Interactions between copper(II) and DOM in the urban stormwater runoff: modeling and characterizations.
Dissolved organic matter (DOM) can strongly interact with both organic and inorganic contaminants to influence their transportation, transformation, bioavailability, toxicity and even their ultimate fate. Within this work, DOM was extracted from urban stormwater runoff samples collected from a regular sampling site of a typical residential area in Beijing, China. Copper(II) ions were selected as model to investigate the interactions between DOM and typical heavy metals. Both ultraviolet (UV) absorbance and fluorescence titration methods were introduced to determine the complex capacities (CL) and conditional stability constants (log KM) of bonding between DOM and copper (II) ions, which revealed that the values of CL were 85.62 and 87.23 μmol mg-1 and the log KM values were 5.37 and 5.48, respectively. The results suggested the successful complexation between DOM and copper(II) ions. Furthermore, morphology of the DOM binding to copper(II) ions was confirmed by both energy-dispersive X-ray spectroscopy (EDX) and X-ray photoelectron spectroscopy (XPS), which can facilitate to clarify the corresponding mechanism. The Cu 2p3/2 peak at 933.7 eV and the characteristic shake-up peaks of Cu-O were found in the XPS spectra, implying that copper(II) ions might coordinate with hydroxyl (aliphatic or phenolic) or carboxyl groups. With these profitable results, it can be concluded that DOM in urban stormwater runoff has a strong binding affinity with copper(II) ions, which may further lead to potentially significant influence on their migration and transformation.


Effects of cigarette smoking on hemorheologic parameters, plasma osmolality and lung function.
Cigarette smoking deteriorates human health via vascular disorders, cancer and especially respiratory diseases. The aim of this study is to investigate effects of cigarette smoking on hemorheologic parameters, plasma osmolality and lung function in individuals without diagnosis of chronic obstructive pulmonary disease (COPD). Patients diagnosed without COPD utilizing respiratory function test were enrolled in the study with three groups, ex-smokers (n = 21), current-smokers (n = 35) and never-smokers (n = 43). Hemorheologic parameters and plasma osmolality were measured in hemorheology laboratory. SPSS 17.0 was used for statistical analysis. Blood and plasma viscosity, fibrinogen and hematocrit levels, mean corpuscular volume and mean corpuscular hemoglobin concentration were significantly elevated in ex-smokers and current-smokers compared to never-smokers. The standardized red blood cell deformability and oxygen delivery index and lung function were statistically lower in current-smokers than never-smokers. Pulmonary blood flow rate was statistically lower in current-smokers and ex-smokers than never-smokers. Plasma osmolality was statistically significantly higher in ex-smokers and current-smokers than never-smokers. Our findings clearly show that cigarette smoking has severe effects on hemorheologic parameters, plasma osmolality and lung function even in individuals without COPD. Blood and plasma viscosity with plasma osmolality might be useful markers to detect early hemorheologic-hemodynamic alterations in cigarette smokers.


Hypoglycemia attributable to insulin-like growth factor-II prohormone-producing metastatic leiomyosarcoma.
To review the causes of nonpancreatic tumor-associated hypoglycemia and report the first case of hypoglycemia attributable to a leiomyosarcoma, which did not cause hypoglycemia in its primary site but only after metastasizing. A case report is presented of a 62-year-old man with a gastric leiomyosarcoma diagnosed and surgically treated 8 years previously, who was found to have 14 large, rounded masses in his liver and a blood glucose level of 19 mg/dL. Biopsy of the largest mass revealed a leiomyosarcoma. Evaluation of the cause of the hypoglycemia revealed that circulating insulin, connecting peptide, proinsulin, insulin-like growth factor-I (somatomedin C), and insulin-like growth factor-II levels were below normal, whereas the insulin-like growth factor-II prohormone concentration was increased twofold. Basal and corticotropin-stimulated serum cortisol values were normal. This is the first case report of hypoglycemia occurring only after metastasis of a leiomyosarcoma. A possible causal relationship between the hypoglycemia and the increased circulating insulin-like growth factor-II prohormone is suggested, and alternative explanations and treatment are discussed.


[Change in peroxidation and in the phospholipid content in the brain in hyperoxia and the protective action of urea].
The rate of lipid peroxidation (by content of the lipid peroxide transformation end product--malonic dialdehyde) in homogenates of rat brain was studied as affected by hyperoxia and with a protective effect of urea in experiments in vivo and in vitro. In both cases an increase is observed in the malonic aldehyde yield with the effect of oxygen under higher pressure. Urea in physiological concentrations lowers the yield under the effect of hyperoxia in vitro. In experiments in vivo introduction of urea also evokes a decrease in the rate of peroxidation. It is established that hyperoxia and urea affect mainly the ascorbate-dependent system of peroxidation. The compositon of phospholipids in the rat brain was studied under the effect of hyperoxia and urea. No changes were found in the number of fractions under the effect of 6at oxygen, only quantitative changes are observed. With introduction of urea before hyperoxia there occurs a normalization in the phospholipid composition. The authors suppose the protective effect of urea to be due to its influence on membranes.


Highly efficient nitration of phenolic compounds in solid phase or solution using Bi(NO3)3.5H2O as nitrating reagent.
[reaction: see text] Bi(NO(3))(3).5H(2)O was used as an efficient nitrating reagent in the nitration of phenolic compounds to give nitrated phenols in good to high yields. The nitration reaction proceeded smoothly by grinding 1 equiv of phenol, 2-methylphenol, 4-methylphenol, or 4-chlorophenol and Bi(NO(3))(3).5H(2)O, and the nitration of other phenolic compounds could be performed in acetone at ambient temperature (22-30 degrees C).


Experimental and theoretical investigations on the catalytic hydrosilylation of carbon dioxide with ruthenium nitrile complexes.
Ruthenium complexes, mer-[RuX(3)(MeCN)(3)] and cis/trans-[RuX(2)(MeCN)(4)] with X=Br, Cl, were investigated as precatalysts in homogeneously catalyzed hydrosilylation of CO(2). The oxidation state of ruthenium and nature of the halide in the precatalysts were found to influence the catalytic activity in the conversion of Me(2)PhSiH to the formoxysilane Me(2)PhSiOCHO, with Ru(III) having chloride ligands being most active. Monitoring the reactions by in-situ IR spectroscopy in MeCN as the solvent indicates an interaction of the precatalyst with the silane prior to activation of CO(2). In the absence of CO(2), hydrosilylation of the MeCN solvent occurs. Catalytic activity in CO(2) hydrosilylation is enhanced by Me(2)PhSiCl, generated during reduction of Ru(III) in mer-[RuX(3)(MeCN)(3)] to Ru(II) or, when added as promoter to Ru(II) precatalysts. The reaction mechanism for the catalytic cycle has been calculated by DFT methods for the reaction of Me(3)SiH. The key steps are: Transfer of the Me(3)Si moiety to a coordinated halide ligand, resulting in an L(n)RuH(XSiMe(3)) intermediate --> CO(2) coordination --> Me(3)Si transfer to CO(2) --> reductive elimination of formoxysilane product. This reaction sequence is more favorable energetically for chloride complexes than for the analogous bromide complexes, which accounts for their differences in catalytic activity. Calculations also explain the rate increase observed experimentally in the presence of Me(2)PhSiCl. A parallel reaction pathway leads to (Me(3)Si)(2)O as a minor byproduct which arises from the condensation of two initially formed Me(3)SiOH molecules.


Cysts of Gastrointestinal Origin in Children: Varied Presentation.
Abdominal cysts of gastrointestinal origin are rare. Their rarity and varied clinical presentations make their pre-operative diagnosis difficult. Fourteen patients with histological diagnosis of cysts of gastrointestinal origin admitted between 2009 and 2015 were retrospectively analyzed with respect to age, sex, clinical presentation, diagnostic modality, site and type of cyst, management, outcome and follow-up. The mean age at presentation was 4 years and there were six males and eight females. Abdominal pain was the most common presenting symptom. Five patients had an acute presentation-three had distal ileal mesenteric cysts and two had ileal duplication cyst sharing a common wall with ileum. Six patients presented with chronic abdominal pain and lump-three patients had omental cysts and three had mesenteric cysts-two of these in distal ileum and one in sigmoid colon. Two patients presented with antenatally diagnosed palpable abdominal lump. One had a mesenteric cyst of the ileum and the other had a distal ileal duplication cyst which required excision with resection and anastomosis. One patient had an atypical presentation. He was a known case of sickle cell trait and had presented with vague abdominal pain, recurrent cough and multiple episodes of haemoptysis over a period of one year. At laparotomy, gastric duplication cyst was found which was excised completely. Histopathology confirmed the diagnosis. Cysts of gastrointestinal origin are rare and have varied presentation. Surgical excision is the mainstay of treatment. The results and prognosis are good.


Construction of a ribozyme directed against human interleukin-6 mRNA: evaluation of its catalytic activity in vitro and in vivo.
We have designed a ribozyme (Rz) that cleaves human interleukin-6 (IL-6) mRNA in vivo. This Rz was tested in vitro, and was found to give expected size fragments. It was then incorporated into a mammalian expression vector containing the constitutive cytomegalovirus (CMV) immediate early promoter and transfected into human U amniotic cells (UAC). Cell clones that stably express this catalytic RNA have been obtained. Some of them displayed a marked reduction of tumor necrosis factor (TNF)-induced IL-6 production. Their reduced ability to express IL-6 was related to the amount of Rz they produced and to the extent of IL-6 mRNA cleavage as observed by a ribonuclease protection assay. These data provide a method to study further the role of IL-6 production in various biologic situations, and suggest the feasibility of developing Rzs directed against various cytokines to study their biologic role and mechanism of action.


Plasma and urinary metanephrines determined by an enzyme immunoassay, but not serum chromogranin A for the diagnosis of pheochromocytoma in patients with adrenal mass.
Adrenal pheochromocytomas are neoplasms characterized by catecholamine excess. Determination of metanephrines by high-pressure liquid chromatography has been well established for the diagnosis of pheochromocytomas, demonstrating high sensitivity and specificity. This study evaluates the diagnostic value of newly available enzyme immunoassays for metanephrines in plasma and urine. Chromogranin A was studied as a potential additional diagnostic tool. Spontaneous blood samples and 24-h urine samples were collected in 149 subjects, including 24 histologically proven pheochromocytomas, 17 aldosterone-secreting and 21 cortisol-secreting adrenal adenomas, 30 nonfunctioning adrenal masses, 15 patients with essential hypertension and 42 healthy normotensive volunteers. Plasma and urinary metanephrine and normetanephrine as well as chromogranin A were determined and putative thresholds were calculated by ROC analysis. Plasma free normetanephrine was found to be the best single parameter with the highest sensitivity (89.5%) and specificity (98.3%) using a threshold of 167 pg/ml. Analysis of the combination of plasma free metanephrines revealed a similar sensitivity with lower specificity of 90.0%. Considering both urinary parameters demonstrated a slightly higher sensitivity (92.9%) with lower specificity (77.6%). ROC analysis revealed a threshold of 215 µg/l for chromogranin A with rather low sensitivity (73.9%) and specificity (74.2%). A weak positive correlation was found between the tumor size of pheochromocytomas and plasma metanephrine (r = 0.53, p ≤ 0.05) as well as chromogranin A (r = 0.60, p ≤ 0.01). In conclusion, plasma free and urinary metanephrines measured by enzyme immunoassays are convenient and reliable parameters for the diagnosis of pheochromocytoma. In contrast, CgA demonstrated poor sensitivity and specificity.


Expression of estrogen receptor-beta messenger ribonucleic acid in oxytocin and vasopressin neurons of the rat supraoptic and paraventricular nuclei.
The regulatory actions of estrogen on magnocellular oxytocin (OT) and vasopressin (VP) neurons of the paraventricular (PVN) and supraoptic (SON) nuclei are well documented. To date it is still debated whether the effect of estrogens is exerted directly or mediated by estrogen-sensitive interneurons. Previous immunocytochemical (ICC) and in situ hybridization (ISH) studies detected either low levels or absence of the classical estrogen receptor (ER-alpha) in the PVN and the SON of the rat. The present experiments using a combined ICC and ISH method were undertaken to examine the expression of the recently cloned beta form of ER (ER-beta) in OT- and VP-immunoreactive (IR) neuronal systems of the rat hypothalamus. The results demonstrate that the highest cellular levels of ER-beta messenger RNA (mRNA) in OT-IR neurons can be visualized in the caudal portion of the PVN and in an area ventro-medial to the central core of VP-IR cells. These neurons were previously shown to project caudally to the brain stem and the spinal cord to regulate autonomic functions. In addition, the whole rostro-caudal extent of the PVN and the SON contained OT-IR neurons that coexpressed variable levels of ER-beta mRNA. Similarly, the presence of ER-beta mRNA was seen in a large population of VP-IR paraventricular and supraoptic neurons. In the SON, somewhat stronger hybridization signal was detected in VP-IR neurons as compared with OT-IR neurons. Together, these findings provide strong support for the concept that the functions of OT- and VP-IR neurons in the PVN and the SON are regulated directly by estrogen and that the genomic effects of estrogens are mediated by ER-beta.


Intra-arterial therapy for acute ischemic stroke under general anesthesia versus monitored anesthesia care.
Recent studies have shown that intra-arterial recanalization therapy (IAT) for acute ischemic stroke (AIS) is associated with worse clinical outcomes when performed under general anesthesia (GA) compared to local anesthesia, with or without conscious sedation. The reasons for this association have not been systematically studied. We retrospectively reviewed 190 patients who underwent IAT for anterior circulation AIS from January 2008 to December 2012 at our institution. Baseline demographics, vessels involved, acute stroke treatment including intravenous tissue type plasminogen activator (tPA) use, use of GA vs. monitored anesthesia care (MAC), location of thrombus, recanalization grade, radiologic post-procedural intracerebral hemorrhage, and 30-day outcomes were collected. Relevant clinical time points were recorded. Detailed intra-procedural hemodynamics including maximum/minimum heart rate, systolic blood pressure (BP), diastolic BP, mean BP, use of pressors and episodes of hypotension were collected. Our study's outcomes were as follows: in-hospital mortality, 30-day good outcome (mRS ≤2), successful recanalization and radiologic post-procedural intracerebral hemorrhage. Ninety-one patients received GA and 99 patients received MAC. There was no significant difference in the NIHSS score between the two groups but the GA group had a higher number of ICA occlusions (31.9 vs. 18.2%, p = 0.043). The time from the start of anesthesia to incision (23.0 ± 12.5 min vs. 18.7 ± 11.3 min, p = 0.020) and the time from the start of anesthesia to recanalization (110 ± 57.2 vs. 92.3 ± 43.0, p = 0.045) was longer in the GA group. The time from incision to recanalization was not significantly different between the two groups. mRS 0-2 was achieved in 22.8% of patients in the MAC group compared to 14.9% in GA (p = 0.293). Higher mortality was seen in the GA group (25.8 vs. 13.3%, p = 0.040). Successful recanalization (TICI 2b-3) was similar between the GA and MAC (57.8 vs. 48.5%, p = 0.182) groups, but GA had a higher number of parenchymal hematomas (26.3 vs. 10.1%, p = 0.003). There was no difference in the intra-procedural hemodynamic variables between the GA and MAC groups. Anesthesia type was an independent predictor for mortality (along with age and initial NIHSS), and the only independent predictor for parenchymal hematomas, with MAC being protective for both. Our study has confirmed previous findings of GA being associated with poorer outcomes and higher mortality in patients undergoing IAT for AIS. Detailed analysis of intra-procedural hemodynamics did not reveal any significant difference between the two groups. Parenchymal hematoma was the major driver of the difference in outcomes.


Genetic variations in the osteopontin promoters T-443C and G-156GG increase carotid intima-media thickness.
Carotid intima-media thickness (CIMT) is a clear predictor of atherosclerosis. The increase of CIMT is affected by mutations in the osteopontin (OPN) promoters. The purpose of this study was to examine genetic variations in OPN promoters T-443C and G-156GG, identified in Javanese children with ischemic stroke parents, and to investigate their relationship with the increase of CIMT. A case-control analytic study was performed on 20 case and 12 control samples. Case samples were Javanese children aged between 10 to 21 years with ischemic stroke parents. Control samples were children with healthy parents. Mutations of T-443C and G-156GG were determined by employing polymerase chain reaction. Results of sequencing were analyzed using CLC Main Workbench 6.0. CIMT was defined using ultrasound. Genetic variations of T-443C were identified in six samples. Likewise, genetic variations of G-156GG were identified in six samples. Genetic variations in the OPN promoters T-443C and G-156GG were not potential risk factors in an increase of CIMT (P=0.654 and P=0.654). This study proves that genetic variations could be identified at the points of T-443C and G-156GG in children with ischemic stroke parents. Although statistically insignificant, the tendency to increase CIMT occurs in children with genetic variations. Children with ischemic stroke parents have thicker CIMT than children of healthy parents.


Cooperative binding of bifunctionalized and click-synthesized silver nanoparticles for colorimetric co(2+) sensing.
Bifunctionalized silver nanoparticles (triazole-carboxyl Ag NPs) were synthesized through a click reaction and have a cooperative effect on recognition of Co(2+), resulting in appreciable changes in color and absorption properties over other metal ions tested, including Fe(2+), Mn(2+), Hg(2+), Ni(2+), Cd(2+), Cu(2+), Zn(2+), Pb(2+), Li(+), Na(+), K(+), Cs(+). The functionalized silver nanoparticles became aggregated in solution in the present of Co(2+) through cooperative metal-ligand interaction. The colorimetric sensor allows a rapidly quantitive assay of Co(2+) down to the concentration of 7.0 x 10(-6) M. Moreover, the triazole-carboxyl AgNPs can be capable of evaluating the exceeding standard of Co(2+) in drinking water.


Association between Dix-Hallpike test parameters and successful repositioning maneuver in posterior semicircular canal benign paroxysmal positional vertigo: a case-control study.
Nystagmus (i.e., involuntary eye movement) provoked by the Dix-Hallpike test (DHT) is considered the gold standard for diagnosing posterior semicircular canal benign paroxysmal positional vertigo (psc-BPPV). However, robust evidence regarding this diagnostic maneuver's treatment efficacy is still lacking. This study aimed to investigate the parameters of positional nystagmus in the DHT as prognostic factors for unilateral psc-BPPV. We reviewed 357 patients with unilateral psc-BPPV who underwent the computer-controlled canalith repositioning procedure (CCRP), which mimics the Epley maneuver. Additionally, positional nystagmus in the DHT was observed through a video-oculography. Patients were retrospectively divided into two groups according to resistance to the CCRP. Univariable and multivariable analyses were performed on age, gender, blood pressure, and nystagmus parameters of the affected side in the DHT in order to reveal associated factors causing resistance to the CCRP. With univariate and multivariate analysis, we observed a decrease in vertical time course during slow phase nystagmus on the affected side (odds ratio, OR 0.77, P=0.011 vs. OR 0.80, P=0.027). Moreover, an increased vertical velocity amplitude in the DHT during slow phase nystagmus (OR 3.16, P=0.029 vs. OR 2.96, P=0.035) remained an associated factor of maneuver resistance. Decreased canalith weight on the affected side was associated with resistance to the CCRP. This association corresponded to the observation that psc-BPPV patients with a decreased time course and increased velocity in the slow phase of recording nystagmus have a worse prognosis of their BPPV persisting after a single CCRP.


The physical stability of the recombinant tuberculosis fusion antigens h1 and h56.
The recombinant fusion proteins hybrid 1 [H1 (Ag85B-ESAT-6)] and hybrid 56 [H56 (Ag85B-ESAT-6-Rv2660c)] derived from Mycobacterium tuberculosis are promising antigens for subunit vaccines against tuberculosis. Both antigens are early batches of antigens to be enrolled in human clinical trials and it is therefore important to characterize their conformational stability in solution as well as upon interaction with adjuvants. In this study, the physical stability of the two antigens was characterized using a number of biophysical techniques. Dynamic light scattering and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analyses demonstrated that both antigens exist as a distribution of multimeric states under nonstressed conditions. Their conformational stability was monitored as a function of pH and temperature and visualized in three-index empirical phase diagrams. Both antigens showed a gradual loss of secondary as well as tertiary structure as a function of temperature, with no cooperative transitions observed. Preformulation studies with the Th1-inducing cationic adjuvant CAF01 showed that the antigens were almost completely surface adsorbed. Upon adsorption, the liposome size increased; however, the physical stabilities of the bound and the unbound antigens were comparable. This study provides important information about the biophysical properties of H1 and H56 and highlights the analytical challenges of characterizing complex vaccine formulations.


Safety and Efficacy of Percutaneous Nephrolithotomy in Patients with Severe Skeletal Deformities.
Treatment of renal calculi in patients with severe skeletal deformities can be challenging. We present our experience in order to provide an assessment of technical difficulties, associated complications, and outcomes of percutaneous nephrolithotomy (PCNL) as a treatment option in this special patient group. Our study included eight patients treated with PCNL for renal stones. All had severe skeletal deformities including six with severe kyphoscoliosis, one with osteogenesis imperfecta, and another withrickets. After pre-operative evaluation the procedure was performed under fluoroscopic and/or ultrasonic guidance. In all but one case, PCNL was performed with the patient in the prone position. Silicone rolls and soft padded bolsters were used to obtain the best positioning for the procedure. Clearance rates and complications were assessed. Complete stone-free rate was achieved in six patients (75%) after first-PCNL. The two patients with residual stones underwent a second-look PCNL, after which one was completely cleared. The overall completestone-free rate after second PCNL was 87%. Only minor complications were seen in two patients (25%). We found PCNL to be safe and effective for managing kidney stones in patients with severe skeletal deformities.


Access to excess: how do adolescents deal with unhealthy foods in their environment?
Easy access to unhealthy foods is believed to contribute to the current overweight epidemic. It remains unclear, however, how access to unhealthy foods is related to self-regulation of food intake. This study tests the hypothesis that using self-regulation strategies buffers the negative influences of easy access to unhealthy foods. Cross-sectional survey data from 2764 adolescents aged 10-17 years from four European countries (The Netherlands, UK, Poland and Portugal) about use of self-regulation strategies, access to unhealthy foods and intake of unhealthy foods (sweet and salty snacks and sugar-sweetened beverages) were used. Both access to unhealthy foods and use of self-regulation strategies were independently, but in opposing directions, related to intake of unhealthy foods. Easy access to unhealthy food products was associated with higher consumption, but this effect could be attenuated by use of self-regulation strategies to facilitate healthy eating even when the food environment tempts one to do otherwise. Health promotion policy and programs should not only address the food environment but could also teach young people better strategies to deal with it.


Ultrathin Hexagonal 2D Co₂GeO₄ Nanosheets: Excellent Li-Storage Performance and ex Situ Investigation of Electrochemical Mechanism.
Two-dimensional (2D) nanostructures are a desirable configuration for lithium ion battery (LIB) electrodes due to their large open surface and short pathway for lithium ions. Therefore, exploring new anode materials with 2D structure could be a promising direction to develop high-performance LIBs. Herein, we synthesized a new type of 2D Ge-based double metal oxides for lithium storage. Ultrathin hexagonal Co2GeO4 nanosheets with nanochannels are prepared by a simple hydrothermal method. When used as LIB anode, the sample delivers excellent cyclability and rate capability. A highly stable capacity of 1026 mAhg(-1) was recorded after 150 cycles. Detailed morphology and phase evolutions were detected by TEM and EELS measurements. It is found that Co2GeO4 decomposed into Ge NPs which are evenly dispersed in amorphous Co/Li2O matrix during the cycling process. Interestingly, the in situ formed Co matrix could serve as a conductive network for electrochemical process of Ge. Moreover, aggregations of Ge NPs could be restricted by the ultrathin configuration and Co/Li2O skeleton, leading to unique structure stability. Hence, the large surface areas, ultrathin thickness, and atomically metal matrix finally bring the superior electrochemical performance.


Harnessing emotional mental imagery to reduce anxiety and depression in young people: an integrative review of progress and promise.
Emotional mental imagery is a powerful part of our mental landscape. Given its capacity to depict, process, and generate emotional events, mental imagery could have an important role in psychological therapies. This Series paper explores whether harnessing emotional mental imagery is meaningful to young people; ways in which interventions use emotional mental imagery; contextual and individual factors influencing intervention effectiveness; and mechanisms underpinning imagery techniques. We completed a systematic review of imagery interventions and consulted young people with lived experience (n=10) and leading international experts (n=7). The systematic search identified 86 papers covering a diverse range of imagery interventions. Across the seven categories of techniques reviewed, imagery rescripting for aversive memories, techniques targeting positive imagery, and imagery-enhanced protocols indicated the most potential. The report suggests that harnessing emotional mental imagery in psychological interventions could be a promising approach to reduce anxiety and depression and that mental health science could inform the development of new interventions and help to maximise intervention effectiveness.


Circadian rhythms of melatonin release from individual superfused chicken pineal glands in vitro.
The pineal gland of birds contains one or more circadian oscillators that play a major role in overall temporal organization. We have developed a flow-through culture system for the isolated pineal by which we can measure the release of melatonin continuously from superfused glands over long periods of time. Chicken pineals release melatonin rhythmically, and these rhythms persist in vitro with a circadian oscillation. In light cycles the release of melatonin is strongly rhythmic; however, in constant conditions the amplitude of the rhythm is lower and appears to be damping. Light has at least two effects upon the isolated pineal: cyclic light input synchronizes the rhythm, and acute light exposure at night rapidly inhibits melatonin release. The cultured avian pineal clearly offers great potential as a model system for the study of vertebrate circadian oscillators and may open the way for an analysis of mechanism.


Mild hyperlactatemia in stable septic patients is due to impaired lactate clearance rather than overproduction.
A prospective study was conducted on 34 stable septic patients to determine whether mild hyperlactatemia is a marker of lactate overproduction or an indicator of lactate underutilization during sepsis. Plasma lactate clearance and lactate production were evaluated by modeling the lactate kinetic induced by an infusion of 1 mmol/kg L-lactate over 15 min. The patients were divided in two groups depending on their blood lactate: < or = 1.5 mmol/L (n = 20, lactate = 1.2+/-0.2 mmol/L) or > or = 2 mmol/L (n = 10, lactate = 2.6+/-0.6 mmol/L). The hyperlactatemic patients had a lower lactate clearance (473+/-102 ml/kg/h) than those with normal blood lactate (1,002+/-284 ml/kg/h, p < 0.001), whereas lactate production in the two groups was similar (1,194+/-230 and 1,181+/-325 micromol/kg/h, p = 0.90). A second analysis including all the patients confirmed that the blood lactate concentration was closely linked to the reciprocal of lactate clearance (r2 = 0.73, p < 0.001) but not to lactate production (r2 = 0.03, p = 0.29). We conclude that a mild hyperlactatemia occurring in a stable septic patient is mainly due to a defect in lactate utilization.


Hand-Held Stereovision System for Image Updating in Open Spine Surgery.
Image guidance in open spinal surgery is compromised by changes in spinal alignment between preoperative images and surgical positioning. We evaluated registration of stereo-views of the surgical field to compensate for vertebral alignment changes. To assess accuracy and efficiency of an optically tracked hand-held stereovision (HHS) system to acquire images of the exposed spine during surgery. Standard midline posterior approach exposed L1 to L6 in 6 cadaver porcine spines. Fiducial markers were placed on each vertebra as "ground truth" locations. Spines were positioned supine with accentuated lordosis, and preoperative computed tomography (pCT) was acquired. Spines were re-positioned in a neutral prone posture, and locations of fiducials were acquired with a tracked stylus. Intraoperative stereovision (iSV) images were acquired and 3-dimensional (3D) surfaces of the exposed spine were reconstructed. HHS accuracy was assessed in terms of distances between reconstructed fiducial marker locations and their tracked counterparts. Level-wise registrations aligned pCT with iSV to account for changes in spine posture. Accuracy of updated computed tomography (uCT) was assessed using fiducial markers and other landmarks. Acquisition time for each image pair was <1 s. Mean reconstruction time was <1 s for each image pair using batch processing, and mean accuracy was 1.2 ± 0.6 mm across 6 cases. Mean errors of uCT were 3.1 ± 0.7 and 2.0 ± 0.5 mm on the dorsal and ventral sides, respectively. Results suggest that a portable HHS system offers potential to acquire accurate image data from the surgical field to facilitate surgical navigation during open spine surgery.


The Lem2 gene promoter of barley directs cell- and development-specific expression of gfp in transgenic plants.
Transgenic approaches to combating fungal pathogens, such as Fusarium graminearum, require the targeting of antifungal gene expression in tissues of developing seed spikes of cereal grains, especially lemmas and epicarps. The Lem2 gene of barley encodes a lectin-like protein that is strongly up-regulated by salicylic acid and is preferentially expressed in lemmas, paleas (lemma/palea) and coleoptiles. Transient expression studies have indicated that the proximal -75/+70 region (relative to the transcription start site) determines organ specificity. In the present study, Golden Promise barley stably transformed with Morex Lem2 promoter/gfp reporter constructs displayed cell- and development-specific expression of gfp (green fluorescent protein gene). This expression corresponded to the expression seen in Northern blots of Morex organs. Under the full-length promoter, strong GFP fluorescence was observed in the lemma/palea, glumes, coleoptile, auricle and ligule. Weak GFP fluorescence was also observed in the rachis, tips of primary leaves and the leaf sheath. Unexpectedly, strong expression occurred in the epicarp, even though Lem2 is not expressed in this organ in Morex. Studies showed that the Lem2 promoter is more highly methylated in the epicarp than in the lemma of Morex. In the lemma/palea, gfp underwent a temporal shift in expression from the mesophyll to specialized epidermal cork cells. Similar to the lemma/palea, expression in the leaf sheath was localized in the cork cells. Progressive 5' deletions of the promoter to nucleotide -75 gradually reduced the level of gfp expression, but tissue- and cell-specific expression was retained.


Blindness from uveitis in a hospital population in Sierra Leone.
A retrospective study was conducted to assess the causes of blindness and visual impairment in patients who visited an eye hospital in Sierra Leone, West Africa, in 1989 and 1992. These data were compared with figures from 1981. Throughout the years, senile cataract was the major cause of blindness, followed by uveitis (including onchocerciasis). Uveitis remained the second most important cause of blindness in this population, despite the significant decrease in blindness from onchocerciasis (from 30% in 1981 to 15% in 1992). An increasing number of patients with uveitis from non-onchocercal origin was observed: almost 10% of the blindness found in 1992 was due to uveitis of non-onchocercal origin. A reduction in visual handicap in patients with non-onchocercal uveitis could be achieved if local hospitals could obtain more accurate diagnoses in these patients.


Where do HIV-infected adolescents go after transfer? - Tracking transition/transfer of HIV-infected adolescents using linkage of cohort data to a health information system platform.
To evaluate long-term outcomes in HIV-infected adolescents, it is important to identify ways of tracking outcomes after transfer to a different health facility. The Department of Health (DoH) in the Western Cape Province (WCP) of South Africa uses a single unique identifier for all patients across the health service platform. We examined adolescent outcomes after transfer by linking data from four International epidemiology Databases to Evaluate AIDS Southern Africa (IeDEA-SA) cohorts in the WCP with DoH data. We included adolescents on antiretroviral therapy who transferred out of their original cohort from 10 to 19 years of age between 2004 and 2014. The DoH conducted the linkage separately for each cohort and linked anonymized data were then combined. The primary outcome was successful transfer defined as having a patient record at a facility other than the original facility after the transfer date. Secondary outcomes included the proportion of patients retained, with HIV-RNA <400 copies/ml and CD4 > 500 cells/µl at 1, 2 and 3 years post-transfer. Of 460 adolescents transferred out (53% female), 72% transferred at 10-14 years old, and 79% transferred out of tertiary facilities. Overall, 81% of patients transferred successfully at a median (interquartile range) of 56 (27-134) days following transfer date; 95% reached the transfer site <18 months after transfer out. Among those transferring successfully, the proportion retained decreased from 1 to 3 years post-transfer (90-84%). There was no significant difference between transfer and 1-3 years post-transfer in the proportion of retained adolescents with HIV-RNA <400 copies/ml and CD4 > 500 cells/µl except for HIV-RNA <400 copies/ml at 3 years (86% vs. 75%; p = 0.007). The proportion virologically suppressed and with CD4 > 500 cells/µl was significantly lower at 1 and 2 years post-transfer in those transferring at 15-19 vs. 10-14 years of age. Using laboratory data alone over-estimated time to successful transfer. Linking cohort data to health information system data allowed efficient assessment of post-transfer outcomes. Although >80% of adolescents transferred successfully with nearly 85% of them retained for 3 years post-transfer, the decline in the proportion virologically suppressed and poorer outcomes in older adolescents are concerns..


A Novel Glucose Isomerase from Caldicellulosiruptor bescii with Great Potentials in the Production of High-Fructose Corn Syrup.
Glucose isomerase (GI) that catalyzes the conversion of D-glucose to D-fructose is one of the most important industrial enzymes for the production of high-fructose corn syrup (HFCS). In this study, a novel GI (CbGI) was cloned from Caldicellulosiruptor bescii and expressed in Escherichia coli. The purified recombinant CbGI (rCbGI) showed neutral and thermophilic properties. It had optimal activities at pH 7.0 and 80°C and retained stability at 85°C. In comparison with other reported GIs, rCbGI exhibited higher substrate affinity (Km = 42.61 mM) and greater conversion efficiency (up to 57.3% with 3M D-glucose as the substrate). The high catalytic efficiency and affinity of this CbGI is much valuable for the cost-effective production of HFCS.


Use of incentive spirometry in portable chest radiography.
The degree of lung inflation seen on a chest radiograph is dependent on the point during the patient's respiratory cycle at which the radiographer exposes the image receptor. Exposing the image receptor at the exact peak of inflation can be difficult because of the limited time available in which to capture the inspiratory pause. An incentive spirometer can indicate the moment of peak inhalation. This study tested whether images taken with and without an incentive spirometer display different levels of image quality. This is a paired, prospective, single-blinded study of 30 patients undergoing portable chest radiography. The radiographs were acquired with and without the use of an incentive spirometer. Visual grading analysis was performed using the 1996 European Guidelines on Quality Criteria for Diagnostic Radiographic Images. The mean patient age was 53 years. Sixty images were acquired, 30 with the use of incentive spirometry and 30 without. The most common indication for portable chest radiography was "postlung lobectomy." Scoring on the radiologist's ability to see the sixth rib, spine, trachea, and cardiac border was not affected significantly by the use of incentive spirometry. Use of an incentive spirometer was associated with significant improvement in ability to see the 10th rib (P ≤ .004), vascular pattern (P ≤ .001), retrocardiac lung (P ≤ .013), and the costophrenic angles (P ≤ .005). This study introduces a technique to improve the quality of portable chest radiographs. The use of incentive spirometry improved inspiratory depth and image quality for portable chest radiographs.


Pediatric paraneoplastic neuromyelitis optica spectrum disorder associated with ovarian teratoma.
Neuromyelitis optica spectrum disorder is an inflammatory condition of the central nervous system typically manifesting as myelitis, optic neuritis, and/or area postrema syndrome. Here, we present a pediatric patient who developed symptoms consistent with area postrema syndrome with positive anti-aquaporin-4 (AQP4) antibodies who was also found to have an ovarian teratoma. Pathological specimens revealed the presence of aquaporin-4. This was felt to be the antigenic trigger that led to the patient's condition. She suffered no further clinical attacks and seroconverted to negative AQP4 status upon teratoma removal. This case varies from others, in that the paraneoplastic presentation occurred in a pediatric patient and in that the patient has not required maintenance immunotherapy after teratoma removal.


Travel agent and tour guide perceptions on travel health promotion in Bali.
The increasing number of travelers to Bali has been accompanied by the increased risks of travel-related health problems. Travel agents and tour guides are in a key position to inform travelers about these matters; nonetheless, little evidence was found on their role in the promotion of travel health. This article aims to assess travel agent and tour guide perceptions on their possible involvement in promoting travel health measures in Bali. A cross-sectional study was conducted between July and October 2015, involving 500 respondents (250 travel agents and 250 tour guides), who were chosen systematically from the Bali-based members of the Association of the Indonesian Tours and Travel Agencies. Data were collected using questionnaires, and perception indicators were developed using concepts from social learning theory and health belief model. Both groups have good levels of knowledge of general travel health issues, with mean percentages (SD) of 67.1 (11.9) and 66.2 (10.0) for travel agents and tour guides, respectively. Tour guides were more likely than travel agents to deliver information on health risks [PR (95%CI) = 1.31 (1.10-1.56); p = 0.003]; and on safety hazards during travel [PR (95%CI) = 1.22 (1.01-1.46), p = 0.04]. Overall, the majority of respondents (>68%) have positive and very positive perceptions of possible involvement in travel health and safety programs, although tour guides have statistically better perceptions (z = -2.2, p = 0.03). Based on perception levels, previous experiences and levels of knowledge, travel agents and tour guides have great potential to be involved in travel health promotion programs in Bali.


The Breast Cancer Detection Demonstration Project 25 years later.
The Breast Cancer Detection Demonstration Project was initiated 25 years ago to demonstrate the feasibility of large-scale screening for breast cancer. A retrospective view shows that it has more than fulfilled its mission; among other important accomplishments it has significantly advanced both the notion and science of population-based breast cancer screening and provided a huge data base for epidemiologic research.


Proteomic Study of a Parkinson's Disease Model of Undifferentiated SH-SY5Y Cells Induced by a Proteasome Inhibitor.
Parkinson's disease (PD) is one of the most common nervous system degenerative diseases. However, the etiology of this disease remains elusive. Here, a proteasome inhibitor (PSI)-induced undifferentiated SH-SY5Y PD model was established to analyze protein alterations through proteomic study. Cultured undifferentiated SH-SY5Y cells were divided into a control group and a group treated with 2.5 µM PSI (PSI-treated group). An methyl thiazolyl tetrazolium (MTT) assay was applied to detect cell viability. Acridine orange/ethidium bromide (AO/EB), α-synuclein immunofluorescence and hematoxylin and eosin (H&E) staining were applied to evaluate apoptosis and cytoplasmic inclusions, respectively. The protein spots that were significantly changed were separated, analyzed by 2D gel electrophoresis and DIGE De Cyder software, and subsequently identified by MALDI-TOF mass spectrometry and database searching. The results of the MTT assay showed that there was a time and dose dependent change in cell viability following incubation with PSI. After 24 h incubation, PSI resulted in early apoptosis, and cytoplasmic inclusions were found in the PSI-treated group through H&E staining and α-synuclein immunofluorescence. Thus, undifferentiated SH-SY5Y cells could be used as PD model following PSI-induced inhibition of proteasomal function. In total, 18 proteins were differentially expressed between the groups, 7 of which were up-regulated and 11 of which were down-regulated. Among them, 5 protein spots were identified as being involved in the ubiquitin proteasome pathway-induced PD process. Mitochondrial heat shock protein 75 (MTHSP75), phosphoglycerate dehydrogenase (PHGDH), laminin binding protein (LBP), tyrosine 3/tryptophan 5-monooxygenase activation protein (14-3-3ε) and YWHAZ protein (14-3-3ζ) are involved in mitochondrial dysfunction, serine synthesis, amyloid clearance, apoptosis process and neuroprotection. These findings may provide new clues to deepen our understanding of PD pathogenesis.


Cholangiocellular Carcinoma.
Cholangiocarcinomas (CCAs) are aggressive malignancies that display features of biliary differentiation. According to their anatomical location, CCAs are commonly classified as intrahepatic and extrahepatic tumors, the latter entity being further subdivided into perihilar CCAs, also termed as Klatskin tumors, and distal tumors. While a majority of CCAs occur sporadically, established risk factors such as liver fluke infestation or primary sclerosing cholangitis exist. Due to lack of efficient early screening markers, CCAs are frequently diagnosed at an advanced stage when curative surgical resection is not an option. Chemotherapy with gemcitabine and cisplatin is currently the standard palliative treatment that prolongs overall survival by 3.6 months as compared to monotherapy with gemcitabine. For CCA patients who progress under gemcitabine/cisplatin, the paucity of prospective, randomized trials is detrimental, and there is currently no recommended second-line regimen with respect to chemotherapy or loco-regional treatment modalities. Molecular profiling of CCAs supports the implementation of targeted approaches, and it is reasonable that personalized therapy will become a mainstay of CCA treatment. In addition, the advent of immunotherapy holds considerable promise, yet, similar to targeted treatment, needs to be prospectively evaluated in clinically and genetically thoroughly characterized patients. (1) CCA is a genetically diverse and highly aggressive malignancy. (2) Gemcitabine in combination with cisplatin or oxaliplatin is the current first-line chemotherapy in non-resectable patients. (3) Loco-regional treatment modalities exist but need to be evaluated in prospective randomized trials in the context of systemic chemotherapy. (4) Targeted therapies in molecularly defined subgroups of patients and immunotherapies alone or in combinations will most likely improve survival in the future.


Intestinal Life Cycle of Eimeria caliginosa (Apicomplexa: Eimeriidae) From the Dusky Rice Rat, Melanomys caliginosus (Rodentia: Cricetidae: Sigmodontinae), In Costa Rica.
The endogenous life cycle of Eimeria caliginosa was studied in experimentally infected dusky rice rats, Melanomys caliginosus. All endogenous stages were located in the epithelial cells of villi in the small intestine. Both Giemsa-stained mucosal scrapings and histological sections were studied for the diagnosis of all the life-cycle stages. Eimeria caliginosa has 3 generations of meronts (M) that differ by size, shape, and number of merozoites (m), which also differ in their size, shape, and location of their nuclei within the cytoplasm of the meronts. The 3 meront types, M1-M3, respectively, had 20-33 (m1), 5-9 (m2), and 13-16 (m3) merozoites. Macrogametocytes and microgametocytes, as well as macrogametes and microgametes, completed the sexual cycle, which concludes with the formation of unsporulated oocysts. This parasite's endogenous development produced severe intestinal lesions in the experimentally infected dusky rice rats. In our ongoing work to understand the biodiversity present in plants and animals of the protected Reserva Biológica Alberto Manuel Brenes (ReBAMB) field station in Costa Rica, we now have discovered 3 new Eimeria species, and this is the second complete life cycle in which we document both the asexual and sexual stages.


Ovarian cancer targeted adenoviral-mediated mda-7/IL-24 gene therapy.
We have previously shown that adenoviral-mediated melanoma differentiation-associated gene-7 (Ad.mda-7) therapy induces apoptosis in ovarian cancer cells. However, the apoptosis induction was low and directly correlated with infectivity of Ad.mda-7. The objective of this study was to derive ovarian cancer targeted infectivity-enhanced adenoviral vectors encoding mda-7 and evaluate their enhancement in therapeutic efficacy for ovarian carcinoma. Infectivity-enhanced adenoviral vectors encoding mda-7 Ad.RGD.mda-7 and Ad.RGD.pK7.mda-7 were derived by incorporation of RGD and or RGD and Pk7 motifs in the fiber knobs by genetic modification. Viruses were validated by PCR for presence of mda-7 and by Western blot for expression of MDA-7 protein. To test the enhancement of therapeutic efficacy of these viruses, a panel of human ovarian carcinoma cells, OV-4, HEY, SKOV3, SKOV3.ip1, were infected by either Ad.mda-7 or Ad.RGD.mda-7 and Ad.RGD.pK7.mda-7 or their respective control viruses and the cell killing was evaluated by crystal violet staining in vitro. Further, therapeutic efficacy was evaluated in vivo using human ovarian cancer xenograft mouse models. Both Ad.RGD.pK7.mda-7 and Ad.RGD.mda-7 showed significant increase in cell killing in vitro compared to unmodified Ad.mda-7 with Ad.RGD.pK7.mda-7 showing highest cell killing. Further, Ad.RGD.pK7.mda-7 showed a significant increase in survival of mice bearing human ovarian cancer xenografts compared to Ad.mda-7 and other control groups. Infectivity-enhanced Ad.RGD.mda-7 and Ad.RGD.pK7.mda-7 viruses significantly enhanced ovarian cancer tumor cell killing in vitro. Significant prolongation of survival by Ad.RGD.pK7.mda-7 in murine ovarian cancer models demonstrates the high clinical translational potential of these viruses for ovarian cancer therapy.


The inverse autotransporters of Yersinia ruckeri, YrInv and YrIlm, contribute to biofilm formation and virulence.
Yersinia ruckeri causes enteric redmouth disease (ERM) that mainly affects salmonid fishes and leads to significant economic losses in the aquaculture industry. An increasing number of outbreaks and the lack of effective vaccines against some serotypes necessitates novel measures to control ERM. Importantly, Y. ruckeri survives in the environment for long periods, presumably by forming biofilms. How the pathogen forms biofilms and which molecular factors are involved in this process, remains unclear. Yersinia ruckeri produces two surface-exposed adhesins, belonging to the inverse autotransporters (IATs), called Y. ruckeri invasin (YrInv) and Y. ruckeri invasin-like molecule (YrIlm). Here, we investigated whether YrInv and YrIlm play a role in biofilm formation and virulence. Functional assays revealed that YrInv and YrIlm promote biofilm formation on different abiotic substrates. Confocal microscopy revealed that they are involved in microcolony interaction and formation, respectively. The effect of both IATs on biofilm formation correlated with the presence of different biopolymers in the biofilm matrix, including extracellular DNA, RNA and proteins. Moreover, YrInv and YrIlm contributed to virulence in the Galleria mellonella infection model. Taken together, we propose that both IATs are possible targets for the development of novel diagnostic and preventative strategies to control ERM.


The use of amniotic membrane plus heparin to prevent postoperative adhesions in the rabbit.
Fifteen female rabbits which were divided into three groups were used in this study. Amniotic membrane with or without heparin was used to cover experimentally injured uterine horns. Four weeks later all animals underwent second laparotomy and adhesion formation was examined. Our data showed that amniotic membrane plus heparin was an effective combination in reducing adhesion formation.


The prevalence and service utilisation associated with mental and substance use disorders in Lao People's Democratic Republic: findings from a cross-sectional survey.
An epidemiological survey was conducted to determine the prevalence of the mental and substance use disorders and ascertain patterns of mental health services utilisation in Lao People's Democratic Republic (Lao PDR) with the aim of evaluating existing gaps and opportunities in the provision of mental health services. This study was a cross-sectional, household survey of adults living within Vientiane Capital province, Lao PDR. We collected data on participant demographics, mental and physical health status, family history of mental illness and exposure to potential risk factors. It also collected data on mental health service utilisation patterns, types of health professionals and treatment being accessed, barriers to treatment and perceived need for care. The MINI International Neuropsychiatric Interview (MINI v.6.0) was also administered to assess mental disorder prevalence. Age- and sex-standardised current prevalence of any disorder was estimated at 15.2% (95% CI 11.0-20.7). Alcohol dependence (5.5% (95% CI 3.2-9.6)), was the most prevalent followed by anxiety disorders (5.2% (95% CI 3.2-8.3)) and mood disorders (2.5% (95% CI 1.5-4.4)). 11.0% (95% CI 5.8-20.1) of participants with a mental and/or substance use disorder suffered from other comorbid disorders. A number of variables demonstrated significant effects in final logistic regression models, including family history, education and employment for mental disorders; and gender, numbers of hours worked per week and number of dependants for substance use disorders. Having a mental or substance use disorder was associated with an OR of 11.6 of suicidality over participants without a mental or substance use disorder (95% CI 2.8-58.5). Of the 101 participants who met criteria for a current mental or substance use disorder, only two (2.1% (95% CI 0.5-8.0)) had accessed services for their mental health in the past 12 months. No participants who had seen a health professional in the past 12 months reported getting as much help as they needed. The vast majority (89.2% (95% CI 76.5-95.4)) of participants meeting criteria for a current mental or substance use disorder reported that they had not experienced mental health problems in the past 12 months. This study presents the first epidemiological estimates for a range of mental and substance use disorders in the general population of the most populous province in Lao PDR. A large treatment gap exists for mental and substance use disorders in Lao PDR. This research adds value for health care and has been an important precursor to developing informed and targeted mental health policy, services and health system reform in Lao PDR.


Targeting NS5B RNA-dependent RNA polymerase for anti-HCV chemotherapy.
The global prevalence of persistent hepatitis C virus (HCV) infection and the lack of a highly effective and well-tolerated antiviral therapy have spurred intensive efforts to discover and develop novel anti-HCV therapy in the pharmaceutical industry. HCV NS5B RNA-dependent RNA polymerase (RdRp), the centerpiece for viral replication, constitutes a valid target for drug discovery. Compared to the host RNA and DNA polymerases, NS5B RdRp has distinct subcellular localization at the interface of the endoplasmic reticulum (ER) membrane and cytoplasm, a novel catalytic mechanism and many unique structural features, all of which make it an attractive target for developing effective anti-HCV therapeutics. High genetic variation among the major HCV genotypes commands that any efficacious NS5B inhibitors have to be broadly active against NS5Bs from various genotypes. Rapid viral replication and its inherent genetic diversity will certainly culminate drug resistance to any NS5B inhibitors. Therefore, iterative drug design and combination therapies of drugs that intervene with different steps in the HCV replicative cycle are needed to combat the viral infection. Many classes of nucleoside and non-nucleoside inhibitors of NS5B RdRp have been identified and appeared in literatures and patent applications. These progresses hold a considerable promise to the development of novel, specific and highly effective therapeutics to achieve sustained response and ultimately the eradication of HCV infection.


Keratoplasty in children.
One hundred sixty-two eyes of children less than 14 years of age with corneal disease underwent keratoplasty over a period of eight years. The cases were divided into two groups and different subgroups, and the results were compared. The results of the recent group of cases after introduction of microsurgery were definitely better. However, being a referral center, the cases came to us at a late stage with complications and required larger grafts. Interestingly, graft transparency has a direct correlation with the size of the graft and type of corneal disease. Lastly, there was a marked reduction in frequency of therapeutic keratoplasty later, a result of the availability of various drugs.


[Clinical efficacy of the antimicrobial drug furamag in nosocomial urinary tract infections].
To evaluate the efficacy of the combined drug furamag (furasidine potassium and magnesium hydroxycarbonate) in combination with the third-generation cephalosporin cefotaxime versus cephalosporin monotherapy for nosocomial urinary tract infections (NUTI). The randomized open-label comparative parallel group clinical trial enrolled 52 male and female patients aged over 18 years with a documented diagnosis of NUTI. Group 1 (a study group) took oral furamag 300 mg/day in combination with intravenous cefotaxime 6 g/day; Group 2 (a control group) received cefotaxime monotherapy. The duration of therapy in both groups was 7 to 10 days until the efficiency levels were achieved. A final efficiency analysis was made in 24 and 25 patients from Groups 1 and 2 who had different forms of NUTI (catheter-associated NUTI, cystitis, pyelonephritis). On day 3 of treatment, most patients were noted to have a decreased systemic inflammatory response; lower C-reactive protein and procalcitonin levels being in the study group patients. The clinical efficiency of antibacterial therapy, which had been evaluated both immediately after treatment termination and during further control, did not substantially differ in the furamag/cefotaxime combination and control groups although there was an obvious tendency towards the more marked effect of combined therapy 7-14 days after treatment (11.8% efficiency differences; p>0.05). Analysis of bacteriological efficacy revealed its most pronounced and clinically significant differences between the groups: the cefotaxime/furamag combination led to higher pathogen eradication in all follow-up periods: after 3 days of treatment (82.6%) and following a complete therapy cycle (95.8%) versus the cefotaxime monotherapy group (43.5 and 70.8%, respectively; p<0.01). Microbiological results showed that the major NUTI pathogens (Escherichia coli, enterococci) were more susceptible to potassium furasidine (furamag) versus cefotaxime. The in vitro higher activity of furamag versus cefotaxime was attended by the significantly higher eradication of one of the two important NUTI pathogens - Enterococcus faecalis. Furamag used in combination with the third-generation cephalosporin cefotaxime showed a higher bacteriological efficacy and a rapider reduction in the symptoms of a systemic inflammatory response in patients with NUTI. On the basis of the findings, the above combination of furamag and cefotaxime may be recommended as first-line therapy for NUTI when multidrug- resistant nosocomial infection pathogens are widely distributed now.


A phase I dose escalation study of biweekly gemcitabine and carboplatin in completely resected stage IB-IIIA nonsmall cell lung cancer.
We conducted a phase I dose escalation study to determine the maximum tolerated dose, recommended dose, and safety profile of a biweekly gemcitabine and carboplatin combination regimen in the treatment of patients with completely resected nonsmall cell lung cancer (NSCLC). Patients with completely resected pathologically documented stage IB, II, or IIIA NSCLC, performance status (ECOG) 0-1, with adequate bone marrow, renal, liver, and cardiac functions, were treated with gemcitabine and carboplatin. The starting dose was gemcitabine 800 mg/m2 on days 1 and 15 and carboplatin area under the time-concentration curve (AUC) 4 mg/mL/min on day 1. Gemcitabine was increased to 1000 mg/m2 (level 3). Carboplatin was increased to AUC 5 (level 2, 3). The regimen was performed every 4 weeks. The dose-limiting toxicity of the regimen was assessed during the first chemotherapy cycle. Nine patients were enrolled in this study. All patients were assessed for safety. Grade 3 leukopenia occurred in 1 patient (11%) and grade 3/4 neutropenia occurred in 3 patients (33%). No other grade 3/4 toxicity was observed. No dose-limiting toxicity was experienced at dose levels 1, 2, and 3 of this schedule. Maximum tolerated dose was not reached in this study. Considering treatment continuation, the recommended dose for a phase II study is gemcitabine 1000 mg/m2 on days 1 and 15 and carboplatin AUC 5 on day 1, every 4 weeks. Biweekly administration of gemcitabine and carboplatin is a feasible and well-tolerated regimen for the treatment of patients with completely resected NSCLC as adjuvant chemotherapy.


Redistribution of Electron Equivalents between Magnetite and Aqueous Fe2+ Induced by a Model Quinone Compound AQDS.
The complex interactions between magnetite and aqueous Fe2+ (Fe2+(aq)) pertain to many biogeochemical redox processes in anoxic subsurface environments. The effect of natural organic matter, abundant in these same environments, on Fe2+(aq)-magnetite interactions is an additional complex that remains poorly understood. We investigated the influence of a model quinone molecule anthraquinone-2,6-disulfonate (AQDS) on Fe2+(aq)-magnetite interactions by systematically studying equilibrium Fe2+(aq) concentrations, rates and extents of AQDS reduction, and structural versus surface-localized Fe(II)/Fe(III) ratios in magnetite under different controlled experimental conditions. The equilibrium concentration of Fe2+(aq) in Fe2+-amended magnetite suspensions with AQDS proportionally changes with solution pH or initial AQDS concentration, but independent of magnetite loadings through the solid concentrations that were studied here. The rates and extents of AQDS reduction by Fe2+-amended magnetite proportionally increased with solution pH, magnetite loading, and initial Fe2+(aq) concentration, which correlates with the corresponding change of reduction potentials for the Fe2+-magnetite system. AQDS reduction by surface-associated Fe(II) in the Fe2+-magnetite suspensions induces solid-state migration of electron equivalents from particle interiors to the near-surface region and the production of nonmagnetic Fe(II)-containing species, which inhibits Fe2+(aq) incorporation or electron injection into the magnetite structure. This study demonstrates the significant influence of quinones on reductive activity of the Fe2+-magnetite system.


A General Approach To Fabricate Fe3O4 Nanoparticles Decorated with Pd, Au, and Rh: Magnetically Recoverable and Reusable Catalysts for Suzuki C-C Cross-Coupling Reactions, Hydrogenation, and Sequential Reactions.
A facile strategy has been explored for loading noble metals onto the surface of ferrite nanoparticles with the assistance of phosphine-functionalized linkers. Palladium loading is shown to occur with participation of both the phosphine function and the surface hydroxyl groups. Hybrid nanoparticles containing simultaneously Pd and Au (or Rh) are obtained by successive loading of metals. Similarly, ferrite nanoparticles decorated with Pd, Au, and Rh have also been formed by using the same strategy. The catalytic properties of the new nanoparticles are evidenced in processes such as reduction of 4-nitrophenol or hydrogenation of styrene. Besides, the sequential process involving a cross-coupling reaction followed by reduction of 1-nitrobiphenyl has been successfully achieved by employing Pd/Au decorated nanoferrite particles.


Efficacy of esmolol versus alfentanil as a supplement to propofol-nitrous oxide anesthesia.
In 97 outpatients undergoing ambulatory arthroscopic procedures, we compared esmolol with alfentanil when used to supplement propofol-N2O-atracurium anesthesia according to a randomized, double-blind protocol. After an initial intravenous dose of 16 micrograms/kg alfentanil, or 2 mg/kg of esmolol, a variable-rate infusion of alfentanil or esmolol was administered to maintain a stable heart rate. After induction of anesthesia with 2.5 mg/kg of propofol, mean arterial pressure decreased to a larger extent in the alfentanil-treated patients. Although heart rate and mean arterial pressure increased in both groups after tracheal intubation, alfentanil more effectively blunted the hemodynamic response to this stimulus. Maintenance of anesthesia was adequate in both treatment groups. After discontinuation of anesthesia, patients in the esmolol group opened their eyes earlier (7.2 +/- 2.4 min vs 9.8 +/- 4.6 min) than those in the alfentanil group. Esmolol-treated patients also reported less sedation in the first 15 min of recovery than those receiving alfentanil. However, there were no differences in times to ambulation and discharge between the groups. Esmolol-treated patients reported more postoperative pain for the first 15 min of recovery and more esmolol-treated patients required postoperative opioid analgesia than those treated with alfentanil. There were no significant differences in the incidences of nausea and vomiting between the two groups. The authors conclude that esmolol may be used in place of alfentanil to supplement propofol-N2O-atracurium anesthesia in outpatients undergoing arthroscopic procedures. However, hemodynamic responses to tracheal intubation were larger with esmolol, and avoidance of alfentanil did not decrease the incidence of postoperative nausea and vomiting in this outpatient population.


Surface Plasmon Resonance Clinical Biosensors for Medical Diagnostics.
The design and application of sensors for monitoring biomolecules in clinical samples is a common goal of the sensing research community. Surface plasmon resonance (SPR) and other plasmonic techniques such as localized surface plasmon resonance (LSPR) and imaging SPR are reaching a maturity level sufficient for their application in monitoring biomolecules in clinical samples. In recent years, the first examples for monitoring antibodies, proteins, enzymes, drugs, small molecules, peptides, and nucleic acids in biofluids collected from patients afflicted with a series of medical conditions (Alzheimer's, hepatitis, diabetes, leukemia, and cancers such as prostate and breast cancers, among others) demonstrate the progress of SPR sensing in clinical chemistry. This Perspective reviews the current status of the field, showcasing a series of early successes in the application of SPR for clinical analysis and detailing a series of considerations regarding sensing schemes, exposing issues with analysis in biofluids, and comparing SPR with ELISA, while providing an outlook of the challenges currently associated with plasmonic materials, instrumentation, microfluidics, bioreceptor selection, selection of a clinical market, and validation of a clinical assay for applying SPR sensors to clinical samples. Research opportunities are proposed to further advance the field and transition SPR biosensors from research proof-of-concept stage to actual clinical applications.


Structural characteristics of dibromoborylated benzene derivatives.
The crystal structures of five dibromobenzene derivatives, namely dibromoborylbenzene, C(6)H(5)BBr(2), (I), 1-dibromoboryl-4-(trimethylsilyl)benzene, C(9)H(13)BBr(2)Si, (II), 4-bromo-1-(dibromoboryl)benzene, C(6)H(4)BBr(3), (III), dibromo(dimethylamino)(phenyl)borane, C(8)H(12)BBr(2)N, (IV), and dibromo(dimethylsulfanyl)[4-(trimethylsilyl)phenyl]borane, C(11)H(19)BBr(2)SSi, (V), have been determined. Compounds (I)-(IV) crystallize with one molecule in the asymmetric unit, but the molecule of (V) is located on a crystallographic mirror plane, implying twofold disorder of the central aromatic ring, the S atom and one of the methyl groups bonded to the S atom. In (I), (II) and (III), the B atom is three-coordinated, and in (IV) and (V) it is four-coordinated. The geometric parameters of the -BBr(2) group in these five structures agree well with those of comparable structures retrieved from the Cambridge Structural Database. The C-B and B-Br bond lengths in the molecules with a three-coordinated B atom are significantly shorter than those in the molecules with a four-coordinated B atom. In the compounds with a three-coordinated B atom, the -BBr(2) group tends to be coplanar with the aromatic ring to which it is attached.


The use of theophylline in 'irreversible' chronic obstructive pulmonary disease. An update.
The use of theophylline in patients with "irreversible" chronic obstructive pulmonary disease is controversial. Possible favorable actions of theophylline, including improved mucociliary clearance, stimulation of respiratory drive, enhanced cardiovascular function, and increased diaphragmatic contractility and endurance, have either been shown to be minor in degree, or have not been demonstrated in patients with irreversible chronic obstructive pulmonary disease. No well-designed trial has yet shown improved exercise capacity following theophylline treatment in these patients. Nevertheless, considering that some patients benefit symptomatically in the absence of objective improvement, a cautious trial of theophylline appears indicated in patients with severe irreversible chronic obstructive pulmonary disease, with discontinuation if there is no objective or subjective improvement. Theophylline therapy should be initiated via the intravenous route during acute exacerbations, but otherwise should start with sustained-release oral preparations of anhydrous theophylline. Oral therapy should begin at low doses in stable patients to avoid side effects, and dosing should take into account the many factors, such as age, cardiovascular and liver function, smoking status, and possible drug interactions, that can affect theophylline metabolism.


Nature's Timepiece-Molecular Coordination of Metabolism and Its Impact on Aging.
Circadian rhythms are found in almost all organisms from cyanobacteria to humans, where most behavioral and physiological processes occur over a period of approximately 24 h in tandem with the day/night cycles. In general, these rhythmic processes are under regulation of circadian clocks. The role of circadian clocks in regulating metabolism and consequently cellular and metabolic homeostasis is an intensively investigated area of research. However, the links between circadian clocks and aging are correlative and only recently being investigated. A physiological decline in most processes is associated with advancing age, and occurs at the onset of maturity and in some instances is the result of accumulation of cellular damage beyond a critical level. A fully functional circadian clock would be vital to timing events in general metabolism, thus contributing to metabolic health and to ensure an increased "health-span" during the process of aging. Here, we present recent evidence of links between clocks, cellular metabolism, aging and oxidative stress (one of the causative factors of aging). In the light of these data, we arrive at conceptual generalizations of this relationship across the spectrum of model organisms from fruit flies to mammals.


Effect of CYP2B6 genotype on the pharmacokinetics of sibutramine and active metabolites in healthy subjects.
Sibutramine is a pharmacologic intervention for the treatment of obesity. The effect of CYP2B6 genotypes on the pharmacokinetics of sibutramine and its active metabolites (desmethylsibutramine [M1] and didesmethylsibutramine [M2]) was evaluated in 57 healthy subjects. Each subject received a single oral dose of 10 or 15 mg sibutramine, and blood samples were collected up to 72 hours after dosing. The relationship between the genotypes and the pharmacokinetics of sibutramine, M1, and M2 was examined. A statistically significant difference in the elimination half-life (t(1/2)) of sibutramine M1 was found among the 3 genotype groups (P = .0006), between the *1/*1 and *1/*6 groups (P = .0001), and between the *1/*4 and *1/*6 groups (P = .012). The mean value of M1 t(1/2) in *1/*6 (33.3 ± 10.5 hours) was about 58% and 61% greater than that of the *1/*1 group (21.0 ± 7.4 hours) and the *1/*4 group (20.7 ± 9.8 hours), respectively. No significant differences in area under the concentration-time curve or maximum plasma drug concentration were observed between the groups. The CYP2B6*6 allele may be associated with a lower metabolic clearance of the M1 metabolite of sibutramine in human subjects.


Inactivation of retrotransposon Tos17 Chr.7 in rice cultivar Nipponbare through CRISPR/Cas9-mediated gene editing.
Retrotransposons are mobile genetic elements capable of transposition via reverse transcription of RNA intermediates. Rice cultivar Nipponbare contains two nearly identical genomic copies of Tos17, an endogenous copia-like LTR retrotransposon, on chromosomes 7 (Tos17 Chr.7) and 10 (Tos17 Chr.10), respectively. Previous studies demonstrated that only Tos17 Chr.7 is active in transposition during tissue culture. Tos17 Chr.7 has been extensively used for insertional mutagenesis as a tool for functional analysis of rice genes. However, Tos17 Chr.7 transposition might generate somaclonal mutagenesis with undesirable traits during rice transformation, which would affect the evaluation or application of transgenes. In this study, we generated a Tos17 Chr.7 knockout mutant D873 by using CRISPR/Cas9 gene editing system. The gene-edited allele of Tos17 Chr.7 in D873, designated as Tos17 D873, has an 873-bp DNA deletion in the pol gene of Tos17 Chr.7, which caused the deletion of the GAG-pre-integrase domain and the integrase core domain. Although the transcription of Tos17 D873 was activated in D873 calli, no transposition of Tos17 D873 was detected in the regenerated D873 plants. The results demonstrate that the GAG-pre-integrase domain and the integrase core domain are essential for Tos17 Chr.7 transposition and the deletion of the two domains could be not complemented by other LTR retrotransposons in rice genome. As the Tos17 Chr.7-derived somaclonal mutagenesis is blocked in the D873 plants, the generation of the Tos17 D873 allele will be helpful in production of transgenic rice plants for gene function study and genetic engineering. Similar approach can be used to inactivate other retrotransposons in crop breeding.


Army Soldiers and Suicidal Thoughts: The Impact of Negative Relationship Dynamics Moderated by the Dissolution of Romantic Relationships.
Suicide among United States active-duty Army soldiers rapidly increased over the past two decades. Using a sample of 322 soldiers from the Army STARRS study, the researchers examined if romantic relationship factors (i.e., hostile disagreements and relationship distress) were linked with suicidal thoughts in Army soldiers, and if these associations were moderated by a recent separation or divorce. Hostile disagreements and relational distress were both significantly associated with higher rates of suicidal ideation. These associations were significantly amplified in magnitude when in the context of a recent separation or divorce. Implications include novel assessment, prevention, and treatment efforts focused on romantic relationships that may reduce the likelihood of soldiers experiencing thoughts of suicide.


Immunofluorescent localization of the Ca2+-dependent proteinase and its inhibitor in tissues of Crotalus atrox.
The native 108,000 dalton Ca2+-dependent proteinase (CDP) and its 115,000 dalton protein inhibitor (CDPI) were purified from bovine skeletal muscle using native polyacrylamide gel electrophoresis and were used to elicit antibody production in rabbits and BALB/c mice. Polyclonal antibodies were purified as IgG fractions by column chromatography; monoclonal antibodies were produced by the hybridoma technique. Indirect immunofluorescence localization of CDP and CDPI in tissues of Crotalus atrox show both proteins to be ubiquitous. Both occur in the cytoplasm and are absent from the cell membrane and the nucleus; CDPI is also present in the I-band of skeletal muscle.


The management of influenza in people of working age.
Influenza is common, causing considerable morbidity and sickness absence from work in most winters. Influenza vaccines have been available for >40 years, but are not extensively used in the workforce (in the UK). Amantadine has been available for 25 years as a treatment and prophylactic against influenza A infection, but has scarcely been used. In the last 3 years, two neuraminidase inhibitor antivirals, zanamivir and oseltamivir, have been introduced to the market for the treatment and prophylaxis of influenza A and B infections. This review focuses on aspects of prevention and treatment of influenza appropriate to people of working age. Decisions based on the cost-effectiveness of prevention and treatment options differ when viewed from the perspective of the healthcare provider, the employer or the employee. Options currently available need to be directed to a wider range of people than those conventionally regarded as the target risk group.


Perceived difficulties and complications in learners of phacoemulsification: A principal component analysis model.
To evaluate the difficulty perceived of each step of phacoemulsification and analyze the factors affecting them. Overall, 12 trainee residents were allotted 10 cases of phacoemulsification of eyes with senile cataract, under a single observer, and the steps of each surgery were rated from very easy to very difficult with a questionnaire. The completion rates of steps and complications of each surgery were noted. Principal component analysis of the responses to the difficulty level questionnaire was conducted to obtain factors resulting in the perceived difficulty. The lowest difficulty scores were for initial step of incision creation (1.63 ± 0.84), followed by intraocular lens insertion (2.51 ± 0.8). The most difficult step was divide/chop of the nucleus (3.74 ± 0.97) followed by phacoemulsification (3.32 ± 0.82). Highest completion rates were seen for the initial steps of the surgery and the lowest for divide/chop. We identified two major patterns of difficulty among the trainees - one for steps involving high amount of binocularity and the other, for steps involving high precision of hand control. The rate of complication of our study was within acceptable range. Although trainees have practiced phacoemulsification steps on simulation, real-life situation may bring in unprecedented level of difficulty and challenges, which may be documented and used for targeted improvement of surgical skills. Stereopsis and hand control training should form a major part of training modules of cataract surgery both on simulation and real-life scenarios.


Comparison of prostate delineation on multimodality imaging for MR-guided radiotherapy.
With increasing incorporation of MRI in radiotherapy, we investigate two MRI sequences for prostate delineation in radiographer-led image guidance. Five therapeutic radiographers contoured the prostate individually on CT, T2 weighted (T2W) and T2* weighted (T2*W) imaging for 10 patients. Contours were analysed with Monaco ADMIRE (research v. 2.0) to assess interobserver variability and accuracy by comparison with a gold standard clinician contour. Observers recorded time taken for contouring and scored image quality and confidence in contouring. There is good agreement when comparing radiographer contours to the gold-standard for all three imaging types with Dice similarity co-efficient 0.91-0.94, Cohen's κ 0.85-0.91, Hausdorff distance 4.6-7.6 mm and mean distance between contours 0.9-1.2 mm. In addition, there is good concordance between radiographers across all imaging modalities. Both T2W and T2*W MRI show reduced interobserver variability and improved accuracy compared to CT, this was statistically significant for T2*W imaging compared to CT across all four comparison metrics. Comparing MRI sequences reveals significantly reduced interobserver variability and significantly improved accuracy on T2*W compared to T2W MRI for DSC and Cohen's κ. Both MRI sequences scored significantly higher compared to CT for image quality and confidence in contouring, particularly T2*W. This was also reflected in the shorter time for contouring, measuring 15.4, 9.6 and 9.8 min for CT, T2W and T2*W MRI respectively. Conclusion: Therapeutic radiographer prostate contours are more accurate, show less interobserver variability and are more confidently and quickly outlined on MRI compared to CT, particularly using T2*W MRI. Advances in knowledge: Our work is relevant for MRI sequence choice and development of the roles of the interprofessional team in the advancement of MRI-guided radiotherapy.


Pyogenic infection of the sacro-iliac joint. Report of thirteen cases.
Thirteen cases of infectious sacro-iliitis caused by pyogenic organisms are reported and compared with thirty-four cases in the literature. Staphylococcus was the commonest infecting organism (six cases). Two clinical patterns were noted, acute (nine cases) and subacute (four cases). Treatment was by antibiotics and bed rest in all patients. Surgery was indicated for diagnosis in three patients and for abscess in three patients. All of our patients had very good functional recovery.


Mouse interferons: production by Ehrlich ascites tumour cells infected with Newcastle disease virus and its enhancement by theophylline.
Conditions are described for the production of 0.3 to 0.7 NIH mouse reference standard units of interferon per cell from Ehrlich ascites tumour cells cultured as monolayers and induced by infection with Newcastle disease virus (NDV). Inclusion of theophylline (6 mM) in the medium increased the interferon yield three to four times. Cells infected with NDV started to lyse at about 15 p.i., but infected, theophylline-treated cells lysed only 24 p.i. Several other methylxanthines (e.g. theobromine, caffeine and isobutylmethylxanthine) when tested a concentrations similar to that of theophylline, did not boost interferon production. Dibutyryl cyclic AMP (10(-10) to 10(-2)M) did not substitute for theophylline in increasing interferon production, and, if used together with theophylline, did not cause further enhancement.


Pretibial Myxedema Masquerading as a Venous Leg Ulcer.
The authors report a case of pretibial myxedema (PTM) masquerading as a venous leg ulcer to alert wound care clinicians to this diagnostic possibility. Pretibial myxedema is a localized form of mucin cutaneous deposition characterized by indurated plaques most commonly on anterior legs. It is more likely to present in patients with Graves' disease, but it can be found in euthyroid patients as well. The physiopathology of PTM is complex, and there is an accumulation of highly hydrophilic glycosaminoglycans in the dermis. Minimal morbidity is associated with PTM, but the pruritus related to mucin deposition can be intense. The skin around venous leg ulcers and the skin changes related to PTM can have a similar clinical presentation, which may be a reason PTM is under-recognized.


Lasker Laurels for telomerase.
This year the Lasker Foundation pays tribute to telomerase, a medically important enzyme required for chromosome stability and long-term cell proliferation.


Anhedonia among patients with Major Depressive Disorder: A comparison between patients on escitalopram and healthy controls.
Escitalopram has widely been recognized as one of the most frequently used antidepressants, with superior tolerability and great efficacy in preventing major depressive disorder (MDD) relapse and recurrence. However, anhedonia, which is a core symptom of MDD, remains difficult to treat. This study investigates the hedonic levels of MDD patients treated with Escitalopram. A total of 108 participants, 26 of whom with MDD on Escitalopram, were recruited in this cross sectional study. They were evaluated using the Snaith-Hamilton Pleasure Scale (SHAPS) and Beck Depression Inventory (BDI) questionnaires to assess their hedonic state, general mental health condition and level of depression. Our study shows that most items in the SHAPS scores are significantly different between MDD patients on Escitalopram and the controls. The hedonic capacity remains different between the two groups despite patients with MDD are put on Escitalopram treatment. Escitalopram fails to alleviate the hedonic state of MDD patients. Antidepressants that improve both depressive symptoms and hedonic states should be considered when treating MDD patients in clinical settings.


Metformin synergistically enhances antitumor activity of histone deacetylase inhibitor trichostatin a against osteosarcoma cell line.
Oral hypoglycemic agent metformin is commonly used for treating type II diabetes; however, initial reports demonstrated that it could be used for suppressing tumor growth in vitro and in vivo. Moreover, novel potential anticancer drug histone deacetylase (HDAC) and inhibitor trichostatin A (TSA) have been extensively studied for inducing various malignancies growth inhibition, cell cycle arrest, and apoptosis. The object of the present study was to investigate the anti-proliferation and apoptosis induction effects of metformin and TSA in osteosarcoma cell line, and to explore the mechanism of metformin and TSA in combination to inhibit the proliferation of osteosarcoma cells. After treating with metformin and TSA, the viability of osteosarcoma cell lines (MG-63 and LM8) was analyzed by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) at various concentrations, cell cycle analysis of MG-63 and LM8 cell was performed by flow cytometry. Real-time polymerase chain reaction and Western Blotting were performed to determine the expression of apoptosis-related genes and proteins such as Caspase-3, Bcl-2/Bax, Cyclin D1, and p21. Protein expression of the molecules involved in 5'-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway after treatment with combination was determined by Western blotting. Moreover, orthotopic xenograft tumors were challenged in nude mice to establish the murine model; tumor weight and tumor volume were monitored after drug administration separately or combined via the intraperitoneal (i.p.) route. MTT assays showed that the viability of osteosarcoma cell lines in the combination group (10 mM metformin, 0.3 μM TSA) decreased in a concentration- and time-dependent manner; moreover, the cell cycle of MG-63 and LM8 in the combination group could be arrested in G1/G2 phase higher number compared with drug use separately. Furthermore, a combination of these drugs does not act via the AMPK signaling pathway to induce MG-63 osteosarcoma cell line growth inhibition and apoptosis. As data have showed here, metformin cotreatment increased TSA antitumor effects and have a synergistic effect on osteosarcoma cell line proliferation and apoptosis.


The 'Unwell' clinical presentation- an opportunity for admission avoidance?
An 'unwell' patient is a common presentation. We studied all ED 'unwell' admissions over 6 years, assessing factors influencing mortality with logistic regression. From 49,965 admissions, the ED diagnosis was 'unwell' in 3650 (7.3%). 'Unwell' presentations were older and had longer length of stay. Mortality was not different 4.2% vs 4.6 % (p=0.28). Respiratory patients and those >=70 years had increased mortality, 8.3% (95%CI: 5.9%, 10.6%) and 7.1% (5.7%, 8.4%) respectively. Being unwell predicted a better outcome - univariate OR 0.35 (95%CI: 0.24, 0.52), multivariable OR 0.68 (95%CI: 0.44, 1.03). A diagnosis of 'unwell' applied to a heterogenous group; clinical trajectories and outcomes were sufficiently different to preclude targeted admission avoidance as a strategy.


Mushroom Bezoar Causing Small Bowel Obstruction.
A bezoar is a concretion of foreign or indigestible matter in the alimentary canal and is usual cause of gastric obstruction. Bezoars can become fragmented and migrate downward leading to intestinal obstruction. Diagnosis of phytobezoar has become challenging in clinical practice due to lack of patient history and inability of patient to correlate preceding events with the episode of bowel obstruction. Bezoar associated small bowel obstruction rarely occurs and is usually found in patients with history of gastrointestinal surgery. Very few cases are reported of small bowel obstruction due to bezoar in healthy population without prior illness or surgery. We present a case of small bowel obstruction due to mushroom bezoar in a 62-year patient with no past history of medical illness or gastric surgery. Enterotomy was performed and a whole piece of undigested mushroom measuring 5 x 3 cm was successfully removed.


Using neurons to maintain autonomy: Learning from C. elegans.
Understanding how biological organisms are autonomous-maintain themselves far from equilibrium through their own activities-requires understanding how they regulate those activities. In multicellular animals, such control can be exercised either via endocrine signaling through the vasculature or via neurons. In C. elegans this control is exercised by a well-delineated relatively small but distributed nervous system that relies on both chemical and electric transmission of signals. This system provides resources to integrate information from multiple sources as needed to maintain the organism. Especially important for the exercise of neural control are neuromodulators, which we present as setting agendas for control through more traditional electrical signaling. To illustrate how the C. elegans nervous system integrates multiple sources of information in controlling activities important for autonomy, we focus on feeding behavior and responses to adverse conditions. We conclude by considering how a distributed nervous system without a centralized controller is nonetheless adequate for autonomy.


Distinctive biophysical features of human cell-types: insights from studies of neurosurgically resected brain tissue.
Electrophysiological characterization of live human tissue from epilepsy patients has been performed for many decades. Although initially these studies sought to understand the biophysical and synaptic changes associated with human epilepsy, recently, it has become the mainstay for exploring the distinctive biophysical and synaptic features of human cell-types. Both epochs of these human cellular electrophysiological explorations have faced criticism. Early studies revealed that cortical pyramidal neurons obtained from individuals with epilepsy appeared to function "normally" in comparison to neurons from non-epilepsy controls or neurons from other species and thus there was little to gain from the study of human neurons from epilepsy patients. On the other hand, contemporary studies are often questioned for the "normalcy" of the recorded neurons since they are derived from epilepsy patients. In this review, we discuss our current understanding of the distinct biophysical features of human cortical neurons and glia obtained from tissue removed from patients with epilepsy and tumors. We then explore the concept of within cell-type diversity and its loss (i.e., "neural homogenization"). We introduce neural homogenization to help reconcile the epileptogenicity of seemingly "normal" human cortical cells and circuits. We propose that there should be continued efforts to study cortical tissue from epilepsy patients in the quest to understand what makes human cell-types "human".


The dynamics of chromosome organization and gene regulation.
With the sequence of the human genome now complete, studies must focus on how the genome is functionally organized within the confines of the cell nucleus and the dynamic interplay between the genome and its regulatory factors to effectively control gene expression and silencing. In this review I describe our current state of knowledge with regard to the organization of chromosomes within the nucleus and the positioning of active versus inactive genes. In addition, I discuss studies on the dynamics of chromosomes and specific genetic loci within living cells and its relationship to gene activity and the cell cycle. Furthermore, our current understanding of the distribution and dynamics of RNA polymerase II transcription factors is discussed in relation to chromosomal loci and other nuclear domains.


[Chemotherapies of negative schizophrenia].
Five years ago, Goldberg claimed that negative symptoms of schizophrenia do respond to neuroleptics. This apparent discovery is, in fact, a very common way of thinking for European schools of psychiatry, specially the French one guided by Delay and Deniker. Initially focused on reserpine and some alerting phenothiazines such as thioproperazine, this opinion has been extended to benzamides in the 1970s. The analysis of the publications devoted to this point indicates that several drugs are actually considered as potent disinhibitors (i.e. active on negative symptoms of schizophrenia): Phenothiazines: As shown in the controlled studies by Itil (1971), Poirier-Littré (1988), fluphenazine and pipotiazine improve the BPRS anergia factor and the SANS score. Butyrophenones: The first description of the "imipramine like" effect of trifluperidol by Janssen (1959) initiated the studies by Gallant (1960), Fox (1963). They compared trifluperidol at low doses versus haloperidol and chlorpromazine at medium and high doses, BPRS anergia factor improved only at low doses. Diphenylbutylpiperidines (DPBP): Meltzer's review (1986) concluded to the efficacy of such drugs on negative symptoms appearing as a specific biochemical relationship effect. A definite analysis about doses leads to a very different interpretation: DPBP low doses and only low doses improved negative symptoms as much as some low doses of phenothiazines. On the opposite, DPBP, phenothiazines and butyrophenones high doses are inefficient.(ABSTRACT TRUNCATED AT 250 WORDS)


Stakeholder perspectives on a telemedicine referral and coordination model to expand medication treatment for opioid use disorder in rural primary care clinics.
Opioid overdose deaths are increasing rapidly in the United States. Medications for opioid use disorder (MOUD) are effective and can be delivered in primary care, but uptake has been limited in rural communities. Referral to and coordination with an external telemedicine (TM) vendor by rural primary care clinics for MOUD (TM-MOUD) may increase MOUD access for rural patients, but we know little about perspectives on this model among key stakeholders. As part of a TM-MOUD feasibility study, we explored TM-MOUD acceptability and feasibility among personnel and patients from seven rural primary care clinics and a TM-MOUD vendor. We conducted virtual interviews or focus groups with clinic administrators (n = 7 interviews), clinic primary care and behavioral health providers (8 groups, n = 30), other clinic staff (9 groups, n = 37), patients receiving MOUD (n = 16 interviews), TM-MOUD vendor staff (n = 4 interviews), and vendor-affiliated behavioral health and prescribing providers (n = 17 interviews). We asked about experiences with and acceptability of MOUD (primarily buprenorphine) and telemedicine (TM) and a TM-MOUD referral and coordination model. We conducted content analysis to identify themes and participants quantitatively rated acceptability of TM-MOUD elements on a 4-item scale. Perceived benefits of vendor-based TM-MOUD included reduced logistical barriers, more privacy and less stigma, and access to services not available locally (e.g., counseling, pain management). Barriers included lack of internet or poor connectivity in patients' homes, limited communication and trust between TM-MOUD and clinic providers, and questions about the value to the clinic of TM-MOUD referral to external vendor. Acceptability ratings for TM-MOUD were generally high; they were lowest among frontline staff. Rural primary care clinic personnel, TM-MOUD vendor personnel, and patients generally perceived referral from primary care to a TM-MOUD vendor to hold potential for increasing access to MOUD in rural communities. Increasing TM-MOUD uptake requires buy-in and understanding among staff of the TM-MOUD workflow, TM services offered, requirements for patients, advantages over clinic-based or TM services from clinic providers, and identification of appropriate patients. Poverty, along with patient hesitation to initiate treatment, creates substantial barriers to MOUD treatment generally; insufficient internet availability creates a substantial barrier to TM-MOUD.