Passively mode-locked Yb:LuVO(4) oscillator.
Passive mode locking of the ytterbium doped orthovanadate crystal Yb:LuVO(4) is reported for the first time. We demonstrate what we believe to be the shortest pulses directly generated with an Yb-doped crystalline laser using a semiconductor saturable absorber. The pulses at 1036 nm have a duration as short as 58 fs for an average power of 85 mW.


Model-Based Exposure-Response Assessment for Spectinamide 1810 in a Mouse Model of Tuberculosis.
Despite decades of research, tuberculosis remains a leading cause of death from a single infectious agent. Spectinamides are a promising novel class of antituberculosis agents, and the lead spectinamide 1810 has demonstrated excellent efficacy, safety, and drug-like properties in numerous in vitro and in vivo assessments in mouse models of tuberculosis. In the current dose ranging and dose fractionation study, we used 29 different combinations of dose level and dosing frequency to characterize the exposure-response relationship for spectinamide 1810 in a mouse model of Mycobacterium tuberculosis infection and in healthy animals. The obtained data on 1810 plasma concentrations and counts of CFU in lungs were analyzed using a population pharmacokinetic/pharmacodynamic (PK/PD) approach as well as classical anti-infective PK/PD indices. The analysis results indicate that there was no difference in the PK of 1810 in infected compared to healthy, uninfected animals. The PK/PD index analysis showed that bacterial killing of 1810 in mice was best predicted by the ratio of maximum free drug concentration to MIC (fCmax/MIC) and the ratio of the area under the free concentration-time curve to the MIC (fAUC/MIC) rather than the cumulative percentage of time that the free drug concentration is above the MIC (f%TMIC). A novel PK/PD model with consideration of postantibiotic effect could adequately describe the exposure-response relationship for 1810 and supports the notion that the in vitro observed postantibiotic effect of this spectinamide also translates to the in vivo situation in mice. The obtained results and pharmacometric model for the exposure-response relationship of 1810 provide a rational basis for dose selection in future efficacy studies of this compound against M. tuberculosis.


Regional distribution of M1, M2 and non-M1, non-M2 subtypes of muscarinic binding sites in rat brain.
The distribution of subtypes of the muscarinic receptor in homogenates of the rat brain was investigated by measuring the competitive inhibition of the binding [3H]N-methylscopolamine by pirenzepine and AF-DX 116 (11[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5, 11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one). In most brain regions, the competitive binding curves for AF-DX 116 and pirenzepine were consistent with a two-site model. The dissociation constant of pirenzepine for its high-affinity site (M1 receptor) was approximately 10(-8) M, whereas the dissociation constant of AF-DX 116 for its high affinity site (M2 receptor) was approximately 10(-7) M. In many regions, particularly those in the forebrain, the sum of the densities of the M1 and M2 binding sites was substantially less than 100% of the total sites, indicating the existence of a third population of sites lacking high affinity for both pirenzepine and AF-DX 116. We have designated these latter sites as non-M1, non-M2 muscarinic receptors. In general, the densities of the M1 and non-M1, non-M2 binding sites were highest in cerebral cortex, corpus striatum and hippocampus, intermediate in thalamus and hypothalamus, and lowest in midbrain, medulla-pons and cerebellum, whereas the M2 binding site had a relatively low, uniform density throughout the brain. The binding capacity of [3H]N-methylquinuclidinyl benzilate was estimated to be 20 to 30% lower than that of [3H]quinuclidinyl benzilate in various regions of the forebrain, but not in more caudal regions of the brain where the two radioligands had approximately the same binding capacities. Treatment of homogenates of the cerebral cortex with benzilylcholine mustard caused a selective loss of the majority of the [3H]N-methylscopolamine binding sites but spared 25% of the sites labeled by [3H]quinuclidinyl benzilate The results of pirenzepine/[3H]quinuclinyl benzilate competitive binding experiments on cerebral cortex treated with benzilylcholine mustard showed that the residual binding sites for [3H] quinuclidinyl benzilate were enriched in M1 muscarinic receptors.


Evaluating the Efficacy of Polyglycolic Acid-Loading Tetrandrine Nanoparticles in the Treatment of Dry Eye.
Dry eye disease (DED) is a multifactor-induced disease accompanied by increased osmolarity of the tear film and inflammation of the ocular surface. Traditional anti-inflammation agent corticosteroids applied in DED treatment could result in high intraocular pressure, especially in long-term treatment. Therefore, we explored a nano drug that aimed to block the formation pathway of DED which had anti-inflammatory, sustained release, and good biocompatibility characteristics in this study. We prepared a novel nanomedicine (Tet-ATS@PLGA) by the thin film dispersion-hydration ultrasonic method and detected its nanostructure, particle size, and zeta potential. Flow cytometry was used to detect the cell survival rate of each group after 24 h of drug treatment on inflammed Statens Seruminstitut Rabbit Corneal (SIRC) cells. Observed and recorded corneal epithelial staining, tear film rupture time, and Schirmer test to detect tear secretion on the ocular surface of rabbits. The corneal epithelial thickness, morphology, and number of bulbar conjunctival goblet cells were recorded by H&E staining. Finally, we detected the expression of VEGF, IL-1β, PGE2, and TNF-α by cellular immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA). The encapsulation efficiency and drug loading of Tet-ATS@PLGA were 79.85% and 32.47%, respectively. At eye surface temperature, Tet can easily release from Tet-ATS@PLGA while that it was difficult to release at storage temperature and room temperature. After 2 weeks medication, Tet-ATS@PLGA can effectively improve the tear film rupture time and tear secretion time in a DED model (p <0.05). Compared with the normal group (62.34 ± 4.86 mm), the thickness of corneal epithelium in ATS (29.47 ± 3.21 mm), Tet-ATS (46.23 ± 2.87 mm), and Tet-ATS@PLGA (55.76 ± 3.95 mm) gradually increased. Furthermore, the flow cytometry indicated that Tet-ATS@PLGA can effectively promote the apoptosis of inflammatory SIRC cells, and the cellular immunofluorescence and ELISA experiments showed that the expression intensity of inflammatory factors such as VEGF, IL-1β, PGE2, and TNF-α decreased in this process. Interestingly, Tet also had the effect of reducing intraocular pressure. Tet-ATS@PLGA can effectively promote the apoptosis of inflammatory corneal epithelial cells, thus inhibiting the expression of inflammatory factors to block the formation of DED and improve the secretion of tear on the ocular surface.


Endoscopic histoacryl obliteration vs. propranolol in the prevention of esophagogastric variceal rebleeding: a randomized trial.
The obliteration of esophageal and/or gastric varices using Histoacryl is highly effective in controlling active bleeding. However, it is not known whether repeated injections are useful for the long-term eradication of esophagogastric varices. The aim of the study was to compare endoscopic Histoacryl obliteration with propranolol in the secondary prevention of esophagogastric variceal bleeding. Between August 1995 and February 1999, 41 patients with a first bleeding from esophageal (n = 31) or gastric (n = 10) varices were included in the study. After primary hemostasis with obliteration using Histoacryl, patients were randomly allocated either to undergo complete Histoacryl obliteration of the remaining varices (group A, n = 21) or to long-term propranolol administration (group B, n = 20), for the prevention of rebleeding. The two groups were well matched for age, sex, etiology of cirrhosis, Child-Pugh score, renal function, and infection at the time of admission. The median follow-up was 31.9 months (4.8 - 74.7) for group A and 23.2 months (3.0 - 70.0) for group B. Initial hemostasis was achieved in 40/41 patients (97 %). No significant difference was observed between groups A and B with regard to the incidence of early rebleeding (during the first 6 weeks; 5/21 and 3/20), bleeding-related deaths by 6 weeks (3/21 and 6/20), long-term rebleeding (11/21 and 5/20), or overall number of deaths (9/21 and 9/20). The incidence of complications was higher in group A (10/21) than group B (2/20) (P < 0.03). Repeated injections of Histoacryl with the aim of eradicating esophagogastric varices are associated with more complications compared with beta-blocker administration, with similar results in terms of rebleeding rate and survival in the long term.


Prostaglandins versus oxytocin for prelabour rupture of membranes at or near term.
The conventional method of induction of labour is with intravenous oxytocin. More recently, induction with prostaglandins, followed by an infusion of oxytocin if necessary, has been used. The objective of this review was to assess the effects of induction of labour with prostaglandins compared with oxytocin, at or near term. We searched the Cochrane Pregnancy and Childbirth Group trials register. Randomised and quasi-randomised trials of early stimulation of uterine contractions with prostaglandins (with or without oxytocin) versus with oxytocin alone (not combined with prostaglandins) in women with spontaneous rupture of membranes before labour (34 weeks or more gestation). Two reviewers assessed trial quality and extracted data. Seventeen trials were included. Most of the trials were of moderate to good quality. Based on six trials, prostaglandins compared with oxytocin were associated with increased chorioamnionitis (odds ratio of 1.49, 95% confidence interval 1.07 to 2.09) and maternal nausea/vomiting. Based on eight trials, prostaglandins were associated with a decrease in epidural analgesia, odds ratio of 0.85, 95% confidence interval 0.73 to 0.98 and internal fetal heart rate monitoring (based on one trial). Caesarean section, endometritis and perinatal mortality were not significantly different between the groups. Women with prelabour rupture of membranes at or near term having their labour induced with prostaglandins appear to have a lower risk of epidural analgesia and fetal heart rate monitoring. However there appears to be an increased risk of chorioamnionitis and nausea/vomiting with prostaglandins compared to oxytocin.


Endothelial expression of CD40 in renal cell carcinoma.
Recently, the immunoregulative molecule CD40 has also been introduced as a potential surface determinant of endothelial cells that can be induced by various cytokines and thus might be involved in inflammatory vascular reactions. In this study, the ubiquitous endothelial expression of CD40 within the neovascularized areas of renal cell carcinoma is demonstrated. The strong capillary expression of CD40 in 12 tumor samples is contrasted by the absence of endothelial CD40 in the corresponding tumor-free kidney specimens in which only certain tubular segments and few interstitial cells carry CD40. Northern hybridization studies confirmed the presence of CD40 RNA in cytokine-treated endothelial cells and in renal cell carcinoma, whereas no hybridization signal was obtained with normal kidney tissue. That the presence of tumor cells is pertinent to the endothelial expression of CD40 could be substantiated by in vitro experiments, when a renal carcinoma cell line and its supernatant, but not normal kidney cells, could induce CD40 on endothelial cells in culture. According to further experimental results, the carcinoma-derived, CD40-inducing factor(s) is not represented within a variety of pleiotropic cytokines including IFN-gamma, interleukin 1, interleukin 6, and tumor necrosis factor alpha, or common angiogenic factors such as basic fibroblast growth factor, vascular endothelial cell growth factor, angiogenin, and erythropoietin. The immunohistological results showing a widespread, even distribution of CD40 in tumor capillaries suggest that within renal cell carcinoma, the appearance of endothelial CD40 may also be related to angiogenesis in addition to inflammation.


Clinical decision analysis: Incorporating the evidence with patient preferences.
Decision analysis has become an increasingly popular decision-making tool with a multitude of clinical applications. Incorporating patient and expert preferences with available literature, it allows users to apply evidence-based medicine to make informed decisions when confronted with difficult clinical scenarios. A decision tree depicts potential alternatives and outcomes involved with a given decision. Probabilities and utilities are used to quantify the various options and help determine the best course of action. Sensitivity analysis allows users to explore the uncertainty of data on expected clinical outcomes. The decision maker can thereafter establish a preferred method of treatment and explore variables which influence the final clinical outcome. The present paper reviews the technique of decision analysis with particular focus on its application to clinical decision making.


Becker's nevus with ipsilateral breast hypoplasia: improvement with spironolactone.
Ipsilateral breast hypoplasia is a rare abnormality in Becker's nevus. The pathogenesis of the breast hypoplasia is not understood, but an increased level of androgenic receptor in the affected area may play a role. We report a case of Becker's nevus with ipsilateral breast hypoplasia. Spironolactone, an anti-androgenic agent, was tried for treatment of the hypoplasia, and, one month later, breast enlargement was seen in only the hypoplastic breast with Becker's nevus. This finding supports the theory that breast hypoplasia in Becker's nevus is related to an increase in androgenic receptor.


Improved expression and purification of highly-active 3 chymotrypsin-like protease from SARS-CoV-2.
Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is the causative pathogen of coronavirus disease-19 (COVID-19). The COVID-19 pandemic has resulted in millions of deaths and widespread socio-economic damage worldwide. Therefore, numerous studies have been conducted to identify effective measures to control the spreading of the virus. Among various potential targets, the 3 chymotrypsin-like protease (3CLpro), also known as Mpro, stands out as the key protease of SARS-CoV-2, playing an essential role in virus replication and assembly, is the most prospective. In this study, we modified the commercial vector, pETM33-Nsp5-Mpro (plasmid # 156475, Addgene, USA), by inserting an autocleavage site (AVLQ) of 3CLpro and 6 × His-tag encoding sequences before and after the Nsp5-Mpro sequence, respectively. This modification enabled the expression of 3CLpro as an authentic N terminal protease (au3CLpro), which was purified to electrophoretic homogeneity by a single-step chromatography using two tandem Glutathione- and Ni-Sepharose columns. The enzyme au3CLpro demonstrated significantly higher activity (3169 RFU/min/μg protein) and catalytic efficiency (Kcat/Km of 0.007 μM-1.s-1) than that of the 3CLpro (com3CLpro) expressed from the commercial vector (pETM33-Nsp5-Mpro) with specific activity 889 RFU/min/μg and Kcat/Km of 0.0015 μM-1.s-1, respectively. Optimal conditions for au3CLpro activity included a 50 mM Tris-HCl buffer at pH 7, containing 150 mM NaCl and 0.1 mg/ml BSA at 37 °C.


[Procedure in the surgery of portal hypertension].
The observations of 94 patients operated upon in early period of chronic hepatitis and hepatocirrhosis and 248 lethal outcomes of hepatocirrhosis are analyzed. The follow-up observation reached 15 years. The authors have shown that the earlier the operation was performed the better were the remote results. The analysis of lethal outcomes has shown that patients with portal hypertension are usually passed to surgeons too late. They believe that it is necessary to have a dispensary registration of patients with cirrhosis of the liver and portal hypertension.


A novel and sensitive radioreceptor assay for serum melatonin levels.
A simple and sensitive radioreceptor assay (RRA) has been developed to measure melatonin levels in serum. The assay is based on competition between 2-[125I]iodomelatonin ([125I]MEL) and melatonin for binding to high-affinity binding sites in chick forebrain. To measure the amount of melatonin present in a serum sample, it was extracted with dichloromethane and added to the assay medium. The percentage inhibition of radioligand binding in the presence of the extracted serum was determined and compared to the percent displacement by known amounts of melatonin in a standard curve. There was little or no cross-reactivity with other structurally related compounds. The sensitivity of the assay is approximately 1.5pg/0.15 mL and the intra- and inter-assay variations are approximately 8%. Since the RRA results are comparable to that of an established radioimmunoassay (RIA), it provides a sensitive and rapid alternative to the more time consuming RIA.


Six year follow up of lung function in men occupationally exposed to formaldehyde.
The long term effects of formaldehyde on the respiratory tract have been investigated in a group of 164 workers exposed daily to the chemical during the production of urea formaldehyde resin, together with 129 workers not exposed to free formaldehyde. Exposure was classified as high (corresponding to an eight hour time weighted exposure of more than 2.0 ppm), medium (0.6 to 2.0 ppm), or low (0.1 to 0.5 ppm). Twenty five per cent of workers had had high exposure at some time and 17% moderate exposure. Both the exposed and unexposed groups had an annual assessment that included lung function. The proportion with self reported respiratory symptoms was similar in the two groups, 12% and 16% reporting breathlessness on hurrying and 26% and 20% wheezing. The initial forced expiratory volume in one second (FEV1) was within 0.5 l (approximately one standard deviation (SD)) of the predicted value (by age and height) in 65% of the exposed and 59% of unexposed workers and more than 0.5 l below the predicted value in 9% of exposed and 11% of unexposed workers. The mean decline in FEV1 was 42 ml a year (SD 45) in the exposed group and 41 ml a year in the unexposed group (SD 40 ml a year). The rate of decline showed the expected association with smoking in the unexposed group, but in the exposed group the mean rate of decline in the never smokers was similar to that in current smokers. There were, however, relatively few never smokers and considerable variation in the rates of decline. In the exposed group no association was found between the rate of decline and indices of exposure to formaldehyde. Thus there is no evidence from this study of an excess of respiratory symptoms or decline in lung function in the workers exposed to formaldehyde. The similar rate of decline of FEV1 however in never smokers and smokers of the exposed group is consistent with findings of other studies for workers exposed to formaldehyde and to toluene di-isocyanate.


Influence of carbohydrate ingestion on oxidative stress and plasma antioxidant potential following a 3 h run.
Concentrations of reactive oxygen species (ROS) increase during exercise secondary to increased oxygen uptake, xanthine oxidase activity, and immune system activation. Carbohydrate compared to placebo beverage ingestion is associated with an attenuated cortisol and catecholamine response. Catecholamines can undergo autooxidation to form ROS. We hypothesized that during intense exercise, ingestion of carbohydrate compared to placebo would diminish oxidative stress. Sixteen experienced marathoners ran on treadmills for 3 h at approximately 70% VO2(max) on two occasions while receiving carbohydrate or placebo beverages (11/h, double-blinded) in a randomized, counterbalanced order. Blood samples were collected before and immediately after exercise, snap frozen in liquid nitrogen, and stored at -80 degrees C until analysis. Plasma samples were analyzed for F2-isoprostanes (FIP) and lipid hydroperoxides (ROOH) as measures for lipid peroxidation, ferric reducing ability of plasma (FRAP) as a measure of plasma antioxidant potential and for cortisol. The pattern of change in cortisol was significantly different between carbohydrate and placebo conditions (P = 0.024), with post-exercise levels higher in the placebo condition. Under both carbohydrate and placebo conditions, significant increases in FIP, ROOH, and FRAP were measured, but the pattern of increase was not different (FIP, interaction effect, P = 0.472; ROOH, P = 0.572; FRAP, P = 0.668). Despite an attenuation in the cortisol response, carbohydrate compared to placebo ingestion does not counter the increase in oxidative stress or modulate plasma antioxidant potential in athletes running 3 h at 70% VO2(max).


Physical fitness is inversely related to heart disease risk: a factor analytic study.
We measured cardiorespiratory endurance, muscular strength and endurance, anaerobic run time, coronary risk factors, and dietary habits in male fire fighters (n = 779, ages 18 to 64 years) and performed factor analysis to determine the interrelationships and underlying factor structure of the data set. Principal component analysis produced nine factors (eigenvalues greater than 1.0) accounting for 61% of the total variance. However, the variable loadings were inconsistent, preventing a meaningful interpretation of the factor solution. These problems were solved through the principal axis method of common factor analysis, which revealed three factors (eigenvalues greater than 1.0) accounting for 29% of the total variance. Orthogonal rotation (varimax method), showed Factors 1, 2, and 3 accounting for 52%, 29%, and 19%, respectively, of the common variance. Factor 1, labeled physical fitness capacity (PFC), included age, situps, treadmill performance time, pushups, maximum exercise heart rate, and anaerobic run time. Factor 2, designated coronary risk status (CRS), included body mass index, resting systolic and diastolic blood pressure, triglycerides, and the total cholesterol-high density lipoprotein cholesterol ratio. Factor 3, termed food frequency intake (FFI), included the weekly intake of fried foods, beef, pork, eggs, caffeine, and cheese. Percentage body fat loaded on both PFC and CRS. Measures such as blood pressure, grip strength, resting heart rate, maximum exercise systolic blood pressure, cigarettes smoked per day, and weekly frequency of milk, fish, fowl, and alcohol intake contributed little to the factor solution. Correlation coefficients after oblique rotation showed PFC to be inversely related to CRS (r = -0.48). However, FFI was independent of PFC (r = 0.07) and CRS (r = -0.10).(ABSTRACT TRUNCATED AT 250 WORDS)


Motivating signage prompts safety belt use among drivers exiting senior communities.
Senior drivers are vulnerable to automobile crashes and subsequent injury and death. Safety belts reduce health risks associated with auto crashes. Therefore, it is important to encourage senior drivers to wear safety belts while driving. Using an AB design, replicated five times, we evaluated the short- and long-term effects of a sign with the message "BUCKLE UP, STAY SAFE" attached to a stop sign at the exits of five different senior communities. Safety belt use was stable during two pretreatment assessments averaged across the five sites and 250 drivers (72% and 68% usage), but significantly increased following installation of these signs (94% usage). Six months after installation of the signs, the effect persisted (88% usage). Use of such signs may be a cost-effective way of promoting safety belt use.


Review article: Can venous blood gas analysis replace arterial in emergency medical care.
The objectives of the present review are to describe the agreement between variables on arterial and venous blood gas analysis (in particular pH, pCO(2) , bicarbonate and base excess) and to identify unanswered questions. MEDLINE search of papers published from 1966 to January 2010 for studies comparing arterial and peripheral venous blood gas values for any of pH, pCO(2) , bicarbonate and base excess in adult patients with any condition in an emergency department setting. The outcome of interest was mean difference weighted for study sample size with 95% limits of agreement. The weighted mean arterio-venous difference in pH was 0.035 pH units (n= 1252), with narrow limits of agreement. The weighted mean arterio-venous difference for pCO(2) was 5.7 mmHg (n= 760), but with 95% limits of agreement up to the order of ±20 mmHg. For bicarbonate, the weighted mean difference between arterial and venous values was -1.41 mmol/L (n= 905), with 95% limits of agreement of the order of ±5 mmol/L. Regarding base excess, the mean arterio-venous difference is 0.089 mmol/L (n= 103). There is insufficient data to determine if these relationships persist in shocked patients or those with mixed acid-base disorders. For patients who are not in shock, venous pH, bicarbonate and base excess have sufficient agreement to be clinically interchangeable for arterial values. Agreement between arterial and venous pCO(2) is too poor and unpredictable to be clinically useful as a one-off test but venous pCO(2) might be useful to screen for arterial hypercarbia or to monitor trends in pCO(2) for selected patients.


Malignant tumours of the nasopharynx.
A series of 115 patients with malignant tumours of the nasopharynx were primarily irradiated. All the cases of carcinoma were TNM classified in retrospect. 60Co irradiation appeared to afford a somewhat better prognosis than conventional irradiation previously used. The 5-year crude survival rate for the patients with lymphoma and with carcinoma was 40.0 per cent and 23.8 per cent respectively. A distinctly better prognosis was found for women than for men and the prognosis was independent of whether or not lymph node metastases were present. There seems to be no indication for maintaining lympho-epithelial carcinoma as a special group of tumour. Surgical procedures are rarely indicated in the treatment of malignant nasopharyngeal tumours.


Contractile effects of some polypeptides on the isolated urinary bladder of guinea-pig, rabbit, and rat.
In isolated detrusor from guinea-pigs and rats substance P (SP) induced concentration-dependent phasic contractions. Rabbit detrusor strips responded to SP with an initial phasic and an ensuing tonic contraction. The concentration-response curve to SP in this preparation had a biphasic appearance. Eledoisin (E) caused contractile responses similar to those of SP when tested on the guinea-pig detrusor. Somatostatin was tested on the rabbit urinary bladder; it caused a concentration-dependent rise in basal tone, but no phasic contraction. The responses to SP and E were not affected by tetrodotoxin or physostigmine. They were only partly inhibited by high concentrations of atropine and the anticholinergic drug PR 197. Noradrenaline and isoprenaline caused a concentration-dependent inhibition of the peptide induced responses in guinea-pig bladder; at high concentrations in the amines this inhibition was almost complete. Indomethacin did not affect the SP induced contractions in the guinea-pig bladder, reduced the responses in the rabbit detrusor, but increased them in the rat bladder. Contractions elicited by SP and E were rapidly diminished or abolished after 30 min. treatment in a calcium-free medium. The responses were also inhibited by the calcium antagonist nifedipine. In guinea-pig preparations depolarized by potassium (127 mM) both SP and E caused a contractile response approximately 20% of that obtained in normal Tyrode solution. It is concluded that SP and E cause contraction of detrusor by a direct effect on the smooth muscle cells, and that this response is dependent on the extracellular calcium concentration. Prostaglandins may be involved in the SP-induced response of the rabbit detrusor.


Parameters of bacterial killing and regrowth kinetics and antimicrobial effect examined in terms of area under the concentration-time curve relationships: action of ciprofloxacin against Escherichia coli in an in vitro dynamic model.
Although many parameters have been described to quantitate the killing and regrowth of bacteria, substantial shortcomings are inherent in most of them, such as low sensitivity to pharmacokinetic determinants of the antimicrobial effect, an inability to predict a total effect, insufficient robustness, and uncertain interrelations between the parameters that prevent an ultimate determination of the effect. To examine different parameters, the kinetics of killing and regrowth of Escherichia coli (MIC, 0.013 microg/ml) were studied in vitro by simulating a series of ciprofloxacin monoexponential pharmacokinetic profiles. Initial ciprofloxacin concentrations varied from 0.02 to 19.2 microg/ml, whereas the half-life of 4 h was the same in all experiments. The following parameters were calculated and estimated: the time to reduce the initial inoculum (N0) 10-, 100-, and 1,000-fold (T90%, T99%, and T99.9%, respectively), the rate constant of bacterial elimination (k(elb)), the nadir level (Nmin) in the viable count (N)-versus-time (t) curve, the time to reach Nmin (t(min)), the numbers of bacteria that survived (Ntau) by the end of the observation period (tau), the area under the bacterial killing and regrowth curve (log N(A)-t curve) from the zero point (time zero) to tau (AUBC), the area above this curve (AAC), the area between the control growth curve (log N(C)-t curve) and the bacterial killing and regrowth curve (log N(A)-t curve) from the zero point to tau (ABBC) or to the time point when log N(A) reaches the maximal values observed in the log N(C)-t curve (I(E); intensity of the effect), and the time shift between the control growth and regrowth curves (T(E); duration of the effect). Being highly sensitive to the AUC, I(E), and T(E) showed the most regular AUC relationships: the effect expressed by I(E) or T(E) increased systematically when the AUC or initial concentration of ciprofloxacin rose. Other parameters, especially T90%, T99%, T99.9%, t(min), and log N0 - log Nmin = delta log Nmin, related to the AUC less regularly and were poorly sensitive to the AUC. T(E) proved to be the best predictor and t(min) proved to be the worst predictor of the total antimicrobial effect reflected by I(E). Distinct feedback relationships between the effect determination and the experimental design were demonstrated. It was shown that unjustified shortening of the observation period, i.e., cutting off the log N(A)-t curves, may lead to the degeneration of the AUC-response relationships, as expressed by log N0 - log Ntau = delta log Ntau, AUBC, AAC, or ABBC, to a point where it gives rise to the false idea of an AUC- or concentration-independent effect. Thus, use of I(E) and T(E) provides the most unbiased, robust, and comprehensive means of determining the antimicrobial effect.


Repellent and insecticidal efficacy of a new combination of fipronil and permethrin against three mosquito species (Aedes albopictus, Aedes aegypti and Culex pipiens) on dogs.
Three laboratory studies were conducted to assess the repellent and insecticidal efficacy of a combination of fipronil and permethrin (Frontline Tri- Act/Frontect) against three mosquito species (Aedes albopictus, Aedes aegypti and Culex pipiens) on dogs. In each study, 16 healthy adult dogs were allocated to two groups. Eight dogs were treated with the new topical spot-on combination of fipronil and permethrin on Day 0 and the other eight dogs served as untreated controls. Each dog was exposed to mosquitoes on Days 1, 7, 14, 21 and 28 (and also on Day 35 in the A. aegypti study). After a 1-h exposure period, all mosquitoes were counted and categorized as live or dead and fed or non-fed. Live mosquitoes were kept in an insectary and observed for mortality counts 4, 24 and 48 h post-exposure (PE) for Aedes spp. and 24 and 48 h PE for C. pipiens. Repellency and insecticidal efficacies were defined as the percent reduction in the number of fed and live mosquitoes, respectively, in the treated group as compared to the untreated control group. Repellency against A. albopictus was ≥93.4% through Day 21 and 86.9% on Day 28. It was ≥91.0% through Day 35 against A. aegypti and ≥90.4% through Day 28 against C. pipiens. Insecticidal efficacy against A. albopictus was ≥97.1% at 24 h PE from Day 7 to Day 28. It was ≥98.0% for the first 3 weeks and still 75.7% on Day 35 against A. aegypti at 24 h PE. For C. pipiens, insecticidal efficacy ranged from 93.8% (Day 7) to 30.9% (Day 28) at 48 h PE. A single topical administration of the combination of fipronil and permethrin provides repellency against mosquitoes on dogs for at least 4 weeks. The product may therefore significantly reduce the potential for the transmission of vector-borne pathogens through the inhibition of mosquito feeding, as well as the discomfort associated with mosquito bites. Moreover, mosquito mortality was induced by contact with the treated dogs, which could aid in the control of mosquitoes, and hence the control of mosquito-borne diseases, in the local vicinity of treated dogs.


(131)I-MIBG treatment of pheochromocytoma: low versus intermediate activity regimens of therapy.
Since the second half of the 1980s, (131)I-MIBG has been widely used for treatment of patients with malignant pheochromocytoma. In 1991, at the International Meeting in Rome, it was agreed that (131)I-MIBG therapy induces significant tumor responses in about 30-50% of cases, long-term stabilization of disease in several cases and significant reduction of cathecolamine-related symptoms in almost all patients. Nevertheless, more than 20 years later, its therapeutic use in malignant phaeochromocytoma has not yet been standardized. Aim of the present study was to compare the use of low versus intermediate activity of MIBG to achieve better results in a shorter time with higher activities. Two different modalities of (131)I-MIBG therapy were performed: before 2001, 12 patients (Group 1) received a fixed activity of 5.55 GBq/session. From 2001 to 2009, 16 patients (Group 2) were treated with 9.25-12.95 GBq/session. As expected, the overall response rate in Group 2 are slightly better. The most important result of increasing the single session activity was the shorter median time to achieve a significant response (7 versus 19 months), which was obtained with a lower median cumulative activity (11 versus 22 GBq) in a lower median number of sessions (2 versus 7). We demonstrated that intermediate single session activity shortened to one third the global treatment time, with similar efficacy and a moderate increment of toxicity. Consequently, the increase of (131)I-MIBG activity, without reaching myeloablative levels, can be recommended for standard treatment of pheochromocytoma and paraganglioma patients.


Ultrafiltration Failure and Impaired Sodium Sieving During Long-Term Peritoneal Dialysis: More Than Aquaporin Dysfunction?
Fifteen years ago, our group reported the case of a 67-year-old man on peritoneal dialysis for 11 years, in whom ultrafiltration failure and impaired sodium sieving were associated with an apparently normal expression of aquaporin-1 (AQP1) water channels in peritoneal capillaries. At that time, AQP1 dysfunction was suggested as the cause of impaired free-water transport. However, recent data from computer simulations, and structural and functional analysis of the peritoneal membrane of patients with encapsulating peritoneal sclerosis, demonstrated that changes in the peritoneal interstitium directly alter osmotic water transport. In light of these insights, we challenge the initial hypothesis and provide several lines of evidence supporting the diagnosis of encapsulating peritoneal sclerosis in this patient and suggesting that severe peritoneal fibrosis accounted for the loss of osmotic conductance developed during the course of peritoneal dialysis.


Neuroendocrine function and associated mental health outcomes following mild traumatic brain injury in OEF-deployed service members.
Mild traumatic brain injury (mTBI) has been linked to mental health disorders (MHDs) and pituitary function alterations. Due to the complex relationship of mTBI, the neuroendocrine system, and MHDs, we propose that neuroendocrine dysfunction (NED) may play a role in negative long-term health outcomes. The goal of this study was to determine if blast-concussed service members (SMs) have a stronger likelihood of developing NED. We hypothesized that NED either pre- or post-injury is associated with poor mental and physical health outcomes. Serum samples from the Armed Forces Health Surveillance Branch were obtained from concussed (n = 59) and non-concussed (n = 72) SMs treated at the Concussion Restoration Care Center (CRCC) in Afghanistan. Serum was collected within 2 years prior to deployment and one or two times within 3 years following their CRCC visit. Samples were analyzed for luteinizing hormone (LH), testosterone, human growth hormone, cortisol, and prolactin to assess post-injury neuroendocrine function. Results indicate that SMs who incurred an mTBI exhibited long-term LH and testosterone deficiencies 3 years following injury compared to controls. Specifically, 47.6% of head-injured SMs displayed hypofunction in at least one of five hormones at 3 years post-injury. Anxiety disorders were the most common MHD observed in concussed SMs with hypopituitarism, while there was also a trend for SMs with chronic pituitary dysfunction to have MHD diagnoses. Findings indicate blast-related mTBI may be associated with long-term health outcomes following a period of incubation. Neuroendocrine screenings may increase treatment opportunities, inform rehabilitation strategies, and improve overall quality of life for patients.


Determination of alpha-adrenergic blocking potency.
Determination of the alpha-adrenergic blocking potency of drugs in humans is usually done by measuring the shift in the blood pressure versus logarithm of intravenous phenylephrine dose-response relationship. Change in blood pressure activates homeostatic reflexes that may change this relationship. This study examines the effect of autonomic (beta 1- and beta 2-adrenergic, parasympathetic, and alpha-adrenergic) blockade on the dose versus blood pressure response relationship to sequential doses of phenylephrine in humans. Phenylephrine dose responses were conducted under controlled conditions, during propranolol and atropine infusion, during prazosin-induced alpha 1-adrenergic blockade, and during prazosin, propranolol, and atropine administration. Propranolol-atropine infusion decreased the threshold dose of phenylephrine required to increase mean blood pressure (p less than 0.00001), increased the slope of the phenylephrine dose versus increase in mean blood pressure relationship (p = 0.019), and and decreased the dose of phenylephrine required to increase mean blood pressure by 20 mm Hg (p less than 0.00001). Determination of the alpha-adrenergic blocking potency of prazosin was not affected by autonomic blockade with propranolol and atropine (dose ratio 5.2 before and 5.0 after autonomic blockade; p = 0.465). We conclude that beta 1- and beta 2-adrenergic and muscarinic blockade increase sensitivity to phenylephrine by increasing the slope and decreasing the threshold dose of the phenylephrine dose-response curve, and that alpha-adrenergic-blocking potency of prazosin may be determined with or without blocking homeostatic blood pressure regulatory mechanisms in humans.


Cross-contamination with Salmonella on a broiler slaughterhouse line demonstrated by use of epidemiological markers.
To investigate contamination of surfaces on a poultry slaughter line from infected poultry and subsequent cross-contamination of non-infected poultry. A broiler slaughterhouse was investigated for the presence of Salmonella on 17 defined points over two 1-week periods. Flocks supplied to slaughter and neck skin samples from processed chicken were likewise investigated. Salmonella was detected in 10 out of 18 flocks at ante-mortem inspection, while seven flocks tested positive in the finished products. Equipment at all but one control point at the slaughter line tested positive at least once during the study. The chicken receiving area was the most contaminated. By comparison of typing results from serotyping, plasmid profile typing and phage typing, direct evidence for cross-contamination with Salm. serotype Typhimurium, Salm. Serotype 4.12:b:- and Salm. serotype Virchow on the slaughter line was obtained for four of the flocks. The cleaning procedure in place did not remove all Salmonella from the contaminated areas. Evidence for contamination of equipment on a slaughter line and subsequent cross-contamination to non-infected chicken was provided by typing methods. This study has provided detailed information on cross-contamination on a slaughter line by the use of phage typing and plasmid profiling. The study stresses the importance of controlling Salmonella in the primary production, as contamination of the equipment on the slaughter line will act as a vehicle to contaminate finished products. Cleaning procedures on slaughter lines cannot be expected to control this problem with the current equipment.


Impact of non-alcoholic fatty pancreas disease on glucose metabolism.
With the increasing global epidemic of obesity, the clinical importance of non-alcoholic fatty pancreas disease (NAFPD) has grown. Even though the pancreas might be more susceptible to ectopic fat deposition compared with the liver, NAFPD is rarely discussed because of the limitation of detection techniques. In the past, NAFPD was considered as an innocent condition or just part of clinical manifestations during the course of obesity. Recently, a growing body of research suggests that NAFPD might be associated with β-cell dysfunction, insulin resistance and inflammation, which possibly lead to the development of diabetes and metabolic syndrome. The present review summarized the current literature on the epidemiology, potential pathophysiology, diagnostic techniques, impact of NAFPD on β-cell function and insulin resistance, and the clinical relevance of the interplay between NAFPD and glucometabolic disorders.


Parenclitic networks for predicting ovarian cancer.
Prediction and diagnosis of complex disease may not always be possible with a small number of biomarkers. Modern 'omics' technologies make it possible to cheaply and quantitatively assay hundreds of molecules generating large amounts of data from individual samples. In this study, we describe a parenclitic network-based approach to disease classification using a synthetic data set modelled on data from the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) and serological assay data from a nested set of samples from the same study. This approach allows us to integrate quantitative proteomic and categorical metadata into a single network, and then use network topologies to construct logistic regression models for disease classification. In this study of ovarian cancer, comprising of 30 controls and cases with samples taken <14 months to diagnosis (n = 30) and/or >34 months to diagnosis (n = 29), we were able to classify cases with a sensitivity of 80.3% within 14 months of diagnosis and 18.9% in samples exceeding 34 months to diagnosis at a specificity of 98%. Furthermore, we use the networks to make observations about proteins within the cohort and identify GZMH and FGFBP1 as changing in cases (in relation to controls) at time points most distal to diagnosis. We conclude that network-based approaches may offer a solution to the problem of complex disease classification that can be used in personalised medicine and to describe the underlying biology of cancer progression at a system level.


Percutaneous placement of an implantable arm port through an internal mammary venous pathway: Case report.
Current chemotherapeutic regimens often require long-term central venous access for their administration. Obtaining a durable form of vascular access in patients with recurrent cancer can be a challenge due to direct tumor involvement and prior surgical, chemotherapeutic or radiation therapy. We describe a case of a peripherally inserted access port in a patient with recurrent head and neck cancer, in whom radiation therapy planned for metastatic mediastinal disease prevented placement of a chest port. At the time of port implantation, venography revealed central venous occlusion. Using mediastinal venography, a collateral pathway to the superior vena cava was identified between the left and right internal mammary veins. By employing this technique, an arm port system was successfully navigated through the collateral pathway percutaneously with the tip of the port tubing placed at the cavoatrial junction. This case illustrates technical nuances and emphasizes the importance of thorough venography when attempting to achieve difficult vascular access.


Renal hemodynamic responses to increased renal venous pressure: role of angiotensin II.
Studies were performed to quantitate the effects of progressive increases in renal venous pressure (RVP) on renin secretion (RS) and renal hemodynamics. RVP was raised in 10 mmHg increments to 50 mmHg. Renin secretion rate increased modestly as RVP was increased to 30 mmHg and then increased sharply after RVP exceeded 30 mmHg. Glomerular filtration rate (GFR), renal blood flow (RBF), and filtration fraction (FF) did not change significantly when RVP was elevated to 50 mmHg. GFR and RBF were also measured after the renin-angiotension system (RAS) was blocked with the angiotensin converting enzyme inhibitor (CEI) SQ 14225. After a 60-min CEI infusion, RBF was elevated (32%), GFR was unchanged, FF was decreased, and total renal resistance (TRR) was decreased. As RVP was increased to 50 mmHg, GFR and FF decreased to 36.3 and 40.0% of control, respectively, RBF returned to a value not significantly different from control, and TRR decreased to 44.8% of control. The data indicate that the RAS plays an important role in preventing reductions in GFR during increased RVP because blockade of angiotensin II (ANG II) formation by the CEI results in marked decreases in GFR at high RVPs. The decreases in GFR after ANG II blockade and RVP elevation were not due to lack of renal vasodilation, since TRR was maintained below while RBF was maintained either above or at the pre-CEI levels.


The relationship between anemia and quality of life in cancer patients.
Anemia is a common occurrence in patients with cancer, and especially in those who undergo chemotherapy. Traditionally, significantly decreased hemoglobin levels have been considered to be < or = 8 g/dl and have been associated with physiologic manifestations. More recent data have shown that milder anemia (hemoglobin levels 10-12 g/dl) has functional consequences as well. This article reviews several community-based studies that have analyzed changes in hemoglobin concentrations, transfusion requirements, and QOL parameters in anemic patients with cancer before and after treatment with epoetin alfa. The results of these studies have been consistent and show an increase in hemoglobin and a reduction in transfusion requirements when compared with baseline. Furthermore, a relationship between increasing hemoglobin levels and an improvement in QOL is suggested that is independent of tumor response. Additional studies are evaluating the optimal hemoglobin levels for the greatest incremental improvement in QOL.


Occult mood disorders in 104 consecutively presenting children referred for the treatment of attention-deficit/hyperactivity disorder in a community mental health clinic.
To ascertain the prevalence of mood disorders among consecutively evaluated prepubertal children presenting for the treatment of attention-deficit/hyperactivity disorder (ADHD) in a community mental health clinic. 104 children received systematic assessments designed to identify individuals meeting the DSM-IV criteria for major depressive disorder (MDD), mania, and ADHD. "Standard" and "modified" criteria for mania were employed. Modified criteria, in an effort to minimize false-positive diagnoses of mania, required the presence of euphoria and/or flight of ideas. A child meeting the criteria for MDD or either set of criteria for mania was categorized as having a mood disorder. Mood disorders in first-degree relatives were assessed using a systematic interview. Data were gathered from 2000 to 2002. Sixty-two children (59.6%) had a mood disorder. Compared with those who did not have a mood disorder, they were 3.3 times more likely (54.8% vs. 16.7%) to have a family history of any affective disorder (p <.0001) and 18.3 times more likely (43.5% vs. 2.4%) to have a family history of bipolar disorder (p <.0001). Twenty (32.3%) of the children with and none without a mood disorder had psychotic features (p <.0001). Compared with those meeting only the standard criteria for mania, those meeting the modified criteria were 9.1 times more likely (69.8% vs. 7.7%) to have a family history of an affective disorder (p <.0001) and 7.3 times more likely (55.8% vs. 7.7%) to have a family history of bipolar disorder (p =.002). Children who presumably have ADHD often have unrecognized affective illness. Our findings support the view that children meeting the modified criteria for mania have veritable bipolar disorder. These findings, which were derived in the course of delivering routine clinical services in a community mental health clinic, are consistent with those obtained in research settings suggesting that children presenting with ADHD often have occult mood disorders, especially unrecognized bipolarity. We suggest that clinicians encountering children with prominent features of ADHD inquire about the presence of euphoria and flight of ideas. We submit that the presence of these "classic" manifestations of mania strongly suggests the presence of occult bipolarity, even if course of illness otherwise markedly deviates from "classic" descriptions.


Abnormal platelet response to thromboxane A2.
To determine the pathogenetic mechanism of a hereditary primary platelet release disorder, arachidonic acid metabolism via the cyclooxygenase pathway was investigated. The propositus' platelets exhibited defective release reaction and second-wave aggregation when stimulated by sodium arachidonate or U46619, a thromboxane A2 (TXA2) agonist. The lack of platelet response to U46619 suggested that the defect was beyond the thromboxane synthetase level. Furthermore, thromboxane B2 (TXB2) formation in the propositus' platelets (558.52 ng/10(8) platelets) was within the normal range (574.29 +/- SD 27.39 ng/10(8) platelets) and TXA2 formation appeared to be adequate for aggregating normal platelets. The results were indicative of an abnormal platelet response to TXA2. Failure of the propositus' platelets to aggregate in response to TXA2 formed in normal platelet-rich plasma induced by arachidonate confirmed this notion. To gain further insight, platelet cyclic (c) AMP content was determined. Prostacyclin induced a significant elevation of the propositus' platelet cAMP level comparable to normal values. U46619 suppressed prostaglandin I2-induced cAMP elevation in normal subjects but had no such effect in the patient. We conclude that the primary release disorder observed in this kindred is due to an abnormal platelet respnse to TXA2 possibly because of TXA2/PGH2 receptor abnormalities.


Effects of respiratory muscle training on performance in athletes: a systematic review with meta-analyses.
The purpose of this study was to perform a systematic review to determine if respiratory muscle training (RMT) improves sport performance and respiratory muscle strength and endurance. Methodology followed the Cochrane Collaboration protocol. MEDLINE, CINAHL, SPORTDiscus, PEDro, EMBASE, EBM reviews, and COCHRANE electronic databases were searched until July 2011. Articles were included if: (a) participants were athletes; (b) RMT was compared with sham or control in a randomized controlled design and included outcomes of respiratory muscle and sport performance; and (d) published in English. Quality assessment using PEDro and data abstraction was performed by 2 authors. Outcomes evaluated were measures of sport performance, exercise capacity, spirometry, and respiratory muscle strength and endurance. Meta-analyses were performed on outcomes reported in 2 or more papers. Results of this systematic review revealed that of the 6,923 citations retrieved from the search strategy, 21 met the inclusion criteria. Meta-analyses demonstrated a significant positive effect of RMT on sport performance outcomes of time trials, exercise endurance time, and repetitions on Yo-Yo tests. Inspiratory muscle strength and endurance improved in most studies, which in part, was dependent on the type of RMT employed. Determination of the type of athlete that may benefit most from RMT was limited by small sample sizes, differing RMT protocols, and differences in outcome measures across studies. In conclusion, RMT can improve sport performance. Closer attention to matching the ventilatory demands of RMT to those required during athletic competition and more aggressive progression of training intensity may show greater improvements in future studies.


Adult Onset Still's Disease and Radiotherapy treatment for breast cancer: Case report about management of this rare association and literature review.
This manuscript focuses on the first experience in literature of a patient with a complicated Adult Onset Still's Disease-related heart failure who thereafter underwent adjuvant radiotherapy for left breast cancer. AOSD is a rare autoimmune inflammation-related disease, in which life-threatening pulmonary and cardiac complications can occur. In literature, AOSD is often associated with cancer, as paraneoplastic syndrome, but there are few data about primary AOSD and management of oncological therapies. A patient who needed adjuvant breast cancer radiotherapy underwent tumour board evaluation to define feasibility of an RT in a patient with of a history of a heart life-threatening complication 2 years before AOSD. Results of the review were discussed by a multidisciplinary panel of experts that chose the type of surgery, radiotherapy and monitoring of patient. Literature review confirmed association of AOSD with BC in some pts and uniqueness of this treatment management experience. Patient underwent RT according to schedule of 40.05/2.67 Gy/fx on residual left breast and 10/2 Gy/fx on tumour bed with the gating technique. The panel chose to keep immunosuppressive therapy with anakinra. No complications were observed at clinical, ECG and laboratory examinations. Maximum toxicity was G2 skin. At first follow up AOSD signs of flare were negative. In conclusion, when oncological treatments, especially radiotherapy, are mandatory for AOSD pts, multidisciplinary management and tailored monitoring are necessary to avoid acute adverse effects and allow pts to complete therapies.


Improving Contact Interfaces in Fully Printed Carbon Nanotube Thin-Film Transistors.
Single-walled carbon nanotubes (CNTs) printed into thin films have been shown to yield high mobility, thermal conductivity, mechanical flexibility, and chemical stability as semiconducting channels in field-effect, thin-film transistors (TFTs). Printed CNT-TFTs of many varieties have been studied; however, there has been limited effort toward improving overall CNT-TFT performance. In particular, contact resistance plays a dominant role in determining the performance and degree of variability in the TFTs, especially in fully printed devices where the contacts and channel are both printed. In this work, we have systematically investigated the contact resistance and overall performance of fully printed CNT-TFTs employing three different printed contact materials-Ag nanoparticles, Au nanoparticles, and metallic CNTs-each in the following distinct contact geometries: top, bottom, and double. The active channel for each device was printed from the dispersion of high-purity (>99%) semiconducting CNTs, and all printing was carried out using an aerosol jet printer. Hundreds of devices with different channel lengths (from 20 to 500 μm) were fabricated for extracting contact resistance and determining related contact effects. Printed bottom contacts are shown to be advantageous compared to the more common top contacts, regardless of contact material. Further, compared to single (top or bottom) contacts, double contacts offer a significant decrease (>35%) in contact resistance for all types of contact materials, with the metallic CNTs yielding the best overall performance. These findings underscore the impact of printed contact materials and structures when interfacing with CNT thin films, providing key guidance for the further development of printed nanomaterial electronics.


Loss of HLA-C locus specificities from stored lymphocytes and de novo synthesis following incubation at 37 degrees C.
The variable expression of the C locus specificities at the cell surface is a major problem in HLA typing and the phenomenon was clearly documented by the International Cell Exchange Program. In contrast with HLA-A and -B, the C locus specificities are readily lost from cells following storage at room temperature for a few days or in overnight incubation at 37 degrees C in the presence of protein synthesis inhibitors. These specificities can be made to reappear by making the cells metabolize at 37 degrees C for 8 to 20 h in nutrient medium. Sixty-nine per cent of the positive C locus reactions lost after 7-day storage at room temperature were recovered after overnight incubation at 37 degrees C. The reappearance was dependent on protein synthesis since presence of cyclohexamide during incubation completely blocked the recovery. A simple overnight incubation is very useful in enhancing C locus expression on older cells.


A practical model for economic evaluation of tissue-engineered therapies.
Tissue-engineered therapies are being developed across virtually all fields of medicine. Some of these therapies are already in clinical use, while others are still in clinical trials or the experimental phase. Most initial studies in the evaluation of new therapies focus on demonstration of clinical efficacy. However, cost considerations or economic viability are just as important. Many tissue-engineered therapies have failed to be impactful because of shortcomings in economic competitiveness, rather than clinical efficacy. Furthermore, such economic viability studies should be performed early in the process of development, before significant investment has been made. Cost-minimization analysis combined with sensitivity analysis is a useful model for the economic evaluation of new tissue-engineered therapies. The analysis can be performed early in the development process, and can provide valuable information to guide further investment and research. The utility of the model is illustrated with the practical real-world example of tissue-engineered constructs for corneal endothelial transplantation. The authors have declared no conflicts of interest for this article.


[The effectiveness of dynamic proprioceptive correction in patients with cerebral palsy with cognitive impairment].
One hundred and sixty-seven patients with cerebral palsy (CP), aged 11-16 years, with spastic diplegia (n=87) and hemiparetic forms (n=80), with subgroups of mental retardation (MR) or intellectual delay (ID) have been studied. Standard treatment and application of a method of dynamic proprioceptive correction (MDPC) in the complex rehabilitation with the use of a medical and loading Adeli suit were used. Cognitive deficit in patients was characterized by the relative integrity of short-term nonverbal memory and marked impairment of verbal memory, verbal and nonverbal intellect. CP patients with intellectual delay demonstrated the predominant impairment of verbal functions. CP patients with mental retardation have the deficiency of both verbal and non-verbal cognitive functions. An individual profile of brain functional asymmetry in patients with CP was more lateralized than in healthy peers that can represent a mechanism for irregular development of cognitive functions in CP. Implementing the MDPC into comprehensive rehabilitation promotes the improvement of postural regulation and cognitive functions in children with CP compared to traditional methods of treatment. This is accompanied by the changes in functioning of the associative brain areas and hemispheric interaction.


Inflammatory cells in tissues of gout patients and their correlations with comorbidities.
The major pathological finding of gout is the deposition of monosodium urate monohydrate (MSU) crystals with inflammatory infiltrate in the tissue. There have been many reports of in vitro analysis of inflammatory mechanism and comorbidities in gout. However, the associations of immune response cells and comorbidities of gout have not been well documented. Our studies aimed to examine the immune cell types and quantity in gout tissues, and to define the association of individual cell type with comorbidities. Surgically resected or biopsied tissues from 48 patients diagnosed as gout were used for this study. Cell count was performed on Hemotoxylin and Eosin stained sections for macrophages, plasma cells, neutrophils and on immunostained slides for T and B lymphocytes. Hyperlipidemia, hypertension and diabetes mellitus were seen in 70.8%, 87.5% and 37.5% of patients, respectively. There were 35.6% and 37.8% of patients who admitted history of smoking and alcohol intake, respectively. Mean serum uric acid level was 8.5 mg/dl. The average body mass index was 30.1 kg/m(2). H&E stained tissue sections demonstrated the crystalline deposits rimmed by palisading multinucleated giant cells, macrophages, neutrophils, plasma cells, T and B cells. Significant correlations between the clinical features and tissue inflammatory cells were observed in hyperlipidemia with number of T cells (p = 0.0363), hypertension with number of T cells and B cells (p = 0.0138 and 0.0033, respectively), diabetes mellitus with macrophages (p = 0.0016), and uric acid level with giant cells (p = 0.0088). Comorbidity factors including hyperlipidemia, hypertension and diabetes are significantly associated with the inflammatory cells in the tissues.


Erdheim-Chester disease presenting with cough, abdominal pain, and headache.
Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytic disorder. The diagnosis was based on the relationship between radiologic findings, clinical manifestations, and pathologic features of the bone biopsy. We report a case of ECD with unusual presenting symptoms: a 56 year-old man presented with cough, abdominal pain, and recurrent episodes of headache associated without any seizures. Peculiar computer tomography (CT) findings were key for the diagnostic suspicion. Bone biopsy and other radiological investigations confirmed the diagnosis. CT findings can help raise the suspicion of ECD. CT is easy to perform and widely available in comparison with kinetic cardiac magnetic resonance imaging and nuclear imaging. Therefore, CT findings of ECD can reduce the therapeutic delay between diagnosis and therapy prescription.


Radiation sensitization of glioblastoma by cilengitide has unanticipated schedule-dependency.
We investigated whether cilengitide could amplify the antitumor effects of radiotherapy in an orthotopic rat glioma xenograft model. Cilengitide is a specific inhibitor of alphav series integrins, and acts as an antiangiogenic. U251 human glioma cells express alphavbeta3 and alphavbeta5 integrins. We used in vitro assays of adhesion and growth of tumor and endothelial cells to evaluate cytotoxicity and the potential for cilengitide to enhance radiation toxicity. Treatment was then evaluated in an orthotopic model to evaluate synergy with therapeutic radiation in vivo. In vitro, cilengitide blocked cell adhesion, but did not influence the effects of radiation on U251 cells; cilengitide strongly amplified radiation effects on endothelial cell survival. In vivo, radiotherapy prolonged the survival of U251 tumor-bearing rats from 50 to over 110 days. Cotreatment with cilengitide and radiation dramatically amplified the effects of radiation, producing survival over 200 days and triggering an enhanced apoptotic response and suppression of tumor growth by histology at necropsy. Signaling pathways activated in the tumor included NFkappab, a documented mediator of cellular response to radiation. Because cilengitide has a short plasma half-life (t((1/2)) approximately 20 min), antiangiogenic scheduling typically uses daily injections. We found that a single dose of cilengitide (4 mg/kg) given between 4 and 12 hr prior to radiation was sufficient to produce the same effect. Our results demonstrate that blockade of alphav integrins mediates an unanticipated rapid potentiation of radiation, and suggests possible clinical translation for glioma therapy.


Chorea-acanthocytosis: A Case Report with Review of Oral Manifestations.
Chorea-acanthocytosis (ChAc) is an autosomal recessive, progressive neurological disorder due to mutation in VPS13A gene causing defects in sorting of protein making the cell membrane unstable, leading to star-shaped erythrocytes. This neurological disorder includes features such as elevated creatinine kinase, atrophy of basal ganglia, and oral manifestations such as frequent cheek and tongue biting. It is a rare neurological condition with an estimate of <1000 cases worldwide. A case of 47-year-old male patient with a history of seizures and neurological problems presenting with oral ulceration has been discussed. The diagnosis of ChAc was confirmed by molecular investigations showing VPS13A gene mutation. The physical appearance includes chorea and dystonia with impaired gait. We attempt to highlight the oral features of ChAc. The oral manifestations include frequent tongue and cheek biting occurring due to dystonia affecting the muscles of head and neck region.


Detecting circulating tumor cells: current challenges and new trends.
Circulating tumor cells (CTCs) in the blood stream play a critical role in establishing metastases. The clinical value of CTCs as a biomarker for early cancer detection, diagnosis, prognosis, prediction, stratification, and pharmacodynamics have been widely explored in recent years. However, the clinical utility of current CTC tests is limited mainly due to methodological constraints. In this review, the pros and cons of the reported CTC assays are comprehensively discussed. In addition, the potential of tumor cell-derived materials as new targets for CTC detection, including circulating tumor microemboli, cell fragments, and circulating DNA, is evaluated. Finally, emerging approaches for CTC detection, including telomerase-based or aptamer-based assays and cell functional analysis, are also assessed. Expectantly, a thorough review of the current knowledge and technology of CTC detection will assist the scientific community in the development of more efficient CTC assay systems.


[Allergic rhinitis in children and adults - international recommendations adapted to the clinical situation in Sweden].
Allergic rhinitis is the most common chronic disease in Sweden, with impact on quality of life and with a heavy economic burden for the society. More than 20 years have passed since national recommendations were launched, and meanwhile both ARIA (Allergic rhinitis and its impact of asthma) and EUFOREA (The European Forum for Research and Education in Allergy and Airway Diseases) have presented international guidelines which in this article have been adapted to the clinical situation in Sweden. Visual analogue scale (VAS) is recommended for symptom evaluation, and the importance of correct allergen analysis and examination for coexisting asthma is emphasized. Treatment is recommended according to EUFOREA. Follow-up is important, and if VAS is ≥5 the disease is regarded as uncontrolled and must lead to a change of treatment. Since self-treatment is common in allergic rhinitis the importance of patient cooperation and information is underlined.


Transdermal iontophoretic peptide delivery: in vitro and in vivo studies with luteinizing hormone releasing hormone.
Protein and peptide drugs are not orally active. Their large molecular size and charged character make them poor candidates for passive transdermal delivery. With an applied electromotive force, these drugs can be forced through the skin to be absorbed by the systemic circulation. The present study investigates the transdermal iontophoretic delivery of a peptide hormone in an in vitro model system, the isolated perfused porcine skin flap, as well as in vivo. It is shown that with knowledge of the systemic disposition of the drug, transdermal fluxes can be utilized to accurately predict in vivo serum concentrations. It is also shown that the iontophoretically delivered hormone retains both its immunologic and biologic activity.


Minimum variance brain source localization for short data sequences.
In the electroencephalogram (EEG) or magnetoencephalogram (MEG) context, brain source localization methods that rely on estimating second-order statistics often fail when the number of samples of the recorded data sequences is small in comparison to the number of electrodes. This condition is particularly relevant when measuring evoked potentials. Due to the correlated background EEG/MEG signal, an adaptive approach to localization is desirable. Previous work has addressed these issues by reducing the adaptive degrees of freedom (DoFs). This reduction results in decreased resolution and accuracy of the estimated source configuration. This paper develops and tests a new multistage adaptive processing technique based on the minimum variance beamformer for brain source localization that has been previously used in the radar statistical signal processing context. This processing, referred to as the fast fully adaptive (FFA) approach, can significantly reduce the required sample support, while still preserving all available DoFs. To demonstrate the performance of the FFA approach in the limited data scenario, simulation and experimental results are compared with two previous beamforming approaches; i.e., the fully adaptive minimum variance beamforming method and the beamspace beamforming method. Both simulation and experimental results demonstrate that the FFA method can localize all types of brain activity more accurately than the other approaches with limited data.


Barriers to the use of preventive health care services for children.
This article describes findings from interviews of parents targeted for outreach efforts that encouraged them to use Medicaid's Early and Periodic Screening, Diagnosis and Treatment(EPSDT) Program. Begun in the 1970s, the EPSDT program held out the promise of ensuring that needy children would receive comprehensive preventive care. With only one-third of eligible children in the United States receiving EPSDT checkups, the program has yet to fulfill its promise. This study sought to understand parents' perceptions of barriers to using EPSDT by interviewing (a) 110 parents who did not schedule EPSDT checkups for their children after being exposed to outreach efforts and (b) 30 parents who did. Although the EPSDT Program is designed to provide health care at no charge and to provide assistance with appointment scheduling and transportation, these low-income parents identified significant barriers to care. Reasons for not using EPSDT services included (a) competing family or personal issues and priorities; (b) perceived or actual barriers in the health care system; and (c) issues related directly to problems with the outreach efforts. Parents who successfully negotiated these barriers and received EPSDT services encountered additional barriers, for example, scheduling and transportation difficulties, long waiting room times, or care that they perceived to be either unresponsive to their medical needs or interpersonally disrespectful. The implications for future outreach efforts and improving access to preventive health care services are discussed.


[Effect of bilirubin and serum albumin on the Na,K-ATPase activity in the synaptosomal membrane].
The absorption spectrum of visible light, characteristic of the free bilirubin being in the aqueous medium, with a single maximum at 440 nm and with the shoulder in the region of 410-420 nm is transformed into the spectrum with two maxima in the region of 460 and 500 nm, respectively, when the pigment is bound in vitro by the synaptosomal membrane. There are two types of sites for bilirubin binding in the membrane particles, differing in the values of constants of association (Ka = 0.6 . 10(5) and approximately 2.02 . 10(5) M-1, respectively) and in the values of the maximum binding of bilidiene (5.0 and 7.0 nmoles/mg of membrane proteins, respectively). The binding of bilirubin by the synaptosomal membrane leads to a decrease in the specific activity of the membrane Na+,K+-ATPase. The enzyme activity is further decreasing when suspension of the membrane particles is exposed to the blue light (lambda max = 450-460 nm) in the presence of bilirubin. The addition of the serum albumin into the incubation medium potentiates the inhibition effect of bilirubin, when the suspension of membrane particles is lighted in the presence of bilirubin. The alkalization of the medium up to pH 7.8 (from pH 7.2) removes this potentiation effect of the addition of serum albumin.


Understanding How Experts Do It: A Conceptual Framework for the Open Transversus Abdominis Release Procedure.
The safe and effective performance of a posterior component separation via a transversus abdominis release (TAR) requires intraoperative judgement and decision-making skills that are difficult to define, standardize, and teach. We herein present the first qualitative study which builds a framework upon which training and objective evaluation of a TAR can be based. Hierarchical and cognitive task analyses for a TAR procedure were performed using semistructured interviews of hernia experts to describe the thoughts and behaviors that exemplify optimal performance. Verbal data was recorded, transcribed, coded, and thematically analyzed. A conceptual framework was synthesized based on literary sources (4 book chapters, 4 peer-reviewed articles, 3 online videos), 2 field observations, and interviews of 4 hernia experts [median 66 minutes (44-78)]. Subject matter experts practiced a median of 6.5 years (1.5-16) and have completed a median of 300 (60-500) TARs. After 5 rounds of inductive analysis, 80 subtasks, 86 potential errors, 36 cognitive behaviors, and 17 decision points were identified and categorized into 10 procedural steps (midline laparotomy, adhesiolysis, retrorectus dissection, etc.) and 9 fundamental principles: patient physiology and disease burden; tactical modification; tissue reconstruction and wound healing; task completion; choice of technique and instruments; safe planes and danger zones; exposure, ergonomics, environmental limitations; anticipation and forward planning; and tissue trauma and handling. This is the first study to define the key tasks, decisions, and cognitive behaviors that are essential to a successful TAR procedure.


Contraception for adolescents.
A working knowledge of contraception will assist the pediatrician in both sexual health promotion as well as treatment of common adolescent gynecologic problems. Best practices in adolescent anticipatory guidance and screening include a sexual health history, screening for pregnancy and sexually transmitted infections, counseling, and if indicated, providing access to contraceptives. Pediatricians' long-term relationships with adolescents and families allow them to help promote healthy sexual decision-making, including abstinence and contraceptive use. Additionally, medical indications for contraception, such as acne, dysmenorrhea, and heavy menstrual bleeding, are frequently uncovered during adolescent visits. This technical report provides an evidence base for the accompanying policy statement and addresses key aspects of adolescent contraceptive use, including the following: (1) sexual history taking, confidentiality, and counseling; (2) adolescent data on the use and side effects of newer contraceptive methods; (3) new data on older contraceptive methods; and (4) evidence supporting the use of contraceptives in adolescent patients with complex medical conditions.


Mirabegron: β3-adrenergic receptor agonist for the treatment of overactive bladder.
To review the place in therapy of mirabegron, a new oral β3-adrenergic receptor agonist, for the treatment of overactive bladder (OAB). A literature search of MEDLINE and MEDLINE In-Process & Other Non-Indexed Citations Databases (1996-April 2013) was conducted using the key words mirabegron, receptor, adrenergic, beta-3; adrenergic beta-3 receptor; beta-3 receptor, and overactive bladder; urinary bladder; overactive. All published articles regarding mirabegron were included. References of selected articles, data from poster presentations, and abstract publications were additionally reviewed. Available English-language data from reviews, abstracts, presentations, and clinical trials of mirabegron in humans were reviewed; relevant clinical data were selected and included. Mirabegron is the newest option for treatment of OAB with symptoms of urge incontinence. As a β3-receptor agonist, it reduces bladder muscle contractions. In two 12-week, randomized, double-blind, placebo-controlled Phase 3 studies, mirabegron significantly reduced the number of incontinence episodes per 24 hours from baseline (-1.47, -1.63, and -1.13; p < 0.05; and -1.57, -1.46, and -1.17; p < 0.05; all values for mirabegron 50 mg, 100 mg, and placebo). Micturitions per 24 hours were also reduced from baseline (-1.66, -1.75, and -1.05; p < 0.05; and -1.93, -1.77, and -1.34; p < 0.05; all values for mirabegron 50 mg, 100 mg, and placebo). A 12-month trial found mirabegron to have a safety and efficacy profile similar to that of tolterodine. Treatment of OAB initially includes lifestyle and nonpharmacologic intervention; for patients with persistent symptoms despite these treatments, drug therapy represents a next-step approach for symptom control. Mirabegron alleviates symptoms of OAB while having a mechanism of action that provides an alternative for patients who are intolerant of or who have contraindications to anticholinergic agents. The place in therapy of mirabegron relative to anticholinergics in the treatment of urge incontinence has not yet been established.


[Determination of the cell count in sheep's milk].
A prospective study was done to examine the extent to which the 'regulation concerning the method of examining milk using the Coulter counter' was also applicable to sheep's milk. This was found to be the case, provided the milk is previously mixed with a Vortex mixer for 0.5 minutes. In view of the studies done by others, the threshold value was reduced to 4.5 mu. The levels recorded by this method were readily reproducible. Any statement regarding the relationship between the cell counts recorded and the cells actually present in the milk cannot be based on these studies.


Substance MCS-18 isolated from Helleborus purpurascens is a potent antagonist of the capsaicin receptor, TRPV1, in rat cultured sensory neurons.
Extracts of Helleborus roots were traditionally used in the Balkan area for their analgesic action. We report that the pure natural product MCS-18 isolated from this source is a potent, specific and reversible antagonist of the capsaicin receptor, TRPV1, expressed in rat dorsal root ganglion (DRG) neurons. TRPV1 is a non-selective cation channel expressed in a subset of cutaneous and visceral sensory nerve endings and activated by noxious heat, acidity and fatty acid metabolites of arachidonic acid, with a decisive role in inflammatory heat hyperalgesia. MCS-18 inhibited the increase in intracellular calcium concentration evoked in DRG neurons by capsaicin (300 nM) and low pH (5.5) but not by heat (43 degrees C). The substance had no effect on the responses mediated by acid-sensing ion channels (ASICs) or the irritant receptor TRPA1. Whole-cell patch-clamp was used to confirm the inhibition of capsaicin-induced currents by MCS-18 which was dose-dependent. The mechanism of inhibition does not require an intact cell, as capsaicin-induced currents were also inhibited in the excised outside-out configuration. The antagonism of the capsaicin and proton action on native TRPV1 by MCS-18 may be of interest for pain therapy.


Adrenergically induced renin release in conscious indomethacin-treated dogs and rats.
To investigate the role of endogenous prostaglandins in renin release stimulated via adrenergic pathways, isoproterenol, norepinephrine (NE) and NE in the presence of phentolamine (PTA) were infused into conscious sodium-replete rats and dogs. Isoproterenol (1 microgram.kg-1.min-1) infusion into intact rats increased plasma renin activity (PRA) eightfold. AFter pretreatment with the prostaglandin (PG) cyclooxygenase inhibitor indomethacin (5 mg/kg), isoproterenol increased PRA 16-fold. In dogs, isoproterenol (0.4 microgram.kg-1.min-1) increased PRA six-fold before indomethacin and 11-fold during PG inhibition. Infusion of NE into both rats (250 ng.kg-1.min-1) and dogs (1 microgram.kg-1.min-1) failed to increase PRA before indomethacin, but during inhibition of PG synthesis NE increased PRA in both species. During partial alpha-adrenergic blockade with PTA in dogs, PTA alone increased PRA by 38% and NE given during PTA infusion increased PRA further both before indomethacin by twofold and during PG inhibition by fivefold. In rats given NE during PTA infusion, PRA increased only after indomethacin injection. Additionally, in dogs the renin responses to these adrenergic agents were even greater after indomethacin administration than before the drug. These results in both conscious rats and dogs give no indication that renal prostaglandins mediate the renin response to adrenergic stimulation.


Evaluating STC2 gene RNA in peripheral blood serum of gastric cancer patients.
Cancer is one of the leading causes of death in the world. Invasive microscopic and endoscopic methods are not suitable for routine screening of gastric cancer. Therefore, the need for biomarkers that can detect quickly, efficiently, and with high sensitivity in the early stages of cancer is strongly felt. Stanniocalcin plays a role in regulating calcium and phosphorus in the body. In addition, it plays a role in neuron cell differentiation, angiogenesis, wound healing, fertility and embryo development, and cancer. This study investigated the level of expression of the Stanniocalcin 2 (STC2) gene in the serum of patients with gastric cancer. This case-control study was conducted on the samples of 60 patients with gastric cancer (cases) and 60 healthy individuals (controls). Peripheral blood samples from gastric cancer patients and volunteers as control groups were collected in tubes containing EDTA anticoagulant and were immediately subjected to serum separation. After centrifugation, serum RNA was extracted, and after cDNA synthesis, STC2 gene serum RNA level was measured by the Taq Man method and Real-time PCR using specific primers and probes. Then, the results of serum evaluations and clinicopathological information of patients and control group were collected along with the information obtained from reviewing patients' files and demographic findings, regulatory tables, and related charts. SPSS22 software was used to analyze descriptive data. According to the study results, the high expression of the STC2 gene was 31 cases in the case group and 13 cases in the control group. However, there was a significant relationship between the high expression of the STC2 gene and gastric cancer (p = 0.0001). However, there was no significant relationship between the gender of patients and high expression of the STC2 gene. However, the age of 35% of the patients was more than 65 years, and there was a significant relationship between the age of the patients and the high expression of the STC2 gene (P = 0.028). Although there was no significant relationship between the anatomical location of the cancer and the subtypes of the cancer and the high expression of the STC2 gene, there was a significant relationship between the degree of cancer differentiation and the high expression of STC2 gene (P<0.05). In general, STC2 can be used as a biomarker to determine the border and margins of the tumor. Analysis of STC2 gene expression during surgery can reduce surgical error in tumor removal and increase the success of surgery for tumor removal.


Production of collagenase inhibitor by the growth cartilage of embryonic chick bone: isolation and partial characterization.
Production of collagenase and collagenase inhibitors by the explants of epiphyseal, metaphyseal and diaphyseal regions of embryonic chick limbs during development has been investigated. Collagenase-inhibitory activity was first detected in the culture medium of the diaphyseal region of limbs at stage 36 where cartilage matrix erosion began to occur. However, neither active nor latent collagenase was detected in the media of any regions examined. At stage 38 and later, the maximum production of the inhibitory activity was observed in the explants of metaphyseal region (growth cartilage), while collagenase production was only in the diaphyseal region. Two collagenase inhibitors were isolated and purified approximately 150 fold from the culture medium of stage 38 and 43 metaphyseal regions of limbs by anion- and cation-exchange chromatography followed by gel filtration. The inhibitors are cationic proteins with the same molecular weight of approximately 25,000, but slight difference in molecular charge. They are heat-stable and inhibit collagenases from tadpole skin, chick bone and skin and human granulocytes and gelatinases from human granulocytes and chick skin as well as trypsin, but not Clostridium histolyticum collagenase. A possible function of the inhibitors in multistep regulations of the collagen-degrading enzyme system at the region of osteo-chondral transition is discussed.


Regulation of CD95 ligand expression: a key element in immune regulation?
Peripheral deletion of activated T cells has an important function in the regulation of the extent of an immune response. Upon restimulation through the T cell receptor previously stimulated cells have been shown to die by activation-induced cell death. Recent data indicate that this process is mediated by a CD95 (Fas/APO-1)/CD95 ligand interaction which induces apoptosis of the T cell. CD95 ligand (CD95-L) is absent on unactivated T cells but is readily expressed upon stimulation. Here we discuss evidence that CD95-L expression is induced by T cell receptor-mediated signals and is regulated at different levels. Different inhibitors of activation-induced cell death have been found to directly or indirectly act on the signal transduction pathway leading to CD95-L expression. CD95-L seems not only to be induced in T cells after activation but is also found constitutively expressed in many non-lymphoid tissues. This indicates that CD95-L is not only critically involved in activation-induced T cell death, but may have other functions as well. One such function is in the maintenance of immunological privilege, the protection of some tissues from potentially destructive immune responses. Thus, the regulation of CD95 expression in lymphoid and non-lymphoid cells appears to represent a key element in immune regulation.


Healthcare Costs of Treating Privately Insured Patients with Acute Myeloid Leukemia in the United States from 2004 to 2014: A Generalized Additive Modeling Approach.
The primary objective of this study was to predict healthcare cost trajectories for patients with newly diagnosed acute myeloid leukemia (AML) receiving allogeneic hematopoietic cell transplantation (alloHCT), as a function of days since chemotherapy initiation, days relative to alloHCT, and days before death or last date of insurance eligibility (LDE). An exploratory objective examined patients with AML receiving chemotherapy only. We used Optum's de-identified Clinformatics® Data Mart Database to construct cumulative cost trajectories from chemotherapy initiation to death or LDE (through 31 December 2014) for US patients aged 20-74 years diagnosed between 1 March 2004 and 31 December 2013 (n = 187 alloHCT; n = 253 chemotherapy only). We used generalized additive modeling (GAM) to predict expected trajectories and bootstrapped confidence intervals (CIs) at user-specified intervals conditional on dates of alloHCT and death or LDE relative to chemotherapy initiation. Expected costs (in 2017 values) for a hypothetical patient receiving alloHCT 60 days after chemotherapy initiation and followed for 5 years were $US572,000 (95% CI 517,000-633,000); $US119,000 (95% CI 51,000-192,000); $US102,000 (95% CI 0-285,000); $US79,000 (95% CI 0-233,000), for years 1-4, respectively, and either $US494,000 (95% CI 212,000-799,000) or $US108,000 (95% CI 0-230,000) in year 5, whether the patient died or was lost to follow-up on day 1825, respectively. Rates of cost accrual varied over time since chemotherapy initiation, with accelerations around the time of alloHCT and death. GAM is a potentially useful approach for imputing longitudinal costs relative to treatment initiation and one or more intercurrent, clinical, or terminal events in randomized controlled trials or registries with unrecorded costs or for dynamic decision-analytic models.


The waste ban in China: what happened next? Assessing the impact of new policies on the waste management sector in China.
The 2017 ban on the waste import and new policies for the waste management sector in mainland China had wide-spread impact. After decades of poor environmental and public health impacts from the sector, a study is needed which focuses on policies updates and waste management. This provides a direction for the survival of local waste management industries and consider similarities with the ban promulgated in China on the restriction of waste import from other countries. We review the waste management situation in China before national legislation prevented the import of waste, highlight the status of landfill mining in China, and review the dynamics of domestic policies before and after the promulgation of the ban in China. The impact of the COVID19 pandemic on the waste management system is starting to emerge, providing both challenges and opportunities for the sector in China. We see the impact of the ban on the range of imported waste and domestically generated materials. The ban results in price increases for domestic recycling that forces companies to introduce more formal recycling processes and to drive the consumption behaviours to more reasonable and environmentally friendly options. The driver in China is to reduce pollution in the environment and improve health, but a negative impact has been from increased landfill mining which has impeded the original aim of the waste ban and requires further technological development. The dynamic of domestic policies in China shows higher level of activity of updates and revisions or introduction of new policies from 2015 onwards and the concept of 'zero waste cities' brings new hope for improvement of the Chinese waste management system. The pandemic also suggests an important step to establish sustainable management systems despite evidence of increased "fly-tipping". The rebound of the waste ban may have stimulated in the short term negative impacts on local environments both in China and internationally.


Use of bone anchors in perineal hernia repair: a practical note.
Bone anchoring systems are used extensively in orthopaedic surgery but have scarcely been reported as useful in abdominal wall or perineal hernia repair. After coccygectomy or sacrectomy the development of bowel herniation is not uncommon. Considering repair of such a perineal hernia, adequate fixation of the prosthetic mesh is difficult and, therefore, recurrence is rather frequent, mostly due to insufficient anchoring of the mesh to the bony structures. We discuss a patient in which the Mitek GII anchoring system was used to overcome the problem of soft-tissue-to-bone attachment in such cases. Bone anchoring systems seem to be an efficient method to overcome the problems of soft-tissue-to bone attachment in both abdominal and perineal hernia repair.


Dexamethasone and Clonidine, but not Epinephrine, Prolong Duration of Ropivacaine Brachial Plexus Blocks, Cross-Sectional Analysis in Outpatient Surgery Setting.
The primary aim of this study is to determine the effect of adding dexamethasone, clonidine or both with and without epinephrine to ropivacaine and bupivacaine brachial plexus blocks. Observational study of prospectively collected data. Single academic outpatient surgery center. We evaluated 5,515 patient entries who received brachial plexus block (BPB). Multiple, rescue, unsuccessful, and distal nerve blocks of the upper extremity were excluded. The duration was calculated from the time the block was performed until the resolution of the block by patient report. Block durations were compared using Analysis of Variance. After exclusions, 3,706 nerve blocks were analyzed. The median concentration of ropivacaine used was 0.5%. Both clonidine and dexamethasone significantly increased block duration by 1.1 and 3.0 hours, respectively. Combining clonidine and dexamethasone with ropivacaine increased block duration by 6.2 hours (p<0.001) when compared to ropivacaine alone. Dexamethasone and Clonidine increased block duration by 5.2 hours (p<0.001) when compared to clonidine alone and by 3.2 hours (p<0.001) compared to dexamethasone alone. The addition of epinephrine to any of the adjuvants made no statistically significant difference to the duration of action except when it was added to dexamethasone. For brachial plexus blocks, epinephrine did not affect the duration of analgesia when added to ropivacaine. Epinephrine did not enhance the observed increase of block duration induced by clonidine or the combination of clonidine and dexamethasone. The most block duration enhancement was observed when combination of clonidine and dexamethasone were added to ropivacaine.


Total daily energy expenditure relative to resting energy expenditure in clinically stable patients with COPD.
An elevated resting energy expenditure (REE) commonly occurs in patients with chronic obstructive pulmonary (COPD). The purpose of this study was to investigate the effect of an increased REE on total daily energy expenditure (TDE) in 20 patients with COPD (19 men) with mean (SD) forced expiratory volume in one second of 37 (14)% predicted. TDE was measured over a two week interval using doubly labelled water. Fat-free mass (FFM) was calculated from total body water assessed by deuterium dilution. REE was measured by indirect calorimetry using a ventilated hood system. The patients (10 men) with a significantly higher REE than those with a normal REE (median difference 205 kcal/ 24 h, p < 0.05) had a comparable TDE (hypermetabolic at rest: median 2593; range 2127-3083 kcal/24 h, normometabolic at rest: median 2629; range 2032-3179 kcal/ 24 h). There was no difference in mean daily heart rate (HR) between the groups (hypermetabolic at rest: median 92 (range 82-98), normometabolic at rest: median 98 (range 75-116) beats/min) or in the variation in the heart rate during the day. By means of multiple regression analysis it was shown that REE did not correlate significantly with TDE when FEM was taken into account. This study shows that there is no significant difference in free living TDE between clinically stable patients with COPD with a normal REE and those with an increased REE. The variation in TDE in patients with COPD appears to reflect differences in energy expenditure for activities, but not differences in REE.


DNA polymerase epsilon encoded by cdc20+ is required for chromosomal DNA replication in the fission yeast Schizosaccharomyces pombe.
DNA polymerase II (PolII), the homologue of mammalian DNA polymerase epsilon, is essential for chromosomal DNA replication in the budding yeast Saccharomyces cerevisiae and also participates in S-phase checkpoint control. An important issue is whether chromosomal DNA replication in other eukaryotes, including the fission yeast Schizosaccharomyces pombe--in which the characteristics of replication origins are poorly defined--also requires DNA polymerase epsilon. It has been shown that DNA polymerase epsilon is not required for the in vitro replication of SV40 DNA by human cell extracts. We have cloned and sequenced S. pombe pol2+, which is identical to the cell-cycle gene cdc20+, encoding the catalytic polypeptide of DNA polymerase epsilon (Pol epsilon). The predicted amino acid sequence of Pol epsilon is highly homologous to that of S. cerevisiae PolII and human Pol epsilon. Consistent with this, the Pol epsilon polypeptide was recognized by polyclonal antibodies against S. cerevisiae PolII holoenzyme (PolII*). The terminal morphology of cells containing the disrupted pol2 gene was similar to that of DNA replication mutant cells and cdc20 mutant cells. Furthermore, the Pol epsilon activity from temperature-sensitive S. pombe cdc20 mutant cells was temperature-sensitive, and chromosomal DNA replication in the mutant cells was inhibited at the restrictive temperatures. These data strongly suggest that Pol epsilon is required for normal chromosomal DNA replication in S. pombe, as is PolII in S. cerevisiae. Thus, eukaryotic chromosomal DNA is replicated differently from that of viral SV40 DNA.