The quantitation and fractionation of proteins in cerebrospinal fluid.
The quantitation of CSF proteins has important clinical applications. Often the total protein level is quite useful but does not provide sufficient information to differentiate the disease state of the patient. The IgG/albumin index is a parameter frequently used as an indication of IgG production within the central nervous system. Hence, the levels of the albumin and globulin fractions must often be determined. Many methods exist for quantitations of total protein in CSF and the levels of the major protein fractions and for separating the various proteins present into their major protein fractions. For total protein quantitation, the turbidimetric method is common, but the Coomassie brilliant blue method may be the method of the future. For separation and quantitation of protein fractions, electrophoresis or some immunologic method is frequently used. The more sophisticated isoelectric focusing and two-dimensional techniques are limited to use mostly by research laboratories. With further sophistication of techniques for separating proteins and interpretation of the results thereby obtained, the methods which are now limited to research may be adapted by routine laboratories in the future.


Suitability of new chlamydia transport medium for transport of herpes simplex virus.
A new chlamydia transport medium (ChlamydiaPort; Scott Laboratories, Inc., Fiskeville, R.I.) was evaluated for its suitability as a transport medium for herpes simplex virus (HSV). Two laboratory HSV strains (McIntyre and 333) and two clinical isolates (AO218 and AO301) were suspended in ChlamydiaPort, ViraPort (Scott Laboratories), and cell culture medium and maintained at 2 and 22 degrees C. Samples were tested at various time intervals to determine surviving virus. The range of half-lives of the HSV strains held at 2 degrees C in ChlamydiaPort medium was from 3.5 to 10 days, while virus stability was greater in ViraPort and less in cell culture medium. These HSV strains held at 22 degrees C in ChlamydiaPort had half-lives from 1.5 to 6 days, which were significantly greater than the half-lives of the viruses held in either tissue culture medium or ViraPort. Clinical specimens were tested for virus by using the Selecticult-HSV (Scott Laboratories) system to determine the performance of the transport medium under field conditions. Clinical specimens maintained up to 5 days at ambient temperatures in ChlamydiaPort medium appeared suitable for diagnostic testing without detectable loss of positive specimens. In addition, there was a significant decrease in the average time required for diagnosis when compared with a standard transport system, Virocult (Microdiagnostics, Cleveland, Ohio). These results show that HSV infections can be successfully diagnosed in distant virology laboratories by shipping specimens in ChlamydiaPort transport medium at ambient temperatures.


Explicit drinking identity and alcohol problems: The mediating role of drinking to cope.
Drinking identity, or the tendency to view one's self as a drinker, is a unique predictor of alcohol use and related consequences among young adults; yet the mechanism by which it leads to alcohol problems is poorly understood. Based on self-presentation and self-verification perspectives, we examined drinking to cope as a mediator of the association between explicit drinking identity and alcohol-related problems among two samples of young adults. Study data come from two large, longitudinal studies. Participants from Sample 1 and Sample 2 included undergraduates (55% and 59% female, respectively) who reported drinking in the previous three months. Tests of the indirect effects indicated that 3-month drinking to cope significantly mediated the positive association between baseline drinking identity and 6-month alcohol-related problems in both samples. In contrast, 3-month drinking identity did not mediate the association between baseline drinking to cope and 6-month alcohol-related problems. Findings indicate that individuals with a stronger drinking identity are more likely to use alcohol to cope and, subsequently, experience more problems. Thus, drinking identity may be an important intervention target for college students as it appears to temporally proceed drinking to cope in the prediction of alcohol-related problems.


[Study of a pts-gene-linked pleiotropic mutation influencing expression of catabolyte-sensitive genes of Escherichia coli K-12].
Properties of the pleiotropic mutation pts17 are described. This mutation is liked to pts1 gene, which specifies the synthesis of the enzyme I of phosphoenolpyruvate-dependent phosphotransferase system (PTS) in Escherichia coli K-12. Genetic analysis has shown that pts17 mutation is located between purC and pts1 markers and that the wild type allele pts17+ has transdominant character over the mutant allele pts17. The mutant strain J6217, isogenic to parent J62, shows normal growth properties in the minimal salt media with a number of carbohydrates used as a single carbon source. The pts17 mutations does not affect the enzyme I activity, but significantly suppresses the total PTS activity in the bacterial cell extracts. The intact mutant cells reveal the enhanced rate of accumulation and phosphorylation of alpha-methylglucoside. The pts17 bacteria show 3-fold enhanced phosphohydrolase activity with glucose-6-phosphate as substrate. It is established that pts17 mutation decreases the differential rate of the L-tryptophanase synthesis and makes the process of unductions resistant to glucose catabolite repression. It is suggested that this mutation affects the activity of the PTS factor III. One can suppose that the latter mediates the influence of ptsI and ptsH mutations upon the expression of catabolite-sensitive operons in E. coli.


Energy-Based Interface Detection for Phase Change Processes of Monatomic Fluids in Nanoconfinements.
An energy-based liquid-vapor interface detection method is presented using molecular dynamics simulations of liquid menisci confined between two parallel plates under equilibrium and evaporation/condensation conditions. This method defines the liquid-vapor interface at the location where the average kinetic energy of atoms first exceeds the average potential energy imposed by all neighboring molecules. This definition naturally adapts to the location of the menisci relative to the walls and can properly model the behavior of the liquid adsorbed layers. Unlike the density cutoff methods frequently used in the literature that suffer from density layering effects, this new method gives smooth and continuous liquid-vapor interfaces in nanoconfinements. Surface tension values calculated from the equilibrium MD simulations match the Young-Laplace equation better when using the radius of curvatures calculated from this method. Overall, this energy-based liquid-vapor interface detection method can be used in studies of nanoscale phase change processes and other relevant applications.


Phytase inclusion in pig diets improves zinc status but its effect on copper availability is inconsistent.
Complexation of dietary phytate with cations is a major cause of reduced bioavailability of Zn and possibly Cu in pig diets. We conducted 2 studies with 2 treatments in young growing pigs (8 to 40 kg) to estimate potential contributions of phytase to availability and supply of Zn and Cu, respectively. Each treatment comprised 10 pens with 8 pigs each as experimental units. In Exp. 1, 500 phytase units (FTU)/kg of microbial phytase (Natuphos 5000G; BASF) was added to a diet containing 15 mg Zn from ZnSO(4) and 160 mg/kg Cu from CuSO(4) in addition to Cu and Zn from feed ingredients. In Exp. 2, 500 FTU/kg was added to a diet containing 45 mg Zn from ZnSO(4) without added CuSO(4). Feces were collected to determine nutrient digestibility, blood was collected, and pigs were killed to determine Cu and Zn in the liver. In both experiments, phytase inclusion increased (P < 0.001) Zn digestibility by on average 10% units, serum Zn level (P < 0.001) by 0.4 mg/L, and liver Zn content (P < 0.001) by 129 mg/kg DM. In Exp. 1 phytase increased (P = 0.03) Cu digestibility by 6% units but reduced (P = 0.04) liver Cu content by 35 mg/kg DM. In Exp. 2 phytase reduced (P < 0.001) Cu digestibility by 16% units without affecting liver Cu content. Results indicate that the effect of phytase on Cu availability depends on dietary Cu and Zn content and the response variable studied. In conclusion, the consistent effects of phytase on indices of Zn status allow a reduction of Zn inclusion in phytase-supplemented diets.


Freeman-Burian syndrome.
Freeman-Burian syndrome (FBS) is a rare congenital myopathic craniofacial syndrome. Considerable variability in severity is seen, but diagnosis requires the following: microstomia, whistling-face appearance (pursed lips), H or V-shaped chin defect, and prominent nasolabial folds. Some patients do not have limb malformations, but essentially all do, typically camptodactyly with ulnar deviation of the hand and talipes equinovarus. Neuro-cognitive function is not impaired. Population prevalence of FBS is unknown. Environmental and parental factors are not implicated in pathogenesis. Allelic variations in embryonic myosin heavy chain gene are associated with FBS. White fibrous tissue within histologically normal muscle fibres and complete replacement of muscle by fibrous tissue, which behaves like tendinous tissue, are observed. Optimal care seems best achieved through a combination of early craniofacial reconstructive surgery and intensive physiotherapy for most other problems. Much of the therapeutic focus is on the areas of fibrous tissue replacement, which are either operatively released or gradually stretched with physiotherapy to reduce contractures. Operative procedures and techniques that do not account for the unique problems of the muscle and fibrous tissue replacement have poor clinical and functional outcomes. Important implications exist to facilitate patients' legitimate opportunity to meaningfully overcome functional limitations and become well.


Aspirin resistance and compliance with therapy.
Aspirin resistance is associated with increased cardiovascular risk in aspirin-treated patients. Poor compliance may explain many cases of "resistance," yet few clinical studies have used objective measurement of therapy compliance. We did so in a case-controlled study. We enrolled patients within 24 h of ischemic stroke and a group of controls taking aspirin who had never suffered a vascular event on therapy. All claimed to be compliant. We assessed platelet function using platelet function analyser (PFA)-100 and rapid platelet function analyser (RPFA) devices, applying standard definitions of resistance. We used high-performance liquid chromatography for levels of aspirin metabolites in the urine to confirm compliance with therapy. We compared rates of resistance in stroke patients and controls, and performed subgroup analysis restricted to patients with objective confirmation of recent aspirin ingestion. We recruited 90 cases and 90 controls. Complete platelet function tests were available in 177. Resistance rates seen in cases and controls, respectively, were: resistance on one or more test, 30 (34%) versus 21 (25%), P= 0.19; on PFA-100 testing only, 28 (32%) versus 15 (18%), P= 0.031; on RPFA testing only, 16 (18%) versus 12 (14%), P= 0.54; resistance on both tests, 12 (14%) versus 5 (6%), P= 0.037. When only patients with objective evidence of recent aspirin ingestion were considered (n = 71), rates were similar regardless of definition of resistance used. Aspirin resistance is common but poor compliance accounted for nearly half of cases of apparent aspirin "failure." Objective measures to assess compliance are essential in studies of aspirin resistance.


Prostate Cancer Risk and DNA Methylation Signatures in Aging Rats following Developmental BPA Exposure: A Dose-Response Analysis.
Previous studies have uncovered heightened prostatic susceptibility to hormone-induced neoplasia from early-life exposure to low-dose bisphenol A (BPA). However, significant data gaps remain that are essential to address for biological relevance and necessary risk assessment. A complete BPA dose-response analysis of prostate lesions across multiple prostatic lobes was conducted that included internal BPA dosimetry, progression to adenocarcinoma with aging and mechanistic connections to epigenetically reprogramed genes. Male neonatal Sprague-Dawley rats were briefly exposed to 0.1 to 5,000 μg BPA/kg BW on postnatal days (PND) 1, 3, and 5. Individual prostate lobes plus periurethral prostatic ducts were evaluated at 7 mo or 1 y of age without or with adult testosterone plus estradiol (T+E) to promote carcinogenesis. DNA methylation of five genes was quantified by bisulfite genomic sequencing in d-200 dorsal prostates across BPA doses. Serum free-BPA and BPA-glucuronide were quantitated in sera of individual PND 3 pups collected 1 hr postexposure utilizing ultra-high-pressure tandem mass spectrometry (UHPLC-MS-MS). The lowest BPA dose initiated maximal hormonal carcinogenesis in lateral prostates despite undetectable free BPA 1 hr postexposure. Further, prostatic intraepithelial neoplasia (PIN) progressed to carcinoma in rats given neonatal low-dose BPA with adult T+E but not in rats given adult T+E alone. The dorsal and ventral lobes and periurethral prostatic ducts exhibited a nonmonotonic dose response with peak PIN, proliferation and apoptotic values at 10–100 μg/kg BW. This was paralleled by nonmonotonic and dose-specific DNA hypomethylation of genes that confer carcinogenic risk, with greatest hypomethylation at the lowest BPA doses. Developmental BPA exposures heighten prostate cancer susceptibility in a complex dose- and lobe-specific manner. Importantly, elevated carcinogenic risk is found at doses that yield undetectable serum free BPA. Dose-specific epigenetic modifications of selected genes provide a mechanistic framework that may connect early-life BPA to later-life predisposition to prostate carcinogenesis. https://doi.org/10.1289/EHP1050.


Posttranscriptional Upregulation of p53 by Reactive Oxygen Species in Chronic Lymphocytic Leukemia.
Chronic lymphocytic leukemia (CLL) cells multiply and become more resistant to immunochemotherapy in "proliferation centers" within tissues, whereas apoptosis occurs in the periphery. Various models recapitulate these microenvironments in vitro, such as stimulation with CD154 and IL4. Using this system, we observed a 30- to 40-fold induction of wild-type p53 protein in 50 distinct human CLL specimens tested, without the induction of either cell-cycle arrest or apoptosis. In contrast, the mRNA levels for p53 did not increase, indicating that its elevation occurred posttranscriptionally. Mechanistic investigations revealed that under the conditions studied, p53 was phosphorylated on residues associated with p53 activation and increased half-life. However, p53 protein induced in this manner could transcriptionally activate only a subset of target genes. The addition of a DNA-damaging agent further upregulated p53 protein levels, which led to apoptosis. p53 induction relied on the increase in intracellular reactive oxygen species observed after CD154 and IL4 stimulation. We propose that chronic oxidative stress is a characteristic of the microenvironment in B-cell "proliferation centers" in CLL that are capable of elevating the basal expression of p53, but to levels below the threshold needed to induce arrest or apoptosis. Our findings suggest that reactivation of the full transcriptional activities of p53 in proliferating CLL cells may offer a possible therapeutic strategy. Cancer Res; 76(21); 6311-9. ©2016 AACR.


Comparison of treatment of hepatic hydrothorax with catheter drainage versus serial thoracentesis.
Hepatic hydrothorax is a nonmalignant pleural effusion associated with portal hypertension that may cause increased morbidity or mortality in cirrhotic patients. For patients who are refractory to salt restriction and diuretics, thoracentesis and catheter drainage are necessary for symptomatic relief. This review aimed to identify the best drainage method in patients with hepatic hydrothorax. Chest tube placement is discouraged in cases of hepatic hydrothorax due to high complication and mortality rates. Although the complication rate associated with smaller caliber catheter drainage appears lower than with chest tube drainage, patients treated with catheter drainage still had a higher 30-day mortality compared with patients treated by thoracentesis. Catheter drainage was an independent risk factor for 30-day mortality in cirrhotic patients with pleural effusion after adjusting for age, hepatic dysfunction, and other comorbidities. Treating the underlying disorder with liver transplantation can dramatically improve survival in these patients. The recent evidence supports series thoracentesis as the first-line drainage method in cases of hepatic hydrothorax compared with catheter drainage. Further prospective, randomized, controlled trials are necessary to further evaluate the mortality and complication rates of catheter drainage compared with thoracentesis in cirrhotic patients.


[Natural tyrosine-kinase inhibitors].
Changes in the degree of phosphorylation of protein tyrosine residues play a major role in the regulation of cell growth and differentiation. The biological mechanisms which control the activity of enzyme systems involved in these change (i.e. protein tyrosine-kinase [PTKs] and protein tyrosine-phosphatases) remain poorly understood. Similar to other regulation mechanisms, involving phosphorylation-dephosphorylation reactions, these enzyme systems can be regulated by naturally occurring effectors (with inhibitory or activating effects). This paper briefly reviews current knowledge on the few identified natural PTK inhibitors. The phosphoprotein PP 63 produced by rat hepatocytes inhibits insulin-receptors PTK in hepatoma cell cultures and abolishes insulin's mitogenic effect. PP 63 has a slight structural resemblance with Müllerian Inhibiting Substance, a molecule reported to inhibit epidermal growth factor (EGF) receptor PTK and to exhibit anti-mitogenic effects. Two other proteins, protein S-100 isolated from cattle brain and a thermostable factor found in human lymphoid tissues also have anti-PTK effects. Although in the current state of our knowledge, the physiologic role of these inhibitors is unclear, they may have potential value as anti-oncogenic agents as a result of their ability to decrease phosphorylation of protein tyrosine residues.


Eschmann introducer through laryngeal mask airway: a cadaveric trial of an alternate means of rescue intubation.
Laryngeal mask airways (LMAs) are often used as airway rescue devices where laryngoscopy is difficult. The LMA does not protect the airway and is preferably replaced with a cuffed endotracheal tube. There are reports of cases where an Eschmann tracheal tube introducer (ETTI) was successfully used to bridge between a standard LMA and an endotracheal tube. This project was designed to determine whether an Eschmann stylet can reliably be passed through an LMA into the trachea as a means of rescue intubation. Nineteen emergency medicine residents and attending physicians, who were participants in a cadaveric airway course, placed and inflated a size 4 LMA (The Laryngeal Mask Company Ltd., San Diego, CA) on each of six unembalmed human cadavers in the usual fashion. They then attempted to pass a lubricated, 15 Fr, reusable, coude-tipped ETTI (Portex, Smiths Medical, Keene, NH)) through the airspace/handle of the inflated LMA. The LMA was then deflated and removed while the ETTI was held in place. Investigators then determined the location of the ETTI by laryngoscopy. Of 114 attempts at the rescue procedure, 59 resulted in placement of the bougie into the trachea, yielding an overall success rate of 52% (95% CI 48%-56%). There were no significant differences in performance based on level of training of residents or years of experience of attending physicians. While not a primary difficult airway option, the use of a ETTI as a bridge device between LMA and endotracheal tube was successful about 50% of the time.


[COMBINATION OF TAURINE WITH ZINC DIASPARTATE FOR CORRECTION OF METABOLISM DISTURBANSES IN NEPHRONS AND RENAL FUNCTION IN RATS WITH CONTRAST-INDUCED NEPHROPATHY].
The nephroprotective properties of a combination of taurine with zinc diaspartate (taucin) in rats with contrast-induced nephropathy have been estimated. It is established that the combination of taurine with zinc diaspartate (20 and 1 g/mol, respectively, ingested in doses 250 and 500 mg/kg in the stomach during 14 days) produces a dose-dependent nephroprotective action on rats with contrast-induced (sodium and meglumin amidotrizoates, 800 mg/kg/day intraperitoneally, 14 days) nephropathy.


In vivo analysis of mucosal lipids reveals histological disease activity in ulcerative colitis using endoscope-coupled Raman spectroscopy.
The goal of this study is to evaluate endoscopic Raman spectroscopy as a noninvasive technique to determine histological inflammatory status of colitis. Colon mucosal composition was investigated in vivo from patients with ulcerative colitis (UC) and from age- and body mass index (BMI) matched controls using endoscope-coupled Raman spectroscopy. The results were co-registered with histological assessment of inflammatory status at the same locations. Substantial decreases (50-60%) in the content of phosphotidylcholines (PCs) and total lipids were observed in inflamed colon tissue (histology grade 1, 2 and 3) compared to those from the quiescent (histology grade 0) and from the controls. No significant difference was observed in lipids or PC contents between control and grade 0, or among grades 1 - 3. The degree of lipid unsaturation increased in the inflamed tissue regardless of disease severity. The inflammation-associated alterations in lipids and PC are observed independent of BMI or the anatomical locations for data collection. Multivariate analysis using support vector machine (SVM) algorithm classified the spectra of the controls or the inactive colitis from those of inflamed tissue with a sensitivity of 83.5% and 97.1% respectively. Our results showed that mucosal lipid content is related to the microscopic disease activity, and thus could serve as a valuable spectral marker to differentiate active colitis from the quiescent.


A systematic review of vision screening tests for the detection of amblyopia.
To review the test characteristics and the quality of evidence regarding available screening tests for the detection of amblyopia in preschool-aged children to help primary care practitioners select a screening strategy. Systematic review of published studies. The MEDLINE database was searched from 1966 through January 1999 using a broad and inclusive strategy. A total of 9551 citations were identified. All studies that compared the results of commercially available screening tests in preschool-aged children to ophthalmologic examination. The setting of the study, the age of the population, the type of screening test, criteria for a positive screen, criteria for the ophthalmologic examination, test characteristics, and measures of reliability were abstracted by 2 reviewers for each selected study. Four eligible articles were identified that studied the test characteristics of 3 screening tests. None of these studies were performed in a primary care setting. Each study used different criteria for failure of the ophthalmologic examination. None of the studies measured observer or test reliability. Few high-quality data exist regarding the performance of preschool vision screening. Important future work should include the development of a consensus gold standard ophthalmologic examination and evaluation of screening tests in the primary care setting.


53BP1 Supports Immunoglobulin Class Switch Recombination Independently of Its DNA Double-Strand Break End Protection Function.
Class switch recombination (CSR) is a DNA recombination reaction that diversifies the effector functions of antibodies. CSR occurs via the formation and non-homologous end joining (NHEJ) repair of programmed DNA double-strand breaks (DSBs) at the immunoglobulin heavy chain locus. The DNA repair factors 53BP1 and Rif1 promote NHEJ and CSR by protecting DSBs against resection. However, to what extent repression of DNA end resection contributes to CSR is unknown. Here, we show that B lymphocytes devoid of 53BP1-Rif1-dependent DSB end protection activity undergo robust CSR. Inactivation of specific sets of phospho-sites within 53BP1 N-terminal SQ/TQ motifs abrogates Rif1 recruitment and inhibition of resection but only mildly reduces CSR. Furthermore, mutations within 53BP1 oligomerization domain abolish CSR without substantially affecting DNA end processing. Thus, inhibition of DNA end resection does not correlate with CSR efficiency, indicating that regulation of DSB processing is not a key determinant step in CSR.


Targeted in vivo delivery of therapeutic gene into experimental squamous cell carcinomas using anti-epidermal growth factor receptor antibody: immunogene approach.
The "Fab immunogene" is a novel gene transfer vehicle in which the Fab fragment of anti-human epidermal growth factor (EGF) receptor antibody B4G7 is conjugated with poly-L-lysine to form an affinity complex with DNA. It was developed to target delivery of therapeutic genes into EGF receptor-hyperproducing tumor cells. Various characteristic features of the immunogene have been documented (Chen et al., 1998). Here we add further evidence to prove that in vitro transfer of beta-galactosidase/Fab immunogene is exclusively to EGF receptor-positive cells and that the herpes simplex virus thymidine kinase (TK)/Fab immunogene induces substantial suicide effects on A431 tumor cells when treated together with ganciclovir. The in vivo specificity of the immunogene transfer was examined using A431 tumor-bearing nude mice. When these nude mice were injected intraperitoneally with the chloramphenicol acetyltransferase (CAT)/Fab immunogene, CAT DNA was detected in the tumors as well as in liver and kidney but not brain, whereas CAT mRNA and enzyme activity were detected only in the tumors. Local and intraperitoneal injection of the TK/Fab immunogene and subsequent administration of ganciclovir effectively suppressed the growth of A431 tumors transplanted on the backs of nude mice. These observations suggest a possible application of the Fab immunogene system in cancer gene therapy.


Have antipsychotics a different speed of action in the acute treatment of mania? A single-blind comparative study.
Available antipsychotics show different efficacy on manic symptoms of bipolar patients, but few studies have investigated the speed of action of the various compounds. For this reason, purpose of the present paper was to compare antipsychotic mono-therapies in terms of speed of action in a sample of manic bipolar patients. In total, 155 bipolar patients, treated with antipsychotic mono-therapy and followed-up in Inpatient Psychiatry Clinic of University of Milan, were included in this single-blind comparative study. Clinical response was defined as a reduction of Young Mania Rating Scale (YMRS) scores ⩾50%, while remission as a YMRS score <10. After 4 days patients who had been treated with asenapine, were more likely to have achieved a clinical response than those in treatment with haloperidol ( p = 0.001). After 7 days, a more frequent clinical response was achieved by patients treated with asenapine than those who had been treated with haloperidol ( p < 0.001) or olanzapine ( p = 0.047). Asenapine appears to be faster in determining treatment response in manic patients compared with haloperidol and less markedly with olanzapine.


[Identification of an objective reference parameter for the reconstruction of a large incisional hernia following physiological principles].
Repairing a parietal defect of a large incisional hernia should not be limited to the closure of the breach by means of the modern biocompatible prosthetic sheets, but must also be able to restore a correct intra abdominal pressure, otherwise the derangement from the normal respiratory dynamics and the circulatory stasis in the abdominal veins and in those of the lower limbs remain unaltered. Over-correcting the parietal abdominal tension on the contrary can cause a dangerous compartmental syndrome. The attempts of an intraoperative measurement of the correct intra abdominal pressure restoration has been generally hampered from the condition of curarization of the patient during the operation. Using the automatic mechanical ventilator fixed at volume and not at pressure priority, as usual, can offer the possibility to calibrate, following objective parameters, the propriety of the surgical repair still during the final phases of the reparative operation. The simplicity and ingenuity of the here proposed method and the normal availability in every operative theatre of the necessary means for this measurements described, requires attention among the surgeons and a large diffusions of its simple use.


Reevaluating key evidence for the development of rehearsal: phonological similarity effects in children are subject to proportional scaling artifacts.
The size of an individual's phonological similarity effect for visually presented material is assumed to reflect his or her ability to recode, and by implication rehearse, information in verbal short-term memory. Many studies have shown that under these conditions, the size of this effect interacts with age, tending to be nonsignificant in children younger than 7 years and leading to the conclusion that children of this age do not rehearse. In the present study, the size of the phonological similarity effect was assessed in a total of 116 children aged between 5 and 9 years, manipulating the modality of both encoding and retrieval of the memoranda. Although the interaction between age and the size of the phonological similarity effect was replicated with visual presentation and verbal recall of material, this interaction was also present in other conditions that do not require recoding. In addition, the data from this "classic" condition were simulated by a model that assumed that the size of the similarity effect is (a) proportional to an individual's recall of dissimilar items and (b) constrained by a functional floor to recall of similar items. These findings undermine the evidence for a qualitative change in recoding and rehearsal at 7 years and question the extent to which rehearsal is necessary to explain the development of verbal short-term memory performance.


Alfentanil as procedural pain relief in newborn infants.
To assess the need for, and the suitability of, alfentanil for pain relief during tracheal suction used in assisted ventilation in newborn infants. In a randomised, controlled, double blind, crossover trial, placebo (10 micrograms/kg) and 20 micrograms/kg alfentanil were infused in random order two minutes before three separate endotracheal suctions, at least six hours apart, to 10 infants. Measurements were made of physiological variables, behaviour, and stress hormones. After placebo infusion heart rate significantly increased (median 14; interquartile range 12-16 beats/minute) as did behavioural pain score (5; 3-5). Alfentanil (20 micrograms/kg) attenuated the heart rate increase, normalised the pain score, and caused a decrease in plasma adrenaline activity (0.3; 0.2-0.7 nmol/l). Noradrenaline concentration showed a nonsignificant decreasing trend with increasing alfentanil dose and beta endorphin was unchanged. Rigidity was noted in the placebo (n = 2), 10 micrograms/kg (n = 2), and 20 micrograms/kg (n = 5) alfentanil groups, respectively. Tracheal suction is a painful procedure. The dose of alfentanil required for pain relief (20 micrograms/kg) causes a high incidence of rigidity and thus should be used only with muscle relaxant.


[Regional (conduction) anesthesia: new solutions of old problems].
Despite the constant improvements, local and total anesthesia are often regarded as alternative methods while selecting anesthesia. Modern anesthesiology aiming at the maximal regulation and safety of anesthesiological care, by no means confined to mere analgesia, clearly demonstrated the disagreement between the traditional approach to local anesthesia and the practical requirements. It is obvious that today we can speak about a revision of our attitude to local anesthesia. Use of novel technologies helps solve all problems involved in the attaining and maintaining the regional blocking. A great variety of local anesthetics, appreciably differing from the traditional agents by their physicochemical and clinical characteristics, creates objective prerequisites for solving numerous practical problems requiring stable many-hour analgesia, reliable regional immobilization, or selective effects of sympathetic blocking in individual regions. That is why the traditional limitations connected with the local and total-system toxicity, similarly as the regional and total-system hemodynamic effects, should not be regarded as contraindications, but taken into consideration when choosing not only the method of conduction blocking, but the local anesthetic as well. The authors consider that at present the strategic problem of regional anesthesia-regulation and safety of its pharmacological effects-is solved. Such anesthesia is as readily regulated as different variants of total anesthesia, and it may be even safer. This permitted not only extending the indications to regional anesthesia, but using the selective effects of regional blocking as the main or special component of anesthesiology.


Influence of landscape on the population genetic structure of the alpine butterfly parnassius smintheus (Papilionidae)
Four microsatellite DNA markers were developed which were used to examine the relationship between landscape and population genetic structure among a set of populations of the butterfly Parnassius smintheus located in the foothills of the Canadian Rockies. Detailed information on the dispersal of adult butterflies among this same set of populations was available. Simple and partial Mantel tests were used to examine the relationships between genetic distances, predicted rates of dispersal, and a number of landscape variables, all measured pairwise for 17 sample sites. Nei's standard genetic distance was negatively correlated with predicted dispersal. We observed a significant pattern of isolation by distance at a very small spatial scale. The distance between sites that was through forest was a stronger predictor of genetic distance than the distance through open meadow, indicating a significant effect of landscape on population genetic structure beyond that of simple isolation by distance. Our results suggest that rises in the tree-line in alpine areas, caused by global warming, will lead to reduced gene flow among populations of P. smintheus.


Some notes on the Vértesszöllös occipital.
An examination of the Vértesszöllös occipital bone indicates the need for takings its condition and preservation as well as certain aspects of its morphology into account prior to a metric assessment of its features. This analysis confirms the presence of extrasutural bones on the lambdoidal suture as well as some distortion in the sagittal curvature of this region. The advisability of using the endocranial sutures as well as other data for defining lambda in cases such as this is discussed, and a procedure for determining the position of opisthion is indicated. A metric and morphological analysis is used to support the claim that the specimen can be considered a large late representative of Homo erectus in Europe.


Nitric oxide induces Zn2+ release from metallothionein by destroying zinc-sulphur clusters without concomitant formation of S-nitrosothiol.
The reaction of nitric oxide (NO) with metallothionein (MT) has been investigated at neutral pH under strictly anaerobic conditions. It is observed that NO mediates zinc release from MT by destroying zinc-sulphur clusters, but that it does not by itself S-nitrosylate MT in contrast to common belief. Zinc release and loss of thiolate groups under anaerobic conditions is found to be much slower than under aerobic conditions. The observed percentage loss of Zn(2+) and thiolate groups after 3 h of NO treatment are 62 and 39%, respectively. The reaction of NO with cysteine is reinvestigated and it is found that cysteine is quantitatively converted to cystine after 5 min of NO treatment at pH 7.3. At lower pH, a much lower rate of conversion is observed confirming the base-catalysed nature of the reaction of NO with thiols. On the basis of these results, a reaction mechanism involving electrophilic attack of NO on thiolate groups and subsequent formation of a nitrogen-centred radical, MTSN(. )OH, as intermediate is proposed for the reaction of NO with MT that leads to zinc release.


The SPT6 gene is essential for growth and is required for delta-mediated transcription in Saccharomyces cerevisiae.
Mutations in the Saccharomyces cerevisiae SPT6 gene were originally identified as one class of extragenic suppressors of Ty and delta insertion mutations in the 5' noncoding regions of HIS4 and LYS2. We cloned SPT6 and constructed a null allele by gene disruption. Haploid spores carrying the spt6 null allele were inviable, indicating that the SPT6 gene is essential for mitotic growth. SPT6 was mapped to the right arm of chromosome VII, 44 centimorgans (cM) from ADE6 and 9 cM from CLY8. We showed that spt6 mutations suppress delta insertion mutations at the level of transcription but have no qualitative or quantitative effect on Ty transcription. In addition, we observed interesting SPT6 gene dosage effects. An SPT6 strain containing a high-copy-number plasmid clone of SPT6 showed suppression of delta insertion mutations, and a diploid strain with half its normal dose of SPT6 (SPT6/spt6 null) also exhibited suppression of delta insertion mutations. Therefore, having either too many or too few copies of SPT6 causes a mutant phenotype. Finally, this study and that in the accompanying paper (L. Neigeborn, J. L. Celenza, and M. Carlson, Mol. Cell. Biol. 7:679-686, 1986) showed that spt6 and ssn20 mutations (isolated as suppressors of snf2 and snf5 [sucrose nonfermenting] mutations) identify the same gene. SPT6 and SSN20 have the same genetic map position and share an identical restriction map. Furthermore, spt6 and ssn20 mutations fail to complement each other, and ssn20 mutations suppress solo delta insertion mutations at HIS4 and LYS2. These results, taken in conjunction with the SPT6 dosage effects and the fact that SPT6 is an essential gene, suggest that SPT6 plays a fundamental role in cellular transcription, perhaps by interaction with other transcription factors.


Saccharin. Review of safety issues. Council on Scientific Affairs.
This report reviews the experimental and epidemiologic data related to the carcinogenicity of saccharin. The results of animal studies suggest a species and organ effect. In single-generation studies in rats, mice, hamsters, and monkeys, saccharin did not induce cancer in any organ. In two-generation studies involving rats, however, there was evidence that the incidence of bladder tumors was significantly greater in saccharin-treated males of the second generation than in controls; the development of bladder tumors in rats seems to be a species- and organ-specific phenomenon for which there is currently no explanation. In humans, available evidence indicates that the use of artificial sweeteners, including saccharin, is not associated with an increased risk of bladder cancer. Until there is firm evidence of its carcinogenicity in humans, saccharin should continue to be available as a food additive, and reports of adverse health effects associated with its use should be monitored.


Rapid migration of CO2-rich micro-fluids in calcite matrices.
The transport of supercritical fluids is a determining factor for several geological processes and fundamental in predicting natural resource accumulation and distribution. Calcite, ubiquitous in most geological environments, may contain supercritical CO2 trapped under the form of fluid inclusions that may move through grain boundaries affecting the rock physical properties. However, despite macroscopic evidence for this process, until recent it was not possible to characterize this process at the nano-scale due to the difficulty of such observations. In this study, we report nanometer-scale observations on calcite crystal surfaces and demonstrate that stress with absence of visible deformation produces fluid leakage from fluid inclusions. Atomic Force Microscopy scanning experiments on freshly cleaved calcite crystals containing visible fluid inclusions revealed the spontaneous formation of nanometer-scale hillocks on flat crystal terraces in only a few minutes, without evidence of surface dissolution. The fact the hillocks formed on flat surface in a short time was unexpected and suggests deposition of material from the inner crystal to the surface through small-scale fluid migration. We estimated the rate of this fluid mobility is by several orders of magnitude higher than the diffusion rate through vacancies estimated in calcite crystals showing that CO2-rich fluids through micro-pore and nano-pore spaces is in reality much higher than previously assumed using current predictive models.


The pathophysiology of myocardial ischaemia.
In this review paper on the pathophysiology of myocardial ischaemia, the recent concepts of the ischaemic cascade, as well as the concepts of stunning and hibernating myocardium, are discussed. It is clear that painful ischaemia is the final phenomenon in the ischaemic cascade and that it is preceded by biochemical disturbances, diastolic and systolic dysfunction and electrocardiographic abnormalities. Silent ischaemia remains a difficult research field.


Self-organizing neural networks to support the discovery of DNA-binding motifs.
Identification of the short DNA sequence motifs that serve as binding targets for transcription factors is an important challenge in bioinformatics. Unsupervised techniques from the statistical learning theory literature have often been applied to motif discovery, but effective solutions for large genomic datasets have yet to be found. We present here three self-organizing neural networks that have applicability to the motif-finding problem. The core system in this study is a previously described SOM-based motif-finder named SOMBRERO. The motif-finder is integrated in this work with a SOM-based method that automatically constructs generalized models for structurally related motifs and initializes SOMBRERO with relevant biological knowledge. A self-organizing tree method that displays the relationships between various motifs is also presented, and it is shown that such a method can act as an effective structural classifier of novel motifs. The performance of the three self-organizing neural networks is evaluated here using various datasets.


Recovery from ischemic acute renal failure is improved with enteral compared with parenteral nutrition.
To compare measurements of renal function after acute ischemic renal failure in rats fed enterally or parenterally. Prospective, randomized, animal trial. University research laboratory. Male Sprague-Dawley rats (n = 21). Animals were randomized to receive isocaloric (160 nonprotein kcal/kg/day), or isonitrogenous (1.4 g of nitrogen/kg/day [100 mmol/kg/day]) enteral (n = 10), or parenteral nutrition (n = 11) through either a gastrostomy tube or a catheter placed in the jugular vein. After the animals received 7 days of assigned feedings, baseline blood samples were collected. A right nephrectomy and 45-min left renal pedicle occlusion were then performed. One hour after the ischemic injury, assigned feedings were resumed and continued for 3 days. After ischemic injury, daily blood samples were obtained and 24-hr urine collections were performed. On day 11, animals were killed and the kidney was harvested and fixed for subsequent microscopic examination. Urine was analyzed for concentrations of total urea nitrogen, creatinine, protein, and calcium. Serum was analyzed for creatinine and urea nitrogen concentrations. Fixed kidney sections were examined for mitotic figures, tubular calcifications, and casts using light microscopy by an investigator blinded to the nutritional regimen. Data are presented as mean +/- SD or median (range). Percent increase in creatinine clearance from the nadir on day 9 to day 11 was approximately 2.5-fold greater in the enteral compared with the parenteral nutrition group (490 +/- 221% vs. 208 +/- 130%; p = .003). Histologic evaluation demonstrated greater dystrophic tubular calcifications per ten high-power fields in the parenteral compared with the enteral nutrition group (50 [four to 85] vs. three [0 to 37]; p = .001). No differences in urine calcium concentration or 24-hr calcium excretion were seen. Rats given continuous enteral nutrition 7 days before and for 3 days after ischemic acute renal failure have improved renal function compared with rats given parenteral nutrition.


Incidence of myeloid neoplasms in Spain (2002-2013): a population-based study of the Spanish network of cancer registries.
Comprehensive population-based data on myeloid neoplasms (MNs) are limited, mainly because some subtypes were not recognized as hematological cancers prior to the WHO publication in 2001, and others are too rare to allow robust estimates within regional studies. Herein, we provide incidence data of the whole spectrum of MNs in Spain during 2002-2013 using harmonized data from 13 population-based cancer registries. Cases (n = 17,522) were grouped following the HAEMACARE groupings and 2013-European standardized incidence rates (ASRE), incidence trends, and estimates for 2021 were calculated. ASRE per 100,000 inhabitants was 5.14 (95% CI: 5.00-5.27) for myeloproliferative neoplasms (MPN), 4.71 (95% CI: 4.59-4.84) for myelodysplastic syndromes (MDS), 3.91 (95% CI: 3.79-4.02) for acute myeloid leukemia, 0.83 (95% CI: 0.78-0.88) for MDS/MPN, 0.35 (95% CI: 0.32-0.39) for acute leukemia of ambiguous lineage, and 0.58 (95% CI: 0.53-0.62) for not-otherwise specified (NOS) cases. This study highlights some useful points for public health authorities, such as the remarkable variability in incidence rates among Spanish provinces, the increasing incidence of MPN, MDS, and MDS/MPN during the period of study, in contrast to a drop in NOS cases, and the number of cases expected in 2021 based on these data (8446 new MNs).


Presumptive identification of group D streptococci: the bile-esculin test.
Six tests commonly used for the presumptive identification of group D streptococci were evaluated. Strains tested included 282 group D streptococci and 366 non-group D. Ratios of percentages of group D to non-group D strains which gave positive reactions for each test are as follows: bile-esculin, 100:2; salt tolerance, 88:24; heat tolerance, 100:80; SF broth, 86:1; KF broth, 99:40; and methylene blue milk reduction, 90:17. These data indicate that the bile-esculin test provided a reliable means of identifying group D streptococci and differentiating them from non-group D streptococci. Methodology for reading and interpreting positive reactions and time of incubation of the bile-esculin medium was defined. Evidence of the need for standardization of salt and heat-tolerance tests was obtained.


A mechanism of paraquat toxicity involving nitric oxide synthase.
Paraquat (PQ) is a well described pneumotoxicant that produces toxicity by redox cycling with cellular diaphorases, thereby elevating intracellular levels of superoxide (O-(2)). NO synthase (NOS) has been shown to participate in PQ-induced lung injury. Current theory holds that NO reacts with O-(2) generated by PQ to produce the toxin peroxynitrite. We asked whether NOS might alternatively function as a PQ diaphorase and reexamined the question of whether NO/O-(2) reactions were toxic or protective. Here, we show that: (i) neuronal NOS has PQ diaphorase activity that inversely correlates with NO formation; (ii) PQ-induced endothelial cell toxicity is attenuated by inhibitors of NOS that prevent NADPH oxidation, but is not attenuated by those that do not; (iii) PQ inhibits endothelium-derived, but not NO-induced, relaxations of aortic rings; and (iv) PQ-induced cytotoxicity is potentiated in cytokine-activated macrophages in a manner that correlates with its ability to block NO formation. These data indicate that NOS is a PQ diaphorase and that toxicity of such redox-active compounds involves a loss of NO-related activity.


Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity.
The endoplasmic reticulum (ER) is the main site of protein and lipid synthesis, membrane biogenesis, xenobiotic detoxification and cellular calcium storage, and perturbation of ER homeostasis leads to stress and the activation of the unfolded protein response. Chronic activation of ER stress has been shown to have an important role in the development of insulin resistance and diabetes in obesity. However, the mechanisms that lead to chronic ER stress in a metabolic context in general, and in obesity in particular, are not understood. Here we comparatively examined the proteomic and lipidomic landscape of hepatic ER purified from lean and obese mice to explore the mechanisms of chronic ER stress in obesity. We found suppression of protein but stimulation of lipid synthesis in the obese ER without significant alterations in chaperone content. Alterations in ER fatty acid and lipid composition result in the inhibition of sarco/endoplasmic reticulum calcium ATPase (SERCA) activity and ER stress. Correcting the obesity-induced alteration of ER phospholipid composition or hepatic Serca overexpression in vivo both reduced chronic ER stress and improved glucose homeostasis. Hence, we established that abnormal lipid and calcium metabolism are important contributors to hepatic ER stress in obesity.


Disruption of hepatic adipogenesis is associated with impaired liver regeneration in mice.
The liver responds to injury with regulated tissue regeneration. During early regeneration, the liver accumulates fat. Neither the mechanisms responsible for nor the functional significance of this transient steatosis have been determined. In this study, we examined patterns of gene expression associated with hepatic fat accumulation in regenerating liver and tested the hypothesis that disruption of hepatic fat accumulation would be associated with impaired hepatic regeneration. First, microarray-based gene expression analysis revealed that several genes typically induced during adipocyte differentiation were specifically upregulated in the regenerating liver prior to peak hepatocellular fat accumulation. These observations suggest that hepatic fat accumulation is specifically regulated during liver regeneration. Next, 2 methods were employed to disrupt hepatocellular fat accumulation in the regenerating liver. Because exogenous leptin supplementation reverses hepatic steatosis in leptin-deficient mice, the effects of leptin supplementation on liver regeneration in wild-type mice were examined. The data showed that leptin supplementation resulted in suppression of hepatocellular fat accumulation and impairment of hepatocellular proliferation during liver regeneration. Second, because glucocorticoids regulate cellular fat accumulation during adipocyte differentiation, the effects of hepatocyte-specific disruption of the glucocorticoid receptor were similarly evaluated. The results showed that hepatic fat accumulation and hepatocellular proliferation were also suppressed in mice with liver specific disruption of glucocorticoid receptor. In conclusion, suppression of hepatocellular fat accumulation is associated with impaired hepatocellular proliferation following partial hepatectomy, indicating that hepatocellular fat accumulation is specifically regulated during and may be essential for normal liver regeneration.


Association Between New-Onset Type 2 Diabetes and Cardiac Conduction Diseases: A Prospective Cohort Study.
Cardiac conduction diseases can lead to life-threatening outcomes. However, the evidence on risk factors for conduction disease that is needed to underpin prevention strategies is limited. The present study aimed to determine the association between type 2 diabetes and cardiac conduction diseases. This study included 101 080 participants free of prevalent diabetes and cardiac conduction diseases at baseline from the Kailuan Study. All participants were monitored biennially until December 31, 2020. During follow-up, 14 397 participants were diagnosed as having type 2 diabetes. For each case subject, 1 control subject was randomly selected, matched for age (±1 year) and sex. The final analysis comprised 10 744 case-control pairs. Cox regression models with age as the underlying time scale were used. During a median follow-up of 5.46 years, 571 incident events occurred, including 164 atrioventricular blocks, 414 bundle-branch blocks (BBBs), 274 right BBBs, and 210 left BBBs. After adjustment for potential confounders, participants with type 2 diabetes diagnosed had greater relative risks for most outcomes relative to controls, with hazard ratios of 1.42 (95% CI, 1.18-1.67) for conduction diseases, 1.40 (95% CI, 1.00-1.96) for atrioventricular blocks, 1.43 (95% CI, 1.16-1.75) for BBBs, and 1.69 (95% CI, 1.15-2.49) for left BBBs. In contrast, no association between diabetes and right BBB was observed. In this study, participants with type 2 diabetes are at an increased risk of cardiac conduction disease but not associated with the development of right BBB.


Synergistic Interaction of Methanol Extract from Canarium odontophyllum Miq. Leaf in Combination with Oxacillin against Methicillin-Resistant Staphylococcus aureus (MRSA) ATCC 33591.
Canarium odontophyllum (CO) Miq. has been considered as one of the most sought-after plant species in Sarawak, Malaysia, due to its nutritional and pharmacological benefits. This study aimed to evaluate the pharmacodynamic interaction of crude methanol and acetone extracts from CO leaves in combination with oxacillin, vancomycin, and linezolid, respectively, against MRSA ATCC 33591 as preliminary study has reported its potential antistaphylococcal activity. The broth microdilution assay revealed that both methanol and acetone extracts were bactericidal with Minimum Inhibitory Concentration (MIC) of 312.5 μg/mL and 156.25 μg/mL and Minimum Bactericidal Concentration (MBC) of 625 μg/mL and 312.5 μg/mL, respectively. Fractional Inhibitory Concentration (FIC) indices were obtained via the chequerboard dilution assay where methanol extract-oxacillin, acetone extract-oxacillin, methanol extract-linezolid, and acetone extract-linezolid combinations exhibited synergism (FIC index ≤ 0.5). The synergistic action of the methanol extract-oxacillin combination was verified by time-kill analysis where bactericidal effect was observed at concentration of 1/8 × MIC of both compounds at 9.6 h compared to oxacillin alone. As such, these findings postulated that both extracts exert their anti-MRSA mechanism of action similar to that of vancomycin and provide evidence that the leaves of C. odontophyllum have the potential to be developed into antistaphylococcal agents.


PBX2 and PBX3, new homeobox genes with extensive homology to the human proto-oncogene PBX1.
Two new homeobox genes, PBX2 and PBX3, were isolated on the basis of their extensive homology to PBX1, a novel human homeobox gene involved in t(1;19) translocation in acute pre-B-cell leukemias. The predicted Pbx2 and Pbx3 proteins are 92 and 94% identical to Pbx1 over a large region of 266 amino acids within and flanking their homeodomains, but all three proteins diverge significantly near their amino and carboxy termini. Chromosome in situ hybridizations demonstrated that the PBX genes are not clustered but map to separate chromosomal loci: PBX1, 1q23; PBX2, 3q22-23; PBX3, 9q33-34. Expression of PBX2 or PBX3 was not restricted to particular states of differentiation or development, as mRNA transcripts of these genes were detected in most fetal and adult tissues and all cell lines, unlike PBX1, which is not expressed in lymphoid cell lines. Similar to PBX1 RNA, PBX3 RNA is alternatively spliced to yield two translation products with different carboxy termini, a feature not observed for PBX2. Their extensive sequence similarity and widespread expression suggest a generalized, overlapping role for Pbx proteins in most cell types. Differences in their amino and carboxy termini may modulate their activities, mediated in part by differential splicing and, for PBX1, protein fusion following t(1;19) chromosomal translocation.


Gintropy: Gini Index Based Generalization of Entropy.
Entropy is being used in physics, mathematics, informatics and in related areas to describe equilibration, dissipation, maximal probability states and optimal compression of information. The Gini index, on the other hand, is an established measure for social and economical inequalities in a society. In this paper, we explore the mathematical similarities and connections in these two quantities and introduce a new measure that is capable of connecting these two at an interesting analogy level. This supports the idea that a generalization of the Gibbs-Boltzmann-Shannon entropy, based on a transformation of the Lorenz curve, can properly serve in quantifying different aspects of complexity in socio- and econo-physics.


Hearing Aid Uptake, Benefit, and Use: The Impact of Hearing, Cognition, and Personal Factors.
Purpose The purpose of this study was to explore the effects of hearing, cognition, and personal factors on hearing aid (HA) uptake, use, and benefit. Method Eighty-five older adults aged 60-80 years (M = 70.23, SD = 5.17) participated in the study. Hearing was assessed using pure-tone audiometry and the Listening in Spatialised Noise-Sentences test. Cognition was measured using the Cogstate Brief Battery and the Cogstate Groton Maze Learning task. Personal demographics were recorded from participants' answers on a series of take-home questionnaires. HA benefit and use was subjectively reported at 3 and 6 months post HA fitting for those who chose to use HAs. Results Stepwise-regression and mixed-effects models indicated that stronger psychomotor function predicted greater reported use of HAs at 3 and 6 months post HA fitting. Greater family interaction scores also predicted greater HA use at 3 months after fitting. Participants who chose to be fitted with HAs had significantly poorer self-reported health and poorer audiometric thresholds. Poorer hearing was also significantly related with greater reported HA benefit. Conclusions A combination of cognitive, psychosocial factors and hearing impacted HA outcomes for the older Australians in this study. Self-reported HA use was significantly greater in participants with better psychomotor function. Furthermore, those with poorer self-reported health were more likely to choose to use HAs. These factors should be considered in audiological rehabilitation to best maximize patient HA outcomes.


Adjuvant Systemic Therapy and Adjuvant Radiation Therapy for Stage I to IIIA Completely Resected Non-Small-Cell Lung Cancers: American Society of Clinical Oncology/Cancer Care Ontario Clinical Practice Guideline Update.
Purpose The panel updated the American Society of Clinical Oncology (ASCO) adjuvant therapy guideline for resected non-small-cell lung cancers. Methods ASCO convened an update panel and conducted a systematic review of the literature, investigating adjuvant therapy in resected non-small-cell lung cancers. Results The updated evidence base covered questions related to adjuvant systemic therapy and included a systematic review conducted by Cancer Care Ontario current to January 2016. A recent American Society for Radiation Oncology guideline and systematic review, previously endorsed by ASCO, was used as the basis for recommendations for adjuvant radiation therapy. An update of these systematic reviews and a search for studies related to radiation therapy found no additional randomized controlled trials. Recommendations Adjuvant cisplatin-based chemotherapy is recommended for routine use in patients with stage IIA, IIB, or IIIA disease who have undergone complete surgical resections. For individuals with stage IB, adjuvant cisplatin-based chemotherapy is not recommended for routine use. However, a postoperative multimodality evaluation, including a consultation with a medical oncologist, is recommended to assess benefits and risks of adjuvant chemotherapy for each patient. The guideline provides information on factors other than stage to consider when making a recommendation for adjuvant chemotherapy, including tumor size, histopathologic features, and genetic alterations. Adjuvant chemotherapy is not recommended for patients with stage IA disease. Adjuvant radiation therapy is not recommended for patients with resected stage I or II disease. In patients with stage IIIA N2 disease, adjuvant radiation therapy is not recommended for routine use. However, a postoperative multimodality evaluation, including a consultation with a radiation oncologist, is recommended to assess benefits and risks of adjuvant radiation therapy for each patient with N2 disease. Additional information is available at www.asco.org/lung-cancer-guidelines and www.asco.org/guidelineswiki .


Circulating soluble fms-like tyrosine kinase-1, soluble endoglin and placental growth factor during pregnancy in normotensive women in KwaZulu-Natal, South Africa.
Based on the increased pre-eclampsia and HIV antenatal incidence in South Africa, we determined the angiogenic profiles due to its mechanistic link in preeclampsia development, throughout uncomplicated pregnancies in HIV positive and negative women. To determine the angiogenic profiles throughout uncomplicated pregnancies in HIV positive and HIV negative women. We explored possible correlations between angiogenic serum levels and selected maternal characteristics (HIV status, gestational age, maternal factors, and pregnancy outcomes). This study was conducted at a primary health care facility in Durban, South Africa. Forty-six pregnant women aged 18-45 years, were enrolled at 10-20, 22-30 and 32-38 weeks' gestation, respectively through convenient sampling. Serum samples were collected and quantitatively evaluated using ELISAs. Clinical and epidemiological data were analysed using STATA (version 14). A probability level of p < 0.05 was considered statistically significant. Of those enrolled, 28.3% were nulliparous, 82% were HIV positive and none developed pre-eclampsia. Systolic and diastolic blood pressure increased slightly throughout pregnancy. Fluctuating angiogenic and anti-angiogenic levels were demonstrated during pregnancy. This study contributes to the current angiogenic knowledge in normotensive pregnancies, and may assist as a reference range against which these factors may be compared in HIV complicated pregnancies.


Vancomycin treatment for enterococcal meningitis.
Although clinical disease due to enterococcus is common, there has been only limited experience in the treatment of central nervous system infections by this pathogen. In particular, there have been few reports regarding the treatment of such infections in the penicillin-allergic individual. We present two cases of meningitis due to enterococci, including one case with a brain abscess, in patients with strong histories of penicillin sensitivity. We treated these patients with vancomycin hydrochloride and an aminoglycoside. Vancomycin with an aminoglycoside seems to be a reasonable treatment for enterococcal central nervous system infections.


Is 50% oxygen harmful?
Pulmonary gas exchange after tracheal extubation was evaluated in 25 patients to determine the effect of 50% oxygen administered during mechanical ventilation following aortocoronary bypass grafting. Twenty-five patients received postoperative mechanical ventilation for 16 to 24 h, 13 with an inspired oxygen fraction (FIO2) of no more than 0.30 and 12 with an FIO2 of 0.50. After tracheal extubation, all patients spontaneously breathed room air (FIO2 0.21). Postextubation the calculated venous admixture of patients who had received 50% oxygen (0.20 +/- 0.03 [SD]) was significantly (p less than .01) greater than that calculated for patients who received lower oxygen concentrations (0.13 +/- 0.04). Consequently, the PaO2 of patients who had received 50% oxygen (60 +/- 5 torr) was significantly (p less than .03) lower than the PaO2 of patients who had received no more than 30% oxygen (66 +/- 7 torr). Thus, administration of 50% oxygen, supposedly nontoxic, to mechanically ventilated patients may cause impairment of pulmonary gas exchange after tracheal extubation. Although high concentrations of supplemental oxygen are sometimes required, unnecessary elevation of FIO2 is not likely to significantly increase oxygen delivery and may contribute to postextubation pulmonary dysfunction.


Observations on the use of the ICD-10 guide for mental retardation.
In acknowledgement of the challenges posed by the diagnosis of mental disorders in people with intellectual disability (ID), the World Health Organization (WHO) has recently published a multi-axial guide to assist clinicians in applying the ICD-10 to this group of people. The WHO has invited users to review of the ICD-10 Guide for Mental Retardation. In order to review its usefulness in clinical practice, the present authors used the Guide together with the ICD-10 in the psychiatric assessment of 106 young people with ID, and emotional and behavioural problems of varying severity. Strengths and weaknesses in the utility of the Guide were noted. As a result of the clinical audit process, the present authors identified a number of inconsistencies, significant gaps and assertions unsupported by the available literature in the Guide. They also noted aspects of the ICD-10 itself which are problematic when applied to people with ID. Despite these limitations, the Guide is a valuable first attempt to establish a standardized structure for multi-axial diagnosis in this population. A number of suggestions for major changes and refinements to future editions are made, and a strategy for development of research to establish validity and reliability is proposed.


Propionibacterium acnes: A Treatable Cause of Constrictive Pericarditis.
In this case report we share a case of infective Pericarditis caused by Propionibacterium acnes (P. acnes) in an immune-competent, nonsurgical patient. This case and review will illustrate the importance of considering P. acnes as a cause of idiopathic pericardial effusion and effusive constrictive disease. The patient was a 61-year-old male with history of osteoarthritis of the knee. He received an intra-articular steroid injection in July 2013. Two months later, he presented with atrial fibrillation and heart failure. He was found to have pericardial and bilateral pleural effusions which grew P. acnes. This organism was initially considered to be contaminant; however, as P. acnes was isolated from both pleural and pericardial fluids, he was started on oral amoxicillin. He was noted to have recurrence of effusions within 2 weeks with evidence of constrictive physiology by echocardiography. Treatment was subsequently changed to intravenous Penicillin G with marked symptomatic improvement, resolution of pericardial/pleural effusions, and no echocardiographic evidence of constrictive pericarditis at 10 weeks follow-up. Pursuit and treatment of P. acnes could lead to prevention of constrictive pericarditis. We believe that further studies are needed to assess prevalence of P. acnes and response to intravenous Penicillin G in patients presenting with effusive constrictive disease.


Vaccines, our shared responsibility.
The Developing Countries Vaccine Manufacturers' Network (DCVMN) held its fifteenth annual meeting from October 27-29, 2014, New Delhi, India. The DCVMN, together with the co-organizing institution Panacea Biotec, welcomed over 240 delegates representing high-profile governmental and nongovernmental global health organizations from 36 countries. Over the three-day meeting, attendees exchanged information about their efforts to achieve their shared goal of preventing death and disability from known and emerging infectious diseases. Special praise was extended to all stakeholders involved in the success of polio eradication in South East Asia and highlighted challenges in vaccine supply for measles-rubella immunization over the coming decades. Innovative vaccines and vaccine delivery technologies indicated creative solutions for achieving global immunization goals. Discussions were focused on three major themes including regulatory challenges for developing countries that may be overcome with better communication; global collaborations and partnerships for leveraging investments and enable uninterrupted supply of affordable and suitable vaccines; and leading innovation in vaccines difficult to develop, such as dengue, Chikungunya, typhoid-conjugated and EV71, and needle-free technologies that may speed up vaccine delivery. Moving further into the Decade of Vaccines, participants renewed their commitment to shared responsibility toward a world free of vaccine-preventable diseases.


Parent-Child Pain Relationships from a Psychosocial Perspective: A Review of the Literature.
Chronic or recurrent pain is a widespread health issue that affects a large proportion of the population, including adults and children. Family factors in the development of pain have received increasing attention of late as research has shown that pain tends to run in families, A burgeoning literature has also demonstrated the influence of parental factors in children's responses to chronic and laboratory pain. This review attempts to integrate: first,) the literature documenting an association between parent and child pain both within the clinical chronic pain and laboratory pain literatures; and second,) research accounting for likely mechanisms explaining the parent-child pain association. To this end, we present a conceptual model that incorporates a number of parent and child specific characteristics, such as parental responses, coping and gender role socialization as well as broader socio-demographic factors such as parent and child age and sex, family functioning, socioeconomic status, and race/ethnicity. It is anticipated that consideration of such variables will lead to needed research exploring the mechanisms of parent-child pain relationships, and to interventions designed to prevent and ameliorate child pain sensitivity when it correlates with poor adaptation to pain.


Herd protection by a bivalent killed whole-cell oral cholera vaccine in the slums of Kolkata, India.
We evaluated the herd protection conferred by an oral cholera vaccine using 2 approaches: cluster design and geographic information system (GIS) design. Residents living in 3933 dwellings (clusters) in Kolkata, India, were cluster-randomized to receive either cholera vaccine or oral placebo. Nonpregnant residents aged≥1 year were invited to participate in the trial. Only the first episode of cholera detected for a subject between 14 and 1095 days after a second dose was considered. In the cluster design, indirect protection was assessed by comparing the incidence of cholera among nonparticipants in vaccine clusters vs those in placebo clusters. In the GIS analysis, herd protection was assessed by evaluating association between vaccine coverage among the population residing within 250 m of the household and the occurrence of cholera in that population. Among 107 347 eligible residents, 66 990 received 2 doses of either cholera vaccine or placebo. In the cluster design, the 3-year data showed significant total protection (66% protection, 95% confidence interval [CI], 50%-78%, P<.01) but no evidence of indirect protection. With the GIS approach, the risk of cholera among placebo recipients was inversely related to neighborhood-level vaccine coverage, and the trend was highly significant (P<.01). This relationship held in multivariable models that also controlled for potentially confounding demographic variables (hazard ratio, 0.94 [95% CI, .90-.98]; P<.01). Indirect protection was evident in analyses using the GIS approach but not the cluster design approach, likely owing to considerable transmission of cholera between clusters, which would vitiate herd protection in the cluster analyses. NCT00289224.


Hopping of water in a glassy polymer studied via transition path sampling and likelihood maximization.
Diffusion of small molecules in amorphous polymers is known to follow a form of so-called hopping motion: penetrant molecules are trapped in microscopic cavities for extended time periods; diffusion is made possible by rare but fast jumps between neighboring cavities. Existing understanding of the hopping mechanism is based on the inspection of molecular images during individual molecular-dynamics trajectories. We focus on the diffusion of water molecules in a hydrophilic polymer below its glass transition temperature. The transition path ensemble of one hopping event is sampled with aimless shooting, a type of transition path sampling technique. In these trajectories, configurations of both the penetrant and the polymer change during the transition. Statistical analysis of the ensemble using likelihood maximization leads to a reaction coordinate of the transition, whose key components include the penetrant configuration and distances between penetrant-host atom pairs that have strong electrostatic interactions. Polymer motions do not contribute directly to the reaction coordinate. This result points toward a transition mechanism dominated by the penetrant movement. Molecular insights from this study can benefit the development of computational tools that better predict material transport properties, facilitating the design of new materials, including polymers with engineered drying properties.


Patients' Preferences for Primary Colorectal Cancer Screening: A Survey of the National Colorectal Cancer Screening Program in Korea.
The adoption of colonoscopy as a primary colorectal cancer (CRC) screening technique has been argued for in Korea, without evidence of patient preferences. This study aimed to investigate patients' preferences for the primary CRC screening test for the National Cancer Screening Program (NCSP). Between June and August 2016, 414 individuals aged ≥50 years who participated in the NCSP were prospectively invited to complete a questionnaire regarding their preferences for the primary CRC screening test and the reasons for their selection. Among the 396 respondents who completed the questionnaire, 124 individuals (31.3%) preferred the fecal immunochemical test (FIT), whereas 272 individuals (68.7%) preferred colonoscopy. Elderly participants preferred the FIT (p<0.001), whereas participants with a higher education level (p=0.030), a higher income level (p=0.009), or individuals with a family member (p=0.028) or acquaintance (p=0.013) with a history of CRC preferred colonoscopy. Only 12.9% of participants had a bad experience with a previous FIT; however, 39.3% of participants had a bad experience with a previous colonoscopy. Colonoscopy was preferred to FIT in a 2.2:1 ratio as the primary CRC screening test for the NCSP. Patients' preference for colonoscopy should be considered for the NCSP in Korea.


Vocal identity and species recognition in male Australian sea lions, Neophoca cinerea.
The acoustic channel is important for communication in otariids (fur seals and sea lions). Discrimination between species, sex or individuals is essential in communication; therefore insight into the role of vocalisations in recognition is vital to understanding otariid social interactions. We measured vocalisations and their use in discriminating sex and species in male Australian sea lions (Neophoca cinerea). Barking calls of mature males were recorded and analysed based on five acoustic parameters. A discriminant function analysis classified calls to the correct individual at a classification rate of 56%, suggesting that male barking calls are individually distinctive with the potential to facilitate individual vocal recognition. Playback experiments were used to assess the role of vocalisations in sex and species recognition both in and out of the breeding season. Males showed significantly stronger reactions to both conspecific and heterospecific males than they did to conspecific females and were most responsive during the breeding season. Australian sea lion males have the most depauperate vocal repertoire of any otariid. This simple repertoire may reflect the ecological circumstances in which these animals breed, with very low colony densities, asynchronous breeding and low levels of polygyny. Yet even in this simple system, males are able to discriminate between males and females of their own species, and distinguish the calls of conspecifics from other species. The barking calls of male Australian sea lions have sufficient information embedded to provide the potential for individual discrimination and this ability will be assessed in future studies.


Metabolism of T4 bacteriophage ghost-infected cells: effect of bacteriophage and ghosts on the uptake of carbohydrates in Escherichia coli B.
Ghosts of T4 bacteriophage inhibit the uptake of thiomethyl-beta-galactoside (TMG), alpha-methylglucoside, glucose-6-phosphate, and glycerol in Escherichia coli B. The transport of orthonitrophenyl-beta-galactoside (ONPG) is also inhibited to a lesser degree and without alteration of the apparent K(m) of transport. These effects of ghosts parallel those of energy poisons on these systems. However, no one energy poison can produce such pronounced inhibitory effects in all these systems. The effect of the intact phage in these systems was either absent or very slight relative to the ghost. The effect of ghosts on the uptake of TMG was not immediate; at 10 C, no effect of the ghosts was apparent for at least 2 min. This suggests that a step, more temperature dependent than the attachment of the ghost, is necessary for the inhibitory action. The intracellular level of adenosine triphosphate (ATP) in the ghost-infected cells fell to less than 25% of the control value, and the ATP lost from the cell appeared in extracellular medium. Phage, on the other hand, caused no decrease in the intracellular ATP level. This loss of ATP from the cells after ghost infection suggests an alteration of the barrier properties of the membrane so that ATP can leave the cell; however, the accessibility of extracellular ONPG to intracellular beta-galactosidase does not increase. The dissimilarity of the actions of phage and ghosts on all properties examined does not support the model that the initial events in their infections are identical but that the intact phage, unlike the ghost, can provide information for the repair of its effects.


Inhibition of seedling survival under Rhododendron maximum (Ericaceae): could allelopathy be a cause?
In the southern Appalachian mountains a subcanopy species, Rhododendron maximum, inhibits the establishment and survival of canopy tree seedlings. One of the mechanisms by which seedlings could be inhibited is an allelopathic effect of decomposing litter or leachate from the canopy of R. maximum (R.m.) on seed germination, root elongation, or mycorrhizal colonization. The potential for allelopathy by R.m. was tested with two bioassay species (lettuce and cress), with seeds from four native tree species, and with three ectomycorrhizal fungi. Inhibitory influences of throughfall, fresh litter, and decomposed litter (organic layer) from forest with R.m. (+R.m. sites) were compared to similar extractions made from forest without R.m. (-R.m. sites). Throughfall and leachates of the organic layer from both +R.m. and -R.m. sites stimulated germination of the bioassay species above that of the distilled water control, to a similar extent. There was an inhibitory effect of leachates of litter from +R.m. sites on seed germination and root elongation rate of both bioassay species compared with that of litter from -R.m. sites. Native tree seed stratified in forest floor material from both forest types had a slightly higher seed germination rate compared with the control. A 2-yr study of seed germination and seedling mortality of two tree species, Quercus rubra and Prunus serotina, in field plots showed no significant influence of litter or organic layer from either forest type. Incorporating R.m. leaf material into the growth medium in vitro depressed growth of one ectomycorrhizal species but did not affect two other species. Leaf material from other deciduous tree species depressed ectomycorrhizal growth to a similar or greater extent as leaf material from R.m. In conclusion, R.m. litter can have an allelopathic effect on seed germination and root elongation of bioassay species as well as some ectomycorrhizal species. However, this allelopathic affect is not manifest in field sites and is not likely to be an important cause for the inhibition of seedling survival within thickets of R.m.


The regulation and adoption of health technologies under Brazil's Unified Health System: barriers to access to medicines for diseases of poverty?
The study aimed to examine the regulation and adoption of health technologies for the diseases of poverty in the Brazil's Unified Health System (SUS). An exploratory, descriptive study was conducted between January and May 2016 consisting of the search and analysis of relevant documents on the websites of Brazil's National Health Surveillance Agency, the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), the National Commission for the Adoption of Technologies by the SUS, and Saúde Legis (the Ministry of Health's Legislation System). The 2014 version of the Brazilian National List of Essential Medicines (RENAME, acronym in Portuguese) contained 132 medicines for diseases of poverty. Over one-third of these (49) had only one national producer, while 24 were not registered in the country. The number of medicines contained in the RENAME dedicated to this group of diseases increased by 46% between 2006 and 2014. Despite advances in the regulation and incorporation of technologies by the SUS, given the lack of market interest and neglect of diseases of poverty, the government has a vital role to play in ensuring access to the best available therapies in order to reduce health inequalities. It therefore follows that Brazil needs to improve the regulation of medicines that do not attract market interest.


Imaging mass spectrometry of fingermarks on brass bullet casings using sample rotation.
A rotation stage was developed to allow the surface of bullet casings to be imaged under ultra-high vacuum (UHV) conditions using time-of-flight secondary ion mass spectrometry (ToF-SIMS). Experiments were performed over a period of seven months to determine how fingermarks deposited on the surface of Webley MkII revolver rounds change over time. Stitching software written in Python was used to combine image strips that were collected by performing ToF-SIMS analysis along the length of the revolver rounds. The ToF-SIMS analysis was performed by analysing a thin strip along the length of the casings, before rotating them through a few degrees and analysing a new strip. This process was repeated until the entire casing had been imaged. The resulting secondary ion images of the fingermarks were compared to optical images obtained from the same and similar rounds that had been exposed to cyanoacrylate fumes and subsequently stained using Basic Yellow 40 (BY40) dye. ToF-SIMS images were shown to display evidence of ridge and sweat pore level detail on samples that displayed no evidence of fingermarks when developed with cyanoacrylate and BY40. The effects of the curvature of the round casings on the morphology of fingermarks were also assessed. ToF SIMS images were compared to marks that had been deposited onto flat paper surfaces using ink. The distortions caused by differences in surface curvature and the deposition methods were found to be within acceptable limits.


Evaluation of annoyance from low frequency noise under laboratory conditions.
The aim of the study was to investigate the annoyance of low frequency noise (LFN) at levels normally prevailing at workplaces in control rooms and office-like areas. Two different laboratory experiments were carried out. The first experiment included 55 young volunteers and the second one comprised 70 older volunteers, categorized in terms of sensitivity to noise. The subjects listened to noise samples with different spectra, including LFNs at sound pressure level (SPL) of 45-67 dBA, and evaluated annoyance using a 100-score graphical rating scale. The subjective ratings of annoyance were compared to different noise metrics. In both the experiments, there were no differences in annoyance assessments between females and males. A significant influence of individual sensitivity to noise on annoyance rating was observed for some LFNs. Annoyance of LFN was not rated higher than annoyance from broadband noises without or with less prominent low frequencies at similar A-weighted SPLs. In both the experiments, median annoyance rating of LFN highly correlated with A-weighted SPL (L(Aeq,T)), low frequency A-weighted SPL (L(LFAeq,T)) and C-weighted SPL (L(Ceq,T)). However, it is only the two latter noise metrics (i.e. L(LFAeq,T) and L(Ceq,T)) which seem to be reliable predictors of annoyance exclusively from LFN. The young and older participants assessed similar annoyance from LFN at similar L(LFAeq,T) or L(Ceq,T) levels. Generally, over half of the subjects were predicted to be highly annoyed by LFN at the low frequency A-weighted SPL or C-weighted SPL above 62 and 83 dB, respectively.


The neural correlates of inner speech and auditory verbal imagery in schizophrenia: relationship to auditory verbal hallucinations.
Auditory verbal hallucinations are thought to arise from the disordered monitoring of inner speech (thinking in words). We tested the hypothesis that a predisposition to verbal auditory hallucinations would be associated with an abnormal pattern of brain activation during tasks which involved the generation and monitoring of inner speech. The neural correlates of tasks which engaged inner speech and auditory verbal imagery were examined using positron emission tomography in (a) schizophrenic patients with a strong predisposition to auditory verbal hallucinations (hallucinators), (b) schizophrenic patients with no history of hallucinations (nonhallucinators), and (c) normal controls. There were few between-group differences in activation during the inner speech task. However, when imagining sentences spoken in another person's voice, which entails the monitoring of inner speech, hallucinators showed reduced activation in the left middle temporal gyrus and the rostral supplementary motor area, regions which were strongly activated by both normal subjects and nonhallucinators (P < 0.001). Conversely, when nonhallucinators imagined speech, they differed from both hallucinators and controls in showing reduced activation in the right parietal operculum. A predisposition to verbal hallucinations in schizophrenia is associated with a failure to activate areas implicated in the normal monitoring of inner speech, whereas the absence of a history of hallucinations may be linked to reduced activation in an area concerned with verbal prosody.


Activation of the L voltage-sensitive calcium channel by mitogen-activated protein (MAP) kinase following exposure of neuronal cells to beta-amyloid. MAP kinase mediates beta-amyloid-induced neurodegeneration.
Neuronal degeneration in Alzheimer's disease (AD) has been variously attributed to increases in cytosolic calcium, reactive oxygen species, and phosphorylated forms of the microtubule-associated protein tau. beta-Amyloid (betaA), which accumulates extracellularly in AD brain, induces calcium influx in culture via the L voltage-sensitive calcium channel. Since this channel is normally activated by protein kinase A-mediated phosphorylation, we examined kinase activities recruited following betaA treatment of cortical neurons and SH-SY-5Y neuroblastoma. betaA increased channel phosphorylation; this increase was unaffected by the protein kinase A inhibitor H89 but was reduced by the mitogen-activated protein (MAP) kinase inhibitor PD98059. Pharmacological and antisense oligonucleotide-mediated reduction of MAP kinase activity also reduced betaA-induced accumulation of calcium, reactive oxygen species, phospho-tau immunoreactivity, and apoptosis. These findings indicate that MAP kinase mediates multiple aspects of betaA-induced neurotoxicity and indicates that calcium influx initiates neurodegeneration in AD. betaA increased MAP kinase-mediated phosphorylation of membrane-associated proteins and reduced phosphorylation of cytosolic proteins without increasing overall MAP kinase activity. Increasing MAP kinase activity with epidermal growth factor did not increase channel phosphorylation. These findings indicate that redirection, rather than increased activation, of MAP kinase activity mediates betaA-induced neurotoxicity.


Human cord blood (hCB)-CD34+ humanized mice fail to reject human acute myeloid leukemia cells.
Since their appearance, humanized mice carrying human immune system seemed promising tools to study the crosstalk between cancer and immunity. The NOD-scidIL2Rgammanull (NSG) mice engrafted with human cord blood (hCB)-CD34+ cells have been proposed to be a valuable tool to reproduce human immune system in mouse. However, the lack of solid evidences on the functionality of their human immune components limits their usage in immune-oncology. We report that (hCB)-CD34+ cells lose their ability to propagate and originate bone marrow-derived human immune cells after two serial transplantations in NSG mice. We demonstrate that transplants of bone marrow patient-derived acute myeloid leukemias (hAMLs) grow very similarly in the humanized (hCB)-CD34+ NSG and parental NSG mice. The similar extent of engraftment and development of leukemias in (hCB)-CD34+ NSG and controls suggests a poor human immune response against not compatible hAMLs. Our findings suggest that (hCB)-CD34+ NSG mice are transient and/or incomplete carriers of the human immune system and, therefore, represent a suboptimal tool to study the interaction between tumor and immune cells.


Wake-Up Stroke Is Associated With Greater Nocturnal Mean Arterial Pressure Variability.
Wake-up strokes (WUS) account for ≈20% to 30% of ischemic strokes. Studies have shown that increased autonomic instability as measured by blood pressure variability (BPV) is greater in stroke patients than nonstroke patients, but no studies have compared BPV in WUS versus non-WUS patients. From a single-center prospective registry, we identified consecutive ischemic stroke patients. BPV was calculated as the coefficient of variation of the mean arterial pressure during the first 24 hours after hospitalization. We assessed 24-hour BPV as a continuous measure and in quartiles in WUS versus non-WUS patients using univariable and multivariable statistics. Among 369 patients (64.9±16.5 years; 50.1% male; 64.7% white), 78 were WUS (21.1%). Clinical characteristics and medical history were not different between WUS and non-WUS patients except WUS patients were older (69.0 versus 63.8 years; P=0.015) and more frequently had previous ischemic stroke (29.5% versus 17.2%; P=0.012). Initial 24-hour BPV (11.77 versus 10.76; P=0.098) was similar between groups. However, WUS patients had greater nocturnal BPV (10.50 versus 8.95; P=0.030), whereas daytime BPV was similar between groups (10.96 versus 10.47, P=0.459). In multivariate analysis, the highest quartile (≥11.48 mm Hg) of nocturnal BPV was independently associated with WUS (adjusted odds ratio, 1.95; confidence interval, 1.13-3.39; P=0.017). In this single-center study, we observed that greater nocturnal BPV during the first 24 hours after hospitalization occurred in WUS than non-WUS patients. Nocturnal autonomic instability warrants further study as a potential mechanism of WUS.


Improved HPLC method for carbohydrate-deficient transferrin in serum.
There is need for a reference method for transferrin glycoforms in serum to which routine immunologic methods for the alcohol marker carbohydrate-deficient transferrin (CDT) can be traceable. We describe an improved HPLC method for transferrin glycoforms. Transferrin was iron-saturated by mixing the serum with ferric nitrilotriacetic acid, and lipoproteins were precipitated with dextran sulfate and calcium chloride. Separation of glycoforms was performed on a SOURCE 15Q anion-exchange column using salt gradient elution. Quantification relied on selective absorbance of the iron-transferrin complex at 470 nm. The relative amount of each glycoform was calculated as a percentage of the area under the curve, using baseline integration. The HPLC system provided reproducible separation and quantification of the asialo-, monosialo-, disialo-, trisialo-, tetrasialo-, pentasialo-, and hexasialotransferrin glycoforms. Most importantly, disialo- and trisialotransferrin were almost baseline separated. The intra- and interassay CV for disialotransferrin were <5%. Serum and the pretreated samples were stable for at least 2 days at 22 or 4 degrees C. Sera from 132 healthy controls contained [mean (SD)] 1.16 (0.25)% disialotransferrin, 4.77 (1.36)% trisialotransferrin, 80.18 (2.01)% tetrasialotransferrin, and 13.88 (1.69)% pentasialo- + hexasialotransferrin. In some cases of a high (>6%) trisialotransferrin, monosialotransferrin was detected at <0.25%. Asialotransferrin was not detected in control sera, but was detected in 57% of chronic heavy drinkers and in 62% of sera with >/=2% disialotransferrin. The HPLC method fulfills the requirements of a preliminary reference method for CDT and should work for any combination of serum transferrin glycoforms. This method could also be useful for confirming positive CDT results by immunoassays in medico-legal cases.


Spermatic cord abscess with concurrent prostatic abscess involving the seminal vesicle.
Prostatic abscess involving the seminal vesicle has become rare following the development of effective antibiotic treatments. To our knowledge, we report the first case in the English-language literature of a patient with a spermatic cord abscess and a concurrent prostatic abscess. We examined an 81-year-old man for swelling and pain in the left inguinal region and performed computed tomography (CT) that later confirmed the suspected diagnosis of left inguinal hernial strangulation. We performed urgent surgical drainage of a left spermatic cord abscess; and under the correct diagnosis by CT, he was successfully treated further with antibiotics and transperineal drainage of a prostatic abscess extending to the seminal vesicle. We highlight that familiarity with such a rare condition is overwhelmingly essential for patient management and that CT is the most valuable imaging procedure for diagnosing such cases.


Physical activity interventions for cancer-related fatigue: A scoping review of randomized controlled trials from a Nursing Science Precision Health Model perspective.
The Nursing Science Precision Health (NSPH) Model has the potential to guide research on the development, testing, and targeting of interventions. This scoping review examines the relationship between physical activity (PA) and cancer-related fatigue (CRF) within the context of the NSPH Model. The Joanna Briggs Institute scoping review methodology and Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guided this review. We included randomized controlled trials in people with cancer that investigated PA interventions and measured change in CRF as an outcome. A total of 181 studies met the eligibility criteria. Over 20 different instruments were used to measure CRF. The most common PA interventions were strength training (48%), walking (36%), cycling (26%), and yoga (15%). A limited number of studies reported phenotypic characteristics (32/181, 17%) or biomarkers (31/181, 17%) associated with CRF. This scoping review identified the body of existing research exploring CRF and PA from a precision health perspective.


Helminth infection and type 1 diabetes.
The increasing incidence of type 1 diabetes (T1D) and autoimmune diseases in industrialized countries cannot be exclusively explained by genetic factors. Human epidemiological studies and animal experimental data provide accumulating evidence for the role of environmental factors, such as infections, in the regulation of allergy and autoimmune diseases. The hygiene hypothesis has formally provided a rationale for these observations, suggesting that our co-evolution with pathogens has contributed to the shaping of the present-day human immune system. Therefore, improved sanitation, together with infection control, has removed immunoregulatory mechanisms on which our immune system may depend. Helminths are multicellular organisms that have developed a wide range of strategies to manipulate the host immune system to survive and complete their reproductive cycles successfully. Immunity to helminths involves profound changes in both the innate and adaptive immune compartments, which can have a protective effect in inflammation and autoimmunity. Recently, helminth-derived antigens and molecules have been tested in vitro and in vivo to explore possible applications in the treatment of inflammatory and autoimmune diseases, including T1D. This exciting approach presents numerous challenges that will need to be addressed before it can reach safe clinical application. This review outlines basic insight into the ability of helminths to modulate the onset and progression of T1D, and frames some of the challenges that helminth-derived therapies may face in the context of clinical translation.