Longevity of 5-azacytidine-mediated gene expression and re-establishment of silencing in transgenic rice.
Epigenetic silencing of a bialaphos resistance (bar) gene in R1 progeny of a transgenic rice line was found to be meiotically stable since selfed (R2) progeny were also susceptible and the bar locus highly methylated. A high proportion of R2 seedlings germinated in the presence of 5-azacytidine (AzaC) were herbicide-resistant and also contained at least one unmethylated copy of the bar gene, further establishing the relationship between silencing and methylation. Restored bar gene expression was typically maintained for 20-50 days, but eventual methylation and silencing of the bar locus underscores the ability of the recipient genome to recognize and inactivate intrusive DNA.


The proteasome inhibitor PS-341 overcomes TRAIL resistance in Bax and caspase 9-negative or Bcl-xL overexpressing cells.
We demonstrate that PS-341, a small molecule inhibitor of the proteasome, markedly sensitizes resistant prostate, colon, and bladder cancer cells to TNF-like apoptosis-inducing ligand (TRAIL)-induced apoptosis irrespective of Bcl-xL overexpression. PS-341 treatment by itself does not affect the levels of Bax, Bak, caspases 3 and 8, c-Flip or FADD, but elevates levels of TRAIL receptors DR4 and DR5. This increase in receptor protein levels is associated with the ubiquitination of the DR5 protein. When PS-341 is combined with TRAIL, the levels of activated caspase 8 and cleaved Bid are substantially increased. In Bax-negative TRAIL-resistant HC-4 colon cancer cells, the combination of PS-341 and TRAIL overcomes the block to activation of the mitochondrial pathway and causes SMAC and cytochrome c release followed by apoptosis. Similarly, murine embryonic fibroblasts lacking Bax undergo apoptosis when exposed to the combination of PS-341 and TRAIL; however, fibroblasts lacking Bak are significantly resistant. Taken together, these findings indicate that PS-341 enhances TRAIL-induced apoptosis by increasing the cleavage of caspase 8, causing Bak-dependent release of mitochondrial proapoptotic proteins.


Incretins beyond type 2 diabetes.
Incretin-based therapies, in particular glucagon-like peptide-1 (GLP-1) receptor agonists, have been evaluated in other forms of diabetes, but randomised controlled trials are mainly limited to people living with type 1 diabetes. In this review we present the evidence issuing from these trials and discuss their clinical implications as well as the difficulties in interpreting the data. In type 1 diabetes, the addition of GLP-1 receptor agonists to intensive insulin therapy lowers weight and required insulin doses compared with placebo, but the effects on glucose control (HbA1c, risk of hypoglycaemia) are dependent on the different study protocols. Side effects are limited to the gastrointestinal complaints of nausea, vomiting and diarrhoea. We briefly discuss the potential for using GLP-1 receptor agonists as (adjunct) therapies in other forms of diabetes, where the evidence to date is scarce.


Theoretical investigation of the addition reaction of the aluminum chlorosilylenoid H(2)SiAlCl(3) with ethylene.
The addition reaction of the aluminum chlorosilylenoid H2SiAlCl3 with ethylene was investigated using the M06-2X and QCISD methods for the first time. The calculated results demonstrate that the addition reaction proceeds via two pathways: path I involves just one transition state, while path II involves two transition states. Path I is more feasible dynamically, as it has a lower barrier height than path II. The effect of the solvent CH2Cl2 was taken into consideration using the PCM model. The results indicated that the addition reaction is less likely to occur in CH2Cl2 solvent than in vacuum. This work has therefore highlighted a new pathway for the synthesis of silicon heterocyclic compounds. Graphical Abstract Relative energies (in kJ·mol(-1)) of the stationary points along the potential energy surfaces of the addition reaction of H2SiAlCl3 with C2H4 (values in parentheses were calculated in CH2Cl2 solvent).


Digital cell image analysis of verapamil-induced effects in chemosensitive and chemoresistant neoplastic cell lines.
We used chemosensitive and chemoresistant variants of the neoplastic mouse MXT mammary and human J82 and T24 bladder cell lines to characterize verapamil-induced cell proliferation and morphonuclear modifications in drug-treated and untreated cells. Chemoresistance to vinorelbine (Navelbine, a Vinca alkaloid derivative), to DIAM3 (an investigational alkylating compound) and to Adriamycin (an intercalating agent) in the presence or absence of verapamil was monitored by means of the colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The results showed that verapamil restored a significant level of chemosensitivity in doses such as 1 microM or 10 microM in the three chemoresistant variants. The digital cell image analysis of Feulgen-stained T24-resistant cell nuclei revealed that verapamil restored the drug-treated cell kinetics and morphonuclear features observed in the sensitive counterpart especially with respect to the effects of Adriamycin. Interestingly, verapamil induced a highly significant chromatin decondensation in resistant but not in sensitive variants. Such verapamil-induced decondensation may favour the accessibility of drugs to their DNA targets. Therefore, in addition to the well-known action of the drug on the influx of a cytotoxic compound from the cellular to the intracellular compartment, verapamil might also favour the accessibility of the nucleus, to the drug.


Effect of creatine depletion on myocardial mechanics.
The physiological significance of energy transport by means of shuttling creatine (C) and creatine phosphate (CP) between mitochondria and the energy utilizing sites was examined in C-depleted rat hearts. Feeding a diet containing structural analogues of C [either 1% guanidinoproprionic acid (GPA) or 2% guanidinobutyric acid (GBA)] led to the decrease of total myocardial C (C + CP) by 78% and 75% after seven weeks and by 89% and 82% after ten weeks. Mechanics of isolated papillary muscles were examined under isometric conditions at different temperatures, muscle lengths and frequencies of stimulation. No differences were found in the basic characteristics of contraction and relaxation among the hearts of normal, GPA- and GBA-treated rats at low workloads. However, when paired stimulation was applied, the interval at which fusion occurred was significantly longer in C-depleted than in controls. At high workloads, the developed force (DF) in C-depleted decreased in the same way as in controls, but its subsequent recovery took significantly longer and the recovered DF in C-depleted muscles was smaller than in controls. We conclude that C depletion has greater effects on the excitation to contraction coupling and recovery rather than on the DF during stimulation at high frequencies.


Novel type of hollow hydrogel microspheres with magnetite and silver nanoparticles.
A novel type of microcontainers based on hollow silver alginate microspheres and magnetite nanoparticles is reported as development of recently published technology. Magnetite nanoparticles were incorporated by two methods - co-precipitation with porous calcium carbonate during template formation and adsorption onto CaCO3 particles or microcontainers' shell. Amount of magnetite loaded and microshells size (4.6 to 6.9 μm) were found to depend on the chosen method for magnetite nanoparticles incorporation. Stability of hollow microshells in saline, phosphate buffer and culturing media was studied. Microcontainers' susceptibility to magnetic field was investigated in solutions of varied viscosity, and their group movement velocity under constant magnetic field was evaluated by sequential optical microscopy imaging. Cell viability tests with prepared microshells were performed that demonstrated negligible cytotoxicity effect on human dermal fibroblasts cells. With HeLa cells moderate viability inhibition was found at high carriers:cells ratio at early time points which is attributed to more active and receptor-mediated endocytosis of carriers as well as known cytotoxicity of magnetite in some cancer cells. At 24 and 48 h time points HeLa cells proliferation fully recovers. Reported data opens perspectives for further biomedical-oriented studies and application of this novel kind of microcontainers with a number of techniques applicable for imaging, control and triggered cargo release provided by presence of silver and magnetite nanoparticles in the carriers and their suitability for further versatile functionalization by traditional LbL approach if needed.


GM-CSF-transduced B16 melanoma cells are highly susceptible to lysis by normal murine macrophages and poorly tumorigenic in immune-compromised mice.
Granulocyte-macrophage colony-stimulating factor (GM-CSF)-transduced B16-F10 murine melanoma cells had lower tumorigenicity in both syngeneic and nude mice than parental or LacZ-transduced (control) cells. The subcutaneous (s.c.) tumors producing GM-CSF were densely infiltrated with macrophages, whereas the control tumors were not. In vitro studies showed that GM-CSF-transduced B16 cells were susceptible to lysis mediated by nonactivated murine macrophages, whereas control B16 cells were not. Macrophage-mediated cytotoxicity against GM-CSF-transduced B16 cells was independent of the presence of NO, H2O2, O2-, tumor necrosis factor alpha, and matrix metalloproteinase. Coculture experiments using GM-CSF-producing and -nonproducing B16 cells demonstrated that GM-CSF produced by the transduced B16 cells activated macrophages to kill the bystander non-GM-CSF-producing tumor cells. The results suggest that GM-CSF released by tumor cells can induce macrophage-mediated cytotoxicity, which in turn can inhibit the in vivo growth of GM-CSF-transduced tumor cells.


Contribution of the shunt pathway of mevalonate metabolism to the regulation of cholesterol synthesis in rat liver.
The modulation of the shunt pathway of mevalonate metabolism (Edmond, J., and Popják, G. (1974) J. Biol. Chem. 249, 66-71) has been studied in livers from fed, starved, and diabetic rats perfused with a physiological concentration (300 nM) of [5-14C] + [5-3H]mevalonate. Shunt activity was measured by (i) production of 14CO2 (corrected for loss of label by exchange reactions) and (ii) production of 3H2O. Contribution of exogenous mevalonate to total mevalonate production (0.06-0.11%) was assessed in parallel experiments by the incorporation of 3H2O into sterols. Inhibition of non-saponifiable lipid synthesis by starvation and diabetes is not associated with an inhibition of mevalonate production but with a major increase in shunting (7-34%) of sterol-bound mevalonate. The shunt pathway of mevalonate metabolism appears to participate in the regulation of cholesterol synthesis.


Enhanced effects by mixtures of three estrogenic compounds at environmentally relevant levels on development of Chinese rare minnow (Gobiocypris rarus).
The combined effects of 17β-estradiol, diethylstilbestrol and nonylphenol at environmentally relevant levels were studied on development of Chinese rare minnow. No effects on hatchability of embryos, survival of larvae, body length and body weight were found in the fish exposed to the single chemicals and their mixtures. But significant vitellogenin induction and testis somatical index reduction were observed in adult males exposed to the mixtures. Meanwhile, the sex ratio of adult fish skewed to female was found in the fish exposed to high concentration of the mixture. These results revealed not only that the co-exposure of xenoestrogens can enhance the adverse effects on the development of fish, but that the adverse effects were induced by co-exposure of xenoestrogens below the threshold of similar detectable effects for single xenoestrogen. The observations in the present study highlight the potential ecological hazard posed by the coexistence of xenobiotics in the realistic aquatic environment.


Lost in descent: Complications of cryptorchidism.
Cryptorchidism is a relatively common and important clinical entity and can lead to an array of downstream complications if it is not corrected in a timely manner, most notably with the development of testicular germ cell tumors. However, beyond the development of malignancy, there are other rare complications associated with cryptorchid testicular germ cell tumors which are more commonly seen in females with ovarian germ cell tumors, including torsion, rupture, and paraneoplastic syndromes. Presented is an instructive case (with literature review) of a patient who presented with NMDA encephalitis due to a torsed mixed germ cell tumor of an undescended testis, which subsequently ruptured leading to growing teratoma syndrome.


Investigation of performance enhancement of solar still incorporated with Gallus gallus domesticus cascara as sensible heat storage material.
In this research work, the conventional single slope still (CSS) with egg shells of breed Gallus gallus domesticus cascara as sensible heat storage (SHS) material are studied experimentally to enhance the yield. In this experimental investigation, the proposed single slope still (PSS) with SHS material was made in comparison with the CSS to evaluate the productivity of fresh water under the same ambient conditions. Comparatively, this PSS has higher thermal conductivity than the CSS. The yield obtained from the PSS is 2.46 L/m2, while the yield from the CSS is 2.07 L/m2. The average rate at which the rise of output fresh water obtained from the PSS is 18% more than the fresh water output obtained from the CSS. The daily energy efficiency of the PSS is 26.07%, and for the CSS, it is only 22.25%. The daily exergy efficiency of the PSS is 2.36%, and for the CSS, it is only 1.67%. Since using the egg shell will employ as organic waste management and modification in this still is economical, less initial, and maintenance cost.


Impact of body mass index and weight loss on cancer-specific and overall survival in patients with surgically resected renal cell carcinoma.
This study evaluated the impact of body mass index (BMI) and the influence of preoperative weight loss (WL) in each BMI category on survival in patients with surgically treated renal cell carcinoma (RCC). In total, 834 patients undergoing nephrectomy for RCC were retrospectively reviewed. Overall survival (OS) and cancer-specific survival (CSS) were estimated by Kaplan-Meier analysis. Univariate and multivariate analyses were accomplished to assess the influence of preoperatively assessed clinical parameters, including BMI and WL, on survival. The mean postsurgical follow-up was 85 months (median 79 months, range 12-191 months). Of the patients studied, 251 (30%) presented with a BMI < 25 kg/m², while 362 patients (44%) were overweight (BMI ≥ 25 to < 30 kg/m²) and 221 patients (26%) were obese (BMI ≥ 30 kg/m²). Fifty-two patients (6.2%) experienced WL. While BMI did not significantly influence OS and CSS, WL had a significant impact on survival in patients with a BMI < 30 kg/m², in contrast to obese patients presenting with a BMI of ≥ 30 kg/m². Further analysis showed overweight to influence significantly disorders in wound healing, but neither other complications nor postoperative mortality. This is the first study providing information regarding the influence of BMI in relation to WL in patients with surgically treated RCC. While BMI did not significantly influence the survival of patients in the present series, WL had a significant impact on survival of patients presenting with a BMI < 30 kg/m². Hence, preoperative assessment of WL should be considered for the assessment of individual prognosis.


STAT3-Induced lncRNA SNHG17 Exerts Oncogenic Effects on Ovarian Cancer through Regulating CDK6.
Emerging studies indicate that long noncoding RNAs (lncRNAs) play crucial roles in ovarian cancer (OC). By analyzing high-throughput data, we found that SNHG17 was highly expressed in multiple OC cohorts. However, its functions in OC were not explored. In this study, lncRNA expression in OC was analyzed by a series of microarray data. The functions of SNHG17 were investigated by various in vitro and in vivo assays. Fluorescence in situ hybridization (FISH), RNA pull-down, chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), and luciferase reporter assays were used to reveal the potential mechanisms involved in the effects of SNHG17. We found that SNHG17 was overexpressed in OC and that the oncogenic transcription factor STAT3 was involved in promoting its expression. In addition, high SNHG17 expression was associated with a poor prognosis in OC. Functional analysis revealed that SNHG17 could promote OC cell growth. Mechanistically, SNHG17 was found to be located predominantly in the cytoplasm. It could regulate expression of CDK6, an important cell-cycle regulator, by acting as a molecular sponge for miR-214-3p. In summary, our study suggested that SNHG17 acted as an oncogene in OC, which might serve as a novel target for OC diagnosis and therapy.


Investigating the diversity of bacterial endophytes in maize and their plant growth-promoting attributes.
Maize is a widely known crop in cereals for its importance as staple food, and the endophytic bacteria which dwell within the maize tissues may have impact on the yield and quality of crop. In this study, endophytic bacteria associated with maize were characterized based on their plant growth promoting traits and identified at molecular level to provide valuable information for developing a microbial consortium to enhance the productivity of crop. The bacterial strains having multi-trait plant growth promoting attributes were studied quantitatively, and highest phosphate solubilization was shown by the isolate KL3E1 (573 µg/mL), while K solubilization has reported maximum of 39 mg/L by the isolate PdS3E1, IAA production was found maximum by the isolate LL3E1 (165 μg/mL), and maximum siderophore production (93%) was shown by the isolate VaR3E1 and exopolysaccharide production was found highest by LS3E3 (65 mg/L). The efficient isolates identified by 16S rRNA gene sequencing were found as Gordonia hongkongensis, Microbacterium hydrothermale, Kosakonia radicincitans, Kosakonia cowanii, Priestia megaterium, Priestia aryabhattai, Klebsiella pneumoniae, Cellulosimicrobium funkei, Bacillus licheniformis, Pantoea dispersa, Pseudomonas aeruginosa, and Methylorubrum populi. The results showed that these multi-trait plant growth promoting endophytic bacterial isolates could be used as bio inoculants for sustainable improvement of maize crop productivity.


Gene expression during gonocyte transformation into spermatogonial stem cells is not androgen dependent.
Early germ cell development is deranged in undescended testis, potentially leading to infertility and cancer. Androgens are proposed to regulate gonocyte transformation into stem cells during human 'minipuberty' at 3-12months. We studied genes expressed in germ cells, Sertoli cells, and other somatic cells to determine whether androgen mediates gonocyte transformation. Testes from androgen-receptor knockout (ARKO) and wild-type (WT) littermates were collected at postnatal day P0 (birth), P4, P8 for real-time PCR to measure gene expression of mouse VASA homolog (Mvh), anti-Mullerian hormone (Amh), kit oncogene (c-Kit), matrix metalloproteinase-1 (Mt1-mmp), zinc finger, and BTB domain-containing 16 (Plzf) and octamer-binding protein 4 (Oct4). Data were normalized to ribosomal protein L32 (Rpl32), and reproductive homeobox gene 5 (Rhox5) was a positive control for androgenic response. Changes in gene expression were calculated with GraphPad Prism 5.02. There were no statistical differences (p>0.05) in Mvh, Oct4, c-Kit, Plzf, Amh and Mt1-mmp expression between WT and ARKO testes from P0 to P8. These results show that androgen did not influence gene expression in postnatal mouse testis, which coincides with human 'minipuberty'. The results are consistent with gonocyte transformation being independent of androgens, and that nonandrogenic regulators need to be identified.


Gender-related pharmacokinetics and absolute bioavailability of diosbulbin B in rats determined by ultra-performance liquid chromatography-tandem mass spectrometry.
Diosbulbin B (DB) is the main constituent of furano-norditerpenes in Dioscorea bulbifera Linn., which is widely distributed in China and was usually used as a remedy for sore throat, struma and tumor. Owing to its potential antitumor activity, DB has been considered as a promising candidate for drug development. To study the pharmacokinetic properties and excretion of DB in rats by a sensitive UPLC-MS/MS method. Absolute bioavailability and gender-related pharmacokinetic properties, as well as excretion fractions of DB in urine and feces after oral and intravenous administrations would be addressed for the first time. Sprague-Dawley rats were administrated orally (32mg/kg) and intravenously (0.5mg/kg) of DB, respectively. The concentrations of DB in rat plasma were determined by a sensitive and well-validated LC-MS/MS method. Main pharmacokinetic parameters including area under the plasma concentration-time curve (AUC), elimination half time (t1/2), mean residence time (MRT), apparent volume of distribution (Vd) and clearance rate (CL) were estimated using a non-compartmental pharmacokinetics data analysis software. Urine and feces of rats were collected within 48h after oral administration (32mg/kg) and detected by UPLC-MS/MS and HPLC, respectively. The standard curves of DB in rat plasma and urine showed good linearity in the concentration range of 1.0-515ng/mL in the method, with acceptable selectivity, precisions, recoveries, and stability. The oral absolute bioavailability of DB in female rats was 2.0%, significantly higher than that of males (0.3%) (p<0.05). Female rats demonstrated longer t1/2 and MRT (p<0.01), bigger Vd and higher CL (p<0.05) than males after intravenous administration of DB. Bigger but no significant difference in excretion fractions of urine and feces in female rats were observed, comparing to those in males. A simple and sensitive UPLC-MS/MS method was developed to determine the pharmacokinetic profiles of DB in rats, as well as the excretion in rat urine. Gender exerted a significant influence on the pharmacokinetics and bioavailability of DB in rats. Female rats showed significantly better absorption of DB than males after oral administration.


Survival of a child despite unusually high blood ethanol levels.
A 30-month-old, 13-kg child reportedly ingested up to 16 ounces of a wine containing 20% ethanol. The child was brought into the emergency department by paramedics, and upon arrival was found to be comatose and unresponsive to deep stimuli but breathing spontaneously. The patient remained unconscious and unresponsive for three hours after admission. Despite an initial blood ethanol level of 98.78 mmol/L (455 mg/dL), recovery was complete without sequelae. Treatment consisted of prompt gastric decontamination and maintenance of adequate hydration and euglycemia. Elimination of ethanol was rapid in this child and appeared to follow first-order kinetics instead of the zero-order kinetics usually observed. To our knowledge, this is the highest initial blood ethanol level reported in a child with survival. Additionally, no significant metabolic or cardiorespiratory derangement occurred. Ethanol toxicity, elimination kinetics, and treatment are discussed.


Cryoablation for surgical treatment of chronic atrial fibrillation combined with mitral valve surgery: a clinical observation.
Although the classical Cox-Maze III is the gold standard surgical therapy with a proven efficacy in the treatment of atrial fibrillation (AF), complexity of this procedure has resulted in a search for a simpler, less invasive and more cost-effective method. In this study we evaluated the results of cryosurgical ablation in the treatment of chronic AF in patients undergoing concomitant mitral valve surgery. Ninety patients (mean age: 50.9+/-12 years) with chronic AF who were having mitral valve surgery as the main procedure underwent cryoablation with a newly designed N(2)O-based cryotherapy device. Pulmonary vein isolation with or without left atrial appendage closure (group A) was carried out in 65 cases and cryoablative bi-atrial Cox-Maze III (group B) in 25 patients. This additional procedure took only an extra 10 min for group A and about 20 min for group B. Half of the patients received a beta-blocker following the procedure. The overall success rate of cryoablation was 65.5%. Normal sinus rhythm was achieved in 26.7% in the operating room, 10% in ICU and the remaining cases reverted to sinus rhythm during the follow-up period. There were no major ablation-related complications such as bleeding, thromboembolic events or A-V block. The only predictor for failure of ablative procedure was left atrial size of greater than 6 cm. Although in this study the efficacy rate of cryoablative surgery was not the same as classical Cox-Maze III, it seems that this procedure is safe, simple, cost-effective and at the same time does not increase the operative time significantly. Using cryoablation may enhance the cure rate of chronic AF during mitral valve surgery.


An evaluation of a positive psychological intervention to reduce burnout among nurses.
This quasi-experimental study aimed to evaluate the positive psychological intervention of recording three good things on alleviating nurses' burnout. Eighty-seven nurses with burnout were recruited. Nurses in the study group recorded three good things using communication tool WeChat for six months, no records were made in the control group. After intervention, the score of exhaustion decreased considerably for nurses in the study group. Nurses recording three good things on average twice a week returned the lowest score of exhaustion. This intervention combined with appropriate surveillance and encouragement is recommended to reduce nurses' burnout and create a positive work environment.


GFR after kidney donation: early recovery and subsequent decline.
Recent studies document a small but significant risk of kidney failure after living kidney donation, but they lack data on early glomerular filtration rate (GFR) recovery and subsequent decline that might be linked to harm. Two complementary studies published in this issue overcome this limitation, showing that the GFR decline after recovery is slower than that in well-matched control groups of nondonors.


Characterization and stabilization of progesterone receptors in human benign prostatic hypertrophy.
Experimental conditions for the optimum detection and measurement of the cytosolic progestogen receptor in human prostatic hyperplasia and neoplasia are described. In presence of 20 mM molybdate ion and a reaction time of 0.5-2 h at 0-2 degrees C, we are able to detect the appearance of a [6.7-3H]-17,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione ([3H]-R5020) and [3H]-progesterone binding moiety in human prostatic cytosol. The [3H]-R5020 binding protein sediments at approximately 8-11S in a glycerol density gradient centrifuged in a Sorvall TV865 rotor (vertical rotor). Maximal binding of [3H]-R5020 occurs at 30 min at 25 degrees C and 1 h at 0 degree C. Considerable overall improvement in receptor detection and measurement was made when gradient centrifugation was carried out in a vertical rotor instead of swing bucket rotor. The specifically bound [3H]-R5020 is displaced by progesterone, triamcinolone acetonide and R5020, but not by cortisol, dihydrotestosterone, 17 beta-estradiol, or diethylstilbestrol. High affinity was demonstrated by Scatchard analysis on binding of [3H]-5020 to receptors from cytosol of benign prostatic hypertrophy (BPH) giving a KD of 2.4 X 10(-10)M and a binding site concentration of 50 fmol/mg protein. Molybdate ion maintains the hormone receptor complex in 8-11S form which is totally converted to the 4-5S form in the presence of 0.6 M K Cl. The optimum concentration of fluoride ion for enhancing the specific binding of [3H]-R5020 was determined to be between 20 and 50 mM. Cytosol from human BPH in the presence of 25 mM sodium fluoride contains [3H]-R5020 receptors which sedimented mostly in the 4-5S region of glycerol density gradient. Sodium-molybdate and sodium fluoride stabilize and stimulate the specific [3H]-R5020 receptor complex at 25 and 0 degree C. The loss of specific receptor hormone binding capacity can be reversed by fluoride and, to a lesser extent, by molybdate.


Reconstruction of the lower half of the facial skeleton after removal of the mandible at autopsy.
A method for postmortem removal of the mandible without altering the facial appearance of the deceased is presented. The technique is especially developed to avoid damage to the soft tissues of the face.


Excitatory-inhibitory balance modulates the formation and dynamics of neuronal assemblies in cortical networks.
Repetitive activation of subpopulations of neurons leads to the formation of neuronal assemblies, which can guide learning and behavior. Recent technological advances have made the artificial induction of these assemblies feasible, yet how various parameters of induction can be optimized is not clear. Here, we studied this question in large-scale cortical network models with excitatory-inhibitory balance. We found that the background network in which assemblies are embedded can strongly modulate their dynamics and formation. Networks with dominant excitatory interactions enabled a fast formation of assemblies, but this was accompanied by recruitment of other non-perturbed neurons, leading to some degree of nonspecific induction. On the other hand, networks with strong excitatory-inhibitory interactions ensured that the formation of assemblies remained constrained to the perturbed neurons, but slowed down the induction. Our results suggest that these two regimes can be suitable for computational and cognitive tasks with different trade-offs between speed and specificity.


ClosureFast endovenous radiofrequency ablation for great saphenous vein and small saphenous vein incompetence: Efficacy and anatomical failure patterns.
Recurrence rates and patterns after endovenous radiofrequency ablation (ERFA) are poorly documented. To assess the incidence and anatomical recurrence patterns of saphenous vein reflux after ERFA. Two hundred patients previously treated with ERFA were recalled for clinical assessment and venous-duplex ultrasound at three years post-treatment. A total of 106 patients (68F, 38M) with a mean age of 49.4 years (SD +11.5y) were assessed. Mean follow-up was 42.1 months (SD + 20.1m). Further varicose veins were identified in 31 patients (29.2%). Recanalization/recurrence/failure was diagnosed in 16 patients (15.1%), including 18 trunks (8.7%), 13 great saphenous vein (6.3%) and 5 small saphenous vein (2.4%). Twenty-seven patients (25%) developed neo-incompetence in 31 trunks and 12 non-saphenous veins. All patients with truncal recanalization had a body mass index > 29 (range 29-42). Disease progression was twice as high as the recanalization rate at three years post-treatment using ERFA in this study. Raised body mass index may be a contributing factor; however, further longitudinal studies are required. Patient self-selection bias may have also influenced our results.


Distribution of neurons in the major pelvic ganglion of the rat which supply the bladder, colon or penis.
In male rats a large number of the postganglionic neurons which innervate the pelvic organs are located in the major pelvic ganglion. In the present study we have identified the location within this ganglion of neurons which project to either of three pelvic organs, the penis, colon or urinary bladder. Two fluorescent retrogradely-transported dyes, Fast Blue and Fluoro-Gold, were used. For most animals one dye was injected into the cavernous space of the penis, the wall of the distal colon or the wall of the urinary bladder. In a small number of animals two organs were injected, each with a different dye. One to six weeks after injection the major pelvic ganglia were fixed in buffered formaldehyde. The distribution of fluorescent dye-labelled cells was observed in whole mounts of complete ganglia and, in most cases, also in small accessory ganglia located between the ureter and the prostate. The studies showed a unique pattern of distribution for each organ-specific group of neurons. Most of the colon neurons are located in the major pelvic ganglion near the entrance of the pelvic nerve, whereas almost all of the penis neurons are near or within the penile nerve. Bladder neurons are relatively evenly distributed throughout the ganglion. These results demonstrate a distinct topographical organization of organ-specific neurons of the major pelvic ganglion of the male rat, a phenomenon which has also been observed in other peripheral ganglia.


High-efficiency gene knockdown using chimeric ribozymes in fish embryos.
We report an effective gene knockdown technique in rainbow trout embryos using additional RNA components combined with ribozymes (R(z)s). Chimeric R(z)s (tR(z)Cs) containing tRNA(Val), R(z) against GFP, and a constitutive transport element were microinjected into transgenic embryos. tR(z)Cs induced greater gene interference than R(z)s alone. Control tR(z)Cs did not affect unpaired bases of target RNA, and the tR(z)C did not interfere with non-relevant gene expression, suggesting that the tR(z)C-mediated gene-interference effects were sequence-specific. Furthermore, the tR(z)C-containing expression vector specifically suppressed target GFP expression in transgenic trout. tR(z)Cs enhance R(z) cleavage and could therefore be powerful tools for studying unknown gene function in vertebrates.


Earliest electrocardiographic evidence of myocardial infarction: implications for thrombolytic treatment. The GREAT Group.
To determine the incidence of the earliest electrocardiographic changes in patients with suspected myocardial infarction and their sensitivity and specificity for predicting the final diagnosis of acute myocardial infarction. Retrospective study of paired electrocardiograms recorded at home and on admission to hospital. 29 rural practices in Grampian and teaching hospitals in Aberdeen. 137 patients participating in the early anistreplase trial in the Grampian region, who received placebo at home and for whom paired electrocardiograms were available. Classified electrocardiographic abnormalities and diagnosis at discharge. Electrocardiograms were recorded immediately before injection of placebo at home and anistreplase in hospital at median times of 110 and 240 minutes after the onset of symptoms. Definite or probable myocardial infarction was later confirmed in 93 (68%) patients. Of these, 66 (71%) had the same findings on both electrocardiograms of either ST elevation, bundle branch block, or a non-specific abnormality, while 27 (29%) showed a major change of classification between home and hospital recordings; 21 (23%) had ST elevation or bundle branch block on only one of the paired recordings. Although ST elevation was the commonest abnormality in the 93 patients with myocardial infarction, in only 51 was it recorded at home (sensitivity 55%) and in 49 on admission (sensitivity 53%). Of 57 patients with ST elevation at home, six did not have infarction (specificity 86%), while of 51 with ST elevation on admission, two did not have infarction (specificity 95%). Elevation of the ST segment is a transient electrocardiographic abnormality that has high specificity but low sensitivity for predicting the diagnosis of acute myocardial infarction; it is an unsatisfactory precondition for giving thrombolytic treatment to patients with suspected acute myocardial infarction.


Estimating the prevalence of injecting drug users on the basis of Markov models of the HIV/AIDS epidemic: applications to Italian data.
This paper addresses some important issues related to the estimation of the extent of injecting drug use. The population of injecting drug (heroin) users in Italy is estimated on the basis of a dynamic model of the health consequences, in particular using AIDS incidence data. The use of the prevalence estimates to monitor the impact of health care and law enforcement interventions is outlined.


Unnatural amino acid mutagenesis of GPCRs using amber codon suppression and bioorthogonal labeling.
To advance dynamic, temporal, and kinetic studies of the G protein-coupled receptor (GPCR) signalosome, new approaches are required to introduce non- or minimally perturbing labels or probes into expressed receptors. We report here a series of methods that are based on unnatural amino acid mutagenesis of GPCRs using amber codon suppression technology. We show that labeling reactions at genetically introduced keto moieties (p-acetyl-L-Phe/AcF and p-benzoyl-L-Phe/BzF) are not completely bioorthogonal due to protein oxidation, which causes high background. However, labeling reactions that target p-azido-L-Phe (azF) using the Staudinger-Bertozzi ligation and the strain-promoted alkyne-azide cycloaddition are bioorthogonal and are satisfactory for introducing labels or probes at near quantitative efficiency under mild labeling conditions. To our knowledge, this is the first report of a site-specific modification of an azF residue with a dibenzocyclooctyne-derivatized fluorophore. The methodologies we discuss are general, in that they can be applied in principle to any amino acid position in any expressed GPCR.


Regional distribution of blood flow at the onset of right ventricular diastolic collapse during cardiac tamponade.
The onset of right ventricular diastolic collapse has been shown to be a very sensitive and specific sign of cardiac tamponade in both clinical and conscious canine studies, and is associated with a decline in cardiac output of about 20%. To determine if blood flow to critical regions was affected at the time of onset of right ventricular diastolic collapse, seven unanesthetized, chronically instrumented dogs were studied during cardiac tamponade induced by the intrapericardial infusion of warm saline solution. Aortic blood pressure, heart rate, and cardiac output (electromagnetic flowprobe) were recorded at baseline (drained pericardial space) and at the onset of right ventricular diastolic collapse as seen on two-dimensional echocardiography. Regional blood flow was measured with radionuclide-labeled microspheres. Despite the expected decline in cardiac output, there was no significant change in cardiac, renal, or cerebral cortical blood flow at the onset of right ventricular diastolic collapse. Therefore, this noninvasive marker of early cardiac tamponade begins before vital organ perfusion is compromised, thus strengthening its clinical value.


Loss of virulence in a small plaque mutant of the infectious bursal disease virus.
A variant strain Cu-1 M was established from the infectious bursal disease virus strain Cu-1. This variant strain forms smaller plaques than the wild type; it has a retarded growth rate, does not lead to an overt disease in chickens and causes only minor lesions in the bursa of Fabricius. Infection with this strain induces solid protective immunity against infection with the virulent virus.


Insights into the diagnosis of hepatocellular carcinomas with hepatobiliary MRI.
The incidence of hepatocellular carcinomas (HCCs) has increased worldwide in line with an improved screening by high-resolution imaging of cirrhotic livers. Besides abdominal ultrasonography and computerised tomography, magnetic resonance imaging (MRI) is an important tool to detect HCCs. With commercialisation of MR hepatobiliary contrast agents that cross membrane transporters in hepatocytes or tumour cells, MRI adds new information to detect and characterise HCCs. When tumour cells lose organic anion transporting polypeptides (OATP1B1/B3) in cell membranes facing sinusoidal blood, tumours appear hypointense (decreased contrast agent concentrations) in comparison to surrounding normal or cirrhotic liver that retains OATP1B1/B3 expression. However, expression, regulation, and prognostic significance of transporter evolution along carcinogenesis are not completely known. Moreover, understanding signal intensities in focal lesions also relies on transport functions of cellular efflux transporters. This manuscript reviews all the publications that associate liver imaging with hepatobiliary contrast agents and expression of transporters. The regulation of transporters along carcinogenesis to anticipate the prognosis of focal lesions is also included.


Impact of anaemia and the effect of empagliflozin in heart failure with reduced ejection fraction: findings from EMPEROR-Reduced.
Anaemia is frequent among patients with heart failure (HF) and reduced ejection fraction (HFrEF) and is associated with poor outcomes. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) increase haematocrit and may correct anaemia. This study aims to investigate the impact of empagliflozin on haematocrit and anaemia, and whether anaemia influenced the effect of empagliflozin in EMPEROR-Reduced. Mixed-effects models and survival analysis. A total of 3726 patients (out of 3730) had baseline haematocrit values, 3013 (81%) had no anaemia and 713 (19%) had anaemia. Patients with anaemia were older (70.4 vs. 66.0 years), had lower body mass index (26.6 vs. 28.2 kg/m2 ), lower estimated glomerular filtration rate (54.2 vs. 63.9 ml/min/1.73 m2 ), and higher N-terminal pro-B-type natriuretic peptide (2362 vs. 1800 pg/ml). Compared to patients without anaemia, those with anaemia had 1.5 to 2.5-fold higher rates of cardiovascular and all-cause mortality, total HF hospitalizations, and kidney composite outcomes. The effect of empagliflozin to reduce the primary composite outcome of cardiovascular death or HF hospitalizations, total HF hospitalizations, and kidney composite outcome was not modified by baseline anaemia status (interaction p > 0.1 for all). Compared to placebo, empagliflozin rapidly (as early as week 4) increased haematocrit and haemoglobin and reduced the rates of new-onset anaemia throughout the follow-up (22.6% in placebo vs. 12.3% in empagliflozin; hazard ratio 0.49, 95% confidence interval 0.41-0.59; p < 0.001). Anaemia was associated with poor outcomes. Empagliflozin reduced new-onset anaemia throughout the follow-up and improved HF and kidney outcomes irrespective of anaemia status at baseline.


Adsorption of polyethylene standards from decalin on liquid chromatography column packings.
Linear polyethylene and isotactic polypropylene standards were injected into columns which contained MFI (SH-300 and silicalite) or faujasite (CBV-780) type zeolites. 1,2,4-Trichlorobenzene, cyclohexanone, 2-ethyl-hexanol, decalin and tetralin were used as mobile phases at 140 degrees C. It was found that polyethylene is fully retained on zeolite SH-300 when decalin is used as a mobile phase. Moreover, polyethylene is partially retained on zeolite SH-300 from tetralin and from 1,2,4-tichlorobenzene, on silicalite from decalin and in a very small extent on zeolite CBV-780 from decalin. Using all other solvents, polyethylene and polypropylene were not retained in any of the columns tested. This is the first experimental observation of polyethylene adsorption from a solvent on a chromatographic stationary phase.


Proteomic and metabolomic analyses of mitochondrial complex I-deficient mouse model generated by spontaneous B2 short interspersed nuclear element (SINE) insertion into NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4) gene.
Eukaryotic cells generate energy in the form of ATP, through a network of mitochondrial complexes and electron carriers known as the oxidative phosphorylation system. In mammals, mitochondrial complex I (CI) is the largest component of this system, comprising 45 different subunits encoded by mitochondrial and nuclear DNA. Humans diagnosed with mutations in the gene NDUFS4, encoding a nuclear DNA-encoded subunit of CI (NADH dehydrogenase ubiquinone Fe-S protein 4), typically suffer from Leigh syndrome, a neurodegenerative disease with onset in infancy or early childhood. Mitochondria from NDUFS4 patients usually lack detectable NDUFS4 protein and show a CI stability/assembly defect. Here, we describe a recessive mouse phenotype caused by the insertion of a transposable element into Ndufs4, identified by a novel combined linkage and expression analysis. Designated Ndufs4(fky), the mutation leads to aberrant transcript splicing and absence of NDUFS4 protein in all tissues tested of homozygous mice. Physical and behavioral symptoms displayed by Ndufs4(fky/fky) mice include temporary fur loss, growth retardation, unsteady gait, and abnormal body posture when suspended by the tail. Analysis of CI in Ndufs4(fky/fky) mice using blue native PAGE revealed the presence of a faster migrating crippled complex. This crippled CI was shown to lack subunits of the "N assembly module", which contains the NADH binding site, but contained two assembly factors not present in intact CI. Metabolomic analysis of the blood by tandem mass spectrometry showed increased hydroxyacylcarnitine species, implying that the CI defect leads to an imbalanced NADH/NAD(+) ratio that inhibits mitochondrial fatty acid β-oxidation.


The heat transfer analysis of nanoparticle heat source in alanine tissue by molecular dynamics.
The purpose of this study is to simulate the heat transfer problem when the 3-D Alanine tissue is heated by the gold nanoparticle in the field of molecular dynamics. In this paper, the Alanine molecule is adopted and its parameters are available in the GROMACS protein data bank. A computing algorithm is developed to evaluate the heat transfer phenomena in the nano-scale biological system based on the molecular dynamics and the protein data bank. The value of the thermal conductivity of Alanine is calculated from the autocorrelation function of the Green-Kubo formalism and this result has a roughly approximation with the bulk thermal conductivity reported by experimental data . Two kinds of problems are investigated in the paper. One is the Alanine tissue heated by the constant heat source and the other is by the time-varying heat source. The numerical results show that a temperature jump exists around the source and the temperature profiles drop to the environmental temperature within a very short distance. It concludes that only a small region around the nano-scale heat source is affected by the heated process. Therefore, the results of the nanoparticle-heated method could be applied to the clinical therapy of tumor, and the normal cells are destroyed only within a smaller region than those of chemotherapy or surgery.


Clinical response and plasma levels of 5-fluorouracil in patients with colonic cancer treated by drug infusion.
Concentrations of 5-fluorouracil (FU) were measured in the plasma of patients receiving i.v. infusions of the drug for 5 days as treatment for adenocarcinoma of the gastrointestinal tract. Concentrations of FU varied widely in many patients. Concentration of drug X time of infusion (C X t values) were calculated. Patients showing a partial response or stabilization of disease had significantly higher C X t values than non-responders. Methyl CCNU did not affect the C X t values of FU. Determination of the plasma concentration of FU would allow the dose of the drug to be adjusted to maintain high concentrations of FU in the plasma. Our data suggest that such high concentrations would increase the response rate in this disease.


A novel duplex real-time PCR for HPIV-4 detects co-circulation of both viral subtypes among ill children during 2008.
The two subtypes of the human parainfluenzavirus type 4 (HPIV-4) are rarely sought in testing for acute respiratory illness (ARI) and this may be confounding our understanding of its role. This study presents a novel duplex real-time RT-PCR assay targeting the P gene that can detect and differentiate the two subtypes in a single reaction. Subtype-specific synthetic RNA positive controls were prepared and used to determine an analytical sensitivity of 10 copies per reaction with an 8log(10) dynamic range. The assays were validated using 1140 clinical specimens mostly nasopharyngeal aspirates collected from children during 2008. These included specimens previously determined to be positive for all commonly considered respiratory viruses. The novel assay did not cross-reaction with any other virus. Fourteen HPIV-4 positives, ten detected in the absence of any co-detections (four with rhinovirus), were identified in 2008 and their subtype confirmed by conventional RT-PCR and sequencing of P gene fragments. Most detections were in children two years of age or younger. Our assay proved suitably sensitive and specific for inclusion in future studies seeking to better understand the role HPIV-4 and other respiratory viruses in children with ARI.


The natural history of symptomatic haemorrhoids.
In order to calculate the prognosis for a person who has developed a first episode of second degree haemorrhoids, 186 patients were randomly assigned to either no active treatment (expectant management) (n = 91) or rubber band ligation (n = 98) and reviewed every 6 months. The median follow-up period was 48 months in both groups with a range from 6-48 months in the banding group and from 18-48 months in the expectant management group. Rubber band ligation was performed at most three times with three weekly intervals. There were 6 treatment failures in the banding group in contrast to 31 in the expectant management group (p less than 0.01). The calculated recurrence rate by actuarial analysis among patients initially cured by rubber band ligation was 33% (95% confidence limits: 23-45) at four years and 61% (95% confidence limits: 48-74) in the expectant management group (p less than 0.05). It is concluded that rubber band ligation of symptomatic second degree haemorrhoids in up to three single treatments at three weekly intervals at the time of diagnosis significantly altered the prognosis without causing significant morbidity. However, 25% of the patients treated by expectant management never developed another episode during the four years observation time.


[The role of ultrasonic activation of the thyroid in the development of stress changes in cardiac contractile function].
Ultrasonic activation of the thyroid is characterized by a rise in T3 concentrations in the serum, acceleration of the rat myocardial contractility under isometric loading. Preliminary activation of the thyroid function restrains stress-related changes in thyroid hormone production and cardiac contractility, prevents reduction of iodized thyroglobulins in thyroid colloid under immobilization.


Benzodiazepine receptor recruitment after acute stress in synaptosomal membranes from forebrain of young chicks: action of Triton X-100.
In young chicks submitted to acute stress by forced swimming there was a significant increase in the number of the measurable [3H]-flunitrazepam receptors in synaptosomal membranes from forebrain. In addition, low subsolubilizing concentrations of Triton X-100 caused a significant increase in the measurable [3H]-flunitrazepam receptor number in synaptosomal membranes from non-stressed chicks. However, this Triton X-100 stimulatory effect was not observed when tested in synaptosomal membranes from stressed chicks. In all cases the affinity remained unchanged. This result suggest that: (i) acute stress and Triton X-100 induce receptor recruitment by enhancing [3H]-flunitrazepam accessibility to a pool of receptors which is unmeasurable either before stress or in absence of detergent; (ii) neither recruitment types are additive and they involve receptors coming from the same nonmeasurable pool; (iii) stress induces a maximal recruitment of existing benzodiazepine receptors; (iiii) the pool of nonmeasurable receptors represents about a quarter of the total in control chicks. The recruitment at a short time of stress could be interpreted in terms involving internalization; recycling or modulation of receptors but not its biosynthesis or degradation.


Energy drink consumption and associated health behaviors among university students in an urban setting.
The objective of this study is to describe energy drink consumption and health behaviors among college students attending a predominantly minority university. Undergraduate and graduate students attending a private, minority-serving university were invited to participate in an online survey between September 2009 and August 2010. Out of 2,500 students, 407 participated yielding a response of 16 %. Analysis assessed energy drink consumption as well as participation in sport activities and high-risk behaviors. Energy drink consumption is significantly related with drinking alcohol to inebriation and driving (r = .14, p < .05) and to riding with a drunk driver (r = .15, p < .05). Athletes were more likely to engage in drinking alcohol to inebriation and driving F (1, 186) = 6.12, p < .02. Energy drink consumption is a common practice among racial minority university students. Tailored health promotion strategies and interventions are needed to address misconceptions of energy drink and alcohol mixing.


Cystic fibrosis: a new mutation in the Lebanese population.
Cystic fibrosis is the most common autosomal recessive disorder in Caucasians. Little has been reported on its occurrence in Arab and Lebanese populations where mutation distribution seems to differ from that of Europeans. We report on the occurrence of a frameshift mutation 4016insG in two Lebanese Muslim siblings, products of consanguineous parents. This mutation generates a stop codon instead of Arginine-1301 and has never been reported before. Both probands manifested early onset of severe respiratory and pancreatic involvement. DNA analysis was performed by PCR and sequencing for exons 1, 4, 10, 11, 20, 21 of the CFTR gene. Both probands were found to be homozygous for the 4016insG. Their parents were both heterozygous for the same mutation. The frameshift mutation reported in this article is being described for the first time.


Pitted terrains on (1) Ceres and implications for shallow subsurface volatile distribution.
Prior to the arrival of the Dawn spacecraft at Ceres, the dwarf planet was anticipated to be ice-rich. Searches for morphological features related to ice have been ongoing during Dawn's mission at Ceres. Here we report the identification of pitted terrains associated with fresh Cerean impact craters. The Cerean pitted terrains exhibit strong morphological similarities to pitted materials previously identified on Mars (where ice is implicated in pit development) and Vesta (where the presence of ice is debated). We employ numerical models to investigate the formation of pitted materials on Ceres and discuss the relative importance of water ice and other volatiles in pit development there. We conclude that water ice likely plays an important role in pit development on Ceres. Similar pitted terrains may be common in the asteroid belt and may be of interest to future missions motivated by both astrobiology and in situ resource utilization.


The CAP-Gly of p150: one domain, two diseases, and a function at the end.
In this issue of Neuron, work from Moughamian and Holzbaur (2012) and Lloyd et al. (2012) reveals a role for p150 in initiation of retrograde transport at synaptic terminals. These studies also suggest how mutations of p150's CAP-Gly domain lead to both Perry syndrome and HMN7B disease.


Validation of a registry-derived risk algorithm based on treatment protocol as a proxy for disease risk in childhood acute lymphoblastic leukemia.
Administrative databases and cancer registries are frequently used to conduct population-based research, but often lack clinical data necessary for risk stratification. Our objective was to determine the criterion validity of a risk-stratification algorithm based on treatment characteristics available from a pediatric cancer registry as a proxy for disease risk, by comparing it to traditional biology-based risk classifications. We identified all children with acute lymphoblastic leukemia diagnosed at a single institution between January 2000 and June 2011, and linked them to a population-based cancer registry. Several risk algorithms were then constructed using disease risk variables collected through chart review by a pediatric oncologist, and compared to a risk algorithm based on treatment protocol name and age, available from the registry. Of 596 patients identified, 579 (97.1%) met inclusion criteria and were successfully linked. The registry-based algorithm showed almost perfect agreement with a biology-based algorithm based on age, initial white blood cell count, immunophenotype and cytogenetics (kappa=0.85, 95th confidence interval 0.81-0.90). Discrepant cases were often due to the presence of unusual high risk features not captured by standard disease-risk variables but reflected in clinicians' choices of higher intensity treatment protocols. Protocol name represents a valid proxy of disease risk, allowing for risk stratification while conducting comparative effectiveness research using cancer registries and health services data. Future studies should examine the validity of treatment-based risk algorithms in other malignancies and using other treatment characteristics commonly found in health services data, such as the receipt of specific chemotherapeutic agents.


Adaptation of the rheumatoid arthritis quality of life scale for Estonia.
The aim of the study was to adapt the rheumatoid arthritis quality of life scale (RAQoL) for Estonia and assess its psychometric properties. The RAQoL was translated into Estonian using the dual panel method. The translation was assessed for face and content validity by means of interviews with 15 rheumatoid arthritis (RA) patients. Reproducibility and construct validity were estimated using a further sample of 50 patients. Unidimensionality of the final scale was assessed by Rasch analysis. No major problems occurred in translating the instrument, it was well accepted by interviewees. The Estonian RAQoL had good test-retest reliability, internal consistency and ability to discriminate between groups defined by patient-perceived severity. Predicted convergent and divergent validity was demonstrated. Unidimensionality of the instrument was confirmed by excellent fit to the Rasch model. The RAQoL is appropriate for use in clinical studies and trials involving RA patients.


Phases in the development of a penicillin epileptiform focus in rat neocortex.
Somatosensory evoked potentials and potentials evoked by direct cortical stimulation were recorded from layer IV of the somatosensory area of the cerebral cortex in urethane anaesthetised rats. Penicillin was expelled electrophoretically from the tip of a drug-filled micropipette at constant rates into layer IV. Small fluxes of penicillin (with electrophoretic currents of -50 to -90 nA) resulted in the appearance, after a delay of 1-2 min, of an enhancement of amplitude in the voltage of both types of evoked potential, unaccompanied by any prolongation of the waveform or spontaneous focal epileptiform discharges. The amplitude of the enhanced evoked potential exhibited a strength-response curve which was a scaled-up version of the curve before penicillin, the scaling factor reflecting the enhancement of amplitude. As the interval between a pair of stimuli was increased, the magnitude of the response to the second stimulus recovered, following a time course similar to that before penicillin. With larger fluxes of penicillin (with electrophoretic currents of -250 to -1000 nA) the amplitude of evoked potentials rose more rapidly and to a higher level; as the concentration of penicillin rose, this enhancement of amplitude led into a second phase, in which there was additionally an increase in the duration of the evoked potentials and the appearance of spontaneous epileptiform discharges. The evoked potentials in this situation showed physiological properties different from those before penicillin application. The strength-response curve exhibited a discontinuity, indicating the evoked potential to be the sum of a physiological response and an epileptiform discharge, the former being graded with stimulus strength and the latter being all or none.(ABSTRACT TRUNCATED AT 250 WORDS)


Transcatheter embolization of symptomatic hepatic venous malformations.
The aim of this study was to evaluate our results in treatment and management of symptomatic hepatic venous malformations using transcatheter embolization therapy. From 1991 to 1997 five venous malformations were embolized in one man and four women ranging in age from 31 to 50 years. All patients presented nonspecific abdominal pain and were assessed in the general surgery unit. Percutaneous embolization was recommended. In all cases polyvinyl alcohol was used to embolize the afferent arterioles. Clinical and echographic control follow-up was carried out on an outpatient basis in our Vascular and Interventional Radiology Unit. Embolization was possible in all cases. No complications developed during the procedure, except in one case where the subject suffered a spasm of the hepatic artery. Mean follow-up time was 42 months (6-73 months). Four patients remained asymptomatic during the entire follow-up period, whereas one patient required reembolization. In our experience, transcatheter embolization of hepatic venous malformations is a noninvasive technique which requires few admissions and presents few complications. With further use, it could become the treatment of choice in symptomatic hepatic venous malformations as an alternative to surgery.


Photonic quadrupole topological insulator using orbital-induced synthetic flux.
The rich physical properties of multiatomic crystals are determined, to a significant extent, by the underlying geometry and connectivity of atomic orbitals. The mixing of orbitals with distinct parity representations, such as s and p orbitals, has been shown to be useful for generating systems that require alternating phase patterns, as with the sign of couplings within a lattice. Here we show that by breaking the symmetries of such mixed-orbital lattices, it is possible to generate synthetic magnetic flux threading the lattice. We use this insight to experimentally demonstrate quadrupole topological insulators in two-dimensional photonic lattices, leveraging both s and p orbital-type modes. We confirm the nontrivial quadrupole topology by observing the presence of protected zero-dimensional states, which are spatially confined to the corners, and by confirming that these states sit at mid-gap. Our approach is also applicable to a broader range of time-reversal-invariant synthetic materials that do not allow for tailored connectivity, and in which synthetic fluxes are essential.


High Spinal Anesthesia Enhances Anti-Inflammatory Responses in Patients Undergoing Coronary Artery Bypass Graft Surgery and Aortic Valve Replacement: Randomized Pilot Study.
Cardiac surgery induces many physiologic changes including major inflammatory and sympathetic nervous system responses. Here, we conducted a single-centre pilot study to generate hypotheses on the potential immune impact of adding high spinal anaesthesia to general anaesthesia during cardiac surgery in adults. We hypothesized that this strategy, previously shown to blunt the sympathetic response and improve pain management, could reduce the undesirable systemic inflammatory responses caused by cardiac surgery. This prospective randomized unblinded pilot study was conducted on 14 patients undergoing cardiac surgery for coronary artery bypass grafting and/or aortic valve replacement secondary to severe aortic stenosis. The primary outcome measures examined longitudinally were serum pro-inflammatory (IL-6, IL-1b, CCL2), anti-inflammatory (IL-10, TNF-RII, IL-1Ra), acute phase protein (CRP, PTX3) and cardiovascular risk (sST2) biomarkers. The kinetics of pro- and anti-inflammatory biomarker was determined following surgery. All pro-inflammatory and acute phase reactant biomarker responses induced by surgical stress were indistinguishable in intensity and duration between control groups and those who also received high spinal anaesthesia. Conversely, IL-10 levels were markedly elevated in both intensity and duration in the group receiving high spinal anesthesia (p = 0.005). This hypothesis generating pilot study suggests that high spinal anesthesia can alter the net inflammatory response that results from cardiac surgery. In appropriately selected populations, this may add incremental benefit by dampening the net systemic inflammatory response during the week following surgery. Larger population studies, powered to assess immune, physiologic and clinical outcomes in both acute and longer term settings, will be required to better assess potential benefits of incorporating high spinal anesthesia. ClinicalTrials.gov NCT00348920.


Hospital-presenting self-harm and ideation: Comparison of incidence, profile and risk of repetition.
The aim of this study was to describe presentations to hospital as a result of self-harm or suicidal ideation and to examine patterns of repetition. Presentations made to hospital emergency departments in Northern Ireland following self-harm and ideation between April 2012 and March 2017 were recorded by the Northern Ireland Registry of Self-harm. Person-based rates per 100,000 were calculated using national population estimates. Risk of repeat attendance to hospital was examined using Kaplan-Meier analyses. A total of 62,213 presentations to emergency departments following self-harm or with ideation were recorded. The rate of self-harm was more than twice the rate of hospital-presenting ideation. Rates of ideation were higher among men, and both self-harm and ideation rates peaked for girls aged 15-19 and men aged 20-24 years. The cumulative probability of repeat attendance to hospital was higher following ideation (52% after 12 months), primarily because 12% of ideation presentations were followed by a subsequent self-harm presentation, whereas 4% of self-harm presentations were followed by ideation. Our findings indicate that hospital presenters with ideation are at high risk of future self-harm. The transition from ideation to suicidal behaviour is important to consider and research could inform effective and early intervention measures.


Selective hypoxic loading of the ventrolateral medulla inhibits cholinergic outflow to the airways.
In these studies we determined the effects of local hypoxia confined to the superficial structures of the ventral medulla on cholinergic outflow to the airways. Studies were performed in alpha-chloralose anesthetized, paralyzed and mechanically ventilated cats. Topical application or microinjection of sodium cyanide to the intermediate area of the ventrolateral medulla significantly decreased tracheal tone, measured by changes in pressure in a balloon placed in bypassed segment of the trachea (Ptseg). The changes were reversible. When parasympathetic activity was abolished by atropine methylnitrate and tracheal tone was restored with serotonin, cyanide acting centrally had no effect on tracheal pressure. These data indicate that local hypoxic loading confined to the ventrolateral medullary structures may significantly modulate parasympathetic outflow to the airways, and alter airway related protective reflex responses.


Child maltreatment in Germany: prevalence rates in the general population.
Child maltreatment and its consequences are considered a major public health problem. So far, there is only one study from Germany reporting prevalence rates on different types of maltreatment. A representative sample of the German general population was examined for experiences of child maltreatment using the Childhood Trauma Questionnaire (CTQ) between September and November 2016. A total of 2510 (53.3% female) participants between 14 and 94 years (M = 48.8 years) were enrolled. Besides the CTQ, a range of sociodemographic information was collected. The interrelatedness of different types of maltreatment was examined using configuration analysis and predictors for maltreatment were identified by performing binary logistic regression analyses. Overall, 2.6% (f: 3.9%, m: 1.2%) of all participants reported severe emotional abuse, 3.3% (f: 3.4%, m: 3.3%) severe physical abuse, 2.3% (f: 3.7%, m: 0.7%) severe sexual abuse, 7.1% (f: 8.1%, m: 5.9%) severe emotional neglect and 9% (f: 9.2%, m: 8.9%) severe physical neglect. Women were more likely to report at least moderate sexual and emotional abuse than men. The largest difference between age groups was reported for physical neglect, with participants aged over 70 years reporting the highest rates. Participants who reported childhood maltreatment were more likely to be unemployed or have lower educational outcomes. The most common combination of maltreatment types were physical and emotional neglect, all five types of maltreatment combined and physical and emotional neglect and physical abuse combined. Child maltreatment, especially physical neglect is common in the German population. Women seem to be at greater risk for sexual and emotional abuse than men. Knowledge about different types of maltreatment based on the Childhood Trauma Questionnaire (CTQ) can help to put findings of future studies into an epidemiological and societal context.


A Case of Streptococcus thoraltensis Bacteremia and Prosthetic Valve Endocarditis in a 68-Year-Old Vietnamese Man.
BACKGROUND Streptococcus thoraltensis is a rare cause of human disease. This report describes a patient with infective endocarditis caused by S. thoraltensis and complicated by ischemic stroke. CASE REPORT A 68-year-old man was admitted for a 12-day duration of fever. He had a history of severe aortic valve stenosis, for which he underwent prosthetic valve replacement, and type 2 diabetes mellitus. Echocardiography revealed vegetation attached to the right coronary cusp of the prosthetic aortic valve and rupture of the sinus of Valsalva into the right ventricle. Blood cultures were positive for S. thoraltensis. He experienced an ischemic stroke involving the vegetation of the aortic valve and died of acute heart failure. CONCLUSIONS S. thoraltensis may be considered an emerging pathogen in patients with infective endocarditis.


Effects of venom from Conus striatus on the delayed rectifier potassium current of molluscan neurons.
The effect of crude venom extracted from venom ducts of Conus striatus on the delayed rectifier potassium current (IK) of the marine mollusc Aplysia californica was studied using voltage clamp techniques. Initial experiments indicated that the venom had phospholipase activity which destroyed the cells. The use of phospholipase inhibitors prevented destruction of the cell and permitted long-term electrophysiological measurements to be made. Application of the venom to unclamped cells caused a dramatic increase in the frequency of action potentials associated with a depolarization of the membrane potential. A broadening of the action potential was also observed. Three separate effects of the venom were observed on IK in voltage clamped cells: an increase in peak current (effect I), a slowing of both the activation and inactivation kinetics (effect K) and a decrease in the peak current (effect D). All three effects were dose dependent and both effects on peak current were greater at more depolarized membrane potentials. The data suggest that the three effects on IK are caused by different components of the venom. Effect D appears to be caused by a heat-labile compound of molecular weight greater than 50,000, effect I by a heat-stable compound of less than 50,000 and effect K by a heat-stable compound of intermediate molecular size.


Hairy Polyp of the Nasopharynx Arising from the Eustachian Tube.
Hairy polyps of the nasopharynx display characteristic radiological imaging findings, including the presence of fat in the polypoid mass. Furthermore, diagnostic imaging is useful for delineating the site of origin of these lesions, which can facilitate surgical planning. For instance hairy polyps that arise from the right Eustachian tube can be amputated via a trans-nasal approach with endoscopy, but may necessitate a two stage approach in order to avoid injury to critical structures, such as the internal carotid artery. On histology, hairy polyps comprise an outer keratinizing squamous epithelium with adnexal tissue, including hair follicles, and central fibroadipose and cartilaginous tissue. These features are exemplified in this sine qua non radiology-pathology correlation article.


Risk stratification of patients with chest pain or anginal equivalents in the emergency department.
We studied whether previously developed cardiac risk scores-including history, ECG, age, risk factors, and troponin (HEART); Thrombolysis in Myocardial Infarction (TIMI); Global Registry of Acute Coronary Events (GRACE); and Emergency Department Assessment of Chest Pain (EDACS)-could be applied to predict major adverse cardiac events (MACE) in patients with possible coronary artery disease, including anginal equivalents. Patients with chest pain or anginal equivalents who underwent coronary computed tomographic angiography were included. The primary outcome was 30-day MACE. We compared the cardiac risk scores by the area under the receiver-operating characteristic curves (AUC). The primary outcome occurred in 200 patients (16.0%) of the 1247 patients included. For the prediction of MACE, the AUC of the HEART score (0.765) was superior to those of the TIMI (0.726), GRACE (0.612), and EDACS (0.631) scores. Among patients identified by each score as being at low risk, the MACE rate was the lowest for the HEART score (5.7%), followed by the TIMI (8.8%), EDACS (11.2%), and GRACE (12.2%) scores. At a sensitivity level of a < 2% rate of misses, the negative predictive value of the HEART score (1.0) outperformed those of the GRACE (0.932) and EDACS (0.964). The HEART score appeared to be more predictive of MACEs than the TIMI, GRACE, and EDACS in patients with chest pain or anginal equivalents. However, previously suggested cutoff could not safely identify low-risk patients for early discharge because of the unacceptably high rate of missed MACEs.


Risk factors for recurrence of laryngeal amyloidosis treated by microforceps and CO2 laser.
Laryngeal amyloidosis is a benign, slowly progressive disease. The factors affecting the recurrence of LA have not been studied before for the rarity and incomplete understanding of this disease. To investigate the risk factors for the laryngeal amyloidosis treated by microforceps or carbon dioxide laser under microlaryngoscope, a retrospective review was conducted. One hundred and four patients (42 male and 72 female, with an average age of 51.3 years) with laryngeal amyloidosis were identified. The cases were collected from January 1989 to May 2014 at the Eye, Ear, Nose, and Throat Hospital of Fudan University. Seventy-five patients complained of hoarseness, 36 patients complained of hoarseness and dyspnea, and 3 patients complained of foreign body sensation. All patients underwent surgical removal of the amyloid deposits (via microforceps, CO2 laser and tracheotomy). Thirty patients developed recurrences requiring further treatments. The duration from onset to the treatment and age affected the recurrence of laryngeal amyloidosis, the surgery method, stenotic degree and stenotic area of subglottic area and trachea did not affect the recurrence of the disease. Early diagnosis and treatment of laryngeal amyloidosis may reduce the recurrence of the disease. Regular follow-up is necessary to find any recurrence.


PrEP uptake and HIV viral suppression when PrEP is integrated into Ugandan ART clinics for HIV-negative members of HIV-serodifferent couples: A stepped wedge cluster randomized trial.
Global scale-up of HIV pre-exposure prophylaxis (PrEP) includes services to HIV-negative people in partnerships with people living with HIV (serodifferent couples). Data are needed on HIV outcomes, including uptake and adherence to PrEP and antiretroviral treatment (ART), to describe the impact of integrating PrEP into an existing HIV program. Using a stepped-wedge cluster randomized trial design, we launched PrEP delivery for HIV-negative members of serodifferent couples in Uganda by integrating PrEP into existing ART programs for people living with HIV. The program provided PrEP training for ART providers, ongoing technical assistance, and a provisional supply chain mechanism for PrEP medication. Primary data on PrEP initiation, PrEP refills, ART initiation, and HIV viremia at 6 months (measured at 42-270 days) were collected through data abstraction of medical records from HIV-serodifferent couples sequentially enrolling at the ART clinics. Modified Poisson regression models, controlling for time and cluster, compared viral suppression (<1000 copies/ml) before and after launch of the PrEP program. This trial was registered at ClinicalTrials.gov, NCT03586128. From June 1, 2018-December 15, 2020, 1,381 HIV-serodifferent couples were enrolled across 12 ART clinics in Kampala and Wakiso, Uganda, including 730 enrolled before and 651 after the launch of PrEP delivery. During the baseline period, 99.4% of partners living with HIV initiated ART and 85.0% were virally suppressed at 6 months. Among HIV-negative partners enrolled after PrEP launched, 81.0% (527/651) initiated PrEP within 90 days of enrolling; among these 527, 11.2% sought a refill 6 months later. In our powered intent-to-treat analysis, 82.1% and 76.7% of partners living with HIV were virally suppressed, respectively, which was not a statistically significant difference (RR=0.94, 95% CI: 0.82-1.07) and was stable across sensitivity analyses. Integration of PrEP into ART clinics reached a high proportion of people in HIV-serodifferent relationships and did not improve the already high frequency of HIV viral suppression among partners living with HIV. National Institute of Mental Health (R01MH110296).


Cervical chromosome 9 polysomy: validation and use as a surrogate endpoint biomarker in a 4-HPR chemoprevention trial.
Several genetic alterations have been described in cervical cancers including: human papillomavirus (HPV) E6 and E7 oncoproteins, subtle sequence changes, alterations in chromosome number, chromosome translocations, and gene amplifications. This report focuses on establishing chromosome 9 polysomy as a cervical biomarker of chromosome instability and using it in a chemoprevention trial. Chromosomal instability is a feature of most human cancers and is probably an early event in the process. We used 37 cervical cone specimens to validate chromosome 9 polysomy as a biomarker and then tested its modulation in a randomized clinical trial of 4-hydroxyphenylretinamide (4-HPR) in 39 patients with three blinded histopathologic reviews. No confounders were identified. In the present study, immunohistocytochemical analysis of Chromosome 9 polysomy was carried out and quantitatively measured. The Cell Index, the ratio of the number of total chromosome 9 copies to the total number of ells, increases significantly in archival samples as the cervix changes from normal to CIN to invasive cancer. In the chemoprevention trial, chromosome 9 polysomy was used as a biomarker and supported the histological analysis showing that 4-HPR impaired the natural regression response. Chromosome 9 polysomy appears to be a marker of genetic instability that can be used in chemoprevention trials as a surrogate endpoint biomarker. In this randomized trial of 4-HPR, the chromosome 9 polysomy measurements supported the clinical histopathologic reading in a quantitative manner suggesting that 4-HPR at 200 mg/day may have been inhibiting the regression seen in the placebo arm by inducing genetic instability.


Marginal structural models might overcome confounding when analyzing multiple treatment effects in observational studies.
We review marginal structural models (MSMs) and show how they are useful when comparing the effects of multiple treatments on outcomes in observational studies. Until now, MSMs have not been used to compare the effects of more than two treatments. To illustrate the application of MSMs when patients may receive several treatments, we have reanalyzed the effects of antipsychotic medication on achieving remission in schizophrenia using data from the SOHO study, a 3-year observational study of health outcomes associated with the treatment of schizophrenia. The MSM results were, in general, consistent with but less statistically significant than those obtained using conventional methods. The MSM also showed qualitative differences in some comparisons in which the conventional analysis obtained results that were not consistent with previous knowledge. MSMs can be used to analyze multiple treatment effects. MSMs, by using inverse-probability of treatment weights, might provide a better control for confounding than conventional methods by improving the adjustment for treatment group differences in observational studies, which may approximate their results to those of randomized controlled trials.


Cross-linking induces non-haemolytic antigen-loss from transfused red blood cells: a potential role for rheumatoid factor.
Transfusion of cross-match incompatible blood can lead to haemolysis. However, in some cases, incompatible transfused red blood cells are bound by antibody and then converted to being negative for both the incompatible antigen and the direct antiglobulin test. Using a murine model of this phenomenon, we have recently reported that antibodies binding to multiple epitopes are required. Herein, we report that antibodies against one epitope can induce antigen-loss if an anti-immunoglobulin G (IgG) antibody is also present. These findings support a model of cross-linking being required, and raise the possibility that naturally occurring anti-IgG, such as rheumatoid factor, may contribute to antigen-loss.


Chemical oscillations and Turing patterns in a generalized two-variable model of chemical self-replication.
Chemical self-replication of oligonucleotides and helical peptides show the so-called square root rate law. Based on this rate we extend our previous work on ideal replicators to include the square root rate and other possible nonlinearities, which we couple with an enzimatic sink. Although the nonlinearity is necessary for complex dynamics, the nature of the sink is the essential feature in the mechanism that allows temporal and spatial patterns. We obtain exact general relations for the Poincare-Adronov-Hopf and Turing bifurcations, and our generalized results include the Higgins, autocatalator, and templator models as specific cases.


Effects of surfactant head group modification on vertically oriented mesoporous silica produced by the electrochemically assisted surfactant assembly method.
Production of mesoporous silica films with vertically oriented pores has been a challenge since interest in such systems developed in the 1990s. Vertical orientation can be achieved by the electrochemically assisted surfactant assembly (EASA) method using cationic surfactants such as cetyltrimethylammonium bromide (C16TAB). The synthesis of porous silicas using a series of surfactants with increasing head sizes is described, from octadecyltrimethylammonium bromide (C18TAB) to octadecyltriethylammonium bromide (C18TEAB). These increase pore size, but the degree of hexagonal order in the vertically aligned pores reduces as the number of ethyl groups increases. Pore accessibility is also reduced with the larger head groups.


Application and functional characterization of POVACOAT, a hydrophilic co-polymer poly(vinyl alcohol/acrylic acid/methyl methacrylate) as a hot-melt extrusion carrier.
The aim of this study was to evaluate the applicability of POVACOAT™, a hydrophilic PVA copolymer, as a solid dispersion (SD) carrier for hot-melt extrusion (HME). Bifendate (DDB), a water-insoluble drug, was chosen as the model drug. DDB was hot-melt extruded by a co-rotating twin screw extruder with POVACOAT™. The SD formability of POVACOAT™ was investigated by varying the composition ratios. Solid state characterization was evaluated by differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy and Fourier transformation infrared spectroscopy. In order to have a better knowledge of the mechanism of dissolution enhancement, dissolution study, phase solubility study and crystallization study of DDB from supersaturated solutions were performed. In addition, the storage stability of the extrudate containing 10% DDB was investigated. Physical characterizations showed that DDB was amorphous up to 15% drug loading. The phase solubility study revealed an AL-type curve. Moreover, POVACOAT™ was found to have an inhibitory effect on crystallization from supersaturated solutions. Compared with the pure DDB and physical mixture, the dissolution rate and solubility of extrudates were significantly enhanced and the drug loading markedly affected the dissolution of SDs. Furthermore, the stability test indicated that 10% DDB-SD was stable during storage (40 °C/75% RH). The results of this study demonstrate that POVACOAT™ is a valuable excipient for the formulation of solid dispersions prepared by HME to improve dissolution of poorly water-soluble drugs.


Bovine serum albumin and myoglobin separation by size exclusion SMB.
The separation of the proteins Bovine Serum Albumin (BSA) and Myoglobin (Mb) was achieved by Size-Exclusion Simulated Moving Bed (SE-SMB) and performed experimentally in the FlexSMB® unit, an SMB unit designed and built in the Laboratory of Separation and Reaction Engineering. Before accomplishing the separation experiments in the mentioned unit, separation regions were computed by simulation based on a phenomenological mathematical model to determine appropriate operating conditions. The developed model was validated in advance, against fixed-bed dynamic adsorption experimental results, for pure component and binary mixtures. Then the SMB experiments were carried out, and purities of the Mb on the extract and BSA on the raffinate streams were 98% and 96%, respectively. The achieved recoveries were 80% of Mb on the extract and 94% of BSA on the raffinate. Lastly, productivities of 6.4 gprotein⋅lads-1⋅day-1 for the extract and 28.8 gprotein⋅lads-1⋅day-1 for the raffinate were obtained.


Incorporating human dynamic populations in models of infectious disease transmission: a systematic review.
An increasing number of infectious disease models consider demographic change in the host population, but the demographic methods and assumptions vary considerably. We carry out a systematic review of the methods and assumptions used to incorporate dynamic populations in infectious disease models. We systematically searched PubMed and Web of Science for articles on infectious disease transmission in dynamic host populations. We screened the articles and extracted data in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We identified 46 articles containing 53 infectious disease models with dynamic populations. Population dynamics were modelled explicitly in 71% of the disease transmission models using cohort-component-based models (CCBMs) or individual-based models (IBMs), while 29% used population prospects as an external input. Fertility and mortality were in most cases age- or age-sex-specific, but several models used crude fertility rates (40%). Households were incorporated in 15% of the models, which were IBMs except for one model using external population prospects. Finally, 17% of the infectious disease models included demographic sensitivity analyses. We find that most studies model fertility, mortality and migration explicitly. Moreover, population-level modelling was more common than IBMs. Demographic characteristics beyond age and sex are cumbersome to implement in population-level models and were for that reason only incorporated in IBMs. Several IBMs included households and networks, but the granularity of the underlying demographic processes was often similar to that of CCBMs. We describe the implications of the most common assumptions and discuss possible extensions.


RAGE signaling contributes to neuroinflammation in infantile neuronal ceroid lipofuscinosis.
Palmitoyl-protein thioesterase-1 (PPT1) deficiency causes infantile neuronal ceroid lipofuscinosis (INCL), a devastating childhood neurodegenerative storage disorder. We previously reported that neuronal apoptosis in INCL is mediated by endoplasmic reticulum-stress. ER-stress disrupts Ca(2+)-homeostasis and stimulates the expression of Ca(2+)-binding proteins. We report here that in the PPT1-deficient human and mouse brain the levels of S100B, a Ca(2+)-binding protein, and its receptor, RAGE (receptor for advanced glycation end-products) are elevated. We further demonstrate that activation of RAGE signaling in astroglial cells mediates pro-inflammatory cytokine production, which is inhibited by SiRNA-mediated suppression of RAGE expression. We propose that RAGE signaling contributes to neuroinflammation in INCL.


Helium-induced preconditioning in young and old rat heart: impact of mitochondrial Ca(2+) -sensitive potassium channel activation.
The noble gas helium induces cardiac preconditioning. Whether activation of mitochondrial K(+) channels is involved in helium preconditioning (He-PC) is unknown. The authors investigated whether He-PC (1) is mediated by activation of Ca(2+) -sensitive potassium channels, (2) results in mitochondrial uncoupling, and (3) is age dependent. Anesthetized Wistar rats were randomly assigned to six groups (n = 10 each). Young (2-3 months) control (Con) and aged (22-24 months) control animals (Age Con) were not treated further. Preconditioning groups (He-PC and Age He-PC) inhaled 70% helium for 3 x 5 min. The Ca(2+) -sensitive potassium channel blocker iberiotoxin was administered in young animals, with and without helium (He-PC+Ibtx and Ibtx). Animals underwent 25 min of regional myocardial ischemia and 120 min of reperfusion. In additional experiments, cardiac mitochondria were isolated, and the respiratory control index was calculated (state 3/state 4). Helium reduced infarct size in young rats from 61 +/- 7% to 36 +/- 14% (P < 0.05 vs. Con). Infarct size reduction was abolished by iberiotoxin (60 +/- 11%; P < 0.05 vs. He-PC), whereas iberiotoxin alone had no effect (59 +/- 8%; not significant vs. Con). In aged animals, helium had no effect on infarct size (Age Con: 59 +/- 7% vs. Age He-PC: 58 +/- 8%; not significant). Helium reduced respiratory control index in young animals (2.76 +/- 0.05 to 2.43 +/- 0.15; P < 0.05) but not in aged animals (Age Con: 2.87 +/- 0.17 vs. Age He-PC: 2.87 +/- 0.07; not significant). Iberiotoxin abrogated the helium effect on respiratory control index (2.73 +/- 0.15; P < 0.05 vs. He-PC) but had no effect itself on mitochondrial respiration (2.75 +/- 0.05; not significant vs. Con). Helium causes mitochondrial uncoupling and induces preconditioning in young rats via Ca(2+) -sensitive potassium channel activation. However, these effects are lost in aged rats.


Urinary nitrite in Japanese patients with urinary tract infections.
Urinary nitrite, a precursor of carcinogenic nitrosamines, and nitrate were measured in 73 Japanese patients with urinary tract infections (UTI) and in two control groups. Nitrite was detected in 12% of patients with uncomplicated UTI (226 +/- 161 mumol/l) and in 42% of those with complicated UTI (375 +/- 297 mumol/l). None of the subjects in the control groups excreted detectable amounts of nitrite. The excretion of nitrite in four out of five nitrite excretors continued for at least 14-55 days. The concentrations of urinary nitrite were significantly correlated with those of nitrate- plus nitrite-nitrogen, which reflect dietary nitrate ingestion. The results suggest the importance of close monitoring of nitrite excretor group in UTI patients, to clarify the mechanism of the association between UTI and bladder cancer.


Antihepatotoxic actions of Formosan plant drugs.
One hundred twenty-nine samples of Formosan plants were screened for antihepatotoxic activity in primary cultured hepatocytes to reveal that 19 and 26 plants exhibited more than 50% inhibition against cytotoxicity produced by carbon tetrachloride and D-galactosamine, respectively. Plants which disclosed significant antihepatotoxic activity in both assay methods are: Wedelia chinense, Mallotus repandus, Phyllantus urinaria, Loranthus parasiticus, Ludwigia octovalvis, Onychium japonicum, Tamarix chinensis and Ampelopsis brevipedunculata.


The experiences of older adult members of a combined lunch club and assisted shopping group and the perceived value in their occupational lives: A qualitative study.
Health and social care policies are increasingly focusing on community interventions for older adults with service providers diversifying services to widen their reach. As a result, new concepts are under-researched, and it can be challenging to draw parallels with existing interventions. Evidence of the value of community interventions is often limited and conflicting and few researchers have considered the service-user perspective. This qualitative research explores the experiences of members of a combined lunch club and assisted shopping group based in North-East England to understand the perceived value in their lives from an occupational perspective. Six older adult members were recruited through convenience sampling to participate in individual semistructured interviews January-March 2020. Interview data was subject to thematic analysis using an inductive approach and three key themes were constructed to represent the data. Themes identified were: "Togetherness: promoting social belonging"; "Meaningful engagement for older adults" and "Independence and staying active in later life." Findings indicated largely positive experiences with themes depicting influences that motivate engagement and perceived benefits. Participants particularly valued the opportunity for social engagement, as well as independence through supporting continued engagement with shopping in later life. In conclusion, successful community interventions for older adults need to be meaningful and purposeful.


Female Androgenetic Alopecia: An Update on Diagnosis and Management.
Female androgenetic alopecia (FAGA) is a common cause of non-scarring alopecia in women. The onset may be at any age following puberty and the frequency increases with age. Clinically, it shows a diffuse hair thinning over the central scalp, while the frontal hairline is usually retained. FAGA can have a significant psychological impact, leading to anxiety and depression. For this reason, early diagnosis is very important to stop the progression of the disease. The sex hormonal milieu is the main pathogenetic mechanism studied in FAGA. The role of androgens is not clearly defined and only one-third of women with FAGA show abnormal androgen levels. Endocrinological diseases with hyperandrogenism associated with FAGA comprise polycystic ovarian syndrome (PCOS), hyperprolactinemia, adrenal hyperplasia and, rarely, ovarian and adrenal tumours. Usually the diagnosis of FAGA is made clinically. A complete clinical examination and a blood examination can reveal other signs of hyperandrogenism. Trichoscopy shows the typical hair miniaturization. A scalp biopsy can be useful when the clinical evaluation does not provide a definitive diagnosis or when cicatricial alopecias with hair loss in the distribution of FAGA or alopecia areata are suspected. FAGA is a slowly progressive disease. The goal of therapy is to stop the progression and to induce a cosmetically acceptable hair regrowth. The most important drugs are topical minoxidil and oral anti-androgens. The purpose of this review is to provide an update on FAGA and to create a guideline on diagnosis and management of this frequent hair disease, not always easily recognizable from cicatricial alopecias with a similar distribution.


Cognitive flexibility, central coherence and social emotional processing in males with an eating disorder.
Females are more likely to develop an eating disorder (ED) than males. Studies of affected men may therefore inform models of risk and resilience to EDs. The aim of this study was to examine putative neurocognitive intermediate phenotypes of EDs in affected males. Cognitive flexibility, central coherence (global/detail processing), complex emotion recognition and social-threat sensitivity were investigated in men with EDs and healthy men. Measures of distress, perfectionism, and obsessive compulsivity were collected. Men with EDs were more cognitively inflexible across tasks and had more difficulty integrating global information than healthy men. Unexpectedly, there were no group differences on a visuospatial task of detail processing or on social-emotional processing tasks. Men with EDs had higher scores on measures of distress, perfectionism and obsessive compulsivity than healthy men. Men with EDs share some of the intermediate cognitive phenotype present in women with EDs. Like their female counterparts, males with EDs show an inflexible, fragmented cognitive style. However, relative to healthy men, men with EDs do not have superior detail processing abilities, poor emotion recognition or increased sensitivity to social-threat. It is possible that gender differences in social-threat processing contribute to the female preponderance of EDs.


Aminoglycoside resistance genes sgm and kgmB protect bacterial but not yeast small ribosomal subunits in vitro despite high conservation of the rRNA A-site.
The aminoglycoside resistance genes sgm from Micromonospora zionensis and kgmB from Streptomyces tenebrarius were cloned into a yeast expression vector to test whether the encoded prokaryotic methylases can modify the 18S rRNA A-site and thus confer resistance to G-418. Despite the detectable presence of mRNAs in yeast cells, neither G-418-resistant yeast transformants nor positive western blot signals were obtained. Neither methylase was capable of methylating 40S subunits despite very high conservation of the antibiotic rRNA binding sites. However, the results provide novel insight into the action of Sgm by showing that it methylates the same site as KgmB, i.e. G1405 in 16S rRNA.