Subacute acetaminophen overdose after incremental dosing.
A case of acetaminophen poisoning following the ingestion of 26 g of acetaminophen by incremental dosing over a 25-h period is reported. At presentation, seven h after the last ingestion, the patient experienced hematemesis, the acetaminophen level was 150 micrograms/mL, and the SGOT was normal. The patient recovered uneventfully following N-acetylcysteine therapy. A review of the pharmacology and toxicity of acetaminophen is discussed. The case illustrates the problems of judging hepatotoxic potential in a multiple-dose acetaminophen ingestion and describes the successful use of N-acetylcysteine in a patient with a "subacute" acetaminophen overdose.


Fluorescence-based simultaneous dual oligo sensing of HCV genotypes 1 and 3 using magnetite nanoparticles.
Nucleic acid tests (NATs) have gained an important position in biosensing in the context of the increasing need to meet the stringent requirements for accurate diagnosis of infectious diseases with high sensitivity and selectivity. Recently, the development of new strategies towards multiplex detection of analytes in a single assay is gaining impetus since such an approach would lead to high throughput analysis, leading to substantial benefits in terms of time, infrastructure, labor, and cost. In this work, we demonstrate a facile fluorescence-based simultaneous dual oligo sensing of genotypes 1 and 3 by employing two target sequences (36-mers each) derived from the NS4B and NS5A regions of HCV genome, respectively. A set of 18-mer amine-tagged probes and another set of 18-mer fluorescently-labeled probes that were complementary to each half of the 36-mer target sequences were designed. The amine-tagged probes were immobilized over aldehyde-derivatized magnetite nanoparticles (NPs) via imine bond formation, which was characterized using X-ray photoelectron spectroscopy (XPS) and energy dispersive spectroscopy (EDS) mapping techniques. The successful hybridization between the two probes with their target followed by magnetic removal of the NPs from the solution enabled quantitative analysis of the target by measuring the fluorescence intensity of the residual concentration of the fluorescently-tagged probe. In this manner, the targets corresponding to genotypes 1 and 3 were simultaneously detected with the detection limit in the range of 10-15 nM. The current strategy can potentially be amalgamated with existing nanotechnology-based techniques towards multiplex oligo sensing of several pathogens.


Mucin gene expression and mouse middle ear epithelium.
To investigate the expression of recently identified human mucin genes in an in vitro model of cultured mouse middle ear epithelial cells (MMEEC). MMEEC were established, RNA was extracted and primers were designed for RT-PCR to assess for expression of mucin genes Muc1, Muc2, Muc3, Muc4, Muc5AC, Muc5B, Muc6, Muc7, Muc8, Muc9, Muc10, Muc11/12, Muc13, Muc15, Muc16, Muc17, Muc18, Muc19 and Muc20 expression. Mucin genes Muc1, Muc2, Muc3, Muc4, Muc5AC, Muc5B, Muc9, Muc10, Muc13, Muc15, Muc16, Muc18, Muc19 and Muc20 were identified and expressed in MMEEC. The genes Muc6, Muc7, Muc8, Muc11/12 and Muc17 were not identified. Many of the mucin genes that have been recently identified in human MEE and chinchilla MEE are also expressed in MMEEC. There are differences in expression, however, which may have implications in utilizing various animal models for study of middle ear physiology and pathogenesis; specifically as it relates to mucin gene expression.


A comparative study of composting the solid fraction of dairy manure with or without bulking material: Performance and microbial community dynamics.
The present study compared the development of various physicochemical properties and the composition of microbial communities involved in the composting process in the solid fraction of dairy manure (SFDM) with a sawdust-regulated SFDM (RDM). The changes in several primary physicochemical properties were similar in the two composting processes, and both resulted in mature end-products within 48days. The bacterial communities in both composting processes primarily comprised Proteobacteria and Bacteroidetes. Firmicutes were predominant in the thermophilic phase, whereas Chloroflexi, Planctomycetes, and Nitrospirae were more abundant in the final mature phase. Furthermore, the succession of bacteria in both groups proceeded in a similar pattern, suggesting that the effects of the bulking material on bacterial dynamics were minor. These results demonstrate the feasibility of composting using only the SFDM, reflected by the evolution of physicochemical properties and the microbial communities involved in the composting process.


Using pharmacokinetic-pharmacodynamic modelling as a tool for prediction of therapeutic effective plasma levels of antipsychotics.
In the rat, selective suppression of conditioned avoidance response has been widely reported as a test with high predictive validity for antipsychotic efficacy. Recent studies have shown that the relationship between dopamine D2 receptor occupancy and the suppression of conditioned avoidance response behaviour correlates well with the relationship between human dopamine D2 receptor occupancy and clinical effect. The aim of the present study was to evaluate how pharmacokinetic/pharmacodynamic (PK/PD) predictions of therapeutic effective steady-state plasma levels by means of conditioned avoidance response behaviour in rodents, correlate with clinically relevant plasma exposure for the classical antipsychotic drug haloperidol and four second generation antipsychotics: sertindole, clozapine, risperidone and olanzapine, including selected metabolites. In order to confirm the validity of the present conditioned avoidance response procedure, in vivo striatal dopamine D2 receptor occupancy was determined in parallel using 3H-raclopride as the radioligand. The PK/PD relationship was established by modelling the time-response and time-plasma concentration data. We found the order of dopamine D2 receptor occupancy required to suppress conditioned avoidance response behaviour according to EC50 measurements to be sertindole (+dehydrosertindole)=dehydrosertindole=paliperidone (the metabolite of risperidone)=haloperidol=olanzapine>risperidone>>clozapine. Overall, a good agreement was observed between the rat dopamine D2 receptor occupancy levels providing 50% response in the conditioned avoidance response test and the dopamine D2 receptor occupancy levels reported from responding schizophrenic patients treated with antipsychotics. Predictions of therapeutically effective steady-state levels for sertindole (+dehydrosertindole) and olanzapine were 3-4-fold too high whereas for haloperidol, clozapine and risperidone the predicted steady-state EC50 in conditioned avoidance responding rats correlated well with the therapeutically effective plasma levels observed in patients. Accordingly, the proposed PK/PD model may act as a guide for determining effective plasma concentrations of potential antipsychotics in the clinical setting and thereby accelerating the overall drug development process.


Orexin/hypocretin neurons: chemical phenotype and possible interactions with melanin-concentrating hormone neurons.
We showed earlier that a specific neuron population of the rat lateral hypothalamus, differing from the codistributed melanin-concentrating hormone (MCH) neurons, express both dynorphin (DYN) and secretogranin II (SgII) genes. We demonstrated later that this population corresponds in fact to the newly identified orexin/hypocretin (OX/Hcrt) neurons. In the present study, by revisiting the chemical phenotype of these neurons, we confirm that all of them contain DYN B- and SgII-immunoreactive materials. The roles played by these peptide/protein in OX/Hcrt neurons are still unclear. Double immunocytochemical stainings highlight putative somasomatic, axosomatic and axodendritic contacts between OX/Hcrt and MCH neurons. Adding OX/Hcrt to the culture medium of hypothalamic slices from 8-day-old rats results either in a significant increase of MCH mRNA after 24 h survival or a strong fall after 10 days culture. These results taken together suggest that OX/Hcrt can directly and/or indirectly affect MCH expression, and that both OX/Hcrt and MCH neuron populations interact to respond in a coordinated manner to central and peripheral signals.


A molecular model for the free energy, bending elasticity, and persistence length of wormlike micelles.
An expression for the elastic free-energy density of a wormlike micelle is derived taking into account interactions between its constituent molecules. The resulting expression is quadratic in the curvature and torsion of the centerline of micelle and thus resembles free-energy density functions for polymer chains and helical filaments such as DNA. The model is applied on a wormlike micelle in the shape of a circular arc, open or closed. Conditions under which linear chains in dilute systems transform into toroidal rings are analyzed. Two concrete anisotropic soft-core interaction potentials are used to calculate the elastic moduli present in the derived model, in terms of the density of the molecules and their dimensions. Expressions for the persistence length of the wormlike micelle are found based on the flexural rigidities so obtained. Similar to previous observations, our results indicate that the persistence length of a wormlike micelle increases as the aspect ratio of its constituent molecules increases. A detailed application of the model on wormlike micelles of toroidal geometry, along with employing statistical-thermodynamical concepts of self-assembly is performed, and the results are found to be well consistent with the literature. Steps to obtain the material parameters through possible experiments are discussed.


Keratinolytic activity of purified alkaline keratinase produced by Scopulariopsis brevicaulis (Sacc.) and its amino acids profile.
Sodium dodecyl sulfate-polyacrlyamide gel electrophoresis (SDS-PAGE) was used to assess the purity and molecular weight of the previously purified alkaline keratinase enzyme of Scopulariopsis brevicaulis. The enzyme was homogenous, as seen by a single band of protein, and had an apparent molecular weight of 28.5 kDa. Amino acid profile of the purified keratinase revealed that it was composed of 14 different amino acids with high proportions of glutamic acid (20.86%), alanine (14.52%), glycine (14.21%), leucine (8.59%) and serine (7.81%). The enzyme contained moderate amounts of valine (6.01%), threonine (5.58%) and phenyl alanine (5.22%). The purified enzyme of S. brevicaulis exerted a potent keratinolytic activity and was capable to hydrolyze different keratinaceous materials with highest activity on chicken feathers followed by human nails and human hair.


Postprostatectomy ultrasound-guided transrectal implantation of gold markers for external beam radiotherapy. Technique and complications rate.
Postprostatectomy radiotherapy (RT) improves survival in adjuvant and salvage settings. The implantation technique and complications rate of gold markers in the prostate bed for high-precision RT were analyzed. Patients undergoing postprostatectomy RT for prostate-specific antigen (PSA) relapse or high-risk disease were enrolled in the study. Under transrectal ultrasound guidance, three fine gold markers were implanted in the prostate bed and the technical difficulties of insertion were documented. Patients received our self-designed questionnaires concerning complications and pain. The influence of anticoagulants and coumarins on bleeding was analyzed, as was the effect of potential risk factors on pain. In 77 consecutive patients, failure of marker implantation or marker migration was seen in six cases. Rectal bleeding was reported by 10 patients and 1 had voiding complaints. No macroscopic hematuria persisting for more than 3 days was observed. Other complications included rectal discomfort (n = 2), nausea (n = 1), abdominal discomfort (n = 1), and pain requiring analgesics (n = 4). No major complications were reported. On a 0-10 visual analogue scale (VAS), the mean pain score was 3.7. No clinically significant risk factors for complications were identified. Transrectal implantation of gold markers in the prostate bed is feasible and safe. Alternatives like cone beam computed tomography (CBCT) should be considered, but the advantages of gold marker implantation for high-precision postprostatectomy RT would seem to outweigh the minor risks involved.


Trastuzumab therapy vs tetracycline controlled ERBB2 downregulation: influence on tumour development in an ERBB2-dependent mouse tumour model.
Trastuzumab (Herceptin) has improved therapy of breast cancer. Only patients overexpressing ERBB2 are treated with trastuzumab, whereas its use in tumours without ERBB2 expression is useless. This led to the concept that the subgroup of trastuzumab-sensitive tumours is 'ERBB2-dependent', meaning that ERBB2 signalling is indispensable for growth of these tumours. We used a mouse model that allows anhydrotetracycline (ATc)-controlled downregulation of ERBB2 in tumour tissue. ERBB2 mRNA and protein expression were downregulated below detection limit leading to a macroscopically complete tumour remission within 14 days. Tumour remission was accompanied by a strong decrease in proliferation, a moderate increase in apoptosis, as well as dephosphorylation of ERK1/2 and AKT/PKB. These data clearly indicate ERBB2 dependence. Therefore, a high sensitivity to trastuzumab may be suspected. Surprisingly, trastuzumab caused a much weaker effect compared to ATc-induced ERBB2 downregulation, although a decrease in ERBB2 membrane localisation was induced. Only a slight decrease in proliferation and a weak transient increase in apoptosis were observed. Interestingly, tumours responded to trastuzumab by a sharp fivefold increase in phosphorylated AKT/PKB as well as a 3.5- and 5.3-fold increase in AKT1 and AKT2 mRNA levels, respectively. In conclusion, 'ERBB2 dependence' is not sufficient to define trastuzumab-responsive tumours. The suboptimal effect of trastuzumab compared to the maximally possible effect induced by ATc demonstrates a high potential for improved ERBB2 blocking therapies.


Fermenting molasses and a synthetic odour blend to attract blood-fed Anopheles coluzzii.
Collecting blood-fed mosquitoes to monitor pathogen presence or to gather information on the host blood meal is often challenging. Fermenting molasses can be used to produce carbon dioxide to attract host-seeking mosquitoes, however, earlier work indicated that it may also attract blood-fed mosquitoes in the field. In the current study, these field results were validated in an experimental setting using a large cage setup with Anopheles coluzzii (Diptera, Culicidae). Blood-fed mosquitoes were indeed attracted to fermenting molasses with the highest attraction at 72 hours post feeding, which was used for subsequent experiments. Next, it was tested if fermentation of molasses is required for attraction, and whether it acts as an oviposition attractant, increases egg laying, or increases mosquito survival. The compounds that could be responsible for attraction were identified by combined electrophysiology and chemical analyses and formulated into a synthetic blend. Fermenting molasses attracted blood-fed mosquitoes in the large cage study, while fermenting sugar and non-fermenting molasses did not. The fecundity of blood-fed mosquitoes increased after feeding on fermenting molasses, however, compounds emanating from molasses did not trigger oviposition. The synthetic blend attracted blood-fed mosquitoes and may be used to determine mosquito host selection and for xenomonitoring, as 'flying syringes' to detect non-vector borne pathogens.


Application of the official AOAC chloresterol Method to a wide variety of food products.
This paper presents analytical data on the cholesterol content of selected consumer food products including some fats and oils. The cholesterol data are grouped by food products. To determine the reproducibility of cholesterol values, recovery data were obtained from samples of pure vegetable shortening spiked at 40 and 20 mg cholesterol (as cholesteryl palmitate)/100 g fat. Average recoveries were 97.1% and 95.5% with coefficients of variation of 1.27 and 3.24%, respectively.


Lysosomal enzyme delivery by ICAM-1-targeted nanocarriers bypassing glycosylation- and clathrin-dependent endocytosis.
Enzyme replacement therapy, a state-of-the-art treatment for many lysosomal storage disorders, relies on carbohydrate-mediated binding of recombinant enzymes to receptors that mediate lysosomal delivery via clathrin-dependent endocytosis. Suboptimal glycosylation of recombinant enzymes and deficiency of clathrin-mediated endocytosis in some lysosomal enzyme-deficient cells limit delivery and efficacy of enzyme replacement therapy for lysosomal disorders. We explored a novel delivery strategy utilizing nanocarriers targeted to a glycosylation- and clathrin-independent receptor, intercellular adhesion molecule (ICAM)-1, a glycoprotein expressed on diverse cell types, up-regulated and functionally involved in inflammation, a hallmark of many lysosomal disorders. We targeted recombinant human acid sphingomyelinase (ASM), deficient in types A and B Niemann-Pick disease, to ICAM-1 by loading this enzyme to nanocarriers coated with anti-ICAM. Anti-ICAM/ASM nanocarriers, but not control ASM or ASM nanocarriers, bound to ICAM-1-positive cells (activated endothelial cells and Niemann-Pick disease patient fibroblasts) via ICAM-1, in a glycosylation-independent manner. Anti-ICAM/ASM nanocarriers entered cells via CAM-mediated endocytosis, bypassing the clathrin-dependent pathway, and trafficked to lysosomes, where delivered ASM displayed stable activity and alleviated lysosomal lipid accumulation. Therefore, lysosomal enzyme targeting using nanocarriers targeted to ICAM-1 bypasses defunct pathways and may improve the efficacy of enzyme replacement therapy for lysosomal disorders, such as Niemann-Pick disease.


Using information to deliver safer care: a mixed-methods study exploring general practitioners' information needs in North West London primary care.
The National Health Service in England has given increasing priority to improving inter-professional communication, enabling better management of patients with chronic conditions and reducing medical errors through effective use of information. Despite considerable efforts to reduce patient harm through better information usage, medical errors continue to occur, posing a serious threat to patient safety. This study explores the range, quality and sophistication of existing information systems in primary care with the aim to capture what information practitioners need to provide a safe service and identify barriers to its effective use in care pathways. Data were collected through semi-structured interviews with general practitioners from surgeries in North West London and a survey evaluating their experience with information systems in care pathways. Important information is still missing, specifically discharge summaries detailing medication changes and changes in the diagnosis and management of patients, blood results ordered by hospital specialists and findings from clinical investigations. Participants identified numerous barriers, including the communication gap between primary and secondary care, the variable quality and consistency of clinical correspondence and the inadequate technological integration. Despite attempts to improve integration and information flow in care pathways, existing systems provide practitioners with only partial access to information, hindering their ability to take informed decisions. This study offers a framework for understanding what tools should be in place to enable effective use of information in primary care.


Catalytic anti-oxidative stress for osteoarthritis treatment by few-layered phosphorene.
As one of the most common representations of articular cartilage damage, osteoarthritis (OA) is characterized by the apoptosis and dysfunction of chondrocytes as well as the progressive degradation of extracellular matrix, of which the main components are glycosaminoglycan and type Ⅱ collagen. Few-layered phosphorene (FLP) has been attracting great attentions in biomedical fields owing to the excellent capability of in-situ catalysis for scavenging oxidate-associated molecules, especially the reactive oxygen species (ROS) and reactive nitrogen species (RNS). Herein, FLP has been fabricated and employed for articular cartilage protection by means of deleting oxidate-associated molecules. The in vitro results show that as low as 200 μg/mL FLP is capable of diminishing oxidative damages on the osteoarthritic chondrocytes through the efficient elimination of ROS, H2O2 and NO. Meanwhile, the cartilage matrix protection has also been achieved at 200 μg/mL FLP by the uniform restoration of glycosaminoglycan and type Ⅱ collagen. FLP enables the nanocatalytic treatment for the overloaded oxidative stress in the injured articular cartilage and represents a promising alternative for osteoarthritis therapy.


Spatial heterogeneity, population "regulation" and local extinction in simulated host-parasitoid interactions.
Simulation models have recently been used to suggest that spatial heterogeneity, acting on small spatial scales within local populations, may allow parasitoids and other natural enemies to "regulate" host or prey populations in ways that would not be detected by conventional (k-factor) analyses of life table data. However, additional study of these models suggests that local extinction may be a frequent event in the simulated interactions. The "spreading of risk" concept appears more applicable to the simulated populations than a classical view emphasizing tight regulation around stable equilibrium points. The spreading of risk viewpoint also appears to shed additional light on questions raised in the recent debate between Dempster (1983); Hassel (1985); Dempster and Pollard (1986), concerning the modeling of spatial heterogeneity and "regulation" in temperate-zone insect populations.


Multiplexed electrochemical immunoassay of biomarkers using metal sulfide quantum dot nanolabels and trifunctionalized magnetic beads.
A novel multiplexed stripping voltammetric immunoassay protocol was designed for the simultaneous detection of multiple biomarkers (CA 125, CA 15-3, and CA 19-9 used as models) using PAMAM dendrimer-metal sulfide quantum dot (QD) nanolabels as distinguishable signal tags and trifunctionalized magnetic beads as an immunosensing probe. The probe was prepared by means of co-immobilization of primary monoclonal anti-CA 125, anti-CA 15-3 and anti-CA 19-9 antibodies on a single magnetic bead. The PAMAM dendrimer-metal sulfide QD nanolabels containing CdS, ZnS and PbS were synthesized by using in situ synthesis method, which were utilized for the labeling of polyclonal rabbit anti-CA 125, anti-CA 15-3 and anti-CA 19-9 detection antibodies, respectively. A sandwich-type immunoassay format was adopted for the simultaneous determination of target biomarkers in a low-binding microtiter plate. The subsequent anodic stripping voltammetric analysis of cadmium, zinc, and lead components released by acid from the corresponding QD nanolabels was conducted at an in situ prepared mercury film electrode based on the difference of peak potentials. Experimental results indicated that the multiplexed immunoassay enabled the simultaneous detection of three cancer biomarkers in a single run with wide dynamic ranges of 0.01-50 U mL(-1) and detection limits (LODs) of 0.005 U mL(-1). Intra-assay and inter-assay coefficients of variation (CVs) were less than 7.2% and 10.4%, respectively. No significant differences at the 0.05 significance level were encountered in the analysis of 10 clinical serum specimens between the multiplexed immunoassay and a commercially available enzyme-linked immunosorbent assay (ELISA).


A new SUMO ligase in the DNA damage response.
SUMO is a small ubiquitin-like protein that is attached to target proteins, altering their localization and function. The condensin and cohesin-related Smc5/6 complex has been linked to DNA repair and checkpoint responses, but details of its molecular function have remained obscure. Recent reports show one subunit of the complex is a SUMO ligase, providing another link between protein sumoylation and DNA damage responses.


Histologic and histomorphometric analysis of posterior region of the human temporomandibular disc.
The aim of this study was to analyze histologic and histomorphometric features of the articular disc in groups with and without disc displacement. A sample of 39 temporomandibular joints TMJs (31 case specimens, 8 control specimens) from 28 patients (mean age 31.2 years) were recruited for this study. The patients were considered to be affected and treated surgically with disc repositioning when presenting painful clinical signs of disc displacement after unsuccessful nonsurgical treatment for at least 6 months. Of the control patients, 4 presented condyle fracture which required opening to be reduced for treatment, and 4 displayed active condyle hyperplasia. The posterior region of the disc was removed and sent for histologic and histomorphometric analysis. Histologic (hematoxylin-eosin) and histomorphometric (picro-Sirius red) analyses were performed. Statistically significant differences between the analyzed groups were accessed through the chi-squared test (P <or= .05). The Mann-Whitney U test was used to observe the differences between mean values when variables did not present normal distribution [Kolmogorov-Smirnov(a) test]. There were no significant differences between the groups in relation to the parameters studied by histologic and histomorphometric analysis (using or not using polarization). To the limits of this study, there were no significant histologic and histomorphometric differences in the articular disc between groups with and without TMJ dysfunction.


[Regional and peripheral arterial stiffness measured by pOpmetre® in patients with Cvx risk factor, link with carotid plaques].
Aortic stiffness is a functional and structural consequence of ageing and arteriosclerosis. Regional arterial stiffness can be easily evaluated using pOpmetre(®) (Axelife SAS, France). This new technique assesses the pulse wave transit time (TT) between the finger (TTf) and the toe (TTt). Based on height chart, regional pulse wave velocity (PWV) between the toe and the finger can be estimated (PWVtf). pOpscore(®) index is also calculated as the ratio between PWVtoe and PWVfinger and can be considered as a peripheral vascular stiffness index. The aim of the study was to evaluate the relationship between pOpmetre(®) indices and the presence of carotid plaques in a population with cardiovascular risk factors. In 77 consecutive patients recruited for a vascular screening for atherosclerosis (46 men aged 54 ± 2 years; 31 women aged 49 ± 3 years; ns), the difference between TTt and TTf (called Dt-f), the regional pulse wave velocity between the toe and the finger (PWVtf = constant × height/Dt-fm/s) and pOpscore(®) were measured by pOpmetre(®). Presence of carotid plaques was assessed using ultrasound imaging. The local aortic stiffness (AoStiff) was evaluated by the Physioflow(®) system. No difference was found between patients with or without carotid plaques (n=25 versus 52) for Ankle-Brachial Pressure Index (ABPI: 1.15 ± 0.04 versus 1.12 ± 0.03), nor for diastolic or systolic blood pressure (87 ± 3 versus 82 ± 2; 137 ± 3 versus 132 ± 2 mmHg). The first group was older than the second (59 ± 2 versus 49 ± 2 years, P<0.002) with a larger intimae media thickness (0.69 ± 0.02 versus 0.63 ± 0.01 mm, P<0.004), a higher AoStiff (10.4 ± 0.7 versus 8.2 ± 0.5m/s, P<0.02), and PWVtf (14.3 ± 1.0 versus 10.7 ± 0.7 m/s, P<0.004) and a shorter Dt-f (57.9 ± 5.1 versus 73.5 ± 3.5 ms, P<0.01). PWVtf (r(2)=0.49, P<0.0001) and Dt-f (r(2)=0.54, P<0.0001) correlated with age. A significant difference in pOpscore(®) index was observed between both groups (1.51 ± 0.3 versus 1.41 ± 0.2, P<0.006). Our results show a significant arterial stiffness indices measured by pOpmetre(®) in patients with and without carotid plaques.


Inhibition in vitro of the replication of murine cytomegalovirus or reovirus type 3 by the glutamine analogue acivicin.
The replication of synchronised cultures of Balb/c L-3T3 fibroblasts was shown to require glutamine at a concentration of at least 0.12 mM, but the replication of murine cytomegalovirus (MCMV) or reovirus type 3 in the cells required at least 0.25 mM glutamine. In the presence of 2 mM glutamine, the glutamine analogue acivicin inhibited DNA synthesis at a minimum concentration of 2 microM in uninfected cells but partially inhibited the replication of MCMV at 0.12 microM and reovirus at 0.03 microM, and totally inhibited MCMV production at 1.0 microM and reovirus at 0.5 microM. Although the therapeutic index in this instance is not great, it does offer encouragement to explore other amino acid analogues as possible broad-spectrum antiviral agents.


Benefit of Extended Surveillance of Low-Risk Pancreatic Cysts After 5-Year Stability: A Systematic Review and Meta-Analysis.
Low-risk branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) lacking worrisome features (WF) and high-risk stigmata (HRS) warrant surveillance. However, their optimal duration, especially among cysts with initial 5 years of size stability, warrants further investigation. We systematically reviewed the surveillance of low-risk BD-IPMNs and investigated the incidence of WF/HRS and advanced neoplasia, high-grade dysplasia, and pancreatic cancer during the initial (<5 years) and extended surveillance period (>5-years). A systematic search (CRD42020117120) identified studies investigating long-term IPMN surveillance outcomes of low-risk IPMN among the Cochrane Library, Embase, Google Scholar, Ovid Medline, PubMed, Scopus, and Web of Science, from inception until July 9, 2021. The outcomes included the incidence of WF/HRS and advanced neoplasia, disease-specific mortality, and surveillance-related harm (expressed as percentage per patient-years). The meta-analysis relied on time-to-event plots and used a random-effects model. Forty-one eligible studies underwent systematic review, and 18 studies were meta-analyzed. The pooled incidence of WF/HRS among low-risk BD-IPMNs during initial and extended surveillance was 2.2% (95% CI, 1.0%-3.7%) and 2.9% (95% CI, 1.0%-5.7%) patient-years, respectively, whereas the incidence of advanced neoplasia was 0.6% (95% CI, 0.2%-1.00%) and 1.0% (95% CI, 0.6%-1.5%) patient-years, respectively. The pooled incidence of disease-specific mortality during initial and extended surveillance was 0.3% (95% CI, 0.1%-0.6%) and 0.6% (95% CI, 0.0%-1.6%) patient-years, respectively. Among BD-IPMNs with initial size stability, extended surveillance had a WF/HRS and advanced neoplasia incidence of 1.9% (95% CI, 1.2%-2.8%) and 0.2% (95% CI, 0.1%-0.5%) patient-years, respectively. A lower incidence of advanced neoplasia during extended surveillance among low-risk, stable-sized BD-IPMNs was a key finding of this study. However, the survival benefit of surveillance among this population warrants further exploration through high-quality studies before recommending surveillance cessation with certainty.


Surgical treatment of giant fusiform aneurysm of extracranial internal carotid artery in a child: 1 case report and literature review.
The objective of this study is to report diagnosis and treatment results of giant fusiform aneurysm of extracranial internal carotid artery in a child and review the relative reference to enhance the knowledge of it. A 13-year-old female patient was admitted to the hospital with chief complaint of pulsatile mass in her left cervical area for 1 year, which had abruptly augmented 2 months earlier. No cervical trauma or infection appeared. A 3.5 x 6-cm mass in the left cervical angle of the mandible was observed to beat with pulse without vascular murmur. Digital subtraction angiography and CTA showed a giant fusiform aneurysm 6 cm in length and 3 cm in maximum diameter from the beginning of the left internal carotid artery. After resection of the aneurysm, vascular continuity was restored by interposition of a 6-mm PTFE graft. Pathologic examinations showed hyperplasia in artery wall, fibroplasias and mucous degeneration, hyalinization, chronic inflammatory cell infiltration, and local calcification. The recovery was good without complication. The patient was followed up in 2 years postoperation. The CTA and color Doppler ultrasonography showed good configuration and distribution of the internal carotid artery and good circulation in vascular cavity. Giant fusiform aneurysm of extracranial internal carotid artery in children is rather rare. The main causes are atherosclerosis, infection and trauma, incurring by carotid endarterectomy, and the like. Most of the clinical manifestations are pulsatile nontender mass. It can cause severe complications, such as brain ischemia or cervical hematorrhea incurred by rupture of aneurysm. The therapy includes resection of the aneurysm and restoration of flow with venous, arterial, or prosthetic graft or endovascular stenting.


The design of future cost-benefit studies.
An economic evaluation is designed to prioritize expenditure, aid decision making, and inform medical audit. A good economic evaluation is explicit and clearly describes the alternative therapies to be evaluated. The evaluation takes into consideration the cost of each component and measures outcome in economic benefit and physical, social, and psychologic well-being. A variety of approaches can be used to assess quality of life, and a good economic evaluation will use a range of measures. Costs and outcomes of health care interventions typically accrue across time periods, and the analysis must allow for this. Similarly, data must answer the question; how much does it cost to identify one additional unit of benefit? Because all evaluations are imprecise both in cost and outcome, sensitivity analysis is needed to determine the effect that different assumptions have on the results.


Galanin hyperinnervation upregulates choline acetyltransferase expression in cholinergic basal forebrain neurons in Alzheimer's disease.
Fibers containing galanin (GAL) enlarge and hyperinnervate cholinergic basal forebrain (CBF) nucleus basalis (NB) neurons in late-stage Alzheimer's disease (AD), yet the physiological consequences of this phenomenon are unclear. To determine whether GAL hyperinnervation of cholinergic NB neurons modulates the expression of genes critical to cholinergic transmission [e.g. acetylcholine (ACh) metabolism and ACh receptors] in AD. Single-cell gene expression profiling was used to compare cholinergic mRNA levels in non-GAL-hyperinnervated NB neurons in tissue autopsied from cases classified as having no cognitive impairment (NCI) or late-stage AD (AD/GAL-) and in GAL-hyperinnervated (AD/GAL+) NB neurons from the same AD subjects. AD/GAL+ cells displayed a significant upregulation in choline acetyltransferase (ChAT) mRNA expression compared to NCI and AD/GAL- cells. GAL fiber hyperinnervation of cholinergic NB neurons upregulates the expression of ChAT, the synthetic enzyme for ACh, suggesting that GAL regulates the cholinergic tone of CBF neurons in AD.


Biographical sketch: Sir John Charnley MD, 1911-1982.
This biographical sketch of Sir John Charnley corresponds to the historic text, The Classic: The Bonding of Prostheses to Bone by Cement, available at DOI 10.1007/s11999-010-1545-8 .


A Randomized Control Trial to Evaluate the Effect of Local Instillation of Mitomycin-C at the Porta after Kasai Portoenterostomy in Patients of Biliary Atresia.
Kasai portoenterostomy (KPE) is the initial treatment for biliary atresia (BA). Even after initial jaundice clearance, a significant number of children presented with the reappearance of symptoms due to ongoing fibrosis involving porta and intrahepatic ducts. Mitomycin-C (MMC) is an antifibrotic agent, and the study hypothesized that local application of MMC at porta can decrease fibrosis, which can improve jaundice clearance and lead to better native liver survival (NLS). This prospective randomized control trial included children with BA, who were allocated to groups A or B. The patients in both groups underwent standard KPE; in addition, a 5 French infant feeding tube (IFT) was placed near the porta through the Roux limb in Group B children. During the postoperative period, MMC was locally instilled over the porta in Group B children through IFT. Postoperative jaundice clearance and NLS were assessed and compared. A total of 27 children were enrolled in the study, 16 in Group A and 11 in Group B. Both groups were comparable preoperatively. Although the NLS was not statistically significant in Group B, the survival was quite higher, that was 91%, 81%, and 73% at 6 months, 1 year, and 2 years, respectively, compared to 63%, 50%, and 38% in Group A. Children in Group B clinically showed an early jaundice clearance and a better trend of serial bilirubin levels as well as longer NLS than Group A, but it was not statistically significant. The procedure was technically easy, and no complication was encountered related to surgical technique or MMC instillation.


Impact of an alcohol-based hand sanitizer intervention on the spread of viruses in homes.
The objectives of this study were to determine the movement of a virus throughout a household and the impact of an alcohol-based hand sanitizer (ABHS) on reducing the movement and exposure of the virus to household members. Bacterial virus MS-2 was used as the surrogate for human enteric and respiratory viruses. Seven households with families having at least two children in the age range of 2-18 living in the home were used in this study. The hands of one adult family member were contaminated with 1 × 10(8). MS-2 bacteriophage in each home. After 8 h, the hands of each family member (10 fingers) and 20 frequently touched fomites were sampled to determine baseline contamination without intervention. Within 8 h, MS-2 was detected on all of the family member's hands and most of the fomites. The intervention consisted of providing the families in all selected homes with bottles of an ABHS, which were placed in the kitchen, bathrooms, and nurseries. Smaller individual bottles were provided for each family member greater than 12 years old to place in purses, pockets, backpacks, etc. The families were instructed to use the ABHS one time or three times during the day. For one and three uses, a statistically significant reduction of virus on un-inoculated and inoculated hands of ~99% occurred within 8 h. Similar reductions occurred on fomites throughout the households (97-99%). These results demonstrate that the use of an ABHS can significantly reduce transfer of a virus to the hands, and to the commonly touched surfaces within the household.


Obstacles to cancer immunotherapy: expression of membrane complement regulatory proteins (mCRPs) in tumors.
Monoclonal antibodies (mAbs) are being increasingly used in cancer therapy owing to their ability to recognize specifically cancer cells and to activate complement- and cell-mediated cytotoxicity and/or to induce growth arrest or apoptosis. The therapeutic potential of anticancer antibodies is significantly limited due to the ability of cancer cells to block killing by complement. Of the multiple resistance strategies exploited by cancer cells, the expression of membrane complement regulatory proteins (mCRPs), such as CD46 (membrane cofactor protein (MCP)), CD55 (decay-accelerating factor (DAF)), CD35 (complement receptor type-1 (CR1)) and CD59, has received most attention. CD46, CD55 and CD35 block the complement cascade at the C3 activation stage and CD59 prevents assembly of the membrane attack complex of complement (MAC). These proteins protect normal tissues from accidental injury by activated complement, but also confer resistance on cancer cells, thereby limiting the effect of complement-fixing monoclonal antibodies. Expression of mCRPs on malignant cells is highly variable, yet there is clear indication that certain tumors express higher mCRP levels than the normal tissue from which they have evolved. mCRP level of expression and cellular location may also vary during malignant transformation and between differentiated and undifferentiated tumors. Neutralizing anti-mCRP mAbs have been used in vitro to elucidate the significance of mCRP expression to the tumor complement resistance phenotype. In general, CD59 appears to be the most effective mCRP protecting tumor cells from complement-mediated lysis. Nevertheless, it acts additively, and in certain tumors even synergistically, with CD55 and CD46. It is envisaged that treatment of cancer patients with mCRP blocking antibodies targeted specifically to cancer cells in combination with anticancer complement-fixing antibodies will improve the therapeutic efficacy.


The mean age of menarche among Chinese schoolgirls declined by 6 months from 2005 to 2014.
This study assessed the trends in the age at menarche in Chinese schoolgirls from the majority Han group and 21 ethnic minorities from 2005 to 2014. We also compared the group differences during the study period. A total of 344 230 girls aged 9-18 years were extracted from the 2005, 2010 and 2014 Chinese National Survey on Students' Constitution and Health. The age at menarche for each subgroup was estimated by probit analysis. The chi-square test and Z-test were used to compare the differences between the groups. The overall average age at menarche in Chinese schoolgirls decreased from 12.8 years in 2005 to 12.3 years in 2014. The Han girls and girls from 17 ethnic minorities showed decreasing trends in the age at menarche, while four ethnic minorities demonstrated fluctuating increasing trends over time. The gaps in age at menarche between the Han group and 14 of the ethnic minorities became smaller over the study period and were similar by 2014. The overall findings were a decrease in the age at menarche in China and smaller gaps between the majority Han group and ethnic minority groups. Ethnic-specific public health policies are urgently needed on issues such as contraception.


Diversity in the serine recombinases.
Most site-specific recombinases fall into one of two families, based on evolutionary and mechanistic relatedness. These are the tyrosine recombinases or lambda integrase family and the serine recombinases or resolvase/invertase family. The tyrosine recombinases are structurally diverse and functionally versatile and include integrases, resolvases, invertases and transposases. Recent studies have revealed that the serine recombinase family is equally versatile and members have a variety of structural forms. The archetypal resolvase/invertases are highly regulated, only affect resolution or inversion and they have an N-terminal catalytic domain and a C-terminal DNA binding domain. Phage-encoded serine recombinases (e.g. phiC31 integrase) cause integration and excision with strictly controlled directionality, and have an N-terminal catalytic domain but much longer C-terminal domains compared with the resolvase/invertases. This high molecular weight group also contains transposases (e.g. TnpX from Tn4451). Other transposases, which belong to a third structurally different group, are similar in size to the resolvase/invertases but have the DNA binding domain N-terminal to the catalytic domain (e.g. IS607 transposase). These three structural groups represented by the resolvase/invertases, the large serine recombinases and relatives of IS607 transposase correlate with three major groupings seen in a phylogeny of the catalytic domains. These observations indicate that the serine recombinases are modular and that fusion of the catalytic domain to unrelated sequences has generated structural and functional diversity.


Multiple 5' terminal cap structures in late polyoma virus RNA.
Nuclear and cytoplasmic polyoma virus-specific RNA extracted from 32P-labeled mouse embryo cells late during productive viral infection was analyzed for the presence of 5' terminal capped structures by complete digestion with RNAases T1, T2 and A, followed by two-dimensional electrophoretic fractionation. Seven major cap I structures (m7 GpppNm1pN2p) were observed in both cases. These termini were further characterized by digestion with penicillium nuclease P1, followed by product analysis in a variety of alternative separate systems. Each structure had an individual combination of N1 and N2 nucleotides, where N1 was always a purine nucleotide but N2 was any nucleotide subject to the single exception that m7GpppGmpCp is found only in low yield. Four different cap II derivatives (m7GpppNm1pNm2pN3p) of four of the cap I structures were also detected in cytoplasmic RNA. None of the termini described derived from contaminating host cell RNA. All of these cap structures mapped on the polyoma viral DNA genome between 66 and 71 map units, a region distant from the 5' end of the bodies of two of the three late polyoma mRNAs. All the polyoma virus-specific cap structures, however, were present in each of the purified 16S, 18S and 19s late mRNAs. These data suggested that families of capped leader sequences of varying sizes are attached to the main body of each late polyoma mRNA species by a splicing mechanism.


Effect of low-dose atropine eyedrops on pupil metrics: results after half a year of treatment and cessation.
To evaluate the effect of low-dose atropine eyedrops on pupil metrics. This study was based on a randomized, double-masked, placebo-controlled, and cross-over trial in mainland China. In phase 1, subjects received 0.01% atropine or placebo once nightly. After 1 year, the atropine group switched to placebo (atropine-placebo group), and the placebo group switched to atropine (placebo-atropine group). Ocular parameters were measured at the crossover time point (at the 12th month) and the 18th month. Of 105 subjects who completed the study, 48 and 57 children were allocated into the atropine-placebo and placebo-atropine groups, respectively. After cessation, the photopic pupil diameter (PD) and mesopic PD both decreased (- 0.46 ± 0.47 mm, P < 0.001; - 0.30 ± 0.74 mm, P = 0.008), and the constriction ratio (CR, %) increased (4.39 ± 7.54, P < 0.001) compared with values at the crossover time point of the atropine-placebo group; pupil metrics of the atropine-placebo group had no difference from the values at the crossover time point of the placebo-atropine group. After 6 months of treatment, the photopic PD and the mesopic PD increased (0.54 ± 0.67 mm, P < 0.001; 0.53 ± 0.89 mm, P < 0.001), the CR (%) decreased (- 2.53 ± 8.64, P < 0.001) compared with values at the crossover time point of the placebo-atropine group. There was no significant relationship between pupil metrics and myopia progression during 0.01% atropine treatment. Pupil metrics and the CR could return to pre-atropine levels after cessation. Pupil metrics had no significant effect on myopia progression during treatment.


IN-RATIO: a new test to increase diagnostic sensitivity in ulnar nerve entrapment at elbow.
Motor conduction velocity may yield false-negative results in mild ulnar nerve entrapment at elbow (UNE). There is evidence that the clinical heterogeneity of UNE may be due to the different involvement of fascicles. We hypothesized that, if fibres to FDI are more damaged than fibres to ADM, a relative slowing of motor conduction velocity (CV) at the segment across the elbow recording from FDI (FDI-CV) versus CV at the same segment recording from ADM (ADM-CV) would occur. We calculated the ratio between FDI-CV and ADM-CV (IN-RATIO) in 60 consecutive UNE patients, 40 norms, and 16 patients with lower cervical radiculopathy. The UNE sample consisted of (1) patients with neurophysiological evidence (UNE NF+), (2) patients without neurophysiological evidence (UNE NF-). We evaluated the possible usefulness of the IN-RATIO to increase sensitivity in diagnosing UNE. The IN-RATIO was lower in the UNE NF- than in norms (p<0.001) and cervicobrachialgia sample (p=0.02). We found that if the IN-RATIO is <or=0.97, its sensitivity in diagnosing UNE NF- is 68%, specificity 91%. Fibres to FDI have a higher susceptibility to damage than fibres to ADM, and the IN-RATIO is a useful neurophysiological parameter to increase diagnostic sensitivity. Our results demonstrate the usefulness of a new neurophysiological parameter in improving diagnosis of UNE.


Effect of the dietary black gram trypsin inhibitory fraction on the pancreatic activity of male albino mice.
The effect of raw black gram and black gram trypsin inhibitory fraction on the pancreatic function of male albino mice has been evaluated. Animals were fed autoclaved black gram (Group I), raw black gram (Group II) and autoclaved black gram incorporated with black gram trypsin inhibitory fraction (Group III). Pancreatic total protease, trypsin and amylase activities were elevated significantly in Group II and III animals. Analyses of intestinal contents showed a constant level of total protease activity in all the groups, along with a significant reduction in trypsin level in Groups II and III. Increased U-14C-lysine incorporation in pancreas and an enhanced level of amylase in intestinal contents show the hyperactivity of the pancreas in Groups II and III. Pancreas weights increased in Groups II and III. Pancreatic protein/mg pancreas and RNA/DNA ratio remained constant in all three groups. It is concluded with histological studies that the black gram trypsin inhibitor increased the pancreatic activity of mice by developing the cellular hyperplasia of the pancreas.


Comparison of the tissue distribution of reverse transcriptase, p30 and type-C virus in a gibbon ape with lymphocytic leukemia.
Tissues obtained at necropsy from a 7 year old male gibbon ape with malignant lymphoma and leukemia were analyzed by electron microscopic, immunological and enzymological techniques to determine the comparative localization of tumor cells and virus throughout the body. In general, the different assays correlated well; the reverse transcriptase (RT) assay and p30 radioimmunoassay (RIA) being the most sensitive, although the RT assay was able to detect activity in one tissue scored negative by p30 RIA. Tissues were infiltrated with tumor cells to varying degrees which correlated well with the level of virus markers in most cases with the exception of the liver and kidney. In these 2 organs there was marked infiltration of free virus and tumor cells but there was no evidence of virus infection or production by these cells.


Myeloma bone disease.
Bone destruction is a hallmark of multiple myeloma, and recent studies demonstrated a strong interdependence between tumor progression and bone resorption. Increased bone resorption as a major characteristic of multiple myeloma is caused by osteoclast activation and osteoblast inhibition (uncoupling). Myeloma cells alter the local regulation of bone metabolism by increasing the receptor activator of NF-kappaB ligand (RANKL) and decreasing osteoprotegerin (OPG) expression within the bone marrow microenvironment, thereby stimulating the central pathway for osteoclast formation and activation. In addition, they produce the chemokines MIP-1alpha, MIP-1beta and SDF-1alpha, which also increase osteoclast activity. Furthermore, myeloma cells suppress osteoblast function by the secretion of osteoblast inhibiting factors, e.g. Dickkopf (DKK)-1. The resulting bone destruction releases several cytokines, which in turn promote myeloma cell growth. Therefore, the inhibition of bone resorption could stop this vicious circle and not only decrease myeloma bone disease, but also the tumor progression. Preclinical studies provided strong evidence that the suppression of the osteoclast activity using bisphosphonates, RANKL blockade or inhibition of MIP-1alpha or MIP-1beta is effective both in reducing myeloma bone disease and tumor growth and therefore may offer an important treatment strategy in multiple myeloma.


Critical incidents associated with pediatric anesthesia: changes over 6 years at a tertiary children's hospital.
Sustained interest is needed in the characteristics of critical incidents in pediatric anesthesia and related changes, for determining the causes and degree of potential harm; this will also improve the quality of medical care. This study aimed to analyze the incidence of critical incidents recorded in 2014-2019, and to compare them with those in 2008-2013. Critical incidents associated with pediatric anesthesia, including cardiac arrest, recorded in a voluntary departmental reporting system between January 2014 and December 2019 were compared with those reported between January 2008 and August 2013 using chi-square test. We identified 295 (0.55%) critical incidents from 53,541 cases of pediatric anesthesia (3,471 cardiothoracic surgeries); this is consistent with the previously reported incidence of 0.46%. Among the critical incidents, the incidences of adverse events, sentinel event, near miss case and no-harm events were 93.9%, 1.7%, 0%, and 6.1% in 2014-2019, whereas those were 98.3%, 2.6%, 1.7%, and 0% in 2008-2013 (P = 0.023, 0.686, 0.080, and < 0.001, respectively). Cardiac arrest accounted for 25 (8.5%) cases of the 295 critical events, which significantly lower than that previously reported (18.3%; P = 0.020). Human factor-related events accounted for 61.0% of all critical incidences; this was similar to the previous data (58.5%). Over six years, there has been no significant difference in the total incidence of critical events. Despite the decrease in the incidence of serious critical events, perioperative care in pediatric anesthesia can be further improved.


Biological specimen banking in Arctic research: an Alaska perspective.
The cryogenic archival of biological specimens for retrospective analysis is of significant value for present and future research on population genetics, pathology, systematics, toxicology and environmental monitoring. This realization is emphasized by the increasing support of this activity by various government agencies, institutions and international groups. The international Arctic community is no exception. Canada has been conducting such activities in association with environmental monitoring programs for many years. Similar efforts appear to be underway in other polar nations. From the perspective of the United States Arctic, the Alaska Marine Mammal Tissue Archival Project (AMMTAP) was the earliest organized effort to develop an environmental specimen bank specifically designed for longterm archival of biological specimens under cryogenic conditions. The AMMTAP emphasizes use of standardized rigorous sampling and archival protocols, procedures that minimize contamination of samples during collection and maintaining a detailed record of sample history. The development of this specimen bank, recent activities of this project and other cryogenic specimen banks being developed in Alaska are described.


Density-dependent injury in larval salamanders.
The effects of initial larval density, food level, and pond drying regime on intraspecific aggression of larval Ambystoma talpoideum were studied in an artificial pond experiment. Aggression was measured by the frequency of injury of feet, limbs, tail, and the extent of tail loss. Initial larval density had a significant effect on the frequency of foot, limb, and tail loss but not on the extent of tail loss. More larvae reared at medium and high densities sustained injuries than larvae reared at low densities but injuries were not more extensive. Food level had no effect on the four measures of injury. Pond drying regime had no effect on foot loss, limb loss, or extent of tail loss but more larvae reared in constant water level ponds had tail loss than in drying ponds. The frequency of limb and tail loss was negatively correlated to density-dependent survival which was the result of intraspecific predation or cannibalism. These results indicate that substantive levels of body injury, particularly tail loss, can occur at high natural larval densities and may result in a subsequent reduction of growth and survival.


Identification, cloning and regulation of cDNA encoding aldo-keto reductase 1B7 in the adrenal gland of two Saharan rodents Meriones libycus (Libyan jird) and Gerbillus gerbillus (gerbil).
Aldo-Keto Reductase 1B7 (AKR1B7) is a mouse aldose reductase-like protein with two major sites of expression, the vas deferens and the adrenal cortex. In the adrenal cortex, Akr1b7 is an adrenocorticotropin (ACTH)-responsive-gene whose product scavenges harmful byproducts of steroidogenesis and limits stress response through the biosynthesis of prostaglandin F2α. The purpose of the present study was to explore the possible expression of AKR1B7 in the adrenal glands of two saharan rodents, Libyan jird and Lesser Egyptian gerbil. Western blot analyses demonstrated that a protein related to murine/rat AKR1B7 was highly expressed in adrenals and absent from vas deferens of both saharan species. Based on conserved sequences between mouse and rat, full length cDNA were cloned and sequenced in both species while hormonal regulation and tissue localization were explored in Libyan jird. Both cDNA encoded the expected 316 amino acids protein typical of AKR1B subfamily and contained the highly conserved catalytic tetrad consisting in Asp-44, Tyr-49, Lys-78 and His-111 residues. The deduced proteins shared higher identities with aldose reductase-like, i.e. AKR1B7 (86-94%), AKR1B8 and AKR1B10 (83-86%) than with aldose reductase group, i.e. AKR1B1 and AKR1B3 (70%). Phylogenetic analysis showed that the Libyan jird and gerbil enzymes were more closely related to murine and rat AKR1B7 than to the other AKR1B members. Northern blot analyses of total RNA from Libyan jird adrenals showed a single mRNA transcript of 1.4 kb whose expression was dependent on circulating ACTH levels. In conclusion, we demonstrate here that adrenal glands of Libyan jird and gerbil express both an ortholog of the murine/rat Akr1b7 gene and that ACTH-responsiveness is at least conserved in Libyan jird.


Incomplete congenital stationary night blindness: electroretinogram c-wave and electrooculogram light rise.
Three cases of congenital stationary night blindness are reported. In all patients a negative electroretinogram was recorded by single bright flash stimulation and changed to positive on sequential reduction of the stimulus intensities. Oscillatory potentials were recognized. Biphasic dark adaptation curves and moderate elevation of the relative logarithmic final threshold of dark adaptation were also found. Values of critical flicker fusion frequency were reduced to a mild or moderate extent. VEP latency was prolonged beyond the normal range in two cases. In all three the electroretinogram c-wave was extinguished despite a normal electrooculogram light-dark ratio. It is hypothesized that in congenital stationary night blindness some disorder may exist in the apical membrane of the retinal pigment epithelium but not in the basal membrane in view of dissociation between the c-wave response and the light rise in the electrooculogram.


[Wound healing of the pelvis following abdominoperineal rectum extirpation. A comparison of 2 drainage procedures in a prospective randomized study].
In a prospectively randomized study we used two different ways of drainage of the sacral space after an abdomino-perineal-resection of the rectum. One group with 25 patients had a drainage anteriorly through the abdominal wall, the other 25 patients got a drainage posteriorly through the buttocks. In each case we used two closed silicone-drainage-systems without active suction. In 60% of the anterior and in 50% of the posterior drained cases we saw an unaffected primary healing of the sacral wound. There was no significant difference. The patients felt the anterior way of drainage to be more convenient. Contamination of the sacral space by disrupture of the rectum during the operation was followed by a sacral abscess in 50%.


Lab in hydrogel portable kit: On-site monitoring of oxalate.
Oxalate is commonly employed as adjuvant of pesticide agent, causing renal injury of human even in trace residues. Despite the great achievements of the existing point-of-care testing (POCT) technology, accurate on-site screening of oxalate remains a tricky issue. To this aim, we proposed a "lab in a tube" platform which integrated portable hydrogel kit with smartphone for real-time monitoring of oxalate to achieve quantitatively precise analysis. In this work, a stimuli-responsive hydrogel-based kit was constructed via embedding manganese dioxide (MnO2) nanosheets into sodium alginate hydrogel system. Based on the intrinsic oxidase-like activity, MnO2 nanosheets-based nanozyme triggered color reaction by introducing a common sensing probe 3,3',5,5'-tetramethylbenzidine. Meanwhile, the presence of oxalate would decompose MnO2 nanosheets, inducing the decrease of nanozyme activity, which resulted in the color response of portable kit. Coupling with ImageJ software, the image information of kit captured via smartphone could be transduced into the hue intensity, which provided a directly quantitative tool to detect oxalate with a detection limit of 8.0 μmol L-1. This portable smartphone biosensor was successfully applied for screening urine sample within 10 min for high-throughput analysis (twelve samples) without the need for any advanced analytical instruments. Based on the merits of simple operation, cost-efficiency, and good selectivity, the availability of the miniaturized biosensor platform for POCT will achieve the requirements of routine screening and disease prevention.


Longitudinal measures of visual function, tumor volume, and prediction of visual outcomes after treatment of optic pathway gliomas.
To examine longitudinal changes in visual acuity, tumor volume, and visual evoked potentials (VEP) before and after treatment in children with optic pathway gliomas. Retrospective cohort study. Twenty-one patients (0.7-9 years of age). Patients initially were treated either by chemotherapy (n = 18) or radiotherapy (n = 3). Patients were followed up with serial magnetic resonance imaging, age-corrected visual acuity measurements in logarithm of the minimum angle of resolution (logMAR) units, and pattern VEP. Longitudinal visual outcome data were obtained on average for 9 years (range, 4-16 years). Tumor volumes before and after treatment were estimated in 15 patients. Multivariate regression was used to predict visual outcomes. Visual acuity, relative tumor volumes, and VEP. Before treatment, 81% of patients had reduced visual acuity and 81% had optic nerve pallor, whereas all had a reduced VEP in 1 or both eyes. After initial treatment, tumor volume decreased in 53%, stabilized in 27%, and progressively increased in 20%. Treatment arrested the rapid decline in visual acuity loss and stabilized visual acuity for 4 to 5 years. The rate of visual acuity decline was not correlated with tumor shrinkage. Sixty-two percent of patients required additional treatment with either chemotherapy or radiation because of tumor growth or progressive loss of visual function. Visual acuity at last examination was stable or improved in 33% of patients, but on average declined 0.4 logMAR units. Visual acuity was 20/200 or better in 1 eye of 62% of patients. The rate of visual acuity decline was predicted weakly by tumor volume at presentation (R(2) = 0.19; P<0.009). Visual acuity at last examination was predicted best by visual acuity and tumor volume at presentation (R(2) = 0.66; P<0.001). Systemic chemotherapy arrested the decline in visual acuity and stabilized vision on average for 5 years. At presentation, VEPs were a more sensitive indicator of optic pathway damage than visual acuity or optic nerve appearance. Although tumor reduction or stabilization was achieved in 80% of patients, pre-existing visual damage, indexed by objective measures of tumor volume and visual function, limited visual outcomes. The author(s) have no proprietary or commercial interest in any materials discussed in this article.


Pneumatosis intestinalis: a rare manifestation of acute appendicitis.
Pneumatosis intestinalis (PI), the presence of gas within the bowel wall, is a rare condition. To our knowledge, only two cases of PI secondary to acute appendicitis have been reported in the literature. We present a new case of a 46-year-old man who complained of abdominal pain and progressive abdominal distension for 4 days and oliguria for 1 day. In the Emergency Department, his abdomen was markedly distended and showed peritoneal signs. Preoperative blood culture grew Bacteroides fragilis. Abdominal computed tomography scan revealed marked bowel distension, bubble-like intramural gas scattered in the proximal small bowel, and localized fluid accumulation in the right lower quadrant of the abdomen. Small bowel ischemia was interpreted preoperatively. Emergency laparotomy revealed that the appendix was gangrenous and perforated, with local abscess formation but no bowel infarction. Hence, only appendectomy was performed, with subsequent uneventful patient recovery. The presence of PI may not always be an ominous sign; rather, it depends on the severity of any underlying diseases.


Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells.
We have previously described the identification of a nucleoside analog transcriptional inhibitor ARC (4-amino-6-hydrazino-7-beta-D-ribofuranosyl-7H-pyrrolo[2,3-d]-pyrimidine-5-carboxamide) that was able to induce apoptosis in cancer cell lines of different origin. Here, we report the characterization of ARC on a panel of neuroblastoma cell lines. We found that these cell lines were more than 10-fold sensitive to ARC than to the well-known nucleoside analog DRB (5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole), and that ARC-induced apoptosis proceeds through mitochondrial injury. Also, we observed that ARC-mediated cell death was accompanied by caspase-3 cleavage and repression of antiapoptotic proteins such as Mcl-1 and survivin. Conversely, we found that overexpression of Mcl-1-protected neuroblastoma cell line NB-1691 from ARC-induced apoptosis. Furthermore, we found that while ARC inhibited the phosphorylation of Akt Ser-473 in multiple cancer cell lines, forced expression of myristoylated Akt promoted resistance to ARC-induced apoptosis in neuroblastoma cells. In addition, we observed that ARC was able to downregulate the protein levels of N-myc, a commonly amplified oncogene in neuroblastomas, and Akt protected N-myc from ARC-induced downregulation. These data suggest that ARC may antagonize different antiapoptotic pathways and induce apoptosis in neuroblastoma cells via multiple mechanisms. Overall, ARC could represent an attractive candidate for anticancer drug development against neuroblastomas.


Sequence analysis of the 3'-untranslated region of HSP70 (type I) genes in the genus Leishmania: its usefulness as a molecular marker for species identification.
The Leishmaniases are a group of clinically diverse diseases caused by parasites of the genus Leishmania. To distinguish between species is crucial for correct diagnosis and prognosis as well as for treatment decisions. Recently, sequencing of the HSP70 coding region has been applied in phylogenetic studies and for identifying of Leishmania species with excellent results. In the present study, we analyzed the 3'-untranslated region (UTR) of Leishmania HSP70-type I gene from 24 strains representing eleven Leishmania species in the belief that this non-coding region would have a better discriminatory capacity for species typing than coding regions. It was observed that there was a remarkable degree of sequence conservation in this region, even between species of the subgenus Leishmania and Viannia. In addition, the presence of many microsatellites was a common feature of the 3'-UTR of HSP70-I genes in the Leishmania genus. Finally, we constructed dendrograms based on global sequence alignments of the analyzed Leishmania species and strains, the results indicated that this particular region of HSP70 genes might be useful for species (or species complex) typing, improving for particular species the discrimination capacity of phylogenetic trees based on HSP70 coding sequences. Given the large size variation of the analyzed region between the Leishmania and Viannia subgenera, direct visualization of the PCR amplification product would allow discrimination between subgenera, and a HaeIII-PCR-RFLP analysis might be used for differentiating some species within each subgenera. Sequence and phylogenetic analyses indicated that this region, which is readily amplified using a single pair of primers from both Old and New World Leishmania species, might be useful as a molecular marker for species discrimination.


Imaging of gynecological disease (3): clinical and ultrasound characteristics of granulosa cell tumors of the ovary.
To describe the clinical and ultrasound characteristics of granulosa cell tumors (GCTs) of the ovary, and to define the ultrasound appearance of GCTs based on pattern recognition. Databases of four gynecological ultrasound centers were searched to identify patients with histologically proven GCTs who had undergone a standard preoperative ultrasound examination. A total of 23 women with confirmed GCT were identified. Twelve (52%) women were postmenopausal, nine (39%) were of fertile age and two (9%) were prepubertal. Clinical symptoms were abdominal distension (7/23, 30%), pain (5/23, 22%) and irregular vaginal bleeding (6/23, 26%). Seven patients (30%) were asymptomatic. Endometrial pathology was found in 54% (7/13) of the patients from whom endometrial biopsies were taken. On ultrasound scan 12/23 (52%) masses were multilocular-solid, 9/23 (39%) were purely solid, one mass (4%) was unilocular-solid and one mass was multilocular (4%). Multilocular and multilocular-solid cysts typically contained large numbers of small locules (> 10). The echogenicity of the cyst content was most often mixed (6/16, 38%) or low level (7/16, 44%). Papillary projections were found in only four women (17%). The GCTs were large tumors with a median largest diameter of 102 (range, 37-242) mm and manifested moderate or high color content at color Doppler examination (color score 3 in 13/23 tumors (57%); color score 4 in 8/23 tumors (35%)). At ultrasound examination, most GCTs are large multilocular-solid masses with a large number of locules, or solid tumors with heterogeneous echogenicity of the solid tissue. Hemorrhagic components are common and increased vascularity is demonstrated at color/power Doppler ultrasound examination. The hyperestrogenic state that is created by the tumor often causes endometrial pathology with bleeding problems as a typical associated symptom.


[Pelvic floor muscle training and pelvic floor disorders in women].
Our goal is to provide an update on the results of pelvic floor rehabilitation in the treatment of urinary incontinence and genital prolapse symptoms. Pelvic floor muscle training allows a reduction of urinary incontinence symptoms. Pelvic floor muscle contractions supervised by a healthcare professional allow cure in half cases of stress urinary incontinence. Viewing this contraction through biofeedback improves outcomes, but this effect could also be due by a more intensive and prolonged program with the physiotherapist. The place of electrostimulation remains unclear. The results obtained with vaginal cones are similar to pelvic floor muscle training with or without biofeedback or electrostimulation. It is not known whether pelvic floor muscle training has an effect after one year. In case of stress urinary incontinence, supervised pelvic floor muscle training avoids surgery in half of the cases at 1-year follow-up. Pelvic floor muscle training is the first-line treatment of post-partum urinary incontinence. Its preventive effect is uncertain. Pelvic floor muscle training may reduce the symptoms associated with genital prolapse. In conclusion, pelvic floor rehabilitation supervised by a physiotherapist is an effective short-term treatment to reduce the symptoms of urinary incontinence or pelvic organ prolapse.


Potential bioactivation pathways for the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
The metabolism of the selective nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been studied in rat brain mitochondrial incubation mixtures. The 1-methyl-4-phenylpyridinium species MPP+ has been characterized by chemical ionization mass spectral and 1H NMR analysis. Evidence also was obtained for the formation of an intermediate product which, with the aid of deuterium incorporation studies, was tentatively identified as the alpha-carbon oxidation product, the 1-methyl-4-phenyl-2,3-dihydropyridinium species MPDP+. Comparison of the diode array UV spectrum of this metabolite with that of the synthetic perchlorate salt of MPDP+ confirmed this assignment. The oxidation of MPTP to MPDP+ but not of MPDP+ to MPP+ is completely inhibited by 10(-7) M pargyline. MPDP+, on the other hand, is unstable and rapidly undergoes disproportionation to MPTP and MPP+. Based on these results, we speculate that the neurotoxicity of MPTP is mediated by its intraneuronal oxidation to MPDP+, a reaction which appears to be catalyzed by MAO. The interactions of MPDP+ and/or MPP+ with dopamine, a readily oxidizable compound present in high concentration in the nigrostriatum, to form neurotoxic species may account for the selective toxic properties of the parent drug.


Isolated lung perfusion with melphalan and tumor necrosis factor for metastatic pulmonary adenocarcinoma.
Isolated left lung perfusion with melphalan and human tumor necrosis factor-alpha for pulmonary metastatic adenocarcinoma in the WAG/Rij rat was studied. Survival was determined for melphalan, human tumor necrosis-alpha. Lung, pulmonary effluent, and serum melphalan were analyzed by chromatography after isolated lung perfusion or intravenous injection. On day 0, rats were injected with 2.0 x 10(6) CC531S cells intravenously. On day 7, rats underwent sham thoracotomy, received melphalan intravenously, or underwent isolated left lung perfusion with saline, melphalan, tumor necrosis factor, and a combination of the latter two. On day 14, tumor nodules were counted. For the doses of 400 microg tumor necrosis factor, 1,000 microg tumor necrosis factor, or both melphalan and tumor necrosis factor (2 mg + 200 microg), survival rates after contralateral pneumonectomy were 33%, 17%, and 80%, respectively. Survival in all other groups was 100%. Left lung melphalan level was significantly higher after isolated lung perfusion compared to intravenous administration. Significantly fewer left lung nodules were found for 0.5 mg isolated lung perfusion with melphalan (28+/-17) compared to isolated administration (200+/-0) (p = 0.001), and for 1.0 mg intravenous lung perfusion with melphalan (16+/-10) compared to controls (171+/-65) (p = 0.00047). Tumor necrosis factor showed no significant effect. Isolated lung perfusion with melphalan is an effective treatment for pulmonary metastases from adenocarcinoma in the rat.


Patient with double heterozygosity for achondroplasia and pseudoachondroplasia, with comments on these conditions and the relationship between pseudoachondroplasia and multiple epiphyseal dysplasia, Fairbank type.
We present a 7 1/2-year-old girl with achondroplasia and pseudoachondroplasia. Her mother has achondroplasia and her father has pseudoachondroplasia. Radiographic manifestations of these two conditions from infancy to age 6 years are outlined. The findings in this patient are compared with those of achondroplastic patients and pseudoachondroplastic patients of similar ages. Our review of radiographs of many pseudoachondroplastic patients and subsequently of those of patients with multiple epiphyseal dysplasia (MED), Fairbank type, reinforced our opinion that pseudoachondroplasia and multiple epiphyseal dysplasia, Fairbank type, are closely related conditions. MED, Fairbank type, may be the mildest form of pseudoachondroplasia. Recently published electron microscopic findings also suggest this.


[Virilism due to an adrenal medullary tumor with ectopic ACTH syndrome (author's transl)].
The case of a 14-year-old girl with hirsutism and virilism due to the secretion of ectopic ACTH by an adrenal medullary tumor is described. At the age of 5 years changes in appearance had begun with masculinization. The effect of ACTH-like material, measured by radioimmunoassay in plasma and in tumor tissue, was compensated partially by the hypothalamo-pituitary-adrenal feedback mechanism. Increased concentrations of dehydroepiandrosterone, estrone and testosterone in plasma and of 17-ketosteroids and free cortisol in urine originated in the adrenals. After operation of the tumor menarche began spontaneously, hirsutism disappeared and testosterone plasma concentrations returned to normal. An adrenogenital syndrome was excluded.


Correction: Inhibitor SBFI26 suppresses the malignant progression of castration-resistant PC3-M cells by competitively binding to oncogenic FABP5.
[This corrects the article DOI: 10.18632/oncotarget.16055.].


Regulation of flagellar motility by temperature-dependent phosphorylation of a 43 kDa axonemal protein in fowl spermatozoa.
Phosphorylation of fowl sperm proteins was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) after incubating the demembranated spermatozoa with [gamma-32P]ATP at 30 degrees C or 40 degrees C. A marked difference of phosphorylation between 30 degrees C and 40 degrees C was observed in a 43 kDa protein. This protein was slightly phosphorylated at 40 degrees C, but strongly phosphorylated at 30 degrees C in a cAMP-independent manner. The motility of demembranated spermatozoa was negligible at 40 degrees C, but vigorous movement was observed at 30 degrees C. These results showed that phosphorylation of a 43 kDa protein is likely to be a regulatory step in the maintenance of fowl sperm motility.


Managing Bell's palsy.
Each year in the UK, around 1 in 5,000 people develop Bell's palsy--a unilateral lower motor neurone facial weakness of rapid onset that can be physically and psychologically disabling. While around 71% of patients recover normal function of the facial muscles without treatment, 13% are left with slight weakness and 16% with moderate to severe weakness resulting in major facial dysfunction. People who recover usually do so quickly, with 85% of them reporting some improvement in the first 3 weeks. There is longstanding controversy about what, if any, treatment should be initiated for Bell's palsy. Here we discuss the management of patients with this condition.


A novel TSC2 c.4511 T > C missense variant associated with tuberous sclerosis complex.
Tuberous sclerosis complex (TSC) is an autosomal-dominant hereditary disease characterized by hamartomas of multiple organ systems, including the brain, skin, heart, kidney and lung. Genetically, TSC is caused by pathogenic variants in the TSC1 or TSC2 gene. We reported a sporadic case of a 32-year-old Han Chinese male diagnosed with TSC, whose spouse had a history of two spontaneous miscarriages and an induced abortion of a 30-week fetus identified with cardiac rhabdomyoma by ultrasound. A novel heterozygous missense variant in the TSC2 gene (Exon35:c.4511 T > C:p.L1504P) was identified in the male patient and the aborted fetus by next-generation sequencing, but not in his wife or both his parents. According to the ACMG/AMP criteria, this variant was classified as a "likely pathogenic" variant. The novel TSC2:c.4511 T > C variant identified was highly likely associated with TSC and could potentially lead to adverse reproductive outcomes. IVF-ET and pre-implantation genetic diagnosis for TSC are recommended for this patient in the future to prevent fetal TSC.


The role of the water tankers market in water stressed semi-arid urban areas:Implications on water quality and economic burden.
Population growth and development are associated with increased water demand that often exceeds the capacity of existing resources, resulting in water shortages, particularly in urban areas, where more than 60% of the world's population resides. In many developing communities, shortages often force households to depend on water tankers amongst other potential sources for the delivery of water for domestic and/or potable use. While water tankers have become an integral part of the water supply system in many countries, the sector is often unregulated and operates with little governmental supervision. Users are invariably unaware of the origin or the quality of purchased water. In an effort to better assess this sector, a field survey of water vending wells and tankers coupled with a water quality sampling and analysis program was implemented in a pilot semi-arid urban area (Beirut, Lebanon) to shed light on the environmental and socio-economic impacts of the water tanker sector. Total dissolved solids (TDS), chloride (Cl-), and microbial loads exceeded drinking water quality standards. While TDS and Cl- levels were mostly due to saltwater intrusion in coastal wells, tankers were found to be a significant source of total coliforms. Delivered water costs varied depending on the tanker size, the quality of the distributed water, and pre-treatment used, with a markup of nearly 8-24 folds of the public water supply and an equivalent economic burden of 16% of the average household income excluding environmental externalities of water quality. The study concludes with a management framework towards consumer protection under integrated supply and demand side measures.


Alpha 1-proteinase inhibitor in psoriasis: reduced activity in symptom-free patients and during flare.
The aim of this study was to quantitate the active fraction of the alpha 1-proteinase inhibitor (alpha 1-PI) in psoriasis. Serum proteinase inhibitory capacity was measured vs porcine pancreatic elastase of a known active fraction against its specific substrate (Suc-Ala3-pNA). The inhibitory capacity was determined in 21 symptom-free patients, 134 patients with skin lesions, and 23 healthy volunteers. Alpha 1-PI was found to be significantly decreased in symptom-free patients and in those with stationary lesions, in a manner similar to the reduced activity of neutrophil proteinases, elastase, and cathepsin G. The synthesis of alpha 1-PI was stimulated during the appearance of active psoriatic lesions, but to a much lesser degree in patients with early onset (less than or equal to 21 years) than in patients with late onset of psoriasis (greater than 21 years). The early onset subgroup differed by a more frequent familial occurrence of psoriasis and a more severe course of the disease. The data indicate that the regulation of the proteinase-alpha 1-PI system in psoriasis is abnormal and this may contribute to the pathogenesis of the disease. The decreased alpha 1-PI during flare may be responsible for the disease activity, at least in patients with early onset of psoriasis.


[A balanced synthetic diet (Berlamin) in colonic surgery (author's transl)].
In preparation for surgery of the colon and rectum 50 patients were fed an oral balanced synthetic diet. Additionally, antibiotics were administered. With the exception of 4 patients the bowel was completely free from faeces. During the preoperative period, averaging 5 days, no pathological laboratory findings were observed. On the 5th day of the oral diet feeding there was a total N-retention rate of +2,8 +/- 1,2 N/day.


Transcriptomics as a tool for assessing the scalability of mammalian cell perfusion systems.
DNA microarray-based transcriptomics have been used to determine the time course of laboratory and manufacturing-scale perfusion bioreactors in an attempt to characterize cell physiological state at these two bioreactor scales. Given the limited availability of genomic data for baby hamster kidney (BHK) cells, a Chinese hamster ovary (CHO)-based microarray was used following a feasibility assessment of cross-species hybridization. A heat shock experiment was performed using both BHK and CHO cells and resulting DNA microarray data were analyzed using a filtering criteria of perfect match (PM)/single base mismatch (MM) > 1.5 and PM-MM > 50 to exclude probes with low specificity or sensitivity for cross-species hybridizations. For BHK cells, 8910 probe sets (39 %) passed the cutoff criteria, whereas 12,961 probe sets (56 %) passed the cutoff criteria for CHO cells. Yet, the data from BHK cells allowed distinct clustering of heat shock and control samples as well as identification of biologically relevant genes as being differentially expressed, indicating the utility of cross-species hybridization. Subsequently, DNA microarray analysis was performed on time course samples from laboratory- and manufacturing-scale perfusion bioreactors that were operated under the same conditions. A majority of the variability (37 %) was associated with the first principal component (PC-1). Although PC-1 changed monotonically with culture duration, the trends were very similar in both the laboratory and manufacturing-scale bioreactors. Therefore, despite time-related changes to the cell physiological state, transcriptomic fingerprints were similar across the two bioreactor scales at any given instance in culture. Multiple genes were identified with time-course expression profiles that were very highly correlated (> 0.9) with bioprocess variables of interest. Although the current incomplete annotation limits the biological interpretation of these observations, their full potential may be realized in due course when richer genomic data become available. By taking a pragmatic approach of transcriptome fingerprinting, we have demonstrated the utility of systems biology to support the comparability of laboratory and manufacturing-scale perfusion systems. Scale-down model qualification is the first step in process characterization and hence is an integral component of robust regulatory filings. Augmenting the current paradigm, which relies primarily on cell culture and product quality information, with gene expression data can help make a substantially stronger case for similarity. With continued advances in systems biology approaches, we expect them to be seamlessly integrated into bioprocess development, which can translate into more robust and high yielding processes that can ultimately reduce cost of care for patients.


Paroxysmal nonepileptic events in children with epilepsy.
The aim of this study was to clarify the characteristics of paroxysmal nonepileptic events (PNEs) suspected as being epileptic seizures by families of children with epilepsy. The video-EEG (vEEG) recordings of habitual paroxysmal events in children with epilepsy at Nagoya University Hospital between October 2006 and January 2016 were reviewed. Based on the doctor's suspicion before the vEEG, the PNEs were divided into two groups that included PNEs suspected as epileptic seizures and PNEs suspected as PNEs. PNEs in the former group were classified based on the suspected seizure type. Of 886 habitual paroxysmal events, vEEG confirmed that 83 events (68 children) were PNEs. The median age of the 68 children was 3.2 years. Concurrent epilepsies included focal epilepsies (n=33), infantile spasms (n=16), and other types (n=19). The most common types of PNEs were sleep myoclonus (n=11), followed by stereotypies (n=9), awake myoclonus (n=8), paroxysmal ocular deviations (PODs, n=8), and tonic posturing (n=8). Even after direct observation or video viewing, the doctors suspected epileptic seizures in all three of the PODs and two of the tonic posturing children. Before the vEEG, however, the accurate visual information led to the speculation that the four psychogenic and two sleep myoclonus events were all PNEs. Myoclonus, stereotypies, and head drops were often misdiagnosed as epileptic spasms, while PODs and tonic posturing were often misdiagnosed as focal seizures with motor components. Additionally, staring and motion arrest during a drowsy state were often misdiagnosed as focal dyscognitive seizures. Seven of eight patients with PODs had epileptic spasms that were concurrent with epileptic seizures. A diffuse cerebral lesion or reduced visual acuity was seen in seven patients with PODs. We re-emphasize that vEEG is essential for accurate diagnosis and provides evidence for listing POD in the differential diagnosis of oculomotor paroxysmal events.


The effect of plasma on the reaction of cyclophosphamide with 4(-p-nitrobenzyl)-pyridine.
Cyclophosphamide is not structurally modified by blood plasma and may be recovered quantitatively from it. The apparent loss of alkylating ability of cyclophosphamide, as measured by its ability to react with 4-(p-nitrobenzyl)-pyridine (NBP), following treatement with plasma is not, as has been reported, due to metabolism of the drug but rather to an inhibition of the colorimetric reaction by a constituent of the plasma. This inhibition is strongly pH dependent, reaching 100% when the pH of the solution of cyclophosphamide in plasma is above 8, and falling to less than 20% when the pH is below 6, but extraction with chloroform at pH 7 separates cyclophosphamide from the inhibitor. Although the nature of the inhibitor has not been elucidated, its presence in plasma is of great importance in the quantitative determination of cyclophosphamide, and may also be of significance in the biological effects of cyclophosphamide and other alkylating agents in vivo.


Pharmacologic control of homeostatic and antigen-driven proliferation to target HIV-1 persistence.
The presence of latent human immunodeficiency virus 1 (HIV-1) in quiescent memory CD4 + T cells represents a major barrier to viral eradication. Proliferation of memory CD4 + T cells is the primary mechanism that leads to persistence of the latent reservoir, despite effective antiretroviral therapy (ART). Memory CD4 + T cells are long-lived and can proliferate through two mechanisms: homeostatic proliferation via γc-cytokine stimulation or antigen-driven proliferation. Therefore, therapeutic modalities that perturb homeostatic and antigen-driven proliferation, combined with ART, represent promising strategies to reduce the latent reservoir. In this study, we investigated a library of FDA-approved oncology drugs to determine their ability to inhibit homeostatic and/or antigen-driven proliferation. We confirmed potential hits by evaluating their effects on proliferation in memory CD4 + T cells from people living with HIV-1 on ART (PLWH) and interrogated downstream signaling of γc-cytokine stimulation. We found that dasatinib and ponatinib, tyrosine kinase inhibitors, and trametinib, a MEK inhibitor, reduced both homeostatic and antigen-driven proliferationby >65%, with a reduction in viability <45%, ex vivo. In memory CD4 + T cells from PLWH, only dasatinib restricted both homeostatic and antigen-driven proliferation and prevented spontaneous rebound, consistent with promoting a smaller reservoir size. We show that dasatinib restricts IL-7 induced proliferation through STAT5 phosphorylation inhibition. Our results establish that the anti-cancer agent dasatinib is an exciting candidate to be used as an anti-proliferative drug in a clinical trial, since it efficiently blocks proliferation and iswell tolerated in patients with chronic myeloid leukemia (CML).


Chronic myeloid leukaemia and hairy cell leukaemia coexisting in a single patient: difficulties at diagnosis and rational of the therapeutic strategy.
Chronic myeloid leukemia (CML) and hairy cell leukemia (HCL) are two distinct haematological disorders. Only one single case of coexistence of the two pathologies at diagnoses has been previously reported. We present a second case of coexistence at diagnosis, indicating the diagnostic procedures involving morphological, immunophenotyping, and molecular testing. We decided to use Interferon as common first-line therapy and Imatinib and Rituximab (anti-CD20 monoclonal antibody), to improve the first-line therapy result, obtaining a complete molecular remission for CML and clinical remission with molecular minimal residual disease for HCL. After a critical analysis of the results, we speculate on the different clonal origin of the two pathologies.


Reducing Healthcare Costs Using ACS NSQIP-Driven Quality Improvement Projects: A Success Story from Sheikh Khalifa Medical City (SKMC).
Surgical complications increase hospital length of stay and costs and lead to poor patient experience. We aim to evaluate our complication rates over time and the financial impact of joining the adult multi-specialty American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) at Sheikh Khalifa Medical City (SKMC). Sheikh Khalifa Medical City is a Joint Commission International-accredited ACS NSQIP member since 2009. For the purpose of quality improvement, we have established several task forces (2010-2014) to decrease high rates of venous thromboembolism (VTE), urinary tract infection (UTI), surgical site infection (SSI), unplanned intubation (UI), and ventilator more than 48 h (Vent > 48 h). Our aim is to evaluate our complication rates over time and calculate the cost savings from prevented occurrences in VTE, UTI, SSI, UI, and Vent > 48 h. Cost savings are calculated using the return on investment calculator from ACS NSQIP. In addition, the cost of joining and maintaining ACS NSQIP at SKMC is calculated to determine the total cost savings after subtracting these costs. During the study period, we performed 8842 cases (2009-2015) and our overall morbidity improved significantly from observed/expected (O/E) 1.61% to (O/E) 0.85%. We prevented 12 VTE cases (2011-2015), 56 UTI cases (2013-2015), 12 SSI cases (2013-2015), 4 UI cases (2014-2015), and 7 Vent > 48 h cases (2014-2015). The cost saving from all these four task forces was $1,680,000. The cost of joining and maintaining ACS NSQIP at SKMC since 2009 was $336,000. Hence, the total saving for SKMC was $1,344,000. ACS NSQIP-driven quality improvement projects have resulted in reduction in complications and healthcare costs at SKMC over a 6-year period.


Introductory guide to the language of molecular genetics.
This special section on molecular genetics was invited in order to raise awareness of the potential of molecular genetic approaches to inform child psychologists, psychiatrists and related professionals. As much of the terminology is specific to the field, this introductory guide aims to aid readers who may be unfamiliar with the approaches of this discipline. Basic terminology and genetic processes are described, with sections covering 'The Human Genome' and 'Genetic Markers'. The range of genetic markers is growing all the time, but those that are thought to be functional and/or are highly variable are particularly useful. Genotyping approaches that offer high efficiency, thus allowing for large numbers of genotypes on large numbers of individuals, are likely to come to the fore in the next few years.


The biosynthesis of nicotinamide adenine dinucleotide during early stages of frog embryonic development of haploid and diploid embryos.
1. Concentration of NAD during embryonic development of haploid and diploid embryos of frog was followed. NAD content in haploid embryonic forms is twice that in diploid embryos. 2. The variation of the NMN adenylyltransferase activity in the oocytes and during the first states of embryonic development as surveyed in the nuclear soluble fraction and the nuclear insoluble fraction (chromatin). 3. The enzyme activity in the soluble fraction is low during embryonic development and shows higher values in haploid embryos. 4. In the nonfertilized mature oocytes, the NMN adenylyltransferase activity is sixfold higher in the insoluble chromatin fraction than in the soluble fraction. 5. The evolution of the NMN adenylyltransferase in the insoluble chromatin fraction also shows higher values in haploid embryos, as compared with diploid forms.


Analysis of the steam injection at the Visalia Superfund Project with fully compositional nonisothermal finite difference simulations.
By injecting steam, over 1.1 million pounds of creosote has been recovered at the Visalia, California Superfund Site from an aquifer 102ft underground. In the first 6 weeks of injection 320,000lb of creosote were recovered or destroyed versus <1lb per day in a pump and treat. The finite difference simulator STARS1, which is widely used in the oil industry to model thermal recovery, has been used to simulate simplified models of the project, to analyze recovery mechanisms, and to demonstrate how the operation of similar projects can be improved. The simulations indicate that vaporization of dense, nonaqueous, phase liquids (DNAPLs) is the most important recovery mechanism, that liquid production is enhanced because a gas phase is present, and that the project could have been completed more rapidly if an additional injector or producer had been added in the center of the site. In addition, the mineralization (conversion to carbon dioxide) of DNAPLs could result from reaction with water, injected air or, most likely, both. The mechanisms are likely to be similar to subcritical water oxidation. While this analysis suggests methods to improve operation of future steam projects, Visalia has been a very successful demonstration of the potential of steam injection to clean up recalcitrant hydrocarbons and will be an inspiration for future projects.


[Prolactinoma causing erectile dysfunction].
Hyperprolactinaemia is an unusual cause of erectile dysfunction, yet erectile dysfunction is a common complaint in patients with hyperprolactinaemia. We present a patient with erectile dysfunction without symptoms suggesting hyperprolactinaemia. Patient consulted with erectile dysfunction for the past 10 years. Decreased time and quality of erection with an IIEF score of 14/30. Lab reports: prolactin 90.2 ng/ml, FSH 1.6 mlU/ml, LH 1.8 UI/L, total testosterone .491 ng/ml. Brain MRI: lateral pituitary micro adenoma, 5mm in diameter. Patient in treatment with cabergoline 1mg per week, after treatment noticed improvement in erectile dysfunction and sexual desire. Actual prolactin 15.4 ng/ml. Up to 5% of patients with erectile dysfunction are diagnosed with a pituitary adenoma. Erectile dysfunction caused by pituitary neoplasms is a multifactorial disease and elevated prolactin has consequences on testosterone, LH, FSH, and dopamine precursor levels.