Forrest 11 bleeding: indications for treatment and results of laser therapy.
Ulcers with stigmata of recent hemorrhage (SRH) but without evidence of active bleeding (Forrest 11 bleeding) are a common endoscopic finding in patients with upper gastrointestinal bleeding. This study considers the problem of identifying patients in this group at risk of further bleeding and death. The high incidence of rebleeding in patients with visible vessel and the low incidence in patients with other SRH or no SRH suggest that endoscopic therapy in the absence of active bleeding is best limited to patients with visible vessels in ulcers that have recently bled. Evidence from controlled trials of laser therapy is presented which suggests that laser therapy can reduce the incidence of rebleeding in such patients with visible vessel.


[Dominant lethal test in mice with repeated application of cadmium chloride].
Reported in this paper are results obtained from a dominant lethal test, following five-day application of CdCl2 (0,3 and 30 mg/kg) to mice. An effort has been made to enhance the informative value of the test by combining histological with teratological examinations. Average loss per female was increased (r < 0,05) in the mating intervals between the 31st and 35th as well as the 36th and 40th days (30 mg/kg) and between the 45th and 48th days after treatment (3.0 and 30 mg/kg). Severe retardation as well as an exencephalocele and histologically detectable changes in the semilunal tubules were some of the conspicuous findings. The coincidence in time of the above phenomena has been considered as evidence to at least moderately mutagenic action of cadmium chloride.


The impact of the highmark employee wellness programs on 4-year healthcare costs.
To determine the return on investment (ROI) of Highmark Inc.'s employee wellness programs. Growth curve analyses compared medical claims for participants of wellness programs versus risk-matched nonparticipants for years 2001 to 2005. The difference was used to define savings. ROI was determined by subtracting program costs from savings and alternative discount rates were applied in a sensitivity analysis. Multivariate models estimated health care expenses per person per year as $176 lower for participants. Inpatient expenses were lower by $182. Four-year savings of $1,335,524 compared with program expenses of $808,403 yielded an ROI of $1.65 for every dollar spent on the program. Using sophisticated methodology, this study suggests that a comprehensive health promotion program can lower the rate of health care cost increases and produce a positive ROI.


Hierarchical phenomena in multicomponent liquids: simulation methods, analysis, chemistry.
Complex, multicomponent, solutions have often been studied solely through the lens of specific applications of interest. Yet advances to both simulation methodologies (enhanced sampling, etc.) and analysis techniques (network analysis algorithms and others), are creating a trove of data that reveal transcending characteristics across vast compositional phase space. This perspective discusses technical considerations of the reliable and accurate simulations of complex solutions, followed by the advances to analysis algorithms that elucidate coupling of different length and timescale behavior (hierarchical phenomena). The different manifestations of hierarchical phenomena are presented across an array of solution environments, emphasizing fundamental and ongoing science questions. With a more advanced molecular understanding in hand, a quintessential application (solvent extraction) is discussed, where significant opportunities exist to re-imagine the technical scope of an established technology.


Effects of castration-induced visceral obesity and antioxidant treatment on lipid profile and insulin sensitivity in New Zealand white rabbits.
Molecular mechanisms, responsible for the impaired insulin-sensitivity state due to the obesity are not fully understood in both humans and animals. The purpose of this study was to investigate the effects of castration-induced visceral obesity and the influence of two antioxidants on constituents of blood lipid profile and insulin sensitivity in New Zealand white rabbits. Twenty-six clinically healthy male New Zealand white rabbits were used in the experiment and were divided into 3 groups: first group (CI, n=7) - castrated-obese and treated with antioxidants "Immunoprotect" for 2months; second group (CO, n=7) - castrated-obese; third group (NC, n=12) - control group (non-castrated, non-obese). At the end of the follow-up period of 2months after castration an intravenous glucose tolerance test (IVGTT) was performed after a 12-h fasting period as the blood samples for determination of glucose and insulin and their kinetic parameters were obtained at 5 and 0min before and at 5, 10, 30, 60 and 120min after the infusion of the glucose. The constituents of lipid profile, triglycerides (TG), total cholesterol (TC) and HDL-cholesterol (HDL-C) were also assessed in the overnight fasting blood samples. The body weight (BW), body mass index (BMI), amount of the visceral fat (VF) and VF/BW ratio were both measured and calculated before the IVGTT and at the end of the experimental period. All measured markers of obesity (BW, BMI, VF, VF/BW) were significantly higher in both groups of castrated rabbits than in the control group. Apart HDL-C, the plasma concentrations of all constituents of lipid profile (TG, TC, HDL-C) were the highest in CO group. There were generally no differences between CI and NC groups for the same traits. After glucose injection blood glucose concentrations and glucose and insulin kinetic parameters were considerably higher (except of glucose elimination rate) in CO rabbits than in NC ones. Castrated rabbits treated with "Immunoprotect" showed lower fasting plasma insulin and improved glucose kinetics dynamics than CO rabbits, but commensurable values of glucose and insulin kinetics parameters than NC group. The results of the current study clearly indicated that castration-induced visceral obesity affected negatively the lipid profile and insulin sensitivity and/or responsiveness. Treatment with antioxidant supplementation, consisted of d-limonene and vitamin E, improved blood lipid profile, fatty liver, glucose homeostasis and insulin sensitivity in obese rabbits. In addition, based on our results we may suggest that castrated male New Zealand white rabbits might be considered as an appropriate animal model to study various metabolic abnormalities related to visceral obesity, such as dyslipidemia and impaired insulin sensitivity.


Articulated minimally invasive surgical instrument based on compliant mechanism.
In minimally invasive surgery, instruments are inserted from the exterior of the patient's body into the surgical field inside the body through the minimum incision, resulting in limited visibility, accessibility, and dexterity. To address this problem, surgical instruments with articulated joints and multiple degrees of freedom have been developed. The articulations in currently available surgical instruments use mainly wire or link mechanisms. These mechanisms are generally robust and reliable, but the miniaturization of the mechanical parts required often results in problems with size, weight, durability, mechanical play, sterilization, and assembly costs. We thus introduced a compliant mechanism to a laparoscopic surgical instrument with multiple degrees of freedom at the tip. To show the feasibility of the concept, we developed a prototype with two degrees of freedom articulated surgical instruments that can perform the grasping and bending movements. The developed prototype is roughly the same size of the conventional laparoscopic instrument, within the diameter of 4 mm. The elastic parts were fabricated by Ni-Ti alloy and SK-85M, rigid parts ware fabricated by stainless steel, covered by 3D- printed ABS resin. The prototype was designed using iterative finite element method analysis, and has a minimal number of mechanical parts. The prototype showed hysteresis in grasping movement presumably due to the friction; however, the prototype showed promising mechanical characteristics and was fully functional in two degrees of freedom. In addition, the prototype was capable to exert over 15 N grasping that is sufficient for the general laparoscopic procedure. The evaluation tests thus positively showed the concept of the proposed mechanism. The prototype showed promising characteristics in the given mechanical evaluation experiments. Use of a compliant mechanism such as in our prototype may contribute to the advancement of surgical instruments in terms of simplicity, size, weight, dexterity, and affordability.


Hepatic triglyceride hydrolysis and development of ketogenesis in rabbits.
Ketogenesis from endogenous fatty acids or exogenous oleate plus carnitine has been studied in isolated hepatocytes from fetal, newborn, and 70-day-old rabbits. During the first 48 h after birth, hepatic triacylglycerol stores decrease by 80%. The hydrolysis of hepatic triacylglycerol stores has been studied in isolated hepatocytes from 24-h-old fasting rabbits by using lysosomal acid lipase inhibitors and lysosomotropic agents. Their addition decreases the rates of ketone body production by 60-70%, suggesting that hepatic triacylglycerol hydrolysis proceeds via an acid lipase located in the lysosomes. Whereas the rates of ketogenesis from endogenous or exogenous fatty acids are very low in isolated hepatocytes from fetal rabbit, an eightfold increase in the rate of ketogenesis occurs between 6 and 24 h after birth; furthermore the hydrolysis of triacylglycerol stores is sufficient to support the ketogenic capacity in the hepatocytes isolated from 24-h-old rabbits. The emergence of ketogenesis in newborn rabbit hepatocytes is triggered by birth-associated factors rather than to an accurate stage of fetal maturation. Fatty acids are mainly oxidized in the mitochondria because peroxisomal oxidation does not exceed 10-15% of the overall beta-oxidation. Isolated hepatocytes incubated with [1-14C]oleate exhibit at birth a preferential channeling of fatty acid into esterification (93% of oleate metabolized) rather than into oxidation. Conversely oleate oxidation represents 50% of total oleate metabolized 24 h after birth. Factors involved in this switch on of the partition of oleate into esterification and oxidation during the 1st day after birth are discussed.


Diagnostic Accuracy of Abdominal Ultrasonography in Pediatric Acute Appendicitis.
To evaluate the diagnostic accuracy of ultrasonography in pediatric acute appendicitis. In this cross-sectional study, 230 children aged 5-15 years with the diagnosis of acute appendicitis were studied. This study included the evaluation of demographic indices, ultrasound findings at diagnosis, and then comparing the results with the description of the patient's procedure and the pathology report of these patients. Patients who did not undergo ultrasound before surgery or their ultrasound did not include the evaluation of appendicitis or their pathologic report was not available were excluded. Overall, we have included a total number of 230 children with clinical diagnosis of acute appendicitis among whom there were 121 (52.6%) girls and 109 (47.4%) boys with mean age of 11.44 ± 2.90 years. Preoperative ultrasound report showed that 51.3% were normal and 48.7% had acute appendicitis. 34.8% had normal appendix and 65.2% had a pathological diagnosis of acute appendicitis. The sensitivity and specificity of ultrasound in these children were 58% and 68%, respectively. Positive and negative predictive values were 77% and 46%, respectively. The area under curve (AUC) was 0.853 (CI 95% 0.788-0.917) indicating a test with moderate accuracy. According to the obtained results, abdominal ultrasonography is of acceptable diagnostic accuracy in pediatric patients with acute appendicitis. The use of auxiliary techniques in ultrasound would increase the sensitivity and specificity in the diagnosis of acute appendicitis in children.


Human mesenchymal stem cells are recruited to injured liver in a β1-integrin and CD44 dependent manner.
Human bone marrow mesenchymal stem cells (hMSCs) have shown benefit in clinical trials of patients with liver disease. Efficient delivery of cells to target organs is critical to improving their effectiveness. This requires an understanding of the mechanisms governing cellular engraftment into the liver. Binding of hMSCs to normal/injured liver tissue, purified extracellular matrices, and human hepatic sinusoidal endothelial cells (HSECs) were quantified in static and flow conditions. To define the mechanisms underpinning hMSC interactions, neutralizing adhesion molecule antibodies were used. Fluorescently labelled hMSCs were infused intraportally into CCl(4) -injured mice with and without neutralizing antibodies. hMSCs expressed high levels of CD29/β1-integrin and CD44. Using liver tissue binding assays, hMSC adhesion was greatest in diseased human liver versus normal liver (32.2 cells/field versus 20.5 cells/field [P = 0.048]). Neutralizing antibodies against CD29 and CD44 reduced hMSC binding to diseased liver by 34% and 35%, respectively (P = 0.05). hMSCs rolled at 528 μm/second on HSECs in flow assays. This rolling was abolished by CD29 blockade on hMSCs and vascular cell adhesion molecule-1 (VCAM-1) blockade on HSECs. Firm adhesion to HSECs was reduced by CD29 (55% [P = 0.002]) and CD44 (51% [P = 0.04]) blockade. Neutralizing antibodies to CD29 and CD44 reduced hepatic engraftment of hMSCs in murine liver from 4.45 cells/field to 2.88 cells/field (P = 0.025) and 2.35 cells/field (P = 0.03), respectively. hMSCs expressed modest levels of chemokine receptors including CCR4, CCR5, and CXCR3, but these made little contribution to hMSC adhesion in this setting. hMSCs bind preferentially to injured liver. Rolling of hMSCs is regulated by CD29/VCAM-1, whereas CD29/CD44 interactions with VCAM-1, fibronectin, and hyaluronan on HSECs determine firm adhesion both in vitro and in vivo as demonstrated using a murine model of liver injury.


Cost analysis of fixed-dose combination of dutasteride and tamsulosin compared with concomitant dutasteride and tamsulosin monotherapy in patients with benign prostatic hyperplasia in Canada.
We estimate the lifetime cost of treatment for moderate/severe symptoms associated with benign prostatic hyperplasia (BPH) in a cohort of Canadian men aged 50 to 59, and we evaluate the costs of 2 daily bioequivalent treatment options: fixed-dose combination (FDC) of dutasteride (0.5 mg) and tamsulosin (0.4 mg), or concomitant administration of dutasteride (0.5 mg) and tamsulosin (0.4 mg) monotherapies. The expected lifetime costs were estimated by modelling the incidence of acute urinary retention (AUR), BPH-related surgery and clinical progression over a patient's lifetime (up to 25 years). A model was developed to simulate clinical events over time, based on a discrete Markov process with 6 mutually exclusive health states and annual cycle length. The estimated lifetime budget cost for the cohort of 374 110 men aged 50 to 59 in Canada is between $6.35 billion and $7.60 billion, equivalent to between $16 979 and $20 315 per patient with moderate/severe symptoms associated with BPH. Costs are lower for FDC treatment, with the net difference in lifetime budget impact between the 2 treatment regimens at $1.25 billion. In this analysis, the true costs of BPH in Canada are underestimated for 2 main reasons: (1) to make the analysis tractable, it is restricted to a cohort aged 50 to 59, whereas BPH can affect all men; and (2) a closed cohort approach does not include the costs of new (incident) cases. Canadian clinical guidelines recommend the use of the combination of tamsulosin and dutasteride for men with moderate/severe symptoms associated with BPH and enlarged prostate volume. This analysis, using a representational patient group, suggests that the FDC is a more cost-effective treatment option for BPH.


UV radiation measurement in a study of elderly subjects.
Elderly subjects were exposed to controlled amounts of sunshine over a 3-month period. Ultraviolet radiation (UVR) was monitored using two types of sensors, polysulphone film and a digital radiation meter. The time periods for sun exposure were computer-derived so as to yield 'safe' exposure times, but these times may have been underestimated. Erythemally effective radiation doses calculated from the sensor readings indicated good agreement between the sensors.


Advances in radiation therapy dosimetry.
During the last decade, there has been an explosion of new radiation therapy planning and delivery tools. We went through a rapid transition from conventional three-dimensional (3D) conformal radiation therapy to intensity-modulated radiation therapy (IMRT) treatments, and additional new techniques for motion-adaptive radiation therapy are being introduced. These advances push the frontiers in our effort to provide better patient care; and with the addition of IMRT, temporal dimensions are major challenges for the radiotherapy patient dosimetry and delivery verification. Advanced techniques are less tolerant to poor implementation than are standard techniques. Mis-administrations are more difficult to detect and can possibly lead to poor outcomes for some patients. Instead of presenting a manual on quality assurance for radiation therapy, this manuscript provides an overview of dosimetry verification tools and a focused discussion on breath holding, respiratory gating and the applications of four-dimensional computed tomography in motion management. Some of the major challenges in the above areas are discussed.


Premature apoptosis of Chlamydia-infected cells disrupts chlamydial development.
The obligate intracellular development of Chlamydia suggests that the bacteria should be vulnerable to premature host cell apoptosis, but because Chlamydia-infected cells are apoptosis resistant, this has never been able to be tested. We have devised a system to circumvent the apoptotic block imposed by chlamydial infection. When the proapoptotic protein Bim(S) was experimentally induced, epithelial cells underwent apoptosis that was not blocked by chlamydial infection. Apoptosis during the developmental cycle prevented the generation of infectious bacteria and caused transcriptional changes of bacterial genes and loss of intracellular ATP. Intriguingly, although apoptosis resulted in destruction of host cell structures and of the Chlamydia inclusion, and prevented generation of elementary bodies, Bim(S) induction in the presence of a caspase inhibitor allowed differentiation into morphologically normal but noninfectious elementary bodies. These data show that chlamydial infection renders host cells apoptosis resistant at a premitochondrial step and demonstrate the consequences of premature apoptosis for development of the bacteria.


In vitro activity of chloramphenicol and thiamphenicol analogs.
The in vitro activity of three fluorine analogs of chloramphenicol in which the hydroxyl group at position 3 had been replaced with a fluorine was compared with that of chloramphenicol and thiamphenicol. Compound SCH 24893 was the most active agent against staphylococci and Bacteroides strains, and compound SCH 25298 was the most active against Haemophilus, Neisseria, enterococcus, and Klebsiella strains. Serratia marcescens and Pseudomonas aeruginosa strains resistant to chloramphenicol were resistant to the compounds. The agents inhibited all of the Shigella, Salmonella, Staphylococcus aureus, and enterococcus strains resistant to chloramphenicol. They inhibited most (82%) of Escherichia coli and half of the Klebsiella pneumoniae strains which were resistant to chloramphenicol. Isolates in which resistance to chloramphenicol was shown to be plasmic mediated and due to chloramphenicol transacetylase were inhibited by all three agents.


Assessing the utility of long-read nanopore sequencing for rapid and efficient characterization of mobile element insertions.
Short-read next generation sequencing (NGS) has become the predominant first-line technique used to diagnose patients with rare genetic conditions. Inherent limitations of short-read technology, notably for the detection and characterization of complex insertion-containing variants, are offset by the ability to concurrently screen many disease genes. "Third-generation" long-read sequencers are increasingly being deployed as an orthogonal adjunct technology, but their full potential for molecular genetic diagnosis has yet to be exploited. Here, we describe three diagnostic cases in which pathogenic mobile element insertions were refractory to characterization by short-read sequencing. To validate the accuracy of the long-read technology, we first used Sanger sequencing to confirm the integration sites and derive curated benchmark sequences of the variant-containing alleles. Long-read nanopore sequencing was then performed on locus-specific amplicons. Pairwise comparison between these data and the previously determined benchmark alleles revealed 100% identity of the variant-containing sequences. We demonstrate a number of technical advantages over existing wet-laboratory approaches, including in silico size selection of a mixed pool of amplification products, and the relative ease with which an automated informatics workflow can be established. Our findings add to a growing body of literature describing the diagnostic utility of long-read sequencing.


Effects of sodium butyrate and 5-azacytidine on DNA methylation in human tumor cell lines: variable response to drug treatment and withdrawal.
The effect of butyrate (Btr) and 5-azacytidine (azaC) on genomic DNA methylation was examined in a variety of human tumor cell lines. Butyrate treatment differentially affected 5-methylcytosine (m5C) content in a cell type-specific manner. For example, incubation of CBT cells (glioblastoma multiforme) for 48 h in medium containing 2 mM Btr resulted in the hypomethylation of their DNA; after removal of the drug, the m5C content was rapidly (24 h) restored to its original level. In contrast, when HeLa cells (cervical carcinoma) were cultured for 48 h in 3 mM Btr, their genomic DNA became more extensively methylated relative to the untreated control, and the hypermethylated state was maintained for long periods in culture. Treatment of HeLa cell lines with azaC resulted in extensive demethylation of their DNA. Following removal of the drug, the DNA was rapidly remethylated to levels equal to or greater than those of the untreated cells. The hypermethylated state has remained stable for over 180 generations. Together, the data suggest that cells respond rapidly to alter drug-induced reductions in the m5C content of their DNA, and this response can subsequently result in overmethylation. In contrast, when drug-induced hypermethylation of genomic DNA occurs, it may persist for many cell generations.


Immunomodulatory Effects Associated with Cladribine Treatment.
Cladribine is a synthetic deoxyadenosine analogue with demonstrated efficacy in patients with relapsing-remitting multiple sclerosis (MS). The main mechanism of action described for cladribine is the induction of a cytotoxic effect on lymphocytes, leading to a long-term depletion of peripheral T and B cells. Besides lymphocyte toxicity, the mode of action may include immunomodulatory mechanisms affecting other cells of the immune system. In order to induce its beneficial effects, cladribine is phosphorylated inside the cell by deoxycytidine kinase (DCK) to its active form. However, the mechanism of action of cladribine may also include immunomodulatory pathways independent of DCK activation. This in vitro study was designed to explore the impact of cladribine on peripheral blood mononuclear cells (PBMC) subsets, and to assess whether the immunomodulatory mechanisms induced by cladribine depend on the activation of the molecule. To this end, we obtained PBMCs from healthy donors and MS patients and performed proliferation, apoptosis and activation assays with clinically relevant concentrations of cladribine in DCK-dependent and -independent conditions. We also evaluated the effect of cladribine on myeloid lineage-derived cells, monocytes and dendritic cells (DCs). Cladribine decreased proliferation and increased apoptosis of lymphocyte subsets after prodrug activation via DCK. In contrast, cladribine induced a decrease in immune cell activation through both DCK-dependent and -independent pathways (not requiring prodrug activation). Regarding monocytes and DCs, cladribine induced cytotoxicity and impaired the activation of classical monocytes, but had no effect on DC maturation. Taken together, these data indicate that cladribine, in addition to its cytotoxic function, can mediate immunomodulation in different immune cell populations, by regulating their proliferation, maturation and activation.


Chemoembolization for hepatocellular carcinoma.
Transcatheter arterial chemoembolization (TACE) is the standard of care for patients with preserved liver function and asymptomatic, noninvasive multinodular hepatocellular carcinoma (HCC) confined to the liver. However, the survival benefit of conventional TACE-including the administration of an anticancer agent-in-oil emulsion followed by embolic agents-reported in randomized controlled trials and meta-analyses was described as modest. Various strategies to improve outcomes for this patient group have become the subject of much ongoing clinical research. The introduction of embolic, drug-eluting beads (DEB) for transarterial administration has been shown to significantly reduce liver toxicity and systemic drug exposure compared to conventional regimens. The addition of molecular targeted drugs to the therapeutic armamentarium for HCC has prompted the design of clinical trials aimed at investigating the synergies between TACE and systemic treatments. Combining TACE with agents with anti-angiogenic properties represents a promising strategy, because TACE is thought to cause local hypoxia, resulting in a temporary increase in levels of vascular endothelial growth factor. Recently, a large phase II randomized, double-blind, placebo-controlled trial (the SPACE study) has shown that the concurrent administration of DEB-TACE and sorafenib has a manageable safety profile and has suggested that time to progression and time to vascular invasion or extrahepatic spread may be improved with respect to DEB-TACE alone. These data support the further evaluation of molecular targeted, systemically active agents in combination with DEB-TACE in a phase III setting.


Nrf2-induced antioxidant protection: a promising target to counteract ROS-mediated damage in neurodegenerative disease?
Neurodegenerative diseases share various pathological features, such as accumulation of aberrant protein aggregates, microglial activation, and mitochondrial dysfunction. These pathological processes are associated with generation of reactive oxygen species (ROS), which cause oxidative stress and subsequent damage to essential molecules, such as lipids, proteins, and DNA. Hence, enhanced ROS production and oxidative injury play a cardinal role in the onset and progression of neurodegenerative disorders. To maintain a proper redox balance, the central nervous system is endowed with an antioxidant defense mechanism consisting of endogenous antioxidant enzymes. Expression of most antioxidant enzymes is tightly controlled by the antioxidant response element (ARE) and is activated by nuclear factor E2-related factor 2 (Nrf2). In past years reports have highlighted the protective effects of Nrf2 activation in reducing oxidative stress in both in vitro and in vivo models of neurodegenerative disorders. Here we provide an overview of the involvement of ROS-induced oxidative damage in Alzheimer's disease, Parkinson's disease, and Huntington's disease and we discuss the potential therapeutic effects of antioxidant enzymes and compounds that activate the Nrf2-ARE pathway.


Early archosauromorph remains from the Permo-Triassic Buena Vista Formation of north-eastern Uruguay.
The Permo-Triassic archosauromorph record is crucial to understand the impact of the Permo-Triassic mass extinction on the early evolution of the group and its subsequent dominance in Mesozoic terrestrial ecosystems. However, the Permo-Triassic archosauromorph record is still very poor in most continents and hampers the identification of global macroevolutionary patterns. Here we describe cranial and postcranial bones from the Permo-Triassic Buena Vista Formation of northeastern Uruguay that contribute to increase the meagre early archosauromorph record from South America. A basioccipital fused to both partial exoccipitals and three cervical vertebrae are assigned to Archosauromorpha based on apomorphies or a unique combination of characters. The archosauromorph remains of the Buena Vista Formation probably represent a multi-taxonomic assemblage composed of non-archosauriform archosauromorphs and a 'proterosuchid-grade' animal. This assemblage does not contribute in the discussion of a Late Permian or Early Triassic age for the Buena Vista Formation, but reinforces the broad palaeobiogeographic distribution of 'proterosuchid grade' diapsids in Permo-Triassic beds worldwide.


Identification of HIV integration sites in infected host genomic DNA.
The integration of the Human Immunodeficiency Virus (HIV) genetic information into the host genome is fundamental for its replication and long-term persistence in the host. Isolating and characterizing the integration sites can be useful for obtaining data such as identifying the specific genomic location of integration or understanding the forces dictating HIV integration site selection. The methods outlined in this article describe a highly efficient and precise technique for identifying HIV integration sites in the host genome on a small scale using molecular cloning techniques and standard sequencing or on a massive scale using 454 pyrosequencing.


Seasonal and diurnal variations of volatile organic compounds (VOCs) in the atmosphere of Hong Kong.
Ambient VOCs samples were collected at three locations (PolyU campus (PU), Kwun Tong (KT), Hok Tsui (HT)) in Hong Kong during the periods of November 2000-February 2001 and June 2001-August 2001. Also the concentrations of VOCs in Cross Harbor tunnel in Hong Kong were obtained in order to determine the vehicular sources of VOCs. Toluene was the most abundant VOC detected in Hong Kong. At the PU station, which is close to a main road, the concentrations of most VOCs were higher in summer than in winter. However, at the background location HT, the concentrations of all VOCs except tetrachloroethene were higher in winter than in summer. Regional physical dispersion/transportation and mixing depth may be the reasons for higher VOC concentrations in winter at HT. The BTEX (benzene:toluene:ethylbenzene:xylene) ratios of PU and KT during winter period were (1.9:10.1:1.0:1.8) and (1.9:10.4:1.0:1.5), and (0.9:8.3:1.0:2.2) and (0.8:29.6:1.0:1.8) for summer season, respectively. The xylene/ethylbenzene (X/E) ratio was used to assess the relative age of the air parcels in this study. The concentrations of VOCs in the atmosphere in Hong Kong were mainly affected by direct emissions from vehicles, evaporation of fuels, photochemical reactions and few industrial emissions. The BTEX ratio in the tunnel was 2:10.4:1:3.2. The BTEX ratios at PU and KT during the winter period were similar to that in tunnel (except for xylenes). The X/E ratio in the tunnel was higher than that in the ambient air. This indicated that the freshly emitted xylenes in the tunnel decayed at different rates from OH-oxidation in the atmosphere. Good BTEX correlations (r>0.8) were found at PU and KT in winter (**P<0.01). Vehicular exhaust was the dominant source at PU and KT stations, and less evaporation of fuel or additive occurred at low temperature in winter. Diurnal variations of mean BTEX concentrations at the roadside monitoring station (PU) showed two peaks associated with traffic density and vehicle type.


Parvalbumin: Targeting calcium handling in cardiac diastolic dysfunction.
Diastolic heart failure (DHF) is a clinical syndrome characterized by depressed myocardial relaxation performance and poor ventricular refilling. Defective intracellular calcium (Ca(2+)) handling underlies one of the fundamental mechanisms of DHF. Manipulating the content and function of Ca(2+) handling proteins in the heart has been the focus of intense study to develop effective therapies for DHF patients. Parvalbumin (Parv), a skeletal muscle Ca(2+) binding protein, has been shown to facilitate myocardial relaxation both in vitro and in vivo. Parv acts as a unique "delayed" Ca(2+) buffer and facilitates Ca(2+) sequestration from cytosol. Here, we summarize studies employing gene transfer of Parv in cultured adult cardiac myocytes and in vivo to redress depressed diastolic function. By targeting defects in cardiac Ca(2+) handling, Parv represents a promising therapeutic candidate for alleviating diastolic dysfunction in DHF.


Successful outcome of hepatectomy as treatment for liver lobe torsion in four domestic rabbits.
4 rabbits (1.5 to 6 years old) were evaluated at the Angell Animal Medical Center from June 2007 to March 2009 because of nonspecific clinical signs including anorexia, lethargy, and decreased fecal output. Physical examination revealed signs of pain in the cranial portion of the abdomen, gas distention of the gastrointestinal tract, and diminished borborygmi. Serum biochemical analyses and CBCs revealed moderately to markedly high alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase activities and mild to moderate anemia with polychromasia. Abdominal radiographic findings were nonspecific. Three of the 4 rabbits underwent abdominal ultrasonography; abnormalities in shape, size, echogenicity, and blood flow of the liver, indicative of liver lobe torsion, were detected. All 4 rabbits underwent surgery, during which liver lobe torsion was confirmed and the affected liver lobe was resected. Histologic examination of sections of the excised lobe obtained from 3 of the 4 rabbits revealed severe, diffuse, acute to sub-acute hepatic ischemic necrosis. All rabbits recovered from surgery; owners reported that the rabbits were doing well 22 to 43 months after surgery. Liver lobe torsions in any species are rarely reported, yet 4 cases of liver lobe torsion in domestic rabbits were treated at 1 referral center in a 2-year period. In rabbits, clinical signs of this condition are nonspecific and results of additional tests, including abdominal ultrasonography and serum biochemical analysis, are necessary for diagnosis. Prompt diagnosis and hepatectomy of the affected lobe are recommended and appear to be associated with an excellent prognosis.


A sensitive hepatocyte-mediated assay for the metabolism of nitrosamines to mutagens for mammalian cells.
A sensitive cell-mediated assay has been developed for testing mutagenesis in Chinese hamster V79 cells by carcinogenic nitrosamines. Mutations were characterized by resistance to ouabain and 6-thioguanine. Since V79 cells do not metabolize nitrosamines, mutagenesis in the V79 cells was tested in the presence of primary hepatocytes capable of metabolizing nitrosamines. The hepatocytes were isolated after collagenase and hyaluronidase digestion of liver slices. All seven liver carcinogens of the nine tested nitrosamines exhibited a mutagenic response in this cell-mediated assay. The potent liver carcinogens nitrosodimethylamine, nitrosodiethylamine, nitrosoethylmethylamine, and nitrosodipropylamine could be detected with doses as low as 1 muM. The noncarcinogenic nitrosodiphenylamine was not mutagenic. Nitrosomethoxymethylamine was the only nitrosamine that exhibited mutagenic activity in the absence of hepatocytes, and this activity was diminished in the presence of hepatocytes. It is suggested that the use of hepatocytes prepared by the slicing method for carcinogen metabolism and mutable V79 cells offers a highly sensitive assay for determining the mutagenic potential of carcinogenic nitrosamines and probably of other classes of hazardous chemicals occurring in the environment.


[The physiological pattern of lumbar intervertebral disk height].
Purpose of this study is to present a new method of quantifying objectively the height of all discs in lateral radiographs of the lumbar spine and of analysing the normal craniocaudal sequence pattern of lumbar disc heights. The new parameter is the ventrally measured disc height corrected for the dependence on the angle of lordosis by normalisation to mean angles observed in the erect posture of healthy persons. To eliminate radiographic magnification, the corrected ventral height is related to the mean depth of the cranially adjoining vertebra. In this manner lumbar disc heights were objectively measured in young, mature and healthy persons (146 males and 65 females). The craniocaudal sequence pattern was analysed by mean values from all persons and by height differences of adjoining discs in each individual lumbar spine. Mean normative values demonstrated an increase in disc height between L1/L2 and L4/L5 and a constant or decreasing disc height between L4/L5 and L5/S1. However, this "physiological sequence of disc height in the statistical mean" was observed in only 36% of normal males and 55% of normal females. The radiological pattern of the "physiological sequence of lumbar disc height" leads to a relevant portion of false positive pathological results especially at L4/L5. An increase of disc height from L4/L5 to L5/S1 may be normal. The recognition of decreased disc height should be based on an abrupt change in the heights of adjoining discs and not on a deviation from a craniocaudal sequence pattern.


Composition, phosphorylation and dynamic organization of photosynthetic protein complexes in plant thylakoid membrane.
The photosystems (PS), catalyzing the photosynthetic reactions of higher plants, are unevenly distributed in the thylakoid membrane: PSII, together with its light harvesting complex (LHC)II, is enriched in the appressed grana stacks, while PSI-LHCI resides in the non-appressed stroma thylakoids, which wind around the grana stacks. The two photosystems interact in a third membrane domain, the grana margins, which connect the grana and stroma thylakoids and allow the loosely bound LHCII to serve as an additional antenna for PSI. The light harvesting is balanced by reversible phosphorylation of LHCII proteins. Nevertheless, light energy also damages PSII and the repair process is regulated by reversible phosphorylation of PSII core proteins. Here, we discuss the detailed composition and organization of PSII-LHCII and PSI-LHCI (super)complexes in the thylakoid membrane of angiosperm chloroplasts and address the role of thylakoid protein phosphorylation in dynamics of the entire protein complex network of the photosynthetic membrane. Finally, we scrutinize the phosphorylation-dependent dynamics of the protein complexes in context of thylakoid ultrastructure and present a model on the reorganization of the entire thylakoid network in response to changes in thylakoid protein phosphorylation.


[Visceral leishmaniasis, pemphigus and immunosuppressive treatment: case report from Morocco].
Atypical forms of visceral leishmaniasis associated with immunosuppressive treatment are difficult to diagnose and cause high mortality. The purpose of this report is to describe a case involving a 42-year-old patient living in a leishmaniasis-endemic area, who was undergoing immunosuppressive treatment using corticosteroids and methotrexate for pemphigus. Despite clinical and laboratory findings consistent with visceral leishmaniasis, detection of Leishmania bodies was a coincidental finding of cytological examination of bone marrow during workup for pancytopenia and associated clinical signs. This case argues in favor of systematic screening for this opportunistic parasitic disease before undertaking immunosuppressive treatment in patients presenting risk factors and consistent clinical/laboratory findings.


Efficacy and tolerability of adding an angiotensin receptor blocker in patients with heart failure already receiving an angiotensin-converting inhibitor plus aldosterone antagonist, with or without a beta blocker. Findings from the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Added trial.
The efficacy and safety of adding an angiotensin receptor blocker (ARB) in heart failure (HF) patients already taking an angiotensin-converting enzyme-inhibitor (ACE-I) plus an aldosterone antagonist is uncertain (especially if taking a beta blocker as well). The CHARM-Added trial describes the largest experience of using multiple inhibitors of the renin-angiotensin-aldosterone system (RAAS) together. 2548 HF patients, taking an ACE-I (936 no spironolactone/no beta blocker; 1175 no spironolactone/beta blocker; 199 spironolactone/no beta blocker; 238 sprionolactone/beta blocker), were randomized to placebo or candesartan and followed for 41 months (median). The primary outcome was cardiovascular death or HF hospitalization. In patients taking both a beta blocker and spironolactone (in addition to an ACE-I) at baseline, the candesartan:placebo hazard ratio was 0.85(95% CI 0.56, 1.29), compared to 0.85(95% CI 0.75, 0.96) in all randomized patients (interaction p value 0.49). The relative risk of discontinuation of candesartan (compared to placebo) because of hypotension, increased serum creatinine or hyperkalemia was not increased in patients taking spironolactone at baseline. An ARB may provide added benefit, at acceptable risk, in HF patients already taking spironolactone as well as an ACE-I and beta blocker. These findings must be confirmed in a prospective randomized trial before this approach can be recommended, routinely.


Integration of vascular, contractile and metabolic responses to hypoxia: effects of maturation and adenosine.
We examined myocardial responses to reduced arterial PO2 and the role of endogenous adenosine in constant-pressure perfused hearts from immature (Imm) and mature (Mat) rabbits. During normoxia, coronary flow and myocardial O2 consumption were similar in both groups. With moderate hypoxia, coronary perfusate flow increased by 125 +/- 16% in Imm but by only 68 +/- 12% in Mat hearts. Imm hearts displayed better maintenance of contractile function (87 vs. 67% in Mat hearts) and metabolic state. Blockade of cardiac adenosine receptors with 25 microM 8-p-sulfophenyltheophylline attenuated vasodilation during hypoxia, reduced contractile function, and abolished age-related differences in one response to hypoxia. Myocardial purine release and extracellular purine levels were threefold higher in Mat compared with Imm hearts and was associated with higher cytosolic 5'-AMP concentration (and lower [ATP]/[ADP].[P(i)], where [ATP], [ADP], and [P(i)] are concentrations of ATP, ADP and P(i), respectively) in Mat hearts. In summary, 1) Imm hearts are functionally and metabolically more tolerant of hypoxic perfusion, largely because of improved hypoxia-induced coronary vasodilation; 2) endogenous adenosine mediates this beneficial vasodilation, enhancing hypoxic tolerance; and 3) improved vascular sensitivity to adenosine allows for enhanced vasodilatory responses in the face of lower adenosine levels and higher energy state in immature hearts.


[Efficacy of local heparinoids on preventing edema and ecchymosis after rhinoplasty].
In this study, the effect of local heparinoids on prevention of periorbital edema and ecchymosis due to rhinoplasty was investigated. Twenty patients (12 males, 8 females, mean age 23.3 years; range 19 to 34 years) who had bilateral osteotomy were randomly administered postoperative local heparinoid on one periorbital region, without performing any care in the other one. One and a half centimeter of heparinoid was applied once a day for nine days. The other periorbital region was used as control group. The heparinoid was applied additionally, 8 mg dexamethasone i.v was administered to all patients 30 minutes before the surgery and 24 hours after the surgery. Photographs of each patient which were taken on postoperative days 1, 3, 5 and 9 were evaluated as double-blind by two observers. Scoring was performed according to edema and ecchymosis scales. There was no statistical difference with respect to edema and ecchymosis between local heparinoid treated and control eyes. No hypersensitivity to drugs occurred in any patients. After analysing the scores, we observed that heparanoids administered locally was not effective in preventing periorbital edema and ecchymosis after rhinoplasty (p>0.05).


Gene-gene-sex interaction in cytokine gene polymorphisms revealed by serum interferon alpha phenotype in juvenile dermatomyositis.
To detect genetic polymorphisms associated with high serum interferon alpha (IFN-alpha) levels in juvenile dermatomyositis (JDM) and explore interactions in associated polymorphisms. Eighty-five children of European ancestry with definite/probable JDM were studied. Selected genetic polymorphisms that were associated with high IFN-alpha levels in 12 untreated patients with newly diagnosed JDM were genotyped in a validation cohort of 73 children with JDM and analyzed for gene-gene and gene-sex interactions. Untreated children with newly diagnosed JDM carrying both the osteopontin (OPN) rs28357094G and tumor necrosis factor alpha (TNF-alpha)-308 A alleles had significantly increased serum IFN-alpha levels. These 2 polymorphisms were genotyped in the validation cohort, and the OPN rs28357094G allele was more common in female subjects with JDM (odds ratio=3.97, P=.012). This OPN allele was most strongly enriched in female carriers of TNF-alpha-308A as compared with male carriers of TNF-alpha-308A (odds ratio>9.0; P=7.2x10(-3)). These data support a complex gene-gene-sex interaction between the OPN and TNF-alpha promoter regions in JDM, defining a high serum IFN-alpha subgroup within JDM. This suggests pathogenic synergy between the OPN and TNF-alpha loci in female subjects with JDM, which may underlie some of the increased incidence of this condition in girls.


Alpine Skiing With total knee ArthroPlasty (ASWAP): metabolism, inflammation, and skeletal muscle fiber characteristics.
We investigated the effect of alpine skiing for 12 weeks on skeletal muscle characteristics and biomarkers of glucose homeostasis and cardiovascular risk factors. Twenty-three patients with a total knee arthroplasty (TKA) were studied 2.9 ± 0.9 years (mean ± SD) after the operation. Fourteen patients participated in the intervention group (IG) and nine in the control group (CG). Blood samples and muscle biopsies were obtained before (PRE) and 7.3 ± 0.8 days after (POST) the intervention, and blood samples again after a retention (RET) phase of 8 weeks. With skiing, glucose homeostasis improved in IG (decrease in fasting insulin, increase in muscle glycogen) but not in CG. Fiber type distribution and size, as well as capillary density and number of capillaries around the fibers (CAF), were not different between the operated and the non-operated leg in either group. The relative number of type I fibers increased with skiing in IG with no change in CG. Inflammatory biomarkers, plasma lipids, and mitochondrial proteins and activity did not change. Alpine skiing is metabolically beneficial and can be used as a training modality by elderly people with TKA.


Non-melanoma skin cancers in elderly patients.
Non-melanoma skin cancers are a common reality worldwide. The principal cause that determines the occurrence of these diseases is the exposition of the sun, which principally causes an alteration in the immune system. Therefore, it is possible that other forms of innate or acquired alterations of the immune system could favor the occurrence of non-melanoma skin cancers. For example, several studies have demonstrated that immunosenescence creates an immunosuppressive state that encourages the development of malignances, and new discoveries have noted the importance of T cells and in particular of T regulatory cells (Treg) and T receptor CD28 in this mechanism. Similar results are obtained analyzing the effect of immunosuppressive drugs. The importance of the immune system and its alteration in the genesis of non-melanoma skin cancers is fundamental for the creation of a new therapeutic and less invasive approach.


Patterns and determinants of psychoactive drug use in Lisbon University students--a population-based study.
To study the patterns and determinants of psychoactive drug use by Lisbon University students. A cross-sectional survey was conducted, from January to April 2000, in a probabilistic sample of 1,147 students. Information about use of psychoactive drugs and co-variates was collected by a questionnaire administered by trained interviewers. Psychoactive drugs were considered to be all medicines classified in group N (nervous system) of the ATC system except the anesthetics (subgroup N01) and the analgesics (subgroup N02). 91 students (7.9%) had taken psychoactive drugs during the fortnight before the interview, 39 of whom (42.8%) mentioned continuous use. The prevalence of use was significantly higher in females (9.6%), older than 25 years (13.1%), married (16%), who considered themselves to have a weak health status (21.7%), as under intense stress (15.5%). After adjustment by multivariate analysis the variables sex, self-evaluation of health status and daily stress retained a higher significant association with psychoactive drug use. A total of 132 drugs were reported as being used in that period. Tranquilizers (ATC = N05B or N05C) were used by 82 students (7.2%), while 22 (1.9%) consumed psychoactive stimulants (N06B) and 19 (1.7%) antidepressants (N06A). In all of these therapeutical subgroups, females had higher consumption prevalence than males, but the difference was statistically significant only for tranquilizers (P < 0.001). Anxiety, depression and insomnia were the most frequently stated health problems. More than 90% of drug consumers considered they had a compliant attitude and about 60% considered themselves well-informed about adverse effects of the drug used. The reported prevalence of self-medication for psychoactive drugs used was 12.8%. The prevalence of psychoactive drug use among students of Lisbon University was higher than expected, considering age group and the usual health status of this population. The administration of a questionnaire was a very useful tool to characterise the pattern of use and the consumer's knowledge about the drugs consumed.


Methodologies for determination of antimony in terrestrial environmental samples.
Methodologies for the environmental analysis of total antimony and aqueous chemical speciation are critically reviewed, including preparation techniques for aqueous and solid matrices and the determination of solid state partitioning and recommendations are given for future research directions. Concentrations of total antimony commonly present in aqueous and solid environmental samples are readily determined using present day analytical techniques. This has resulted primarily from technological advances in microwave digestion for solid matrices and the development of plasma based analyte detection systems. ICP-AES and ICP-MS techniques are both utilised for the environmental analysis of total antimony concentrations. However, ICP-MS is increasingly favoured as a result of reduced spectral interferences and the potential for analyte detection in the pg mL(-1) range. Determination of aqueous antimony speciation presents a number of complex analytical challenges and highly selective separation and identification techniques are required prior to detection. The majority of published techniques including common applications of hydride generation are insufficiently selective for the determination of intrinsic chemical speciation and often only oxidation state data are obtained. The recent in-line applications of HPLC-ICP-MS offer the potential for highly selective separations of aqueous antimony species and determination of detailed chemical speciation data. However, considerable development work is required to optimise chromatographic separations and identify uncharacterised species resident in environmental systems. Analytical techniques to aid the determination of antimony's associations with solid environmental matrices include the application of chemical extraction procedures and leaching experiments. To date, this area of analytical research has received little attention and further studies are required to elucidate this aspect of antimony's environmental chemistry.


[Small intestine graft in Switzerland: indications and potential recipients].
Small bowel transplantation is theoretically the best treatment for patients with short bowel syndrome and receiving total parenteral nutrition (TPN). The aim of our study was to determine the number of potential candidates for small bowel transplantation in Switzerland. We analyzed the clinical parameters of patients treated by TPN for short bowel syndrome obtained from university pediatric clinics, the SVK (Schweizerischer Verband für Gemeinschaftsaufgaben der Krankenkassen) and referring physicians. In 1995, 7 adults and 2 children were under TPN for short bowel syndrome. In the adult group (mean age 57), the causes of short bowel syndrome were 3 cases of mesenteric infarct, 2 cases of mechanical ileus, one Gardner syndrome and one inflammatory bowel disease. In the pediatric group, the causes of intestinal insufficiency were in one chronic enteropathy with malabsorption and in one congenital malformation. The average duration of TPN was 4.4 (1-10) years for the adults and 13 months for the children. The various complications related to TPN were repeated catheter sepsis in 5 patients, 2 cases of catheter thrombotic occlusion and 3 cases of cholestatic hepatopathy. The contraindications to small bowel transplantation were age, a history of malignant tumor, pulmonary hypertension and a psychiatric disorder. 4 patients were considered potential candidates for transplantation: 2 adults and 2 children, corresponding to an incidence of 0.5/million inhabitants. Considering that the prevalence and incidence of short bowel syndrome in Switzerland are comparable to those in other western countries, we think it should be possible to initiate a small bowel transplantation program in Switzerland.


Anthelmintic activity of acetone extracts from South African plants used on egg hatching of <I>Haemonchus contortus</I>.
The nematode, Haemonchus contortus, is responsible for major economic losses in the livestock industry. The management of parasites such as H. contortus has been through the use of synthetic parasiticides. This has resulted in the presence of residues in meat and milk, which affects food safety. The development of resistance to available anthelmintics coupled with their high cost has further complicated matters. This has led to the investigation of alternative methods to manage nematodes, including the use of plants and plant extracts as a potential source of novel anthelmintics. Acetone extracts were prepared from 15 South African plant species and their anthelmintic activity determined using the egg hatch assay (EHA). The leaf extract of Cleome gynandra had the best inhibitory activity (68% ± 3%) at a concentration of 2.5 mg/mL, followed by the stem extract of Maerua angolensis (65% ± 5%). The extracts had a relatively low toxicity on Vero cells determined by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) cellular assay.


Ambulatory blood pressure during once-daily randomised double-blind administration of atenolol, metoprolol, pindolol, and slow-release propranolol.
Intra-arterial ambulatory blood pressure was measured over 24 hours, in 34 patients with newly diagnosed hypertension, both before and after double-blind randomisation to treatment with atenolol (n=9), metoprolol (n=9), pindolol (n=9), or propranolol in its slow-release form (n=7). The dosage of each drug was adjusted at monthly clinic visits until satisfactory control of blood pressure was achieved (140/90 mm Hg or less by cuff) or the maximum dose in the study protocol was reached. A second intra-arterial recording was made after these drugs had been taken once daily at 0800 for three to eight months (mean 5.0+/-SD 1.4) and was started four hours after the last dose.At the end of the 24-hour recordings blood pressure was significantly lower with all four drugs. The extent to which the drugs reduced blood pressure, however, differed over the 24 hours. Atenolol lowered mean arterial pressure significantly throughout all 24 recorded hours, metoprolol for 12 hours, pindolol for 15 hours, and slow-release propranolol for 22 hours. Neither metoprolol nor pindolol lowered blood pressure during sleep. A significant reduction in heart rate was observed over 20 hours with atenolol, 20 hours with metoprolol, 10 hours with pindolol, and 24 hours with slow-release propranolol. Atenolol, metoprolol, and slow-release propranolol continued to slow the heart rate 24 hours after the last tablet was taken; this effect on heart rate, however, was not sustained throughout the second morning in those patients taking atenolol. Pindolol, the only drug studied that has intrinsic sympathomimetic activity, increased heart rate and did not lower blood pressure during sleep.Atenolol and slow-release propranolol are effective as antihypertensive agents over 24 hours when taken once daily, whereas metoprolol and pindolol may need to be taken more frequently. At times of low sympathetic tone, however, such as during sleep, beta-blockers with intrinsic sympathomimetic activity may raise heart rate and attenuate the fall in blood pressure with treatment.


[Diagnostic imaging findings in COVID-19].
This is a review of diagnostic imaging findings in coronavirus disease-2019 (COVID-19). CT findings are frequently bilateral, multilobar and peripheral ground-glass opacities with vascular enlargements. Consolidations often appear during progression as well as crazy paving and reticulation. Lymphadenopathy, pleural effusions and pneumothorax are rare and should raise concern for other disease. Initially the CT can be normal, and the diagnostic performance for COVID-19 is not optimal. However, findings of characteristic ground-glass opacities during the ongoing epidemic should lead to considerations, that the patient may have COVID-19.


Limited transthoracic echocardiogram: so easy any trauma attending can do it.
Limited transthoracic echocardiogram (LTTE) represents an attractive alternative to formal transthoracic echocardiogram (TTE), because it does not require an echocardiogram machine. Our hypothesis is that trauma attendings can learn LTTE effectively with minimal training. Seven attendings at a Level I trauma center received didactic and hands-on training in LTTE and performed this test on hypotensive patients to evaluate for contractility, fluid status, and pericardial effusion. Therapy to improve perfusion (administration of fluids, ionotropes, or vasopressors) was guided by LTTE findings. Perfusion status was determined by serum lactate level before and 6 hours after LTTE. Findings were compared with cardiology-performed TTE. Range of postresidency training was 1 year to 29 years. LTTE teaching entailed 70 minutes of didactics and 25 minutes of hands-on. In all, 52 LTTEs were performed; two patients were excluded due to blunt trauma arrest. Age ranged from 22 years to 89 years with an average of 55 years. Admission diagnosis was blunt trauma (n = 34), penetrating trauma (n = 3), and intra-abdominal sepsis (n = 13). Average time for LTTE was 4 minutes 38 seconds. Cardiology-performed TTE was obtained in all patients, and correlation with LTTE was 100%. A total of 37 patients received intravenous fluid, 9 received vasopressors, and 4 received ionotropes as guided by LTTE findings, with lactate reduction in all patients (p < 0.00001). Attendings scored a mean of 88% in a written test after training. Trauma attendings can successfully learn LTTE with minimal training and use the technique as a resuscitation tool in the hypotensive patient.


Identification and characterization of MmORC4 and MmORC5, two subunits of the mouse origin of replication recognition complex.
Two new members of the mouse origin recognition complex (ORC) have been cloned that are closely related to Saccharomyces cerevisiae ORC4 and ORC5 as well as to their human homolog. Both MmORC4p and MmORC5p have a putative nucleotide triphosphate binding motif. Transcription of MmORC4 and MmORC5 is not suppressed in mouse NIH3T3 fibroblasts made quiescent by serum starvation. The transcription levels of both ORC genes are constantly high in all phases of the cell cycle. A screen based on the two-hybrid approach suggests that the product of the ORC4 gene interacts with the ORC2, but not with the ORC1 protein. The conservation of structure among members of the ORC4- and ORC5-related family of proteins suggests that these proteins play a key role in the initiation of DNA replication in all eukaryotes.


Towards retinoid therapy for Alzheimer's disease.
Alzheimer's disease(AD) is associated with a variety of pathophysiological features, including amyloid plaques, inflammation, immunological changes, cell death and regeneration processes, altered neurotransmission, and age-related changes. Retinoic acid receptors (RARs) and retinoids are relevant to all of these. Here we review the pathology, pharmacology, and biochemistry of AD in relation to RARs and retinoids, and we suggest that retinoids are candidate drugs for treatment of AD.


Water transport facilitated by carbon nanotubes enables a hygroresponsive actuator with negative hydrotaxis.
Hygroresponsive actuators harness minor fluctuations in the ambient humidity to realize energy harvesting and conversion, thus they are of profound significance in the development of more energy-saving and sustainable systems. However, most of the existing hygroresponsive actuators are only adaptive to wet environments with limited moving directions and shape morphing modes. Therefore, it is highly imperative to develop a hygroresponsive actuator that works in both wet and dry environments. In this work, we present a bidirectional actuator responsive to both wet and dry stimuli. Our strategy relies on the introduction of carbon nanotubes to provide transport channels for water molecules. The actuation is enabled by the rapid transport of water in and out of the system driven by the moist/dry surroundings owing to the transport channels. The resultant actuator demonstrates reconfiguration and locomotion with turnover frequency F = 30 min-1, coupled with the capability of lifting objects 6 times heavier and transporting cargos 63 times heavier than itself. Oscillations (24°) driven by dry air flow in a cantilever display a high frequency (2 Hz) and large amplitude. Furthermore, a touchless electronic device was constructed to output varying signals in response to humid and dry environments. Our work provides valuable guidance and implications for designing and constructing hygroresponsive actuators, and paves the way for next-generation robust autonomous devices to exploit energy from natural resources.


Breast cancer and early retirement: Associations with disease characteristics, treatment, comorbidity, social position and participation in a six-day rehabilitation course in a register-based study in Denmark.
The purpose of this register-based study was to identify factors related to disease, treatment, sociodemographics and comorbidity associated with taking early retirement among women treated for breast cancer, and to evaluate the risk for taking early retirement among breast cancer survivors who attended a six-day rehabilitation course. The study population consisted of 856 women who attended the rehabilitation course and a comparison group of 1 805 women who did not attend the course identified through the Danish Breast Cancer Cooperative Group. We obtained information on receipt of unemployment benefits, sickness benefits and early retirement pension for each of the years 1996-2007. Multivariate cox-regression models were used to analyze disease-specific, treatment-related, comorbidity and sociodemographics factors associated with early retirement after breast cancer and to evaluate the effect of attending a rehabilitation course on taking early retirement. The rate of retirement was higher for women with somatic comorbidity (hazard ratio [HR], 1.91; 95% CI, 1.3; 2.9 for score 1, and HR 1.42; 95% CI, 0.7; 2.7 for score ≥2), previous depression (HR, 2.29; 95% CI, 1.7; 3.2) or having received sickness benefits in the year before their breast cancer diagnosis (HR, 3.75; 95% CI, 1.8; 7.8). Living with a partner was associated with a reduced hazard ratio for taking early retirement (HR, 0.70; 95% CI, 0.5-0.9). Having received chemotherapy, alone or in combination with anti-hormone treatment, reduced the hazard ratio (HR, 0.49; 95% CI, 0.3; 0.8 and HR, 0.5; 95% CI, 0.3; 0.8, respectively). The rate of retirement was higher for women the year after attending the rehabilitation course but returned to unity by three years. The results of this study contribute to the identification of at-risk women and point to the need for tailored rehabilitation to avoid unnecessary marginalization of breast cancer survivors due to permanent labor market withdrawal.


Xcat2 RNA is a translationally sequestered germ plasm component in Xenopus.
In Xenopus, the inheritance of germ plasm by a small subset of blastomeres during early development is thought to direct these cells into the germ cell lineage. We show that Xcat2 RNA, related to Drosophila nanos, is a germ plasm component that is translationally repressed during oogenesis. Xcat2 protein was not detected in oocytes at times prior to, or after its RNA was localized in germ plasm, suggesting Xcat2 RNA is functionally sequestered soon after transcription. Indeed, Xcat2 RNA is found in a dense non-polysomal compartment in oocytes. Repression of translation was not relieved by substituting the Xcat2 3'UTR with that of beta-globin. Immunodetection of Xcat2 protein during blastula and gastrula stages coincides with the time of symmetric segregation of the germ plasm and a net increase in the number of primordial germ cells. Xcat2 is capable of binding RNA in vitro and we propose that it may function to translationally regulate other RNAs specific to primordial germ cells.


Development and evolution of distraction devices: Use of indigenous appliances for Distraction Osteogenesis-An overview.
An attempt has been made to review various devices as well as the outstanding studies done in the past for understanding the methodology of distraction for regeneration of bone. Lengthening of underdeveloped bones inclusive of the maxillofacial complex has been obtained by distraction osteogenesis by many authors. This could be achieved by the use of various extraoral or intraoral devices. Devices used for distraction osteogenesis must have a minimum of 2 important characteristics - they should be able to transfer distraction forces directly to the bone and secondly, should offer adequate rigidity for osseous consolidation to occur. With advanced technology and biomechanical engineering, preformed intraoral distraction devices are now available worldwide. The introduction of these intraoral bone-bourne devices have eliminated the need for bulky, cumbersome extraoral distraction devices which had problems such as external scars, pin tract infections, nerve or tooth bud injuries and poor patient compliance. The design of completely internalized custom made appliance has opened new vistas in the field of Oral and Maxillofacial Surgery. Indigenous internal devices are also economical and locally available.


The gene B protein localises to the surface of Leishmania major parasites in the absence of metacyclic stage lipophosphoglycan.
The stage specific Gene B protein (GBP) of Leishmania major localises to the surface of infective metacyclic parasites, where it associates with the developmentally regulated surface glycoconjugate, lipophosphoglycan (LPG). This association has been proposed to aid maintenance of GBP on the parasite surface. In this paper, we show that the abundance of GBP on the extracellular metacyclic cell surface is in the order of 100,000 copies per cell. This level of expression is comparable to that seen in the intracellular amastigote stage, in which GBP is also localised to the surface, despite the lack of metacyclic stage specific LPG. Furthermore GBP expressed from an episome in avirulent parasites, which are unable to synthesise metacyclic LPG or endogenous GBP, also localises to the parasite surface. These data demonstrate that GBP can maintain a surface localisation in the absence of metacyclic LPG, suggesting that it is able to associate with other glycoconjugates on the surface of infective parasites.


Hapln4/Bral2 is a selective regulator for formation and transmission of GABAergic synapses between Purkinje and deep cerebellar nuclei neurons.
Purkinje cells (PCs) convey the sole output of the cerebellar cortex to the deep cerebellar nuclei (DCN). DCN neurons are enwrapped in densely organized extracellular matrix structures, known as perineuronal nets (PNNs). PNNs are typically found around fast-spiking GABAergic interneurons expressing parvalbumin but interestingly also exist surrounding other neurons, such as the neurons in the DCN and medial nucleus of the trapezoid body, which are the post-synaptic neurons of large axo-somatic synapses adapted for fast signaling. This characteristic localization prompted the hypothesis that PNNs might play a role in the maintenance and formation of large fast-signaling synapses. To elucidate the role of the PNN at these synapses, we investigated the electrophysiological and morphological properties of DCN synapses in hyaluronan and proteoglycan binding link protein 4 (Hapln4/Bral2) knockout (KO) mice around postnatal day (P)14. Hapln4/Bral2 is important for PNN structure, as it stabilizes the interaction between hyaluronan and proteoglycan. Here, using immunohistochemistry we show that Hapln4/Bral2 localized closely with GABAergic terminals. In DCN neurons of Hapln4/Bral2 KO mice, inhibitory synaptic strengths were reduced as compared to those in wild-type mice, whereas the properties of excitatory synapses were unaffected. The reduced IPSC amplitudes were mainly because of reduced numbers of releasable vesicles. Moreover, Hapln4/Bral2 deficiency reduced the number of PC GABAergic terminals in the DCN. These results demonstrate that Hapln4/Bral2 is a PNN component that selectively contributes to formation and transmission of PC-DCN synapses in the cerebellum. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.


Self-motion and the hippocampal spatial metric.
Self-motion signals are sufficient for animal navigation ("path integration") and for updating hippocampal location-specific firing. The contributions of ambulatory, vestibular, and optic self-motion signals to CA1 unit activity and EEG were studied while rats either walked or drove a car between locations on a circular track (referred to as WALK and CAR, respectively) or experienced pseudomotion, in which the animal was stationary and the environment was rotated (WORLD). Fewer pyramidal cells expressed place fields during CAR and those that did exhibited substantially larger place fields. The number of theta cycles required to traverse a place field increased, whereas the slope of the theta phase of firing versus position function was reduced. The presence and/or location of place fields were not well correlated between conditions. These effects were even more accentuated during WORLD. These results are not explainable by a simple "smearing out" of place fields but, in terms of size of place fields relative to the track size, are comparable with what would be observed if the track circumference was reduced and the animal moved around it at a correspondingly slower speed. Theta (and its 14-18 Hz harmonic) power were dependent on velocity, but the gain of this function was substantially reduced during CAR and WORLD, again as if the rat were moving more slowly. The spatial scale over which the hippocampal population vector is updated appears to be derived primarily from the gain of a self-motion velocity signal with approximately equal components derived from ambulation, vestibular, and optic-flow signals.


Cell-specific expression of glucose-dependent-insulinotropic polypeptide is regulated by the transcription factor PDX-1.
Glucose-dependent insulinotropic polypeptide (GIP) is a potent stimulator of insulin secretion and comprises an important component of the enteroinsular axis. GIP is synthesized in enteroendocrine K-cells located principally in the upper small intestine. The homeobox-containing gene PDX-1 is also expressed in the small intestine and plays a critical role in pancreatic development and in the expression of pancreatic-specific genes. Previous studies determined that the transcription factors GATA-4 and ISL-1 are important for GIP expression. In this study, we demonstrate that PDX-1 is also involved in regulating GIP expression in K-cells. Using immunohistochemistry, we verified the expression of PDX-1 protein in the nucleus of GIP-expressing mouse K-cells and evaluated the expression of PDX-1, serotonin, and GIP in wild-type and PDX-1(-/-) mice at 18.5 d after conception. Although we demonstrated a 97.8% reduction in the number of GIP-expressing cells in PDX-1(-/-) mice; there was no statistical difference in the number of serotonin-positive cells. Additionally, PDX-1 transcripts and protein were detected in a GIP-expressing neuroendocrine cell line, STC-1. Electromobility shift assays using STC-1 nuclear extracts demonstrated the specific binding of PDX-1 protein to a specific regulatory region in the GIP promoter. Using chromatin immunoprecipitation analysis, we demonstrated binding of PDX-1 to this same region of the GIP promoter in intact cells. Lastly, overexpression of PDX-1 in transient transfection assays led to a specific increase in the activity of GIP/Luc reporter constructs. The results of these studies indicate that the transcription factor PDX-1 plays a critical role in the cell-specific expression of the GIP gene.


Isoelectric focusing of mycoplasma proteins.
Polyacrylamide gel isoelectric focusing (PAGIF) in thin layer was used to resolve proteins of Mycoplasma spp., Acholeplasma spp., and eight strains of Ureaplasma urealyticum (T-strain). A mixture of urea, Triton X-100, and dithioerythritol was used to solubilize sonically disrupted cells. PAGIF was performed in the range of pH 3 to 10. Protein patterns were carefully compared, demonstrating resolved and distinguishable species-specific protein bands. The eight serotypes of U. urealyticum (T-strain) gave identical protein patterns in the pH 3 to 10 range. The characteristic "fingerprints" of a species appeared to correlate with the biochemical nature and not the habitat in each case. Arginine-hydrolyzing species seemed to show more diverse focusing than those that ferment glucose, or prefer an acid environment. Characterization and identification of highly resolved species-specific proteins, ease of performance, and reproducibility of this method suggest that PAGIF might be employed as a taxonomic aid.


Search for kinases related to transition of growth polarity in fission yeast.
In eukaryotes, cell polarity is essential for cell proliferation, differentiation, and development. It is regulated in 3 steps: establishment, maintenance, and transition. Compared to current knowledge of establishment and maintenance, the mechanism regulating the transition of cell polarity is poorly understood. In fission yeast during the G2 phase, growth polarity undergoes a dramatic transition, from monopolar to bipolar growth (termed NETO: new end take off). In this study, we screened systematically for protein kinases related to NETO using a genome-wide kinase deletion library. Analysis of these deletions suggested that 35 and 2 kinases had a putative positive and a negative role, respectively, in NETO. Moreover, 5 kinases were required for NETO-delay in the G1-arrested cdc10 mutant. These results suggest that many signaling pathways are involved in the regulation of NETO.


A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)†.
KRAS mutations are detected in 25% of non-small-cell lung cancer (NSCLC) and no targeted therapies are approved for this subset population. Trametinib, a selective allosteric inhibitor of MEK1/MEK2, demonstrated preclinical and clinical activity in KRAS-mutant NSCLC. We report a phase II trial comparing trametinib with docetaxel in patients with advanced KRAS-mutant NSCLC. Eligible patients with histologically confirmed KRAS-mutant NSCLC previously treated with one prior platinum-based chemotherapy were randomly assigned in a ratio of 2 : 1 to trametinib (2 mg orally once daily) or docetaxel (75 mg/m(2) i.v. every 3 weeks). Crossover to the other arm after disease progression was allowed. Primary end point was progression-free survival (PFS). The study was prematurely terminated after the interim analysis of 92 PFS events, which showed the comparison of trametinib versus docetaxel for PFS crossed the futility boundary. One hundred and twenty-nine patients with KRAS-mutant NSCLC were randomized; of which, 86 patients received trametinib and 43 received docetaxel. Median PFS was 12 weeks in the trametinib arm and 11 weeks in the docetaxel arm (hazard ratio [HR] 1.14; 95% CI 0.75-1.75; P = 0.5197). Median overall survival, while the data are immature, was 8 months in the trametinib arm and was not reached in the docetaxel arm (HR 0.97; 95% CI 0.52-1.83; P = 0.934). There were 10 (12%) partial responses (PRs) in the trametinib arm and 5 (12%) PRs in the docetaxel arm (P = 1.0000). The most frequent adverse events (AEs) in ≥20% of trametinib patients were rash, diarrhea, nausea, vomiting, and fatigue. The most frequent grade 3 treatment-related AEs in the trametinib arm were hypertension, rash, diarrhea, and asthenia. Trametinib showed similar PFS and a response rate as docetaxel in patients with previously treated KRAS-mutant-positive NSCLC. NCT01362296.


Dual specificity phosphatase 6 (DUSP6) is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cells.
Mitogen-activated protein kinase (MAPK) pathway signaling plays an important role in the majority of non-small-cell lung cancers (NSCLCs). In a prior microarray analysis of epidermal growth factor receptor (EGFR) inhibition in NSCLC cell lines, we noted that several dual specificity phosphatases (DUSPs) were among the most highly and immediately regulated genes. DUSPs act as natural terminators of MAPK signal transduction and therefore, we hypothesized a tumor suppressive role via feedback mechanisms. In the current study, we focus on the assessment of DUSP6, a cytoplasmic DUSP with high specificity for extracellular signal-regulated kinase (ERK). We demonstrate that DUSP6 expression tracks in tandem with ERK inhibition and that regulation of DUSP6 is mediated at the promoter level by ETS1, a well-known nuclear target of activated ERK. Small interfering RNA knockdown in DUSP6-high H441 lung cancer cells significantly increased ERK activation and cellular proliferation, whereas plasmid-driven overexpression in DUSP6-low H1975 lung cancer cells significantly reduced ERK activation and cellular proliferation and promoted apoptosis. Also, DUSP6 overexpression synergized with EGFR inhibitor treatment in EGFR-mutant HCC827 cells. Our results indicate that DUSP6 expression is regulated by ERK signaling and that DUSP6 exerts antitumor effects via negative feedback regulation, pointing to an important feedback loop in NSCLC. Further studies assessing the tumor suppressive role of DUSP6 and strategies aimed at modulation of its activity are warranted.


Policy implications of first-dollar coverage: a qualitative examination from the payer perspective.
Immunization against potentially life-threatening illnesses for children and adults has proved to be one of the great public health successes of the 20th century and is extremely cost-effective. The Patient Protection and Affordable Care Act includes a number of provisions to increase coverage and access to immunizations for the consumer, including a provision for health plans to cover all Advisory Committee on Immunization Practices-recommended vaccines at first dollar, or without cost sharing. In this study, we examined payers' perspectives on first-dollar coverage of vaccines and strategies to improve vaccination rates. This was a qualitative study, using a literature review and semistructured expert interviews with payers. Four key themes emerged, including (1) the cost implications of the first-dollar change; (2) the importance of examining barriers to children, adolescents, and adults separately to focus interventions more strategically; (3) the importance of provider knowledge and education in increasing immunization; and (4) the effect of first-dollar coverage on those who decline vaccination for personal reasons. We determined that, while reducing financial barriers through first-dollar coverage is an important first step to increasing immunization rates, there are structural and cultural barriers that also will require collaborative, strategic work among all vaccine stakeholders.


Antibody C219 recognizes an alpha-helical epitope on P-glycoprotein.
The ABC transporter, P-glycoprotein, is an integral membrane protein that mediates the ATP-driven efflux of drugs from multidrug-resistant cancer and HIV-infected cells. Anti-P-glycoprotein antibody C219 binds to both of the ATP-binding regions of P-glycoprotein and has been shown to inhibit its ATPase activity and drug binding capacity. C219 has been widely used in a clinical setting as a tumor marker, but recent observations of cross-reactivity with other proteins, including the c-erbB2 protein in breast cancer cells, impose potential limitations in detecting P-glycoprotein. We have determined the crystal structure at a resolution of 2.4 A of the variable fragment of C219 in complex with an epitope peptide derived from the nucleotide binding domain of P-glycoprotein. The 14-residue peptide adopts an amphipathic alpha-helical conformation, a secondary structure not previously observed in structures of antibody-peptide complexes. Together with available biochemical data, the crystal structure of the C219-peptide complex indicates the molecular basis of the cross-reactivity of C219 with non-multidrug resistance-associated proteins. Alignment of the C219 epitope with the recent crystal structure of the ATP-binding subunit of histidine permease suggests a structural basis for the inhibition of the ATP and drug binding capacity of P-glycoprotein by C219. The results provide a rationale for the development of C219 mutants with improved specificity and affinity that could be useful in antibody-based P-glycoprotein detection and therapy in multidrug resistant cancers.


Rapid change in prescribing behavior in hospitals participating in get with the guidelines-stroke after release of the management of atherothrombosis with clopidogrel in high-risk patients (MATCH) clinical trial results.
Physician prescribing patterns change slowly despite published randomized trials and consensus guidelines. We measure the effect of Management of Atherothrombosis With Clopidogrel in High-Risk Patients (MATCH) trial on discharge prescribing patterns for patients with stroke and those with transient ischemic attack in the Get With The Guidelines (GWTG)-Stroke Program. We analyzed discharge prescribing patterns of antithrombotic medications for patients admitted with ischemic stroke or transient ischemic attack at hospitals participating in GWTG-Stroke between October 2002 to January 2006. Clinical information by quarter was analyzed in relation to publication of the MATCH study. Frequency of discharge prescription of aspirin+clopidogrel post-MATCH publication was compared with the pre-MATCH period after adjusting for patient and hospital characteristics and clustering by hospital. A total of 107 872 patients at 632 sites were eligible to receive antithrombotic therapy at discharge. Use of aspirin+clopidogrel therapy declined from 22.4% to 15.4% of patients after the publication of MATCH (adjusted OR 0.62, 95% CI 0.56 to 0.70, P<0.0001). Analysis by quarter revealed a rapid and sustained decrease in use of aspirin+clopidogrel therapy for the remainder of the study period. A rapid and sustained reduction in the frequency of aspirin+clopidogrel use in ischemic stroke and transient ischemic attack was observed after publication of the MATCH trial in the absence of MATCH-specific GWTG-Stroke initiatives and preceding an American Heart Association guideline update.


A Ten-Year Case-Control Study of Passive Smoke Exposure as a Risk Factor for Pertussis in Children.
The authors conducted a matched case-control study of laboratory-confirmed pertussis cases, occurring from 1/1/1996 to 12/31/2005, in children up to 12 years of age who were members of a large managed care organization. Sixty-five laboratoryconfirmed cases of pertussis were identified. Using multivariable conditional logistic regression analysis, the authors did not detect a statistically significant association between pertussis and household passive exposure to cigarette smoking.


[Screening for asbestos-related conditions].
Screening programs for early detection of asbestos-related cancer have been considered. Conventional X-ray, computed tomography of the thorax, and the biomarkers osteopontin and mesothelin have been critically reviewed in the literature, together with survival data from screening programs in asbestos-exposed populations. Data do not currently support implementation of screening programs for asbestos-exposed persons in Denmark. Since mesothelioma is most often an occupational disease, these patients should be admitted to an occupational clinic for aetiological evaluation.


Ginsenoside Rd attenuates breast cancer metastasis implicating derepressing microRNA-18a-regulated Smad2 expression.
Metastasis remains a major cause of mortality and poor prognosis in breast cancer patients. Anti-metastatic therapies are in great need to achieve optimal clinical outcome in breast cancer patients. Panax Notoginseng Saponins (PNS) has previously been shown to inhibit breast cancer metastasis in mouse. Here the potential anti-metastatic effect of one of the chemical compounds of PNS, ginsenoside Rd (Rd), was further evaluated in mouse mammary carcinoma 4T1 cells. The results revealed that Rd treatment dose-dependently suppressed cell migration and invasion in cultured 4T1 cells. In 4T1 cell-inoculated mice, Rd treatment led to decreased number of tumor lesions in lungs in both spontaneous and experimental metastasis models. Rd treatment resulted in increased expression of Smad2 in cultured 4T1 cells and in tumors grown from inoculated 4T1 cells. Rd treatment decreased the expression of microRNA (miR)-18a in cultured 4T1 cells and in tumors derived from inoculated 4T1 cells. Smad2 was further verified to be a direct target of miR-18a in 4T1 cells. The significant impact of Rd on counteracting miR-18a-medidated downregulation of Smad2 expression was also demonstrated. Together, the current work shows for the first time that Rd treatment attenuates breast cancer metastasis in part through derepressing miR-18a-mediated Smad2 expression regulation.


[5-Fluorouracil and trabeculectomy. A trial of low doses].
Postoperative subconjonctival 5-Fluorouracil (5 FU) may enhance the surgical outcome of trabeculectomies in eyes at high risk of operative failure. 23 patients who received postoperative low doses of subconjonctival 5 Fluorouracil (5 FU) have been studied with a mean follow-up of 10 months. Our indications were: risk factors for a trabeculectomy; postoperative pressure remaining high or absence of filtering bleb. The results were: 42% of complete success (IOP less than 21 mmHg without addition therapy); 29% of qualified success (IOP less than 25 mmHg with additional therapy, or 21 mmHg less than IOP less than 25 mmHg without therapy); 29% of failure. The most frequent complications are corneal, but healed within a short period. The efficacity of the drug remains even with low doses, and with less complications.


Characterization of two distinct chloride channels in cultured dog pancreatic duct epithelial cells.
Cl- secretion by pancreatic duct epithelial cells (PDEC) regulates cellular HCO3- secretion, an important component of the exocrine pancreas. In cystic fibrosis, for example, impaired function of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel results in decreased pancreatic secretion and secondary pancreatic insufficiency. Studies of ion transport by PDEC have been hindered by the lack of a practical in vitro model. We have successfully cultured nontransformed dog PDEC on Vitrogen-coated permeable membranes overlying a feeder layer of myofibroblasts and report the characterization of Cl- channels in these cells. Cl- conductance, assessed through efflux of 125I from PDEC, was stimulated by agents acting via adenosine 3',5'-cyclic monophosphate (cAMP) or cytosolic Ca2+. The Cl- conductances activated by cAMP and Ca2+ were distinct, since they were differentially inhibited by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid and, to a lesser extent, by 5-nitro-2-(3-phenylpropylamino)benzoic acid and diphenylamine-2 carboxylate. Patch-clamp studies confirmed the presence of Cl- channels activated by cAMP and Ca2+, with differential inhibition by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid. The presence of CFTR Cl- channels in PDEC was confirmed by immunoblotting. These cultured PDEC are an optimal model for studies of pancreatic duct secretion.


Sum-frequency generation of continuous-wave light at 194 nm.
Over 2 mW of continuous-wave tunable 194-nm light is produced by sum-frequency mixing approximately 500 mW of 792-nm and 500 mW of 257-nm radiation in beta-barium borate (BBO). The powers in both fundamental beams are enhanced in separate ring cavities whose optical paths overlap in the Brewster-cut BBO crystal. Due to the higher circulating fundamental powers, the sum-frequency-generated power is nearly 2 orders of magnitude greater than previously reported values.


Popular press coverage of eight National Institutes of Health consensus development topics.
The quality of medical journalism has been widely criticized. As part of a larger evaluation study, we analyzed popular press coverage of eight topics selected by the National Institutes of Health for consensus development conferences in 1979 and 1980. Using periodical indexes to identify relevant articles, we analyzed the characteristics of 269 topical articles published in newspapers and magazines in the four years surrounding each conference and examined the role that the conference played in subsequent reporting. Most topics received widespread press interest that culminated around the time of each conference. Consensus findings were widely cited in articles that appeared after the conferences. Articles were mostly factual and balanced, relied on experts, and emphasized major themes covered by the conference. We conclude that the popular press can make an important contribution to the dissemination of new medical information.


The effect of direct cognitive assessment in the Medicare annual wellness visit on dementia diagnosis rates.
To evaluate the relationship between direct cognitive assessment introduced with the Medicare Annual Wellness Visit (AWV) and new diagnoses of dementia, and to determine if effects vary by race. Medicare Limited Data Set 5% sample claims 2003-2014 and the HRSA Area Health Resources Files. Instrumental Variable approach estimating the relationship between AWV utilization and new diagnoses of dementia using county-level Welcome to Medicare Visit rates as an instrument. Three hundred twenty-four thousand three hundred and eighty-five fee-for-service Medicare beneficiaries without dementia when the AWV was introduced in 2011. Annual Wellness Visit utilization was associated with an increased probability of new dementia diagnosis with effects varying by racial group (categorized as white, black, Hispanic/Latino, or Asian based on Social Security Administration data). Hazard ratios (95% confidence intervals) for new dementia diagnosis within 6 months of AWV utilization were as follows: 2.34 (2.13, 2.58) white, 2.22 (1.71, 2.89) black, 4.82 (2.94, 7.89) Asian, and 6.14 (3.70, 10.19) Hispanic (P < .001 for each). Our findings show that estimates that do not control for selection underestimate the effect of AWV on new diagnoses. Dementia diagnosis rates increased with AWV implementation with heterogenous effects by race and ethnicity. Current recommendations by the United States Preventive Services Task Force state that the evidence is insufficient to recommend for or against screening for cognitive impairment in older adults.


Inhibition of G(1) to S phase progression by a novel zinc finger protein P58(TFL) at P-bodies.
We recently reported the translocation of the immunoglobulin (Ig) light chain kappa locus gene with a possible tumor suppressor gene, TFL, in transformed follicular lymphoma. However, the functional significance in cell transformation remains to be elucidated. Here, we first identified two gene products, P58(TFL) and P36(TFL), derived by alternative splicing. The expression was prominent in normal human lymphocytes but defective in some leukemia/lymphoma cell lines. Overexpression of either protein in a mouse pro-B cell line, Ba/F3, and a human leukemia cell line, Jurkat, inhibited G(1) to S phase progression through suppression of retinoblastoma protein (Rb) phosphorylation. The dominant gene product, P58(TFL), colocalized with mRNA-processing body markers, eukaryotic translation initiation factor 2C and DCP1 decapping-enzyme homolog A, but not with a stress granule maker, T-cell intracellular antigen 1, in the cytoplasm. Taken together with the unique CCCH-type zinc finger motif, the present study suggests that P58(TFL) could play an important role in the regulation of cell growth through posttranscriptional modification of cell cycle regulators, at least partially, upstream of Rb.


Speech and language screening for audiologists.
Speech and language screening by audiologists is not new, although few audiologists screen speech and language, which should be an integral component of the audiological evaluation. This article considers ASHA's views about speech and language screening by audiologists, screening tests available to audiologists, and the training of audiologists to screen speech and language.


Clinical Dental Faculty Members' Perceptions of Diagnostic Errors and How to Avoid Them.
Diagnostic errors are increasingly recognized as a source of preventable harm in medicine, yet little is known about their occurrence in dentistry. The aim of this study was to gain a deeper understanding of clinical dental faculty members' perceptions of diagnostic errors, types of errors that may occur, and possible contributing factors. The authors conducted semi-structured interviews with ten domain experts at one U.S. dental school in May-August 2016 about their perceptions of diagnostic errors and their causes. The interviews were analyzed using an inductive process to identify themes and key findings. The results showed that the participants varied in their definitions of diagnostic errors. While all identified missed diagnosis and wrong diagnosis, only four participants perceived that a delay in diagnosis was a diagnostic error. Some participants perceived that an error occurs only when the choice of treatment leads to harm. Contributing factors associated with diagnostic errors included the knowledge and skills of the dentist, not taking adequate time, lack of communication among colleagues, and cognitive biases such as premature closure based on previous experience. Strategies suggested by the participants to prevent these errors were taking adequate time when investigating a case, forming study groups, increasing communication, and putting more emphasis on differential diagnosis. These interviews revealed differing perceptions of dental diagnostic errors among clinical dental faculty members. To address the variations, the authors recommend adopting shared language developed by the medical profession to increase understanding.


Accuracy of chemical shift MR imaging in diagnosing indeterminate bone marrow lesions in the pelvis: review of a single institution's experience.
To re-assess the accuracy of chemical shift imaging in diagnosing indeterminate bone marrow lesions as benign or malignant. We retrospectively reviewed our experience with MR imaging of the pelvis to assess the accuracy of chemical shift imaging in distinguishing benign from malignant bone lesions. Two musculoskeletal radiologists retrospectively reviewed all osseous lesions biopsied since 2006, when chemical shift imaging was added to our routine pelvic imaging protocol. Study inclusion criteria required (1) MR imaging of an indeterminate bone marrow lesion about the pelvis and (2) subsequent histologic confirmation. The study group included 50 patients (29 male, 21 female) with an average age of 67 years (range, 41-89 years). MR imaging results were evaluated using biopsy results as the "gold standard." There were 27 malignant and 23 benign lesions. Chemical shift imaging using an opposed-phase signal loss criteria of less than 20 % to indicate a malignant lesion, correctly diagnosed 27/27 malignant lesions and 14/23 benign lesions, yielding a 100 % sensitivity, 61 % specificity, 75 % PPV, 100 % NPV, and 82 % accuracy. The area under the receiver operator characteristic (ROC) curve was 0.88. The inter-rater and intra-rater agreement K values were both 1.0. Chemical shift imaging is a useful adjunct MR technique to characterize focal and diffuse marrow abnormalities on routine non-contrast pelvic imaging. It is highly sensitive in identifying malignant disease. Despite its lower specificity, the need for biopsy could be eliminated in more than 60 % of patients with benign disease.