetes for 5 years, and attended public, suburban, middle/junior high schools with 300-500 students. Children whose parents reported that school personnel received diabetes training showed significantly better diabetes control than those who reported untrained school personnel. Children who reported their classmates received diabetes training had significantly better QOL than those who reported untrained classmates. Children who reported greater flexibility in performing diabetes care tasks at school had significantly better diabetes control than children who reported less flexibility. Students with diabetes continue to face challenges at school. Training staff and classmates and allowing students the maximum appropriate flexibility in diabetes care appears beneficial for disease control and QOL.


Reliability analysis of nutrient removal from stormwater runoff with green sorption media under varying influent conditions.
To support nutrient removal, various stormwater treatment technologies have been developed via the use of green materials, such as sawdust, tire crumbs, sand, clay, sulfur, and limestone, as typical constituents of filter media mixes. These materials aid in the physiochemical sorption and precipitation of orthophosphates as well as in the biological transformation of ammonia, nitrates and nitrites. However, these processes are dependent upon influent conditions such as hydraulic residence time, influent orthophosphate concentrations, and other chemical species present in the inflow. This study aims to compare the physiochemical removal of orthophosphate by isotherm and column tests under differing influent conditions to realize the reliability of orthophosphate removal process with the aid of green sorption media. The green sorption media of interest in this study is composed of a 5:2:2:1 (by volume) mixture of cement sand, tire crumb, fine expanded clay, and limestone. Scenarios of manipulating the hydraulic residence time of the water from 18 min and 60 min, the influent dissolved phosphorus concentrations of 1.0 mg·L(-1) and 0.5 mg·L(-1), and influent water types of distilled and pond water, were all investigated in the column tests. Experimental data were compared with the outputs from the Thomas Model based on orthophosphate removal to shed light on the equilibrium condition versus kinetic situation. With ANOVA tests, significant differences were confirmed between the experimental data sets of the breakthrough curves in the column tests. SEM imaging analysis helps to deepen the understanding of pore structures and pore networks of meta-materials being used in the green sorption media. Life expectancy curves derived from the output of Thomas Model may be applicable for future system design of engineering processes.


Mycosis fungoides: an updated review of clinicopathologic variants.
Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma. Although it was first described in 1833, our understanding of this disease has continued to evolve. From a diagnostic perspective, the diagnosis of MF can be challenging particularly in the early stages of the disease, because of overlap between the histological features of early MF lesions and many other inflammatory dermatoses. Furthermore, there has been an emergence of numerous clinicopathologic and immunohistochemical variants of MF reported in the literature. Although the prognostic significance of some of the rare variants is still not fully understood, certain variants, such as folliculotropic and bullous MF, have demonstrated less indolent clinical courses compared with classic MF and necessitate aggressive therapeutic measures. Thus, it is important for dermatologists and dermatopathologists to be knowledgeable of the widely varied clinical, histological, and immunohistochemical presentations of MF to arrive at a prompt and accurate diagnosis and initiate appropriate treatment.


Performance Evaluation of the Verigene Gram-Positive and Gram-Negative Blood Culture Test for Direct Identification of Bacteria and Their Resistance Determinants from Positive Blood Cultures in Hong Kong.
A multicenter study was conducted to evaluate the diagnostic performance and the time to identifcation of the Verigene Blood Culture Test, the BC-GP and BC-GN assays, to identify both Gram-positive and Gram-negative bacteria and their drug resistance determinants directly from positive blood cultures collected in Hong Kong. A total of 364 blood cultures were prospectively collected from four public hospitals, in which 114 and 250 cultures yielded Gram-positive and Gram-negative bacteria, and were tested with the BC-GP and BC-GN assay respectively. The overall identification agreement for Gram-positive and Gram-negative bacteria were 89.6% and 90.5% in monomicrobial cultures and 62.5% and 53.6% in polymicrobial cultures, respectively. The sensitivities for most genus/species achieved at least 80% except Enterococcus spp. (60%), K.oxytoca (0%), K.pneumoniae (69.2%), whereas the specificities for all targets ranged from 98.9% to 100%. Of note, 50% (7/14) cultures containing K.pneumoniae that were missed by the BC-GN assay were subsequently identified as K.variicola. Approximately 5.5% (20/364) cultures contained non-target organisms, of which Aeromonas spp. accounted for 25% and are of particular concern. For drug resistance determination, the Verigene test showed 100% sensitivity for identification of MRSA, VRE and carbapenem resistant Acinetobacter, and 84.4% for ESBL-producing Enterobacteriaceae based on the positive detection of mecA, vanA, blaOXA and blaCTXM respectively. Overall, the Verigene test provided acceptable accuracy for identification of bacteria and resistance markers with a range of turnaround time 40.5 to 99.2 h faster than conventional methods in our region.


Acanthamoeba endophthalmitis during treatment for cutaneous disease in a renal transplant patient.
Acanthamoeba infections are difficult to diagnose and treat. We present a renal transplant patient who developed Acanthamoeba endophthalmitis on therapy with posaconazole and miltefosine for cutaneous acanthamobiasis. The patient was maintained on intracameral voriconazole injections, and oral azithromycin, fluconazole, and flucytosine. This case highlights novel presentations and treatments for acanthamoebic infection.


Testing the enemy release hypothesis: abundance and distribution patterns of helminth communities in grey mullets (Teleostei: Mugilidae) reveal the success of invasive species.
The abundance and aggregation patterns of helminth communities of two grey mullet hosts, Liza haematocheilus and Mugil cephalus, were studied across 14 localities in Atlantic and Pacific marine areas. The analysis matched parasite communities of (i) L. haematocheilus across its native and introduced populations (Sea of Japan and Sea of Azov, respectively) and (ii) the introduced population of L. haematocheilus with native populations of M. cephalus (Mediterranean, Azov-Black and Japan Seas). The total mean abundance (TMA), as a feature of the infection level in helminth communities, and slope b of the Taylor's power law, as a measure of parasite aggregation at the infra and component-community levels, were estimated and compared between host species and localities using ANOVA. The TMA of the whole helminth community in the introduced population of L. haematocheilus was over 15 times lower than that of the native population, but the difference was less pronounced for carried (monogeneans) than for acquired (adult and larval digeneans) parasite communities. Similar to the abundance pattern, the species distribution in communities from the invasive population of L. haematocheilus was less aggregated than from its native population for endoparasitic helminths, including adult and larval digeneans, while monogeneans showed a similar pattern of distribution in the compared populations of L. haematocheilus. The aggregation level of the whole helminth community, endoparasitic helminths, adult and larval digeneans was lower in the invasive host species in comparison with native ones as shown by differences in the slope b. An important theoretical implication from this study is that the pattern of parasite aggregation may explain the success of invasive species in ecosystems. Because the effects of parasites on host mortality are likely dose-dependent, the proportion of susceptible host individuals in invasive species is expected to be lower, as the helminth distribution in the invasive host was featured by a higher number of uninfected hosts and a shorter distribution tail when compared with native species.


Forced arterial suction thrombectomy of septic embolic middle cerebral artery occlusion due to infective endocarditis: an illustrative case and review of the literature.
In acute ischemic stroke patients with major intracranial vessel occlusion due to infective endocarditis, treatment modalities are not well established. A 40-year-old woman presented with acute stroke due to left middle cerebral artery occlusion. She was successfully treated with intra-arterial mechanical thrombectomy, and the subsequent clinical outcome was favorable. Pathological analysis of the retrieved clots showed septic thrombi containing gram-positive cocci. Based on literature review and the present case regarding treatment strategies for patients with septic embolic stroke, pharmacological thrombolysis might increase the risk of hemorrhagic complications, which might alter clinical outcome. Therefore, we can consider intra-arterial mechanical thrombectomy as a first-line treatment option in patients with acute stroke resulting from infective endocarditis.


Tumorigenic and Antiproliferative Properties of the TALE-Transcription Factors MEIS2D and MEIS2A in Neuroblastoma.
Neuroblastoma is one of only a few human cancers that can spontaneously regress even after extensive dissemination, a poorly understood phenomenon that occurs in as many as 10% of patients. In this study, we identify the TALE-homeodomain transcription factor MEIS2 as a key contributor to this phenomenon. We identified MEIS2 as a MYCN-independent factor in neuroblastoma and showed that in this setting the alternatively spliced isoforms MEIS2A and MEIS2D exert antagonistic functions. Specifically, expression of MEIS2A was low in aggressive stage 4 neuroblastoma but high in spontaneously regressing stage 4S neuroblastoma. Moderate elevation of MEIS2A expression reduced proliferation of MYCN-amplified human neuroblastoma cells, induced neuronal differentiation and impaired the ability of these cells to form tumors in mice. In contrast, MEIS2A silencing or MEIS2D upregulation enhanced the aggressiveness of the tumor phenotype. Mechanistically, MEIS2A uncoupled a negative feedback loop that restricts accumulation of cellular retinoic acid, an effective agent in neuroblastoma treatment. Overall, our results illuminate the basis for spontaneous regression in neuroblastoma and identify an MEIS2A-specific signaling network as a potential therapeutic target in this common pediatric malignancy.Significance: This study illuminates the basis for spontaneous regressions that can occur in a common pediatric tumor, with implications for the development of new treatment strategies. Cancer Res; 78(8); 1935-47. ©2018 AACR.


Feasibility of intercostal blood flow measurement by echo-Doppler technique in healthy subjects.
Intercostal artery blood flow supplies the external and internal intercostal muscles, which are inspiratory and expiratory muscles. Intercostal blood flow measured by the echo-Doppler (ED) technique has not previously been reported in humans. This study describes the feasibility of this measurement during free and loaded breathing in healthy subjects. Systolic, diastolic and mean blood flows were measured in the eighth dorsal intercostal space during free and loaded breathing using the ED technique. Flows were calculated as the product of the artery intraluminal surface and blood velocity. Ten healthy subjects (42 ± 13·6 years) were included. Integrated electromyogram (iEMG), arterial pressure, cardiac frequency and breathing pattern were also recorded. Mean blood flows were 3·5 ± 1·2 ml min-1 at rest, 6 ± 2·6 ml min-1 while breathing through a combined inspiratory and expiratory resistance and 4·0 ± 1·3 ml min-1 1 min after unloading. Diastolic blood flow was about one-third the systolic blood flow. The changes in blood flows were consistent with those in iEMG. No change in mean blood flow was observed between inspiration and expiration, suggesting a balance in the perfusion of external and internal muscles during breathing. In conclusion, ED is a feasible technique for non-invasive, real-time measurement of intercostal blood flow in humans. In healthy subjects, mean blood flow appeared tightly matched to iEMG activity. This technique may provide a way to assess the vascular adaptations induced by diseases in which respiratory work is increased or cardiac blood flow altered.


Novel route to triethylsilyl-substituted cyclopropanes.
Radical adducts of S-α-ketonyl dithiocarbonates (xanthates) to triethyl vinylsilane are converted into triethylsilyl-substituted cyclopropanes upon ozonolysis followed by exposure to 1,4-dibromobutane and Cs2CO3/18-crown-6 in refluxing acetonitrile. The sequence works best with phenacyl type adducts, and the use of the less bulky trimethysilyl (TMS) derivatives results in extensive desilylation.


A putative mediator of insulin action which inhibits adenylate cyclase and adenosine 3',5'-monophosphate-dependent protein kinase: partial purification from rat liver: site and kinetic mechanism of action.
A novel putative mediator of insulin action which acts to inhibit adenylate cyclase and cAMP-dependent protein kinase has been purified from livers of insulin-treated streptozotocin-diabetic rats. It was increased by short term (5-min) insulin injections in vivo and purified several thousand-fold by Sephadex and HPLC. Its mol wt was somewhat larger (2500) than previous mediators identified, and it was more hydrophobic in character. Its mechanism of action or adenylate cyclase was determined and found to be chiefly directed against the catalytic subunit. Its action on the cAMP-dependent protein kinase was found to be competitive with regard to protein substrate, but noncompetitive with regard to ATP and cAMP. Its relationship to other putative insulin mediators and the mechanism of insulin action is discussed.


Acute pancreatitis and cholangitis: a complication caused by a migrated gastrostomy tube.
Percutaneous endoscopic gastrostomy (PEG) is generally considered safe with a low rate of serious complications. However, dislocation of the PEG-tube into the duodenum can lead to serious complications. An 86-year old Japanese woman with PEG-tube feeding sometimes vomited after her family doctor replaced the PEG-tube without radiologic confirmation. At her hospitalization, she complained of severe tenderness at the epigastric region and the PEG-tube was drawn into the stomach. Imaging studies showed that the tip of PEG-tube with the inflated balloon was migrated into the second portion of the duodenum, suggesting that it might have obstructed the bile and pancreatic ducts, inducing cholangitis and pancreatitis. After the PEG-tube was replaced at the appropriate position, vomiting and abdominal tenderness improved dramatically and laboratory studies became normal immediately. Our case suggests that it is important to secure PEG-tube at the level of skin, especially after replacement.


Small-caliber afferent inputs produce a heterosynaptic facilitation of the synaptic responses evoked by primary afferent A-fibers in the neonatal rat spinal cord in vitro.
1. The effect of brief primary afferent inputs on the amplitude and duration of the synaptic potentials evoked in ventral horn (VH) neurons by the activation of other unconditioned primary afferents was studied by current-clamp intracellular recording in the neonatal rat hemisected spinal cord in vitro. Low-frequency (1 Hz) trains of stimulation were applied to a lumbar dorsal root (Conditioning root) for 20-30 s. Test excitatory synaptic potentials (EPSPs) were evoked by single electrical shocks applied to an adjacent Test dorsal root. 2. Test and Conditioning inputs were generated at stimulation strengths sufficient to activate A beta-, A delta- and C-afferent fibers successively. At A delta- and C-fiber strength the EPSPs lasted for 4-6 s, and, during the repetitive Conditioning inputs, these summated to produce a progressively incrementing cumulative depolarization that slowly decayed back to the control Vm over tens of seconds. 3. Dorsal root conditioning produced heterosynaptic facilitation, defined as an enhancement of Test EPSPs above their DC matched controls, in 7 out of 20 neurons. To facilitate the unconditioned afferent input, the intensity of conditioning stimulation had to exceed the threshold for the activation of thin myelinated (A delta) afferents: conditioning at A beta-fiber strength had no effect, whereas A delta- and C-fiber strength conditioning were equally effective. 4. Heterosynaptic facilitation of only A beta- or A delta-fiber-evoked Test EPSPs was observed, no enhancement of C-fiber strength Test EPSPs could be demonstrated. The facilitation manifested as increases in the EPSP peak amplitude, area or the number of action potentials evoked. 5. Conditioning trials that produced heterosynaptic facilitation generated cumulative depolarizations larger than those produced by ineffective conditioning trials (9.1 +/- 3.1 vs. 3.3 +/- 0.5 mV after 20 s conditioning at resting Vm, mean +/- SE, n = 6 and 13, respectively; P < 0.05). The slope of the Vm trajectory during the summation of the conditioning EPSPs was higher in trials resulting in heterosynaptic facilitation, at 0.31 +/- 0.10 mV/s in neurons with heterosynaptic facilitation and 0.06 +/- 0.02 mV/s in cells without heterosynaptic facilitation (P < 0.05). 5. Four of the 20 VH neurons in our sample responded to A delta/C-fiber conditioning with action-potential windup: all 4 also displayed heterosynaptic facilitation. 6. Heterosynaptic facilitation decayed after the completion of the conditioning stimulus with a time course that was parallel to but not superimposable on that of the slow Vm depolarization evoked by the conditioning.(ABSTRACT TRUNCATED AT 400 WORDS)


Changes in tobacco use at the early stage of the COVID-19 pandemic: Results of four cross-sectional surveys in Hong Kong.
Changes in tobacco use since the COVID-19 outbreak differed by countries and little is known about changes in the use of specific tobacco products. We analyzed data from four cross-sectional telephone/online surveys from April to June 2020 to investigate such changes since the 1st and 2nd wave outbreaks (February to April 2020) in Hong Kong. The respondents were 1595 adults (83.2% male) who used tobacco before the COVID-19 outbreak from our previous intervention study and surveys. We investigated the changes in tobacco use, intention to quit and quit attempts during the outbreak. About two-thirds (65.3%) of respondents reported no change in overall tobacco use, while 23.1% used less (including cessation) and 11.6% used more, resulting in a net decrease of 11.5 percentage points. A greater net decrease was observed for cigarettes (14.3% points) than heated tobacco products (HTPs, 3.3% points) and electronic cigarettes (e-cigarettes, 2.5% points). Decreased use was mainly due to the more extended stay at home (63.2%), health considerations (52.6%) and mask-wearing (47.4%), while increased use was for passing time (75.0%) and releasing stress (46.4%). Eight percent of cigarette, HTP and e-cigarette users reported a higher intention to quit since the pandemic outbreak. Nineteen percent of tobacco users (176/948) attempted to quit during the pandemic. Only 2.9% (46/1569) were abstinent at the time of the survey. Overall tobacco use decreased after the first two waves of the COVID-19 outbreak in Hong Kong. A greater proportion of cigarette users decreased use than HTP and e-cigarette users. Given the different methods used in the four surveys, future studies should aim for a large and representative sample.


An atypical presentation of visual hallucinatory experiences following prolonged blindness.
We report a patient with long-standing blindness experiencing both simple and complex visual hallucinations secondary to a cortical arteriovenous malformation (AVM). The hallucinations were located in the right visual field corresponding to the contra-lateral site of cortical damage. This case contributes to our understanding of neurophysiological mechanisms underlying visual hallucinations and ongoing research investigating the phenomenology of hallucinations with respect to the cause and localization of neural damage.


A Direct Refractory Die Technique for Cast Gold Restorations.
Fabricating accurate cast gold restorations can be challenging for both clinicians and laboratory technicians. Removing the wax pattern from the master die often distorts the pattern, which, in turn, compromises the overall fit and marginal adaptation of the casting. This article demonstrates a laboratory technique in which the final restoration is cast directly on the refractory die without removing the wax pattern. Thus, distortion of the wax pattern is avoided, enabling the production of superbly fitting gold castings for both intracoronal and extracoronal restorations.


Primary treatment of 50 patients with high-tension electrical injuries. I. Fluid resuscitation.
Fifty patients with high-tension electrical injuries referred for primary treatment to the Burn Center at the University of Uppsala, Sweden during the period 1969 to 1982, have been investigated with special regard to the resuscitation and early complications from internal organs. Seven patients (14%) died, five of them prior to 1974, one in cardiac infarction and four in renal failure. Two died after 1974, one in cardiac infarction and the other in severe shock (98% burn). In 1974 an acute intensive prevention of renal failure was instituted based on forced fluid resuscitation, vasodilators, and supply of alkaline solutions in order to avoid myoglobin and hemoglobin casts in the kidneys. Some degree of renal dysfunction (diminished GFR, a lowered concentration capacity, and an increased fractionate excretion of sodium) was often seen but could usually be reversed without problems. Three patients who developed anuria were successfully treated with hemodialysis. During the years 1974-1982, when the "prevention scheme of renal failure" was applied, all patients with high-tension electrical injury combined with severe myoglobinuria (13 patients) have been successfully treated. 60% of the patients had normal ECG. Five of the seven fatal cases had ST-T abnormalities and two of these patients showed cardiac infarction at autopsy. Early angiography was performed in 20 patients (40%). Obliterated arteries were diagnosed on different levels in 18 extremities in ten patients. The arteriography very precisely indicated the level of amputation of the seriously injured extremities.(ABSTRACT TRUNCATED AT 250 WORDS)


Dermoscopy diagnosis of cancerous lesions utilizing dual deep learning algorithms via visual and audio (sonification) outputs: Laboratory and prospective observational studies.
Early diagnosis of skin cancer lesions by dermoscopy, the gold standard in dermatological imaging, calls for a diagnostic upscale. The aim of the study was to improve the accuracy of dermoscopic skin cancer diagnosis through use of novel deep learning (DL) algorithms. An additional sonification-derived diagnostic layer was added to the visual classification to increase sensitivity. Two parallel studies were conducted: a laboratory retrospective study (LABS, n = 482 biopsies) and a non-interventional prospective observational study (OBS, n = 63 biopsies). A training data set of biopsy-verified reports, normal and cancerous skin lesions (n = 3954), were used to develop a DL classifier exploring visual features (System A). The outputs of the classifier were sonified, i.e. data conversion into sound (System B). Derived sound files were analyzed by a second machine learning classifier, either as raw audio (LABS, OBS) or following conversion into spectrograms (LABS) and by image analysis and human heuristics (OBS). The OBS criteria outcomes were System A specificity and System B sensitivity as raw sounds, spectrogram areas or heuristics. LABS employed dermoscopies, half benign half malignant, and compared the accuracy of Systems A and B. System A algorithm resulted in a ROC AUC of 0.976 (95% CI, 0.965-0.987). Secondary machine learning analysis of raw sound, FFT and Spectrogram ROC curves resulted in AUC's of 0.931 (95% CI 0.881-0.981), 0.90 (95% CI 0.838-0.963) and 0.988 (CI 95% 0.973-1.001), respectively. OBS analysis of raw sound dermoscopies by the secondary machine learning resulted in a ROC AUC of 0.819 (95% CI, 0.7956 to 0.8406). OBS image analysis of AUC for spectrograms displayed a ROC AUC of 0.808 (CI 95% 0.6945 To 0.9208). By applying a heuristic analysis of Systems A and B a sensitivity of 86% and specificity of 91% were derived in the clinical study. Adding a second stage of processing, which includes a deep learning algorithm of sonification and heuristic inspection with machine learning, significantly improves diagnostic accuracy. A combined two-stage system is expected to assist clinical decisions and de-escalate the current trend of over-diagnosis of skin cancer lesions as pathological. FUND: Bostel Technologies. Trial Registration clinicaltrials.gov Identifier: NCT03362138.


AlGaInAs intracavity selective absorber for an efficient high-power Nd:YAG laser operation at 1.44 microm.
We develop an AlGaInAs material as a promising intracavity selective absorber for an efficient high-power Nd:YAG laser at 1.44 microm. With the ISA to suppress operation at 1.06 microm, the output coupler at 1.44 microm can be straightforwardly designed and optimized. At a pump power of 16 W an output power of 2.5 W at 1.44 microm, with a slope efficiency of 23%, was achieved.


Synthesis of Wafer-Scale Monolayer Pyrenyl Graphdiyne on Ultrathin Hexagonal Boron Nitride for Multibit Optoelectronic Memory.
Graphdiyne is a new two-dimensional carbon allotrope with many attractive properties and has been widely used in various applications. However, the synthesis of large-area, high-quality, and ultrathin (especially monolayer) graphdiyne and its analogues remains a challenge, hindering its application in optoelectronic devices. Here, a wafer-scale monolayer pyrenyl graphdiyne (Pyr-GDY) film is obtained on hexagonal boron nitride (hBN) via a van der Waals epitaxial strategy, and top-floating-gated multibit nonvolatile optoelectronic memory based on Pyr-GDY/hBN/graphene is constructed, using Pyr-GDY as a photoresponsive top-floating gate. Benefiting from the excellent charge trapping capability and strong absorption of the graphdiyne film, as well as the top-floating-gated structure and the ultrathin hBN film used in the device, the optoelectronic memory exhibits high storage performance and robust reliability. A huge difference in the current between the programmed and erased states (>26 μA μm-1 at Vds = 0.1 V) and a prolonged retention time (>105 s) enable the device to achieve multibit storage, for which eight and nine distinct storage levels (3-bit) are obtained by applying periodic gate voltages and optical pulses in the programming and erasing processes, respectively. This work provides an important step toward realizing versatile graphdiyne-based optoelectronic devices in the future.


Gliomas in children.
Gliomas are the most common brain tumor in children and represent nearly 50 % of all pediatric central nervous system (CNS) tumors. They are a heterogeneous group of diseases, ranging from highly malignant and frequently fatal to histologically benign and curable by surgery alone. A uniform treatment approach to these tumors is not practical, due to their histological and biological heterogeneity. Low-grade gliomas (LGGs) are best treated with maximally safe surgical resection, generally achievable for hemispheric or cerebellar locations. Patients with deep midline, optic pathway/hypothalamic, and brain stem locations should undergo subtotal resection or biopsy only. If a complete resection is not feasible, subtotal resection followed by adjuvant chemotherapy or radiotherapy is the standard approach; however, observation alone with serial neuroimaging is used in some asymptomatic, surgically inaccessible lesions. Chemotherapy is used first-line in cases of residual or progressive disease, to avoid or delay radiation therapy and its associated side effects. Regimens demonstrating objective responses and increased progression free survival (PFS) include carboplatin and vincristine (CV), thioguanine/procarbazine/CCNU/vincristine (TPCV), or weekly vinblastine. High-grade gliomas (HGGs) are less common in children than in adults, though are similar in their aggressive clinical behavior, resistance to therapy, and dismal outcomes. There is not a single "standard of care" therapy for non-metastatic HGGs, but generally accepted is an aggressive attempt at a complete surgical resection, followed by multimodality therapy with focal radiation and chemotherapy. The use of temozolomide (TMZ) during and following radiotherapy is common, though it appeared not to improve the outcome in a cooperative group clinical trial when compared to an historical control cohort. The angiogenesis inhibitor bevacizumab, used alone or in combination with irinotecan, is also commonly used as maintenance therapy after radiation. Current trials are prospectively comparing TMZ to newer agents (vorinostat, bevacizumab) in a randomized phase II trial. Brainstem gliomas are a unique category of childhood gliomas. Approximately 80 % of childhood brainstem gliomas arise within the pons as diffuse intrinsic pontine gliomas (DIPG). When biopsied, these are usually HGGs and carry a dismal prognosis. Standard therapy is focal radiation (54-58 Gy), preferably on a clinical trial testing concurrent chemotherapy or biologic agent. No standard chemotherapy agent has impacted survival. The remaining 20 % of brainstem gliomas are low-grade, arise in the midbrain, dorsal medulla, or cervicomedullary junction, and are indolent in nature with a much better prognosis. Improvement in the outcome of all childhood gliomas will require increased knowledge of the underlying biology of these tumors, in order to treat with more biologically based and precise therapies.