Vasodilator therapy in children: acute and chronic effects in children with left ventricular dysfunction or mitral regurgitation.
To determine the acute and chronic effects of vasodilator therapy in children, vasodilator therapy was evaluated in 13 children (aged 0.2 to 14.5 years) with severe left ventricular dysfunction or mitral regurgitation. In seven children, nitroprusside increased cardiac index by an average of 33% (P less than .01) and increased stroke index by 29% (P less than .01). In eight children, hydralazine caused a 31% increase in cardiac index (P less than .01) and a 27% increase in stroke index (P less than .02). Ten children received chronic oral vasodilator therapy and were followed for 5.7 +/- 1.4 (SEM) months. Early clinical improvement was observed in every child. Symptoms of heart failure diminished in all, and five children became entirely asymptomatic. A significant (P less than .05) improvement was noted in growth velocity, respiratory rate, heart size, and incidence of gallop rhythm after 1 month of therapy. The duration of the beneficial response to vasodilator therapy varied considerably, however, and significant improvement for the group was not found after 1 month. Four children had sustained clinical improvement for 6 months or longer, but the others experienced recurrent heart failure within 1 to 4 months.


Islet cells-tight junctions: changes in its number induced by glucose.
Cell-tight junctions were counted in rat isolated islets incubated for different periods of time in the presence of different extracellular glucose concentrations. The number of tight junctions increased as a function of the length of the incubation period and the concentration of glucose. These results would suggest the involvement of tight junctions in the regulatory process of glucose-induced insulin secretion. Key words: Tight junctions, islet cell ultrastructure, isolated islets, islet incubation, glucose-induced insulin secretion, islet cell secretory function.


Measurements of cortical thickness in experimentally created endosteal bone lesions: a comparison of radiography, CT, MR imaging, and anatomic sections.
The purpose of this study was to evaluate the accuracy of cortical measurements of experimentally created endosteal cortical lesions and to assess the sensitivity of radiography, CT, and MR imaging in the detection and measurement of such lesions. Thirty-six cortical lesions were created in three fresh cadaveric femurs. After performing radiography, CT, and MR imaging, we sectioned the specimens in the axial plane. We then measured the remaining cortex at the lesions and the normal cortex adjacent to the lesions on all images and corresponding anatomic sections. The measurements of thickness of the cortex as seen with the different imaging methods and the anatomic sections were compared. Measurements were repeated to evaluate the influence of different window settings on the MR imaging measurements. When measured on radiographs, cortical thickness was overestimated in 58% of lesions. With CT, cortical thickness was overestimated by 0-15% in 94% of all lesions. With MR imaging, cortical thickness was uniformly underestimated by 3-17%. Measurements made on MR images varied according to different window settings. The proton density-weighted sequence yielded the highest sensitivity in the detection of shallow cortical lesions; the T1-weighted spin-echo sequence was the least sensitive of the MR sequences. In our cadaveric study, cortical thickness in the presence of endosteal lesions was overestimated on radiographs and CT scans and underestimated on MR images. Measurements derived from MR imaging are strongly influenced by the window setting. MR imaging with the proton density-weighted sequence is the most sensitive for detection of shallow cortical lesions and is more sensitive than CT.


Primary Diffuse Large B Cell Lymphoma Mimicking Hyperplastic Reactive Lesion (Lymphoma of the Oral Cavity).
To report a case of a challenging oral diagnosis involving a primary diffuse large B cell lymphoma of the oral cavity mimicking a hyperplastic reactive lesion. A 72-year-old male patient was referred to the Department of Stomatology presenting a proliferative nodular lesion in the anterior region of the mandible involving the anterior teeth. The clinical examination revealed anterior teeth affected by periodontal disease, suggesting the nodular cession hyperplastic reaction. Incisional biopsy was performed under local anesthesia. The histopathological examination revealed a diffuse proliferation of atypical large lymphoid cells. The tumor cells showed immunopositivity for CD20 and Ki67 (100%) and negativity for CD3, CD30, and CD15. The diagnosis of diffuse large B cell lymphoma was established. The patient underwent chemotherapy and progressed to death after nine months. Lymphomas of the oral cavity are rare and may have nonspecific clinical features, mimicking inflammatory and reactive lesions. Therefore, a detailed clinical evaluation associated with histopathological and immunohistochemical analysis should be performed to enable early and accurate diagnoses in suspected oral lesions.


Gallic acid exhibits risks of inducing muscular hemorrhagic liposis and cerebral hemorrhage--its action mechanism and preventive strategy.
Gallic acid (3,4,5-trihydroxybenzoic acid) (GA) occurs in many plants. The adverse effects of GA are seldom cited. GA (6-14 μM) provoked the hemorrhagic liposis of the cervical muscles and intracranial hemorrhage. The cause of these pathological events and the method for prevention are still lacking. Using the chicken embryo model and some selected nutraceutics such as folate, glutathione (GSH), N-acetylcysteine, and vitamin E (Vit E), we carried out this study. Results revealed that the action mechanism of GA involved (i) inducing hypoxia with upregulated gene hif-1α and downregulated ratio vegf-r2/vegf-a, leading to dys-vascularization and myopathy; (ii) impairing cytochrome c oxidase; (iii) stimulating creatine kinase and lactate dehydrogenase release; (iv) eliciting carnitine accumulation and liposis via downregulating gene CPT1; (v) suppressing superoxide dismutase and stimulating NO, H2O2, and malondialdehyde; and (vi) depleting erythrocytic and tissue GSH, resulting in hemorrhage. When both Vit E and GSH were applied to the day 1 chicks, a better alleviation effect was revealed. Conclusively, GA potentially exhibits adverse effect by eliciting hemorrhagic liposis of cervical muscles and cerebral hemorrhage. Supplementation with GSH, Vit E, and N-acetylcysteine is able to ameliorate these adverse effects, warranting the importance of restricting the clinical phytotherapeutic doses of GA and related compounds.


Beta-adrenoceptor antagonist activity of bivalent ligands. 1. Diamide analogues of practolol.
Two series of bivalent ligands (P-X-P) containing the (R,S)-3-[(4-aminoaryl)oxy]-1-(isopropylamino)propan-2-ol pharmacophore and a connecting alpha,omega-dicarbonylpoly(methylene) [X = -OC(CH2)nCO-] or alpha,omega-N,N'-bis(carbonylmethylene) polymethylenediamine [X = -OCCH2NH(CH2)nNHCH2CO-] spanner were synthesized and evaluated for beta-adrenoceptor antagonist activity in rat heart and lung membrane preparations. The target compounds were obtained as a mixture of stereoisomers in modest yields by using a three to four step sequence beginning with N-benzylpractolol. The results from the competitive binding studies indicated that binding affinity increased by a factor of up to 160 by increasing the length of the group spanning the pharmacophore moieties. Modest increases in cardioselectivity were also obtained. The data suggest that further increases in spanner length and lipophilicity and optical resolution may improve the potential of a labeled bivalent beta 1-adrenoceptor antagonist to function as a myocardial imaging agent.


Bacterial study of autopsy specimens.
Autopsy reports were reviewed for the detection of infectious diseases at autopsy and to determine what extent an infectious process was involved in the patient's death. The present study was performed to analyze bacterial data of autopsy specimens in Siriraj Hospital during 1992-1999. Various autopsy specimens were cultured including heart blood, bronchus, lung, brain, cerebro-spinal fluid, pleural fluid, ascitic fluid, peritoneal fluid, liver, kidney, pericardial fluid, spleen and gall bladder From 781 autopsy specimens 502 (64.28%) were positive for bacterial pathogens. The five most common bacterial pathogens isolated from the present study were nonfermentative gram-negative rods followed by Klebsiella pneumoniae, Salmonella serogroup E, Escerichia coli and Acinetobacter anitratus, respectively. The ante mortem diagnosis by clinicians was correct 56% regarding to retrospectively analysis of septicemia/septic shock versus autopsy culture from heart blood


Neural interactions mediating conflict control and its training-induced plasticity.
Cognitive control is of great plasticity. Training programs targeted on improving it have been suggested to yield neural changes in the brain. However, until recently, the relationship between training-induced brain changes and improvements in cognitive control is still an open issue. Besides, although the literature has attributed the operation of cognitive control to interactions between large-scale networks, the neural pathways directly associated with it remain unclear. The current study aimed to examine these issues by focusing on conflict processing. In particular, we employed a training program with a randomized controlled design. The main findings were as follows: 1) In behavior, the training group showed reduced conflict effect after training, relative to the control group; 2) In the pretest stage, the behavioral conflict effect was negatively correlated with a number of neural pathways, including the connectivity from the cingulo-opercular network (CON) to the cerebellum and to sub-regions of the dorsal visual network; 3) increase in the connectivity strength of several network interactions, such as the connectivity from the CON to the cerebellum and to the primary visual network, was associated with behavioral gains; 4) there were also nonlinear correlations between behavioral and neural changes. These findings highlighted a critical role of the modulation of CON on other networks in mediating conflict processing and its plasticity, and raised the significance of investigating nonlinear relationship in the field of cognitive training.


Heparin binding by murine recombinant prion protein leads to transient aggregation and formation of RNA-resistant species.
The conversion of cellular prion protein (PrP(C)) into the pathological conformer PrP(Sc) requires contact between both isoforms and probably also requires a cellular factor, such as a nucleic acid or a glycosaminoglycan (GAG). Little is known about the structural features implicit in the GAG-PrP interaction. In the present work, light scattering, fluorescence, circular dichroism, and nuclear magnetic resonance (NMR) spectroscopy were used to describe the chemical and physical properties of the murine recombinant PrP 23-231 interaction with low molecular weight heparin (LMWHep) at pH 7.4 and 5.5. LMWHep interacts with rPrP 23-231, thereby inducing transient aggregation. The interaction between murine rPrP and heparin at pH 5.5 had a stoichiometry of 2:1 (LMWHep:rPrP 23-231), in contrast to a 1:1 binding ratio at pH 7.4. At binding equilibrium, NMR spectra showed that rPrP complexed with LMWHep had the same general fold as that of the free protein, even though the binding can be indicated by significant changes in few residues of the C-terminal domain, especially at pH 5.5. Notably, the soluble LMWHep:rPrP complex prevented RNA-induced aggregation. We also investigated the interaction between LMWHep and the deletion mutants rPrP Δ51-90 and Δ32-121. Heparin did not bind these constructs at pH 7.4 but was able to interact at pH 5.5, indicating that this glycosaminoglycan binds the octapeptide repeat region at pH 7.4 but can also bind other regions of the protein at pH 5.5. The interaction at pH 5.5 was dependent on histidine residues of the murine rPrP 23-231. Depending on the cellular milieu, the PrP may expose different regions that can bind GAG. These results shed light on the role of GAGs in PrP conversion. The transient aggregation of PrP may explain why some GAGs have been reported to induce the conversion into the misfolded, scrapie conformation, whereas others are thought to protect against conversion. The acquired resistance of the complex against RNA-induced aggregation explains some of the unique properties of the PrP interaction with GAGs.


Nitrendipine in older patients with isolated systolic hypertension: second progress report on the SYST-EUR trial.
This report from the double-blind placebo-controlled SYST-EUR trial investigated whether modern antihypertensive drugs are suitable for maintaining long-term BP control in older (> or = 60 years of age) subjects with isolated systolic hypertension (SBP 160-219 mmHg and DBP < 95 mmHg). Active treatment consisted of nitredipine (10-40 mg/day) with the possible addition of enalapril (5-20 mg/day) and hydrochlorothiazide (12.5-25 mg/day), if necessary to reduce SBP to < 150 mmHg and by > or = 20 mmHg. Matching placebos were used in the control group. This analysis was restricted to 18 months of follow-up. The placebo (n = 456) and active treatment (n = 485) groups had similar characteristics at randomisation (sitting pressure 176/85 mmHg; age 73 years). SBP fell (P < 0.001) on average 10 mmHg more on active treatment than on placebo and DBP 4 mmHg more. Fewer patients remained on monotherapy in the placebo than in the active treatment group (P < 0.001); on placebo the second and third line medications were started earlier (P < 0.001). Nitrendipine tablets were discontinued in nine patients on placebo and in 29 patients assigned to active treatment (P < 0.001). In conclusion, a significant BP reduction can be achieved and maintained in older patients with isolated systolic hypertension treated with a calcium antagonist (associated with a converting-enzyme inhibitor and a thiazide, where necessary). Whether this BP reduction results in a clinically meaningful decrease of cardiovascular complications is under investigation.


Genistein suppresses retinoblastoma cell viability and growth and induces apoptosis by upregulating miR-145 and inhibiting its target ABCE1.
Retinoblastoma is a rare malignancy in developing retina tissue in children with limited therapeutic options. Here we sought to investigate the potential clinical value of genistein, the phytoestrogen derived from the soybean with antioxidant activity, in this disease. Retinoblastoma cells were treated with genistein. Colony formation capacity was measured with soft agar assay. MiRNA was identified with microarray. Post-transcriptional regulation of gene expression was determined with dual-luciferase reporter assay. Cell proliferation and apoptosis were measured with the Cell Counting Kit-8 (CCK-8) method and annexin V-propidium iodide (PI) staining. The xenograft model was administered with genistein, and tumor growth was monitored. The results showed that genistein treatment significantly suppressed proliferation and anchorage-independent growth of the human retinoblastoma cell line Y79 in vitro, which partially attributed to apoptosis induction. MicroRNA array screening identified that miR-145 was upregulated by genistein. Through post-transcriptional regulation of ABCE1, miR-145 functioned as a key downstream effector in genistein-mediated tumor suppression in retinoblastoma. Moreover, the in vivo data consolidated the inhibitory effect of genistein against retinoblastoma xenograft via upregulation of miR-145. The data highlighted the therapeutic potency of genistein in this disease and showed that further clinical investigation is warranted.


Structural implications of mutations in the pea SYM8 symbiosis gene, the DMI1 ortholog, encoding a predicted ion channel.
The Pisum sativum SYM8 gene plays an essential part in both rhizobial and mycorrhizal symbioses. Mutation of sym8 in the original type line R25 blocks nodulation, mycorrhization, and Nod-factor-induced calcium spiking, an early component of the nodulation signaling pathway. We describe four new sym8 alleles of pea, which fall into the same complementation group as R25. The sym8 mutants are phenotypically similar to Medicago truncatula dmi1 mutants and map to a syntenic location. We used sequence homology to isolate the pea ortholog of M. truncatula DMI1 and have shown that the cloned pea ortholog can complement a M. truncatula dmi1 mutant for nodulation. Each of the five pea sym8 mutants carries a mutation in the DMI1 ortholog, confirming that the pea SYM8 is the DMI1 ortholog. Based on predicted structural similarities with an archaebacterial ion channel, we propose that SYM8 forms a tetrameric calcium-gated channel of a predicted structure similar to the archaebacterial potassium channel but containing a filter region that is different. The predicted structure identifies four aspartate residues (one from each subunit) forming the channel opening. We made a mutation changing the aspartate to valine and identified a missense mutation (changing alanine to valine adjacent to the aspartate residues) in this predicted filter region; both mutations caused a loss of function. We also identified a loss-of-function missense mutation (changing arginine to isoleucine) in a domain proposed to link the predicted channel and the gating ring domains, indicating that this mutation may block function by preventing a protein conformational change being transmitted from the gating-ring domain to the pore domain.


Gas-phase solvation of protonated amino acids by methanol.
The enthalpy and entropy changes for the formation of the 1:1 complexes of methanol with various gaseous protonated amino acids have been measured using pulsed-ionization high-pressure mass spectrometry. The enthalpy changes for formation of the clusters Gly(MeOH)H(+), Ala(MeOH)H(+), Val(MeOH)H(+), Leu(MeOH)H(+), Ile(MeOH)H(+), and Pro(MeOH)H(+) have been determined to be -92.0, -83.3, -82.4, -79.5, -78.7, and -73.6 kJ mol(-1), respectively. These values agree very well with the energetic values computed at the MP2(full)/6-311++G(2d,2p)//B3LYP/6-311+G(d,p) level of theory for the lowest energy adducts in each system. Both experimental observations and computational determinations of the potential energy surface for the glycine system suggest that a mixture of low-lying isomers may be present for each of the cluster systems examined. The primary structural motif for these clusters is the coordination of the methanol molecule to the ammonium group of the protonated amino acid via a strong ionic hydrogen bond. For the amino acids studied here, computational results reveal that one methanol molecule does not sufficiently stabilize any zwitterionic structure such that no appreciable extent of proton transfer from the amino acid to methanol was observed.


Senescence of alveolar epithelial progenitor cells: a critical driver of lung fibrosis.
Pulmonary fibrosis comprises a range of chronic interstitial lung diseases (ILDs) that impose a significant burden on patients and public health. Among these, idiopathic pulmonary fibrosis (IPF), a disease of aging, is the most common and most severe form of ILD and is treated largely by lung transplantation. The lack of effective treatments to stop or reverse lung fibrosis-in fact, fibrosis in most organs-has sparked the need to understand causative mechanisms with the goal of identifying critical points for potential therapeutic intervention. Findings from many groups have indicated that repeated injury to the alveolar epithelium-where gas exchange occurs-leads to stem cell exhaustion and impaired alveolar repair that, in turn, triggers the onset and progression of fibrosis. Cellular senescence of alveolar epithelial progenitors is a critical cause of stemness failure. Hence, senescence impairs repair and thus contributes significantly to fibrosis. In this review, we discuss recent evidence indicating that senescence of epithelial progenitor cells impairs alveolar homeostasis and repair creating a profibrotic environment. Moreover, we discuss the impact of senescent alveolar epithelial progenitors, alveolar type 2 (AT2) cells, and AT2-derived transitional epithelial cells in fibrosis. Emerging evidence indicates that transitional epithelial cells are prone to senescence and, hence, are a new player involved in senescence-associated lung fibrosis. Understanding the complex interplay of cell types and cellular regulatory factors contributing to alveolar epithelial progenitor senescence will be crucial to developing targeted therapies to mitigate their downstream profibrotic sequelae and to promote normal alveolar repair.NEW & NOTEWORTHY With an aging population, lung fibrotic diseases are becoming a global health burden. Dysfunctional repair of the alveolar epithelium is a key causative process that initiates lung fibrosis. Normal alveolar regeneration relies on functional progenitor cells; however, the senescence of these cells, which increases with age, hinders their ability to contribute to repair. Here, we discuss studies on the control and consequence of progenitor cell senescence in fibrosis and opportunities for research.


Optimal port placement and enhanced guidance in robotically assisted cardiac surgery.
Optimal port placement and enhanced guidance in robotically assisted cardiac surgery is required to improve preoperative planning and intraoperative navigation. Offline optimal port placement is planned on a three-dimensional virtual reconstruction of the patient's computed tomography scan. Using this data, an accurate in vivo port placement can be performed, which is achieved by augmented reality techniques superimposing virtual models of the thorax and the teleoperator arms on top of the real worldview. A new system incorporating both port placement planning and intraoperative navigation in robotically assisted minimally invasive heart surgery was established to aid the operative workflow. A significant reduction of operation time by improved planning and intraoperative support is anticipated. The enhanced intraoperative orientation possibilities may lead to further decrease in operation time and have the continuing ability to improve quality.


Training a large number of laboratory mice using running wheels and analyzing running behavior by use of a computer-assisted system.
A great many studies in the literature describe the variety of ways to provide physical training to small laboratory animals. Forced running on a treadmill or swimming training require considerable effort from the researcher, but permit the investigator to control the amount of exercise. Another option is to provide animals with access to running wheels, which they can voluntarily operate. Wheels can be used to investigate the running behavior of the animals. Wheel motion usually has been detected with magnets and microswitches and has been recorded using strip chart recorders or electromechanical counters. Computers also have been used in recording, but the measured parameters usually have been able to define only the total distance run in a fixed period. We designed a system, using running wheels, that can be used for long periods, up to years, for training a large number of laboratory mice simultaneously (maximal n = 96). The running parameters estimated by our system include running distance, speed, and time. Cumulative estimates of the running parameters can be produced for any period, as short as 1 sec. It is also easy to perform statistical analyses on the data. Using the system, we investigated the running behavior of 21 young C57BL/6 male mice. After the fast growth period, until 8 weeks of age, the mice ran 4 to 5 km/day at an average speed of 23 m/min, and spent 3 h running each day. This took place during the hours of darkness.


Biomarkers in translational research: focus on discovery, development and translation of protein biomarkers to clinical immunoassays.
The field of biomarker discovery has exhibited a great surge of interest in recent years. Biomarkers can be used for many purposes including diagnosis, prognosis and selecting appropriate patient therapy, and can provide information on disease mechanism or progression. Translation of such markers to clinical testing encompasses phases for their discovery and characterization, assay development, and finally, implementation using automated platforms employed in clinical laboratories. With a focus on protein-based biomarkers and clinical immunoassays, the three phases are discussed in greater detail. The currently used technologies in the clinical laboratory are described, including attributes of existing immunoassay types, and some recent advances in methods development for multiplexed immunoassays. Finally, regulatory considerations that need to be addressed before a biomarker assay is commercialized are discussed briefly.


Exercise interventions and prevention of fall-related fractures in older people: a meta-analysis of randomized controlled trials.
This meta-analysis aimed to determine whether exercise interventions were effective in preventing fall-related fractures in older people. The treatment effects on rate of falls, leg strength and balance were also examined. An electronic database search was conducted in PubMed, EMBASE, the Cochrane library and PEDro up to 1 September 2015. Randomized controlled trials (RCTs) that conducted exercise interventions and reported fall-related fracture data in older people were included. The primary outcome was the treatment effects on fall-related fractures determined by relative risk (RR) and 95% confidence interval (CI). The treatment effects on falls, leg strength and balance were also reported using rate ratio (RaR) with 95% CI and standardized mean difference (SMD) with 95% CI, respectively. Random effects models were used for meta-analysis. Fifteen studies including 3136 participants met the inclusion criteria. Exercise had a beneficial effect on reduction of fall-related fractures, with pooled estimates of RR 0.604 (95% CI 0.453 - 0.840, P = 0.003, I 2 = 0%). The rate of falls (RaR 0.856, 95% CI 0.778 - 0.941, P = 0.001, I 2 = 45%) and leg strength (SMD 0.613, 95% CI 0.119 - 1.107, P = 0.015, I 2 = 76.7%) were also potentially affected by exercise interventions. These only had a marginally beneficial effect on balance (SMD 0.468, 95% CI -0.011 - 0.947, P = 0.055, I 2 = 93.6%). Our findings implied that exercise interventions were effective in preventing fall-related fractures and reducing risk factors of fall-related fractures in older people.


Ingested IFN-alpha has biological effects in humans with relapsing-remitting multiple sclerosis.
Parenterally administered human recombinant type I interferons (hrIFN) in relapsing-remitting multiple sclerosis (RRMS) decrease relapses and spontaneous in vitro IFN-gamma production, reduce clinical progression, and decrease magnetic resonance imaging (MRI)-defined disease activity and lesions. Parenterally administered type I IFN use is limited by clinical and chemical toxicities, and the induction of antibodies that abrogate their activity in vivo correlated with the loss of clinical benefit. Therefore, we determined whether ingested IFN-alpha was non-toxic and had biological effects in humans. Ingested hrIFN-alpha showed no toxicity in normal volunteers or patients with RRMS at doses ranging from 300 to 100,000 units. In subjects with RRMS, a significant decrease in Con A-mediated proliferation and serum soluble intercellular adhesion molecule-1 (sICAM-1), a surrogate measure for disease activity in MS, was found after ingesting 10,000 and 30,000 units IFN-alpha The RRMS subjects also showed decreased IL-2 secretion after ingesting 10,000 units IFN-alpha and decreased IFN-gamma, TGF-beta and IL-10 production after ingesting 30,000 units IFN-alpha. The decreased secretion of IFN-gamma and IL-2 by ingested IFN-alpha suggests that oral IFN-alpha may cause a functional inhibition of Th J-like T helper cells in RRMS, a potential site of intervention at the level of effector T cells in MS. Our studies support the oral use of human IFN-alpha as a biological response modifier in humans.


Direct Observation of Magnetization Reversal by Electric Field at Room Temperature in Co-Substituted Bismuth Ferrite Thin Film.
Using the electric field to manipulate the magnetization of materials is a potential way of making low-power-consumption nonvolatile magnetic memory devices. Despite concentrated effort in the last 15 years on magnetic multilayers and magnetoelectric multiferroic thin films, there has been no report on the reversal of out-of-plane magnetization by an electric field at room temperature without the aid of an electric current. Here, we report direct observation of out-of-plane magnetization reversal at room temperature by magnetic force microscopy after electric polarization switching of cobalt-substituted bismuth ferrite thin film grown on (110)o-oriented GdScO3 substrate. A striped pattern of ferroelectric and weakly ferromagnetic domains was preserved after reversal of the out-of-plane electric polarization.


Somatostatin-14 and somatostatin-25 stimulate glycogenolysis in rainbow trout, Oncorhynchus mykiss, liver incubated in vitro: a systemic role for somatostatins.
The effects of somatostatin-14 (SS-14) and salmon somatostatin-25 (sSS-25) on hepatic glycogenolysis were studied by incubating rainbow trout liver pieces in vitro. Glycogen content in untreated liver pieces cultured for 3 and 5 hr was 28.6 +/- 7.6 mg/g fresh wt. and 21.5 +/- 6.6 U, respectively. Treatment of liver pieces with either SS-14 or sSS-25 resulted in significant glycogen depletion; sSS-25 appeared more potent in this regard. Equimolar concentrations (10(-8) M) of SS-14 or sSS-25 reduced glycogen content to 10.6 +/- 1.6 and 2.6 +/- 2.2 U, respectively, in liver pieces incubated for 3 hr. Alterations in liver glycogen content were reflected in glucose release into medium. Basal release of glucose into culture medium over the course of a 3-hr incubation was 20 +/- 5.6 mumol/g dry wt. Both SS-14 and sSS-25 stimulated a rapid increase (500 and 600%, respectively) in glucose release during the first 0.5 hr of incubation. After 3 hr, SS-14 and sSS-25 stimulated glucose release over basal levels to 116 +/- 9.3 and 153 +/- 16 U, respectively. Both SS-14 and sSS-25 stimulated glucose release in a dose-dependent manner; ED50 for both peptides was ca. 5 X 10(-8) M. These results indicate that both SS-14 and sSS-25 directly mediate hepatic glycogenolysis in rainbow trout.


Digestibility of boiled and oven-dried cassava in infants and small children.
Boiled fresh cassava or oven-dried cassava flour provided 50% of the energy and less than 10% of the protein in diets of convalescent malnourished infants; casein was added to complete 8% of energy as protein, and vegetable oil (soybean-cottonseed) was added to make 20% of energy as fat. Despite high wet weights of feces (172 +/- 42 and 214 +/- 41 g/d), their dry weights (20 +/- 3 and 22 +/- 2 g/d) and their energy (6.9 +/- 0.7 and 7.6 +/- 0.5% of intake) and nitrogen (17 +/- 3 and 20 +/- 3% of intake) contents were low, and their fat content (4.4 +/- 1.3 and 5.2 +/- 1.2% of intake) was very low. Cassava is a surprisingly effective source of energy which interferes little or not at all with digestion of added protein and fat in weaning diets. For its safe use, it is important that home or industrial processing almost completely eliminate its potential hydrocyanic acid content, and that a good quality protein supplement be consumed regularly in nutritionally adequate amounts.


The amino acid residues asparagine 354 and isoleucine 372 of human farnesoid X receptor confer the receptor with high sensitivity to chenodeoxycholate.
The critical steps in bile acid metabolism have remarkable differences between humans and mice. It is known that human cholesterol 7 alpha-hydroxylase, the enzyme catalyzing the rate-limiting step of bile acid synthesis, is more sensitive to bile acid suppression. In addition, hepatic bile acid export in humans is more dependent on the bile salt export pump (BSEP). To explore the molecular basis for these species differences, we analyzed the function of the ligand-binding domain (LBD) of human and murine farnesoid X receptor (FXR), a nuclear receptor for bile acids. We observed a strong interspecies difference in bile acid-mediated FXR function; in the coactivator association assay, chenodeoxycholate (CDCA) activated human FXR-LBD with 10-fold higher affinity and 3-fold higher maximum response than murine FXR-LBD. Consistently, in HepG2 cells human FXR-LBD increased reporter expression more robustly in the presence of CDCA. The basis for these differences was investigated by preparing chimeric receptors and by site-directed mutagenesis. Remarkably, the double replacements of Lys(366) and Val(384) in murine FXR (corresponding to Asn(354) and Ile(372) in human FXR) with Asn(366) and Ile(384) explained the difference in both potency and maximum activation; compared with the wild-type murine FXR-LBD, the double mutant gained 8-fold affinity and more than 250% maximum response to CDCA in vitro. This mutant also increased reporter expression to an extent comparable with that of human FXR-LBD in HepG2 cells. These results demonstrate that Asn(354) and Ile(372) are critically important for FXR function and that murine FXR can be "humanized" by substituting with the two corresponding residues of human FXR. Consistent with the difference in FXR-LBD transactivation, CDCA induced endogenous expression of human BSEP by 10-12-fold and murine BSEP by 2-3-fold in primary hepatocytes. This study not only provides the identification of critical residues for FXR function but may also explain the species difference in bile acids/cholesterol metabolism.


Value of the early electroencephalogram after a first unprovoked seizure.
Studies on the predictive value of the electroencephalogram (EEG) concerning the risk of seizure recurrence have shown contradictory results. We prospectively studied the predictive value of the standard EEG and EEG with sleep deprivation for seizure relapse in adult patients presenting with a first unprovoked seizure. EEGs were performed on 157 adult patients within the first 48 hours of the first seizure. Additional EEGs with sleep deprivation were obtained in 60 cases. The standard EEG was abnormal in 70.7% and significantly associated with an increased risk of seizure recurrence [risk ratio 4.5, 95% confidence interval (CI) 1.8; 11.3, p=0.001]. Subgroup analysis revealed the highest recurrence rates for patients with focal epileptiform activity (risk ratio 2.2, CI 1.2; 4.2, p=0.01). EEGs with sleep deprivation were abnormal in 48.3% of all cases and revealed epileptiform discharges in 13.3% of the patients who had no epileptiform activity in the standard EEG. Routine EEG revealed abnormalities in 60 of 94 patients who presented with normal neurologic status on admission. Further neuroradiological examinations detected previously unknown brain lesions in 19 of these cases, particularly cerebrovascular disease (CVD, n=7), brain tumors (n=6), and posttraumatic scars (n=4). In conclusion, the EEG is important for the early detection of focal nonepileptic and epileptic abnormalities after a first unprovoked seizure in adult patients and may provide valuable information on previously unknown disorders, particularly CVD and cerebral tumors. The abnormal EEG is a highly significant predictor for seizure recurrence. An additional EEG with sleep deprivation is helpful in cases when standard EEG does not reveal epileptiform discharges.


[Clinical features and prognosis of CD20-positive classical Hodgkin lymphoma].
To explore the clinical characteristics and prognosis of CD20-positive classical Hodgkin lymphoma (CHL). Data from CHL patients with CD20 immunohistochemical staining result who were treated in Cancer Hospital of Chinese Academy of Medical Sciences between September 2007 and March 2014 were reviewed. The relationship of CD20 expression in Reed-Sternberg(R-S)cells with CHL subtypes, clinical characteristics, and prognosis were analyzed. Fisher test was used to analyze the differences between groups and Kaplan-Meier for survival analysis. A total of 263 patients were included in this study. Among the 263 patients, 74 (28.1%) were CD20-postitive. CD20-positive cases showed significantly higher proportions of Epstein-Barr virus (EBV) infection-related, mixed cellularity, and lymphocyte-rich CHL subtypes compared with CD20-negeative patients [52.8% (28/53) vs 19.0% (22/116), 37.9% (25/66) vs 31.6% (54/171), 22.7% (15/66) vs 3.5% (6/171), all P<0.05]. Univariate analysis identified EBV infection, age (≥ 40 years, especially ≥ 60 years), and Ⅲ-Ⅳ stage were correlated with reduced 3-year progression-free survival (PFS) and overall survival (OS) (PFS: 70.3 vs 87.7%, 79.2% vs 89.8%, 56.8% vs 91.5%, 70.4% vs 93.2%; OS: 81.0% vs 100%, 92.1% vs 99.4%, 75.4% vs 99.2%, 90.3% vs 100%; all P<0.05); and CD20-positive and not receiving local radiotherapy were associated with reduced PFS (79.7% vs 90.6%, 68.8% vs 90.6%, both P<0.05), not with OS (92.4% vs 98.3%, 94.0% vs 99.4%, both P>0.05). Patients positive in both CD20 expression and EBV-encoded small RNAs (EBER) showed low PFS. CD20 expression in R-S cells in CHL may be closed related with EBV infection. EBV infection is associated with unfavorable prognosis. The effect of CD20-postitive on prognosis may be mediated by the prognostic effect of EBV infection.


Congenital cholesteatoma localized to the tip of the mastoid bone: a case report and possible etiology.
Congenital cholesteatomas of mastoid origin are extremely rare. We reported one in 2007 and experienced an additional case. A male presented with a 5-month history of right-sided ear discharge. Computed tomography of the temporal bone showed a soft tissue density occupying the mastoid tip. At surgery, the cholesteatoma sac was completely isolated from the mastoid antrum and lateral air cell in the mastoid tip area. We now doubt the rarity of this entity. With a brief literature review, we consider how the cholesteatoma localizes to the tip of the mastoid bone.


[PRIER II. The Emilia-Romagna Research and Innovation Programme].
The Emilia-Romagna Programme for Research and Innovation "PRIER" was born in 2005 with the aim of increasing cultural and operational conditions for the development of clinical research, useful both to the Regional Health Service (SSR) and to the private sectors of pharmaceutical and biomedical areas. In this context, the PRIER had from the beginning a double connotation: a space where the SSR can explore issues related to the development of its own research capacity; and a context where new possible ways of relating and comparison with the pharmaceutical and biomedical industry are tested. Over the years the activities of PRIER were defined by: initiatives to strengthen the system of research in SSR; development of tools to monitor activities of the research; production of clinical-organizational recommendations for the governance of innovation. In 2013 a new area of discussion and a common interest have been identified on the subject of clinical registries. In particular, it wanted to build a path of work able to identify all the possible critical and relevant points (points to consider), indispensable, necessary or useful to the construction and use of clinical registries, taking into account the points of view of all actors involved. The course began with defining the rules of the game and continued with workshops that allowed to analyse together the matter. At the end of the second workshop it was decided to make the work carried out visible: first, not to miss the opportunity offered by the past but recent discussion; secondly, to facilitate the discussion both on the issue of registers and to the adopted methodology, which sees the different actors (public and private ones) to reason together in a context for once not influenced by necessities of negotiation and government resources.


Contact dermatitis to temporary tattoo.
The development of contact hypersensitivity to temporary tattoos has been on an increase all over the world. Skin painting with henna is a traditional practice in the Moslems and Hindu, and has recently been increasingly used in western countries. Black henna is obtained by adding paraphenylenediamine to the natural occurring henna. The risk of sensitization increases with the length of contact and increase of the concentration. A case is presented of an 11-year-old boy who developed a severe reaction in the form of redness and edema accompanied by pruritus on the day following the application of a temporary tattoo. A year before, the patient had also developed a skin reaction following temporary tattooing, which had not been recognized as a contact dermatitis. Patch testing was positive for paraphenylenediamine and thiuram compounds. The patient was treated with medium-strength corticosteroids.


Management of acute illness in cats. Feline urologic syndrome.
Lethargy, anorexia and vomiting suggest azotemia in cats with FUS. Clinicopathologic findings may include azotemia, hyperphosphatemia, hyperglycemia, hyperkalemia, and signs of urinary tract inflammation on urinalysis. Treatment of FUS depends on the degree of illness but generally includes removal of the urethral obstruction, bladder lavage, fluid and antibiotic therapy, and subsequent feeding of a canned, low-Mg diet with added table salt.


Large numbers of interleukins-22- and -17A-producing T helper cells in cholangiocarcinoma related to liver fluke infection.
Cholangiocarcinoma (CCA) associated with liver fluke infection involves inflammatory and immune processes; however, whether these involve the proinflammatory cytokine IL-17A and proliferative cytokine IL-22 remains unclear. Here, numbers of IL-22- and IL-17A-producing Th cells and cytokine concentrations in 30 patients with CCA and long-term liver fluke infection, 40 patients with liver-fluke infection but not CCA, and 16 healthy controls were compared. Analyses were performed using immunohistochemistry, flow cytometry, ELISA and RT-PCR. Immunohistochemical staining showed weaker expression of IL-22 and IL-17A in patients with CCA with than in those without liver fluke infection (P < 0.01). Flow cytometry revealed significantly greater median proportions of IL-22-producing T helper cells in patients with CCA (2.2%) than in those without it (0.69%) or controls (0.4%, P < 0.001). Similar results were obtained for IL-17A-producing T helper cells. ELISA revealed plasma concentrations of IL-22 were 1.3-fold higher in patients with CCA than in those without it and 4.6-fold higher than in controls (P < 0.001). Plasma concentrations of IL-17A were 2.5-fold higher in patients with CCA than in those without it, and 21-fold higher than in controls (P < 0.001). Amounts of IL-22 and IL-17A mRNAs in blood were significantly higher in patients with CCA than in the other two groups. Proportions of CD4+ CD45RO+ T cells producing IL-22 correlated with proportions producing IL-17A (r = 0.759; P < 0.001), and plasma concentrations of IL-22 correlated with those of IL-17A (r = 0.726; P < 0.001). These results suggest that both IL-17A and IL-22 affect development of CCA related to liver fluke infection.


Colorful radial Talbot carpet at the transverse plane.
In this work we theoretically and experimentally investigate the diffraction of spatially coherent and collimated white light beam from radial amplitude gratings. Theoretical part of the work is resolved with the Fresnel-Kirchhoff integral. In the experimental part, a collimated wave-front of a white light beam emitting from a halogen lamp is transmitted through a radial amplitude grating. We digitally record the diffraction pattern in various distances from the grating using a CCD camera. The resulted diffraction pattern that we call it "Colorful radial Talbot carpet at the transverse plane" has a shape-invariant form under propagation. The other significant aspects of this pattern are the existence of a quite patternless dark area located around the optical axis and an intense rainbow-like ring in the vicinity of the patternless area. The rainbow color changes radially from the violet in the vicinity of the patternless area to red by increasing the radius in which the purity of the colors in the inner side is dominant. We call this phenomena "diffraction-based rainbow". In addition, the transverse plane Talbot carpet pattern consists colorful self-images of the grating's spokes at the larger radii. The theoretical calculations and experimental results verify each other completely. The introduced diffraction-based rainbow can be utilized in spectrometry.


Are we moving from symptomatic to asymptomatic syphilis: A retrospective analysis.
Syphilis remains a global health problem with recent reports of resurgence from various parts of the world. We undertook this study to analyze the current epidemiological and clinical trends of syphilis in our part of the country. To analyze the changing trends in clinical presentation of syphilis and the current status of HIV/AIDS-syphilis co-infection in our area. This is a hospital-based retrospective analysis of records of sexually transmitted disease (STD) patients enrolled in "Suraksha clinic" in the department of Skin and VD at a Tertiary Care Hospital in North India. Patient records were analyzed from January 2018 to December 2021. The demographic, clinical, and serological profiles of patients were assessed to study the percentage of syphilis patients attending the STD clinic and their clinical presentations. A total of 7153 patients were enrolled in the"Suraksha clinic" from January 2018 to December 2021, these included the venereal disease patients (3137) and nonvenereal disease patients (4016) who were registered for HIV and venereal disease research laboratory (VDRL) screening from the dermatology outpatient department. Out of 3137 sexually transmitted infection (STI) patients, 139 patients tested positive for VDRL. Treponema pallidum hemagglutination was found positive in 137 patients and negative in two patients. Hence, 137 patients were confirmed syphilis cases, constituting 4.36% of total STD cases in our STI clinic in 4 years. Out of 137 patients, 2 (1.45%) presented with primary chancre, 6 (4.37%) with lesions of secondary syphilis and 129 (94.16%) were found serologically reactive without any symptoms or clinical signs, i.e., in latent syphilis. Our records also showed 14 (10.21%) cases of HIV and syphilis co-infection. In our study, a remarkable rise in the number of patients in the latent syphilis stage is observed over primary and secondary syphilis stage. This signifies the persistence of syphilis in subclinical phase in the community and unfortunately, it goes unnoticed. These could be "warning signs" for changing disease pattern of syphilis in India and points toward hidden resurgence of syphilis as being reported in various parts of the world. To actively look for these "hidden cases," there is a need to strengthen "Suraksha clinics." VDRL testing should be mandatory along with routine testing in all patients visiting the hospital irrespective of their disease. We also propose for the central registration of syphilis patients on lines of HIV-infected patients' registry.


Removal of estrone, 17β-estradiol, and estriol from sewage and cow dung by immobilized Novosphingobium sp. ARI-1.
Immobilized bacterial agents (IBA) can increase the cell density and improve the environmental adaptability of bacteria. An estrogen-degrading bacterium, Novosphingobium sp. ARI-1, was immobilized in calcium alginate (CA) using an embedding method and applied to the removal of estrogens from natural sewage and cow dung. The optimum immobilization conditions were as follows: sodium alginate (SA) and CaCl2·2H2O concentrations of 5% (m/v) and 4% (m/v), respectively; a bacterial suspension to SA ratio of 1:2; and cross-linking for 6 h at 4°C. Immobilized strain ARI-1 mediated the biodegradation of estrone (E1), 17β-estradiol (E2), and estriol (E3) either individually or in combination and was tolerant of various temperatures and pH values. Immobilized ARI-1 removed 80.43%, 94.76%, and 100% of E1, E2, and E3 from sewage containing 1.75, 0.71, and 1.52 μg L-1 of the three test estrogens within seven days, respectively. In cow dung containing initial E1, E2, and E3 concentrations of 0.71, 0.64, and 0.66 mg kg-1, respectively, E1 and E2 concentrations were below the limit of detection, and 1.09% of E3 remained after incubation with immobilized ARI-1 for seven days. These results confirmed the utility of immobilized strain ARI-1 for the removal of estrogens from environmental matrices.


Hector Berlioz and other famous artists with opium abuse.
The effect of opium on the creativity and productivity of a famous composer of classical music, an essayist, and poets including Hector Berlioz, Thomas De Quincy, Samuel Taylor Coleridge, John Keats, and Jean Cocteau, is described. Opium is a narcotic drug prepared from the juice of the unripe seed capsules of the opium poppy. It contains alkaloids such as morphine, codeine, and papaverine. Medically it is used to relieve pain and produce sleep. It is used as an intoxicant. Alcohol and opium were commonly relied on in the 19th century, especially by artists, to stimulate creativity and relieve stress. These artists described the effect of opium on their creativity and productivity.


NEVER forget: negative emotional valence enhances recapitulation.
A hallmark feature of episodic memory is that of "mental time travel," whereby an individual feels they have returned to a prior moment in time. Cognitive and behavioral neuroscience methods have revealed a neurobiological counterpart: Successful retrieval often is associated with reactivation of a prior brain state. We review the emerging literature on memory reactivation and recapitulation, and we describe evidence for the effects of emotion on these processes. Based on this review, we propose a new model: Negative Emotional Valence Enhances Recapitulation (NEVER). This model diverges from existing models of emotional memory in three key ways. First, it underscores the effects of emotion during retrieval. Second, it stresses the importance of sensory processing to emotional memory. Third, it emphasizes how emotional valence - whether an event is negative or positive - affects the way that information is remembered. The model specifically proposes that, as compared to positive events, negative events both trigger increased encoding of sensory detail and elicit a closer resemblance between the sensory encoding signature and the sensory retrieval signature. The model also proposes that negative valence enhances the reactivation and storage of sensory details over offline periods, leading to a greater divergence between the sensory recapitulation of negative and positive memories over time. Importantly, the model proposes that these valence-based differences occur even when events are equated for arousal, thus rendering an exclusively arousal-based theory of emotional memory insufficient. We conclude by discussing implications of the model and suggesting directions for future research to test the tenets of the model.


[Latent and manifest iron deficiency conditions. Diagnostic and therapeutic developments].
The developments of the last 15 years rendered possible more exact clinical evidences on stages (cross section diagnoses of the iron state within the body), developmental forms (longitudinal section diagnoses with estimation of the iron balance) and substitution of the iron deficiency. In the stages I (storage iron deficiency with increased intestinal iron absorption) and II (additional decrease of the serum iron) haemoglobin lies within the normal. Iron deficiency anaemias without (III) and with (IV) tissue damage show much decreased serum ferritin values. In the pre-treatment or in complications by infections or tumours the dispersion areas of serum ferritin intersect with the lower dispersion area of the norm of control persons with normal reserves of iron. - The most frequent cause of the non-haemorrhagic iron deficiency developing by an absolute or relatively too small iron supply are pregnancies without an effective iron prophylaxis. The chronic haemorrhagic iron deficiency relapsing without iron supply is caused by hypermenorrhoeas (blood losses per year 1-6 l) and in older patients by blood losses from the gastro-intestinal canal (blood losses per year 1 to more than 30 l). The posthaemorrhagic or postpartal iron deficiency remaining after removal of the causes remits spontaneously with sufficient nutrition. A more exact knowledge about the bioavailability of oral ferroiron preparation and the biotransformation of parenterally administered colloidal iron preparation render possible a better adaptation of the iron substitution to the demand of iron to the limits of tolerability and metabolisability of the remedies administered.


Collaborative treatment for a case of condylar hyperplastic facial asymmetry.
Facial asymmetry can be caused by unilateral condylar hyperplasia. In such cases, it may be difficult to achieve symmetry since there is dentoalveolar compensation on the affected side, and the occlusal cant does not correspond to the frontal mandibular deviation. In the case presented, surgical orthodontic treatment and orthognathic surgery planning was accomplished for a patient with facial asymmetry due to condylar hyperplasia. The surgical plan was devised with particular attention to the severe dentoalveolar compensation. In this case, prior to the two-jaw surgery, the occlusal cant and frontal mandibular plane inclination was corrected through impaction of the left molar region by segmental osteotomy. Facial asymmetry and severe dentoalveolar compensation were successfully corrected after a unilateral segmental osteotomy and two-jaw surgery, resulting in a stable occlusal relationship and facial symmetry as well as good jaw function. Collaboration between the orthodontists and maxillofacial surgeons was essential for the successful treatment of the patient.


NSun2-mediated cytosine-5 methylation of vault noncoding RNA determines its processing into regulatory small RNAs.
Autosomal-recessive loss of the NSUN2 gene has been identified as a causative link to intellectual disability disorders in humans. NSun2 is an RNA methyltransferase modifying cytosine-5 in transfer RNAs (tRNAs), yet the identification of cytosine methylation in other RNA species has been hampered by the lack of sensitive and reliable molecular techniques. Here, we describe miCLIP as an additional approach for identifying RNA methylation sites in transcriptomes. miCLIP is a customized version of the individual-nucleotide-resolution crosslinking and immunoprecipitation (iCLIP) method. We confirm site-specific methylation in tRNAs and additional messenger and noncoding RNAs (ncRNAs). Among these, vault ncRNAs contained six NSun2-methylated cytosines, three of which were confirmed by RNA bisulfite sequencing. Using patient cells lacking the NSun2 protein, we further show that loss of cytosine-5 methylation in vault RNAs causes aberrant processing into Argonaute-associated small RNA fragments that can function as microRNAs. Thus, impaired processing of vault ncRNA may contribute to the etiology of NSun2-deficiency human disorders.


Technical feasibility of isolated Bowman layer graft preparation by femtosecond laser: a pilot study.
To evaluate the technical feasibility of isolated Bowman layer (BL) graft preparation by femtosecond laser (FSL) and to compare the ultrastructural morphology to manually dissected grafts. Five whole globes were placed in custom-made eye holders and debrided of epithelium. After programming a dissection depth of 20 μm, the FSL was docked into position and 5 isolated BL grafts were created. From 5 additional globes, corneoscleral buttons were procured, mounted in artificial anterior chambers, and stripped of BL via the previously described manual technique. Three specimens from both series were randomly selected and assigned to transmission electron microscopy for ultrastructural evaluation and thickness measurements. All dissections were uneventful and 10 total grafts were produced: 5 by FSL and 5 by manual dissection. Mean graft thickness was 37 (±8.6) μm (n = 3) for the FSL group and 11.7 (±1.6) μm (n = 3) for the manually dissected group. Transmission electron microscopy revealed a thick but relatively smooth posterior cut edge in the FSL group, versus a virtually isolated BL with irregular rests of dispersed stroma in the manually dissected group. Femtosecond laser may have potential for harvesting intact BL and with a smooth posterior surface, but accompanied by variable amounts of anterior stroma owing to technical limitations.


Very low Reynolds number causes a monotonic force enhancement trend for a three-dimensional hovering wing in ground effect.
This research reports the numerical results of the ground effect trend for a three-dimensional flapping insect wing at a very low Reynolds number (Re = 10). It demonstrates that the ground effect trend at this Re has a 'single force regime,' i.e. the forces only enhance as the ground distance decreases. This phenomenon is unlike the widely expected non-monotonic trend publicized in previous studies for higher Reynolds numbers, that shows 'three force regimes,' i.e. the forces reduce, recover, and also enhance as the ground distance decreases. The force trend in the ground effect correlates to a similar trend in wing-wake interaction or the downwash strength on the wing's head. At very low Re (10), the very large viscosity causes diffused vortices and less advected vortex wake, while at relatively high Re, the vortices are easily separated from the wing and then advected downwards. This different development of the vortex wake caused different force trends for the flapping wing in the ground effect. Furthermore, by examining only the first stroke when there is no vortex wake, we found that the 'ramming effect' enhances the forces on the wing. This effect increases the pressure of the lower wing surface due to the squeezed air between the wing and the ground. The 'ramming effect', combined with the reduced downwash (or wing-wake interaction) effect, causes the force enhancement of the wing near the ground's vicinity. It is further comprehended that the trend is dependent on Re. As the Re is increased, the trend becomes non-monotonic. The effect of varying angles of attack, flapping amplitude and wing planform at very low Re does not change this trend. This ground effect might help insects by enhancing their lift while they hover above the surface. This finding might prove beneficial for developing micro air vehicles.


Non-insulin-treated ICA positive and negative diabetics are equally insulin resistant.
Insulin action was assessed in 5 cytoplasmic islet cell antibody (ICA) positive non-diabetics, 8 ICA positive (type I) non-insulin-treated diabetics, 7 ICA negative insulin-treated diabetics by measurement of steady state plasma glucose (SSPG) levels during a combined intravenous infusion of propranolol, adrenaline, glucose and insulin. SPPG values of ICA positive and negative non-diabetics were similar and their combined value (4.0 +/- 0.5 mmol/l) was significantly lower (p less than 0.01 and less than 0.01) than those (11.5 +/- 1.9 and 11.3 +/- 2.2 mmol/l) of ICA positive and negative diabetics, indicating that both groups of diabetics were similarly insulin resistant. Similar correlations were observed between SSPG and HbA1 levels when considering all ICA positive subjects (r = 0.89, p less than 0.001) and all ICA negative subjects (r = 0.73, p less than 0.01). Conventional insulin treatment (2.6 months) in 4 ICA positive diabetics improved insulin action in each case with a reduction in mean SSPG concentration from 14.0 +/- 2.3 to 8.5 +/- 3.4 mmol/l. Thus, ICA positive and negative diabetics, of equivalent degree of carbohydrate intolerance, are equally insulin resistant. Insulin treatment may improve, but appears not to normalise, insulin action in ICA positive (type I) diabetics.


Retrospective analysis of relationships among the dose regimen, trough concentration, efficacy, and safety of teicoplanin in Chinese patients with moderate-severe Gram-positive infections.
Teicoplanin, an antibiotic, has poor clinical efficacy when using the current drug label's recommended regimen, which is approved by the China Food and Drug Administration. This study explores the appropriate loading and maintenance doses of teicoplanin and evaluates the therapeutic target of teicoplanin trough concentration (minimum concentration [Cmin]). All patients treated with teicoplanin from February 2015 to August 2016 at Zhengzhou Central Hospital were screened for enrollment. A total of 113 subjects were included and then divided into four groups: A (received three to six doses at a loading dose of 400 mg at 12-hour intervals, followed by maintenance dosing of 400 mg/day), B (received three doses at a loading dose of 400 mg at 12-hour intervals, followed by maintenance dosing of 400 mg/day), C (received two doses at a loading dose of 400 mg at 12-hour intervals, followed by maintenance dosing of 200 mg/day), and D (received one to three doses at a loading dose of 400 mg at 12-hour intervals, followed by maintenance dosing of 200 mg/day). Cmin values of teicoplanin were detected with high-performance liquid chromatography on day 4, 30 minutes before maintenance-dose administration. Teicoplanin Cmin, efficacy, and safety were compared among the four groups. Mean Cmin differed significantly among the four groups (A, 18.11±6.37 mg/L; B, 15.91±4.94 mg/L; C, 17.06±5.66 mg/L; D, 11.97±3.76 mg/L) (P<0.001), with creatinine clearance of 89.62 (53.72-162.48), 49.66 (40.69-59.64), 27.17 (9.7-39.45), and 96.6 (17.63-394.73) mL/min, respectively. The ratio of loading dose for 3 days to creatinine clearance and serum Cmin were significantly correlated (R=0.59, P<0.001). The correlation between the estimated probability of success and teicoplanin Cmin was assessed using binary logistic regression (OR 2.049, P<0.001). Hepatotoxicity- and nephrotoxicity-incidence rates did not significantly differ among the four groups (P=0.859 and P=0.949, respectively). A loading dose of 400 mg at 12-hour intervals three to six times is needed to achieve the early target range (15-20 mg/L) and improve the clinical efficacy rate for normal-renal-function patients. It is urgently necessary to amend the drug label for the recommended regimen.


Development of a screening tool to predict malnutrition among children under two years old in Zambia.
Maternal and child undernutrition is an important issue, particularly in low- and middle-income countries. Children at high risk of malnutrition should be prioritized to receive necessary interventions to minimize such risk. Several risk factors have been proposed; however, until now, there has been no appropriate evaluation method to identify these children. In sub-Saharan Africa, children commonly receive regular check-ups from community health workers. A simple and easy nutrition assessment method is therefore needed for use by semi-professional health workers. The aim of this study was to develop and test a practical screening tool for community use in predicting growth stunting in children under two years in rural Zambia. Field research was conducted from July to August 2014 in Southern Province, Zambia. Two hundred and sixty-four mother-child pairs participated in the study. Anthropometric measurements were performed on all children and mothers, and all mothers were interviewed. Risk factors for the screening test were estimated by using least absolute shrinkage and selection operator analysis. After re-evaluating all participants using the new screening tool, a receiver operating characteristic curve was drawn to set the cut-off value. Sensitivity and specificity were also calculated. The screening tool included age, weight-for-age Z-score status, birth weight, feeding status, history of sibling death, multiple birth, and maternal education level. The total score ranged from 0 to 22, and the cut-off value was eight. Sensitivity and specificity were 0.963 and 0.697 respectively. A screening tool was developed to predict children at high risk of malnutrition living in Zambia. Further longitudinal studies are needed to confirm the test's validity in detecting future stunting and to investigate the effectiveness of malnutrition treatment.


Scanning mutagenesis of regions in the Galpha protein Gpa1 that are predicted to interact with yeast mating pheromone receptors.
The mechanism by which receptors activate heterotrimeric G proteins was examined by scanning mutagenesis of the Saccharomyces cerevisiae pheromone-responsive Galpha protein (Gpa1). The juxtaposition of high-resolution structures for rhodopsin and its cognate G protein transducin predicted that at least six regions of Galpha are in close proximity to the receptor. Mutagenesis was targeted to residues in these domains in Gpa1, which included four loop regions (beta2-beta3, alpha2-beta4, alpha3-beta5, and alpha4-beta6) as well as the N and C termini. The mutants displayed a range of phenotypes from nonsignaling to constitutive activation of the pheromone pathway. The constitutive activity of some mutants could be explained by decreased production of Gpa1, which permits unregulated signaling by Gbetagamma. However, the constitutive activity caused by the F344C and E335C mutations in the alpha2-beta4 loop and F378C in the alpha3-beta5 loop was not due to decreased protein levels, and was apparently due to defects in sequestering Gbetagamma. The strongest loss of the function mutant, which was not detectably induced by a pheromone, was caused by a K314C substitution in the beta2-beta3 loop. Several other mutations caused weak signaling phenotypes. Altogether, these results suggest that residues in different interface regions of Galpha contribute to activation of signaling.


Genetic witness: forensic uses of DNA tests.
"Genetic Witness: Forensic Uses of DNA Tests" summarizes the findings of a 204-page report by the U.S. Congressional Office of Technology Assessment (OTA). It reviews the DNA techniques used in criminal casework, evaluates the validity and reliability of the technologies, examines issues of quality assurance, reviews the legal implications of the use of DNA tests by U.S. courts, and analyzes the privacy implications of forensic DNA tests and computer databanks. It presents a range of actions that could be taken by the U.S. Congress to address five policy issues: standards for forensic uses of DNA typing; funding of crime laboratories, forensic personnel training, and forensic research; the advisability of establishing computer databanks of DNA test results; and privacy considerations of collecting, using, and storing DNA data or samples.


Tumor necrosis factor and monocytes are released during hemorrhagic shock.
Tumor necrosis factor (TNF) is a key mediator involved in many physiologic processes including immunity, inflammation, and metabolism. A relationship between TNF and hemorrhagic shock has not been clearly demonstrated. To help understand the role of TNF in hemorrhagic shock we developed a hemorrhagic shock model to measure TNF and monocyte levels during hemorrhage and resuscitation. Male Sprague-Dawley rats were anesthetized and subjected to a 50% blood loss (30 ml/kg) over 2 min and left in shock for 58 min. The animals were then resuscitated with two times blood loss (60 ml/kg) using lactated Ringers over 1 h. This model results in 75% mortality within 3 days (LD 75). Blood samples (2 ml) were obtained at intervals during shock and resuscitation, and assayed for TNF concentrations and white blood cell counts. Despite a marked fall in total leukocytes (24,600 pre-hemorrhage to 11,300 post-hemorrhage, P < 0.005), monocytes increased in percentage and in total count. Blood levels of TNF were initially undetectable but rose within 10 min after hemorrhage, peaked at 30 min after hemorrhage, and then became undetectable during resuscitation. In this model, macrophages and TNF are released into the circulation after hemorrhagic shock. TNF may play a role as a mediator in the pathophysiology of hemorrhagic shock.


Glycogen content of the donor liver and its relation to postreperfusion hepatic energy metabolism.
Many studies have suggested that glycogen in donor livers is an important fuel during cold ischemic time and at reperfusion. However, it remains unclear as to whether the depression of glycogen content in the graft results in a critical derangement of energy metabolism after reperfusion. The purpose of this study was to assess the possible implications of the glycogen concentration of donor livers for the hepatic energy metabolism after reperfusion. The glycogen content of 28 donor livers and the plasma concentrations of metabolic substrates were measured during liver transplantation. Gluconeogenesis was maintained even in the glycogen-depleted graft at reperfusion. However, glycogen-depleted grafts produced more ketone bodies until 24 h after reperfusion. Free carnitine concentrations in these patients were significantly higher than those in the patients with glycogen-nondepleated grafts until 48 h after reperfusion. A glycogen-depleted liver graft may restore essential metabolic function by producing energy substrates through enhanced ketogenesis in the postreperfusion period. The enhanced production of carnitine by the graft provides a substrate for the production of ketone bodies and thus may be relevant to the enhanced ketogenesis.


Analysis of BHK cell growth kinetics after microinjection of catalytic subunit of cyclic AMP-dependent protein kinase.
The effect of catalytic subunit (C) of cyclic AMP-dependent protein kinase on cell growth kinetics of BHK cells was assessed by microinjection with chicken erythrocyte ghosts as vehicles for introduction of the protein into the cytosol of large populations of cells. The advantage in using chicken erythrocytes for microinjection is that the inactive erythrocyte nuclei serve as a probe for identifying and analyzing microinjection events. By utilizing this procedure, BHK cells were microinjected with an amount of C that was 5- to 10-fold greater than their endogenous levels. Growth kinetics were analyzed by [3H]thymidine incorporation and autoradiography. Cells were stained after autoradiography to more clearly reveal the chicken nuclei, and at each time point, cells were categorized into four groups: (i) not microinjected, not in S phase, (ii) not microinjected, in S phase, (iii) microinjected, not in S phase, (iv) microinjected, in S phase. Those cells not microinjected served as internal controls. Two experimental protocols were used to test the notion that C is involved in blocking cell progression through G1 phase of the cell cycle. First, cells were arrested in G0 phase by serum deprivation, microinjected with C or control proteins, and stimulated to proceed to S phase by the addition of serum or purified growth factors. Second, cells were collected in mitosis, microinjected with C or control proteins, and stimulated to proceed to S phase by the addition of serum. The results of these studies indicate that a 5- to 10-fold increase in the intracellular concentration of C is not a sufficient signal to arrest cell growth in G1 phase. Thus, growth-inhibitory effects of cyclic AMP on BHK cells are unlikely to be the result of activation of cyclic AMP-dependent protein kinase.


DNA density-dependent assembly behavior of colloidal micelles.
A key advantage of DNA-mediated colloidal assembly is the ability to tune the strength of adhesion between particles based on sequence characteristics. In the current study, we have investigated DNA-mediated assembly of polystyrene colloidal particles as a function of sequence length, sequence fidelity, and probe density for DNA sequences patterned from the Salmonella genome. The results of our work indicate that the density of DNA probe strands heavily influences the ability of immobilized sequences to hybridize between surfaces of bidisperse colloidal particles. Incubating suspensions at higher temperatures (to minimize secondary structures that might otherwise compromise duplex formation) was also found to have less effect than duplex density on DNA-mediated particle assembly. We believe these results may add to the understanding and design considerations of directed particle assembly using DNA hybridization, especially in the submicrometer and micrometer size regime.


Generation of a de novo transcriptome from equine lamellar tissue.
Laminitis, the structural failure of interdigitated tissue that suspends the distal skeleton within the hoof capsule, is a devastating disease that is the second leading cause of both lameness and euthanasia in the horse. Current transcriptomic research focuses on the expression of known genes. However, as this tissue is quite unique and equine gene annotation is largely derived from computational predictions, there are likely yet uncharacterized transcripts that may be involved in the etiology of laminitis. In order to create a novel annotation resource, we performed whole transcriptome sequencing of sagittal lamellar sections from one control and two laminitis affected horses. Whole transcriptome sequencing of the three samples resulted in 113 million reads. Overall, 88 % of the reads mapped to the equCab2 reference genome, allowing for the identification of 119,430 SNPs. The de novo assembly generated around 75,000 transcripts, of which 36,000 corresponded to known annotations. Annotated transcript models are hosted in a public data repository and thus can be easily accessed or loaded into genome browsers. RT-PCR of 12 selected assemblies confirmed structure and expression in lamellar tissue. Transcriptome sequencing represents a powerful tool to expand on equine annotation and identify novel targets for further laminitis research.


Flexible and Ultrathin Graphene/Aramid Nanofiber Carbonizing Films with Nacre-like Structures for Heat-Conducting Electromagnetic Wave Shielding/Absorption.
Electromagnetic interference (EMI) shielding and electromagnetic wave absorption (EWA) materials with good thermal management and flexibility properties are urgently needed to meet the more complex modern service environment, especially in the field of smart wearable electronics. How to balance the relation of electromagnetic performance, thermal management, flexibility, and thickness in material design is a crucial challenge. Herein, graphene nanosheets/aramid nanofiber (C-GNS/ANF) carbonizing films with nacre-like structures were fabricated via the blade-coating/carbonization procedure. The ingenious configuration from highly ordered alignment GNS interactively connected by a carbonized ANF network can effectively improve the thermal/electrical conductivity of a C-GNS/ANF film. Specifically, the ultrathin C-GNS/ANF film with a thickness of 17 μm shows excellent in-plane thermal conductivity (TC) of 79.26 W m-1 K-1 and superior EMI shielding up to 56.30 dB. Moreover, the obtained C-GNS/ANF film can be used as a lightweight microwave absorber, achieving excellent microwave absorption performance with a minimum reflection loss of -56.07 dB at a thickness of 1.5 mm and a maximum effective absorption bandwidth of 5.28 GHz at an addition of only 5 wt %. Furthermore, the C-GNS/ANF films demonstrate good flexibility, outstanding thermal stability, and flame retardant properties. Overall, this work indicates a prospective direction for the development of the next generation of electromagnetic wave absorption/shielding materials with high-performance heat conduction.


Intercellular interactomics of human brain endothelial cells and th17 lymphocytes: a novel strategy for identifying therapeutic targets of CNS inflammation.
Leukocyte infiltration across an activated brain endothelium contributes to the neuroinflammation seen in many neurological disorders. Recent evidence shows that IL-17-producing T-lymphocytes (e.g., Th17 cells) possess brain-homing capability and contribute to the pathogenesis of multiple sclerosis and cerebral ischemia. The leukocyte transmigration across the endothelium is a highly regulated, multistep process involving intercellular communications and interactions between the leukocytes and endothelial cells. The molecules involved in the process are attractive therapeutic targets for inhibiting leukocyte brain migration. We hypothesized and have been successful in demonstrating that molecules of potential therapeutic significance involved in Th17-brain endothelial cell (BEC) communications and interactions can be discovered through the combination of advanced membrane/submembrane proteomic and interactomic methods. We describe elements of this strategy and preliminary results obtained in method and approach development. The Th17-BEC interaction network provides new insights into the complexity of the transmigration process mediated by well-organized, subcellularly localized molecular interactions. These molecules and interactions are potential diagnostic, therapeutic, or theranostic targets for treatment of neurological conditions accompanied or caused by leukocyte infiltration.


Beta-aminoketones as prodrugs with pH-controlled activation.
N-Mannich bases have been widely applied as prodrugs of amine drugs. The analogous C-Mannich bases (beta-aminoketones) have received rather less attention probably because they are not sufficiently susceptible to elimination at pHs encountered in vivo. Compounds in which there is a thermodynamic advantage to elimination may be an exception. In this study, the physicochemical characteristics of a series of Michael amino addition adducts of chalcone and other carbonyl compounds is explored. The ketone adducts rapidly eliminate at around pH 7.4 (t(1/2) < 15 min) releasing the amine and the ketone but they are stable under acidic conditions. The Michael adducts are more lipophilic than the parent amines and have significantly suppressed ionisation characteristics at biologically relevant pH values.


The utility of the World Health Organization-The Uppsala Monitoring Centre (WHO-UMC) system for the assessment of adverse drug reactions in hospitalized children.
Although the World Health Organization-The Uppsala Monitoring Centre (WHO-UMC) system has been suggested as a practical tool for classifying adverse drug reactions (ADRs), verification of such system has not been examined. The objective of this study was to evaluate the usefulness of the WHO-UMC classification for the diagnosis of ADRs. The gold standard was the results of drug challenges and serum tryptase in cases of anaphylaxis. Twenty-seven children had ADRs classified by the WHO-UMC system. The causality terms were 'certain' in 4/27, 'probable' in 6/27, 'possible' in 10/27 and 'unlikely' in 7/27 of the patients. Skin prick tests and intradermal tests were positive in 1/20 and 1/5 of the patients, respectively. Drug challenges and serum tryptase were positive in 8/26 and 1/3 of the patients, respectively. After complete evaluation, the positive and negative ADRs were documented in 9/27 patients (33.33%) and 18/27 patients (66.67%), respectively. The multi-level likelihood ratios for ADRs using the WHO-UMC system were infinity in causality term 'certain', 2 in 'probable', 0.5 in 'possible', and 0 in 'unlikely'. In conclusion, causality term 'certain' and 'unlikely' of the WHO-UMC system had large impact on the likelihood of ADRs. In contrast, the causality term 'probable' and 'possible' had small impact on the likelihood of ADRs. Drug challenges and serum tryptase were helpful to confirm ADRs categorized by WHO-UMC system.


University students' attributions for abstinence from synthetic cannabinoids and synthetic cathinones.
Synthetic cannabinoids and synthetic cathinones are two increasingly available and potentially dangerous classes of substances. We designed this study to test whether university students rated the influence of different types of reasons for abstaining differently as a function of type of drug (synthetic cannabinoids vs. synthetic cathinones) and gender (male vs. female). Using a web-based survey, 176 male and 437 female undergraduate university students rated the degree to which each of 42 reasons for not taking drugs influenced their abstinence from those two classes of substances. Exploratory factor analyses suggested four subscales of reasons applicable to both substances: (1) psychological and behavioral impairment, (2) somatic and physiological concerns, (3) social approval and self-image concerns, and (4) insufficient knowledge and limited access. Both men and women rated all four subscales of reasons as having more influence on their abstinence from synthetic cathinones than synthetic cannabinoids, and women rated each subscale except somatic and physiological concerns as having more influence than did men. Although there were main effects for type of drug, because students typically reported the same types of reasons as being more or less influential for both classes of substances, prevention interventions could focus simultaneously on reasons to avoid or delay use of both types of substances.


MODERN AND HISTORICAL EVIDENCE FOR NATURAL HYBRIDIZATION BETWEEN SYMPATRIC SPECIES IN MANDARINA (PULMONATA: CAMAENIDAE).
Geographical and temporal variation in gene exchange between two endemic land snail species, Mandarina aureola and Mandarina ponderosa, was studied on Hahajima Island of the Bonin Islands. Allozyme variation in modern samples, and variation in the color and shell morphology of modern and fossil samples, suggest a complex geographical and historical pattern of hybridization. These two species occur in sympatry, and their shell morphologies and protein genotypes are markedly divergent. However, many specimens of M. aureola, collected from the middle region of the island, exhibit intermediate shell morphologies and possess marker alleles of M. ponderosa. Fossil samples of the two species strongly suggest that these intermediates were hybrids with M. ponderosa that were produced since the end of the Pleistocene. Each of these species, in addition, is subdivided into two genetically and morphologically divergent parapatric races. Interspecific hybridization appears to have produced genetical and morphological admixture among these four distinctive groups of populations. The past distribution and geographic variation of M. ponderosa can be traced in the distribution of M. ponderosa-derived genotypes in current populations of M. aureola. Temporal changes of the color pattern in the fossil populations of hybrids suggest that the traits introduced from M. ponderosa to M. aureola have been affected by natural selection and could replace traits of living species when advantageous. Moreover, these introgressed genes appeared to provide novel properties that enabled M. aureola to advance into a new environment. Relatively independent change in shell color and morphology further suggests mosaic evolution following the hybridization events. Connectively, these data reveal how hybridization events may be an important source of evolutionary novelties and make it clear that the phenomenon of reticulate evolution cannot be ignored.


Lacrimal Sac Actinomycosis: A Masquerade of Lacrimal Sac Malignancy.
A 60-year-old woman had blood-stained discharge with intermittent hemolacria from the left eye, of 3 months duration. The ophthalmic examination showed a firm, nontender, and immobile mass in the left lacrimal sac region. The sac regurgitation test was positive with purulent blood-stained discharge. Lacrimal punctum and canaliculi of both sides were normal. CT scan of orbits showed a hyperdense lesion in the left lacrimal sac region without bone erosion. A complete dacryocystectomy was performed, and the histopathology revealed actinomycosis of the lacrimal sac. At 14 months of follow-up visit, the patient has no clinical evidence of recurrence.


The Brazilian Zika virus strain causes birth defects in experimental models.
Zika virus (ZIKV) is an arbovirus belonging to the genus Flavivirus (family Flaviviridae) and was first described in 1947 in Uganda following blood analyses of sentinel Rhesus monkeys. Until the twentieth century, the African and Asian lineages of the virus did not cause meaningful infections in humans. However, in 2007, vectored by Aedes aegypti mosquitoes, ZIKV caused the first noteworthy epidemic on the Yap Island in Micronesia. Patients experienced fever, skin rash, arthralgia and conjunctivitis. From 2013 to 2015, the Asian lineage of the virus caused further massive outbreaks in New Caledonia and French Polynesia. In 2013, ZIKV reached Brazil, later spreading to other countries in South and Central America. In Brazil, the virus has been linked to congenital malformations, including microcephaly and other severe neurological diseases, such as Guillain-Barré syndrome. Despite clinical evidence, direct experimental proof showing that the Brazilian ZIKV (ZIKV(BR)) strain causes birth defects remains absent. Here we demonstrate that ZIKV(BR) infects fetuses, causing intrauterine growth restriction, including signs of microcephaly, in mice. Moreover, the virus infects human cortical progenitor cells, leading to an increase in cell death. We also report that the infection of human brain organoids results in a reduction of proliferative zones and disrupted cortical layers. These results indicate that ZIKV(BR) crosses the placenta and causes microcephaly by targeting cortical progenitor cells, inducing cell death by apoptosis and autophagy, and impairing neurodevelopment. Our data reinforce the growing body of evidence linking the ZIKV(BR) outbreak to the alarming number of cases of congenital brain malformations. Our model can be used to determine the efficiency of therapeutic approaches to counteracting the harmful impact of ZIKV(BR) in human neurodevelopment.


Visualization of membrane RNAs.
Using fluorescence microscopy, we show that previously isolated membrane-binding RNAs coat artificial phospholipid membranes relatively uniformly, except for a frequent tendency to concentrate at bends, membrane junctions, and other unusual sites. Membrane RNAs can also be visualized as single molecules or isolated complexes by atomic force microscopy (AFM) of free RNAs on mica. Finally, RNAs can be seen within membranes by AFM of RNA-liposomes immobilized on hydrophobic mica surfaces. Monomer RNAs appear globular, as expected for small RNAs. When mixed under conditions in which RNAs bind bilayers, RNA 9 and RNA 10 combine to yield about 80% of RNAs as mainly linear oligomers of approximately 2-8 molecules. Once inserted in membranes, the RNAs oligomerize further, yielding larger, irregular ropelike structures that prefer the edges of altered lipid patches. These properties can be interpreted in terms of RNA-RNA loop interactions, and the RNA effects on membranes can be explained in terms of an RNA preference for irregular lipid conformations. The RNA-bilayer system poses new opportunities for combining the properties of membranes and RNA in contemporary cells, and also in the ribocytes of an RNA world.


Pharmacokinetic analysis of dextran sulfate in rats as pertains to its clinical usefulness for therapy of HIV infection.
We administered radiolabeled dextran sulfate (3H labeled on the reducing end, MW approximately 8000) [( 3H]DS) to rats. High-performance liquid chromatography (HPLC) analysis of plasma from animals that were given [3H]DS intravenously revealed an initial plasma half-life of about 30 min. Eleven percent of [3H]DS administered was recovered in the urine in 24 h; this material represented minor breakdown with a molecular weight of 4000 as determined by size exclusion HPLC analysis. When administered orally, the apparent bioavailability of [3H]DS was 6.8%, based on the recovered radioactivity; however, the molecular weight of the radioactive material obtained from the plasma was all less than 200, indicating that no detectable intact dextran sulfate was absorbed upon oral administration. Only 2% of orally administered [3H]DS was found in the 24-h urine; this material also had a molecular weight less than 200. Further less than 2300 had no anti-HIV effect and that in the presence of higher concentrations of human serum, more DS was required for antiviral effect. Although the pharmacokinetics of dextran sulfate in rats can differ from those in humans to some extent, these data suggest that oral administration of DS is unlikely to produce significant antiretroviral effect against HIV in vivo and higher plasma levels of DS may be necessary than those inferred from earlier in vitro data.


A heterozygous mutation of the insulin-like growth factor-I receptor causes retention of the nascent protein in the endoplasmic reticulum and results in intrauterine and postnatal growth retardation.
Mutations in the IGF-I receptor (IGF1R) gene can be responsible for intrauterine and postnatal growth disorders. Here we report on a novel mutation in the IGF1R gene in a female patient. The aim of our study was to analyze the functional impact of this mutation. At birth, the girl's length was 47 cm [-1.82 sd score (SDS)], and her weight was 2250 g (-2.26 SDS). Clinical examination revealed microcephaly and retarded cognitive development. She showed no postnatal catch-up growth but had relatively high IGF-I levels (+1.83 to +2.17 SDS). Denaturing HPLC screening and direct DNA sequencing disclosed a heterozygous missense mutation resulting in an amino acid exchange from valine to glutamic acid at position 599 (V599E-IGF1R). Using various cell systems, we found that the V599E-IGF1R mutant was not tyrosine phosphorylated and had an impaired downstream signaling in the presence of IGF-I. Flow cytometry and live cell confocal laser scanning microscopy revealed a lack of cell surface expression due to an extensive retention of V599E-IGF1R proteins within the endoplasmic reticulum. The V599E-IGF1R mutation interferes with the receptor's trafficking path, thereby abrogating proreceptor processing and plasma membrane localization. Diminished cell surface receptor density solely expressed from the patient's wild-type allele is supposed to lead to insufficient IGF-I signaling. We hypothesize that this mechanism results in intrauterine and postnatal growth retardation of the affected patient. The reported retention of the nascent IGF1R in the endoplasmic reticulum presents a novel mechanism of IGF-I resistance.


Comment on "Curvature capillary migration of microspheres" by N. Sharifi-Mood, I. B. Liu, K. J. Stebe, Soft Matter, 2015, 11, 6768.
In a recent paper, Sharifi-Mood et al. studied colloidal particles trapped at a liquid interface with opposite principal curvatures c1 = -c2. In the theory part, they claim that the trapping energy vanishes at second order in Δc = c1 - c2, which would invalidate our previous result [Phys. Rev. E: Stat., Nonlinear, Soft Matter Phys., 2006, 74, 041402]. Here we show that this claim arises from an improper treatment of the outer boundary condition on the deformation field. For both pinned and moving contact lines, we find that the outer boundary is irrelevant, which confirms our previous work. More generally, we show that the trapping energy is determined by the deformation close to the particle and does not depend on the far-field.


Identification of clinical factors associated with severe dengue among Thai adults: a prospective study.
Dengue is the most common mosquito-borne viral disease in humans. Recently, there has been an epidemic shift of dengue from mainly affecting children to affecting more adults with increased severity. However, clinical factors associated with severe dengue in adults have varied widely between studies. We aimed to identify the clinical factors associated with the development of severe dengue according to the World Health Organization (WHO)'s 2009 definition. We conducted a prospective study of adults with dengue admitted to the Hospital for Tropical Diseases in Bangkok, Thailand, from October 2012 to December 2014. Univariate and stepwise multivariate logistic regression analyses were performed. Of the 153 hospitalized patients with confirmed dengue viral infections, 132 (86.3 %) patients had non-severe dengue including dengue without warning signs (7 patients, 5.3 %) and dengue with warning signs (125, 94.7 %). The rest (21, 13.7 %) had severe dengue including severe plasma leakage (16, 76.2 %), severe organ involvement (16, 76.2 %), and severe clinical bleeding (8, 38.1 %). Using stepwise multivariate logistic regression, clinical factors identified as independently associated with the development of severe dengue were: (1) being >40 years old (odds ratio [OR]: 5.215, 95 % confidence interval [CI]: 1.538-17.689), (2) having persistent vomiting (OR: 4.817, CI: 1.375-16.873), (3) having >300 cells per μL of absolute atypical lymphocytes (OR: 3.163, CI: 1.017-9.834), and (4) having lactate levels ≥2.0 mmol/L (OR: 7.340, CI: 2.334-23.087). In addition, increases in lactate and absolute atypical lymphocyte levels corresponded with severe dengue (p < 0.05). Our study identified several clinical factors independently associated with the development of severe dengue among hospitalized adults with dengue. This can aid in the early recognition and prompt management of at-risk patients to reduce morbidity and mortality.


Reflectance difference microscopy for nanometre thickness microstructure measurements.
The discontinuity of medium at the boundary produces optically anisotropic response which makes reflectance difference microscopy (RDM) a potential method for nanometre-thickness microstructure measurements. Here, we present the methodology of RDM for the edge measurement of ultrathin microstructure. The RD signal of microstructure's boundary is mathematically deduced according to boundary condition and polarization optics theory. A normal-incidence RDM setup was built simply with one linear polarizer, one liquid crystal variable retarder and one 5 × objective. Then, the performance of the developed setup was identified using homogenous reflection mirror and high quality linear polarizer. For demonstration, microstructures array with 100 nm step height was measured. The results show that the RD signal is sensitive to the edge and its sign reflects the change direction of the edge. Furthermore, a height sensitivity of better than 10 nm and a spatial resolution of ∼3 μm offer this technique a good candidate for characterizing ultrathin microstructures.


On global sequence alignment.
We present a dynamic programming algorithm for computing a best global alignment of two sequences. The proposed algorithm is robust in identifying any of several global relationships between two sequences. The algorithm delivers a best alignment of two sequences in linear space and quadratic time. We also describe a multiple alignment algorithm based on the pairwise algorithm. Both algorithms have been implemented as portable C programs. Experimental results indicate that for a commonly used set of gap penalties, the new programs produce more satisfactory alignments on sequences of various lengths than some existing pairwise and multiple programs based on the dynamic programming algorithm of Needleman and Wunsch.


The clinical implementation of sperm chromosome aneuploidy testing: pitfalls and promises.
Severe male infertility has been shown to be associated with improper meiotic recombination and elevated sperm chromosome aneuploidy. Elevated sperm aneuploidy increases the risk of embryo lethality or fetal anomalies. Although difficulties in interpreting aneuploidy data still exist, advances in fluorescent in situ hybridization (FISH) technology have facilitated the study of sperm from patients with severe spermatogenesis defects, which has demonstrated the prudence of evaluating sperm chromosome aneuploidy in men with severe male factor infertility, such as nonobstructive azoospermia or severe ultrastructure defects, especially in cases of previous repeated in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) failure. Testing is also advisable in men with chromosome translocations and unexplained recurrent pregnancy loss, and it may be beneficial in patients with unexplained, repeated IVF failure. Automated FISH imaging and analysis technology is now available and is beneficial in reducing technician time analyzing sperm aneuploidy. Emerging technologies, such comparative genomic hybridization, may be beneficial in further improving the quality of data derived from aneuploidy analysis and reducing the cost of the assay.


Ecgonine methyl ester, a major cocaine metabolite, causes cerebral vasodilation in neonatal sheep.
Maternal cocaine abuse has been associated with fetal and neonatal neurologic abnormalities, including hemorrhagic cerebral infarctions, but the mechanisms for cocaine's cerebral effects are unknown. We previously showed that acute cocaine injection causes cerebral vasodilation in cats and immature sheep; others have shown that cocaine causes cerebral vasoconstriction in piglets and in pressurized neonatal sheep arteries. Although methodologic and species differences may explain these conflicting results, we tested another possibility; that is, that ecgonine methyl ester (EME), a major cocaine metabolite in sheep, causes cerebral vasodilation and may account, in part, for cocaine's vascular effects. We studied the cerebral effects of a single i.v. injection of EME (2.5 mg/kg) in eight chronically catheterized, unanesthetized neonatal sheep (4 +/- 2 d old). We measured cerebral hemisphere blood flow (CBF) using radiolabeled microspheres, mean arterial pressure, heart rate, and arteriovenous oxygen content, and we calculated cerebral oxygen consumption (CMRo2) and cerebrovascular resistance at baseline and 0.5, 2, 5, and 60 min after EME injection. EME injection had no systemic effects, including no changes in mean arterial pressure, heart rate, or arterial blood gases. Within 0.5 min of injection, EME caused a 21% decrease in cerebrovascular resistance, which remained decreased for 60 min. CBF increased by 20% at 0.5, 2, and 5 min. Blood flow to brain regions other than the cerebral hemispheres paralleled changes in CBF, with cerebellar flow remaining increased at 60 min. There was no change in CMRo2. There was a small, but physiologically insignificant, decrease in arterial oxygen content. We conclude that EME causes cerebral vasodilation in neonatal sheep and may account, in part, for cocaine's cerebral vascular effects.