Simulation of clinical fractures for three different all-ceramic crowns.
Comparison of fracture strength and fracture modes of different all-ceramic crown systems is not straightforward. Established methods for reliable testing of all-ceramic crowns are not currently available. Published in-vitro tests rarely simulate clinical failure modes and are therefore unsuited to distinguish between the materials. The in-vivo trials usually lack assessment of failure modes. Fractographic analyses show that clinical crowns usually fail from cracks initiating in the cervical margins, whereas in-vitro specimens fail from contact damage at the occlusal loading point. The aim of this study was to compare three all-ceramic systems using a clinically relevant test method that is able to simulate clinical failure modes. Ten incisor crowns of three types of all-ceramic systems were exposed to soft loading until fracture. The initiation and propagation of cracks in these crowns were compared with those of a reference group of crowns that failed during clinical use. All crowns fractured in a manner similar to fracture of the clinical reference crowns. The zirconia crowns fractured at statistically significantly higher loads than alumina and glass-ceramic crowns. Fracture initiation was in the core material, cervically in the approximal areas.


Evaluating the Impact of Intervention Strategies on the First Wave and Predicting the Second Wave of COVID-19 in Thailand: A Mathematical Modeling Study.
Coronavirus disease 2019 (COVID-19) has spread rapidly worldwide. This study aimed to assess and predict the incidence of COVID-19 in Thailand, including the preparation and evaluation of intervention strategies. An SEIR (susceptible, exposed, infected, recovered) model was implemented with model parameters estimated using the Bayesian approach. The model's projections showed that the highest daily reported incidence of COVID-19 would be approximately 140 cases (95% credible interval, CrI: 83-170 cases) by the end of March 2020. After Thailand declared an emergency decree, the numbers of new cases and case fatalities decreased, with no new imported cases. According to the model's predictions, the incidence would be zero at the end of June if non-pharmaceutical interventions (NPIs) were strictly and widely implemented. These stringent NPIs reduced the effective reproductive number (Rt) to 0.73 per day (95% CrI: 0.53-0.93) during April and May. Sensitivity analysis showed that contact rate, hand washing, and face mask wearing effectiveness were the parameters that most influenced the number of reported daily new cases. Our evaluation shows that Thailand's intervention strategies have been highly effective in mitigating disease propagation. Continuing with these strict disease prevention behaviors could minimize the risk of a new COVID-19 outbreak in Thailand.


Policy issues related to educating the future Israeli medical workforce: an international perspective.
A 2014 external review of medical schools in Israel identified several issues of importance to the nation's health. This paper focuses on three inter-related policy-relevant topics: planning the physician and healthcare workforce to meet the needs of Israel's population in the 21(st) century; enhancing the coordination and efficiency of medical education across the continuum of education and training; and the financing of medical education. All three involve both education and health care delivery. The physician workforce is aging and will need to be replenished. Several physician specialties have been in short supply, and some are being addressed through incentive programs. Israel's needs for primary care clinicians are increasing due to growth and aging of the population and to the increasing prevalence of chronic conditions at all ages. Attention to the structure and content of both undergraduate and graduate medical education and to aligning incentives will be required to address current and projected workforce shortage areas. Effective workforce planning depends upon data that can inform the development of appropriate policies and on recognition of the time lag between developing such policies and seeing the results of their implementation. The preclinical and clinical phases of Israeli undergraduate medical education (medical school), the mandatory rotating internship (stáge), and graduate medical education (residency) are conducted as separate "silos" and not well coordinated. The content of basic science education should be relevant to clinical medicine and research. It should stimulate inquiry, scholarship, and lifelong learning. Clinical exposures should begin early and be as hands-on as possible. Medical students and residents should acquire specific competencies. With an increasing shift of medical care from hospitals to ambulatory settings, development of ambulatory teachers and learning environments is increasingly important. Objectives such as these will require development of new policies. Undergraduate medical education (UME) in Israel is financed primarily through universities, and they receive funds through VATAT, an education-related entity. The integration of basic science and clinical education, development of earlier, more hands-on clinical experiences, and increased ambulatory and community-based medical education will demand new funding and operating partnerships between the universities and the health care delivery system. Additional financing policies will be needed to ensure the appropriate infrastructure and support for both educators and learners. If Israel develops collaborations between various government agencies such as the Ministries of Education, Health, and Finance, the universities, hospitals, and the sick funds (HMOs), it should be able to address successfully the challenges of the 21st century for the health professions and meet its population's needs.


Human MUC1 mucin: a potent glandular morphogen.
Human MUC1 mucin is a high-molecular-weight transmembrane glycoprotein, which is apically expressed in the majority of glandular epithelia. During embryonic development, changes in the pattern of MUC1 mucin expression coincide with the onset of glandular differentiation. This mucin is also frequently overexpressed and aberrantly glycosylated in carcinomas. To investigate the potential role of MUC1 mucin in morphogenesis, a full length MUC1 cDNA was transfected into murine mammary adenocarcinoma (410.4) and Madin-Darby canine kidney (MDCK) cells. This generated four clonal cell lines. Western blotting, FACS analysis, and immunohistochemistry confirmed expression of MUC1. All four MUC1-expressing clones demonstrated altered morphogenesis when cultured in three-dimensional type I collagen gels. While parental and vector control 410.4 cells formed compact spherical structures, the MUC1-expressing clones formed complex branching structures. Similarly, while parental and vector control MDCK cells formed small circumscribed colonies with a central lumen, the MUC1-expressing clones formed elongated tubules. MUC1 expression was also associated with reduced cellular cohesion and enhanced migration on type I collagen-coated surfaces for all except one of the clones, which expressed only low levels of MUC1 on the cell surface. These results show that MUC1 expression stimulates morphogenetic changes in two distinct epithelial cell lines. Taken together with previous observations on MUC1 expression in embryonic development and carcinomas, this finding suggests that MUC1 may induce changes in tissue architecture in both normal development and cancer.


Take your shoes off to reduce patellofemoral joint stress during running.
Elevated patellofemoral joint stress is thought to contribute to the development and progression of patellofemoral pain syndrome. The purpose of this study was to determine if running barefoot decreases patellofemoral joint stress in comparison to shod running. Lower extremity kinematics and ground reaction force data were collected from 22 trained runners during overground running while barefoot and in a neutral running shoe. The kinematic and kinetic data were used as input variables into a previously described mathematical model to determine patellofemoral joint stress. Knee flexion angle, net knee extension moment and the model outputs of contact area, patellofemoral joint reaction force and patellofemoral joint stress were plotted over the stance phase of the gait cycle and peak values compared using paired t tests and standardised mean differences calculated. Running barefoot decreased peak patellofemoral joint stress by 12% (p=0.000) in comparison to shod running. The reduction in patellofemoral joint stress was a result of reduced patellofemoral joint reaction forces (12%, p=0.000) while running barefoot. Elevated patellofemoral joint stress during shod running might contribute to patellofemoral pain. Running barefoot decreases patellofemoral joint stress.


Influence of diffraction on hard-aperture Kerr-lens mode locking.
It is demonstrated that with rigorous inclusion of diffraction on an intracavity hard aperture the values of the nonlinear differential loss coefficient Gamma (which characterizes the efficiency of Kerr-lens mode locking) are several times higher than in the commonly used simplified approach in which diffraction effects are neglected. Diffraction changes modal properties and causes a faster decrease of mode losses with increasing power than predicted by the traditional approach. With this correction, the discrepancy between the Kerr-lens mode-locking theory and the theoretical estimates of the self-starting condition is substantially decreased.


Experimental determination of the chromatic difference of magnification of the human eye and the location of the anterior nodal point.
Theory predicts that retinal image size will vary with wavelength. However, this chromatic difference of magnification (CDM) is likely to be very small (< 1% between 400 and 700 nm) under natural viewing conditions. There has been only one attempt to measure CDM experimentally, and the results were inconsistent with optical theory. Using a technique described by Ogle [Research in Binocular Vision, Hafner, New York (1964)], which is sensitive to even small interocular differences in retinal image size, we measured the apparent tilts in the frontoparallel plane induced by interocular differences in wavelength. We obtained the ocular CDM by determining the afocal lens magnification necessary to cancel the apparent frontoparallel plane tilt caused by interocular differences in wavelength. We show that (1) the ocular CDM can be considerably less than theoretical model predictions, (2) the relationship among delta Rx (wavelength-dependent refractive error), CDM, and pupil position is consistent with our theoretical model, (3) CDM increases considerably when an artificial pupil in front of the eye is used, (4) the location of the anterior nodal point of the eye may be inferred from the data, and (5) unlike in the case for delta Rx, large intersubjective differences may exist for CDM. The results suggest caution in the use of artificial pupils experimentally with polychromatic stimuli because of amplification of CDM and concomitant losses of image contrast.


Potential of urinary biomarkers in early bladder cancer diagnosis.
Carcinoma of urinary bladder ranks among the top ten most common cancers worldwide. Approximately 80% of the disease is superficial (limited to mucosa and lamina propria) at the time of presentation. However, the majority of these tumors recur and 15-20% progress into muscle-invasive disease. Cystoscopic surveillance of the urinary bladder remains the standard of care to identify these recurrences on follow-up. Not only is this an invasive procedure, but the sensitivity of cystoscopy can be as low as 70%, so there can be up to 30% of tumors that are missed. Urinary cytology, with recognized limitations, has been used as an adjunct to this procedure, pending discovery of alternate urinary biomarkers. In the past decade there has been tremendous advancement in producing urinary biomarkers for urinary bladder cancer research, reflecting advancements in genomics and proteomics. An ideal biomarker should be able to replace cystoscopic examination and be cost effective. Unfortunately, most of the identified protein or molecular biomarkers have failed this test. This article critically appraises the status of these urinary biomarkers in urinary bladder cancer, in addition to highlighting some of the difficulties in this research area.


Toll-like receptors, IFN-γ and IL-12 expression in bovine leukemia virus-infected animals with low or high proviral load.
Bovine leukemia virus (BLV) infection is widespread mainly in dairy cattle and 5-10% of infected animals will die due to lymphosarcoma; most cattle remain asymptomatic but 30% develop persistent lymphocytosis (PL). BLV transmission depends on infected cell exchange and thus, proviral load is determinant. Understanding the mechanisms which govern the control of viral dissemination will be desirable for the design of effective therapeutic or preventive strategies for BLV. The development of high proviral load (HPL) or low proviral load (LPL) might be associated to genetic factors and humoral immune responses, however cellular responses are not fully described. We aimed to characterize cytokines and toll-like receptors (TLR) expression related to the proviral load profiles. IFN-γ and IL-12 mRNA expression level was significantly higher in PBMC from infected cattle (LPL n=6 and HPL n=7) compared to uninfected animals (n=5). While no significant differences were observed in IL-12 expression between LPL and HPL group, IFN-γ expression was significantly higher in LPL animals. Infected cattle exhibited higher expression levels of TLR3, 7-9. Animals with HPL had significantly higher expression of TLR7/8 than uninfected cattle. TLR8 and TLR9 were up-regulated in HPL group, and TLR3 was up-regulated in LPL group. This is the first report related to TLR gene expression in BLV infected cattle and represents evidence of the involvement of these receptors in BLV recognition. Further studies on different subpopulations of immune cells may help clarify their role in response to BLV and its consequences on viral dissemination.


Production of a bacteriocin-like inhibitory substance by Leuconostoc mesenteroides subsp. dextranicum 213M0 isolated from Mongolian fermented mare milk, airag.
Strain 213M0 was selected with productivity of a bacteriocin-like inhibitory substance (BLIS) among 235 strains of lactic acid bacteria (LAB) isolated from Mongolian fermented milk 'airag'. Strain 213M0 was species-identified as Leuconostoc mesenteroides subsp. dextranicum by morphological observation, carbohydrate fermentation profiling and sequencing the 16S rRNA gene. Incubation temperature proper to produce the BLIS was 25°C rather than 30 and 37°C, and the production actively proceeded during the exponential growth phase of the producer cells. Antibacterial effect of BLIS 213M0 was limited to all nine strains of Listeria sp. bacteria and seven strains of LAB cocci among 53 tested strains, which corresponds to a typical feature of the class IIa pediocin-like bacteriocins. BLIS 213M0 was not inactivated in every broad pH range solution (pH 2.0-11.0), and was stable against storage at 25°C for 1 week and heating at 121°C for 15 min under pH 4.5. Peptide frame of BLIS 213M0 was confirmed by inactivation with some peptidases, and then its molecular weight was estimated to be 2.6-3.0 kDa using an in situ activity assay following sodium dodecyl sulfate polyacrylamide gel electrophoresis. The estimated size was different from the other Leuconostoc bacteriocins already reported. These results suggest that BLIS 213M0 would be a novel listericidal bacteriocin.


Molecular features of hydration layers probed by atomic force microscopy.
Structurally-ordered layers of water are universally formed on a solid surface in aqueous solution or under ambient conditions. Although such hydration layers are commonly probed via atomic force microscopy (AFM), the current understanding on how the hydration layers manifest themselves in an AFM experiment is far from complete. By using molecular dynamics simulation, we investigate the hydration layers on a hydrophilic or hydrophobic surface probed by a nanoscale tip. We study the density and molecular orientation of water, the free energy, and the force on the tip by varying the tip-surface distance. The force-distance curve oscillates due to the transition between the mono-, bi-, and tri-layers of water confined between the tip and the surface. If both the tip and the surface are hydrophobic, water confined between the tip and the surface evaporates due to the dewetting transition, giving a hydrophobic force without oscillation. The periodicity of oscillation in the force differs from the structural periodicity of water. With a close proximity of the tip, the molecular dipoles align parallel to the surface, regardless of whether the tip and the surface are hydrophilic or hydrophobic.


The airborne mycobiome and associations with mycotoxins and inflammatory markers in the Norwegian grain industry.
Grain dust exposure is associated with respiratory symptoms among grain industry workers. However, the fungal assemblage that contribute to airborne grain dust has been poorly studied. We characterized the airborne fungal diversity at industrial grain- and animal feed mills, and identified differences in diversity, taxonomic compositions and community structural patterns between seasons and climatic zones. The fungal communities displayed strong variation between seasons and climatic zones, with 46% and 21% of OTUs shared between different seasons and climatic zones, respectively. The highest species richness was observed in the humid continental climate of the southeastern Norway, followed by the continental subarctic climate of the eastern inland with dryer, short summers and snowy winters, and the central coastal Norway with short growth season and lower temperature. The richness did not vary between seasons. The fungal diversity correlated with some specific mycotoxins in settled dust and with fibrinogen in the blood of exposed workers, but not with the personal exposure measurements of dust, glucans or spore counts. The study contributes to a better understanding of fungal exposures in the grain and animal feed industry. The differences in diversity suggest that the potential health effects of fungal inhalation may also be different.


[Age-related characteristics of the natural cytotoxicity system in patients with multiple sclerosis and their possible relation to the pathogenesis of the disease].
A study was made of the cytotoxic activity of natural killers (NK) against 3H-uridine labeled K-562 cells and its variability. 56 patients suffering from multiple sclerosis (MS), 33 healthy donors of different age and 34 patients with remitting MS and MS of different standing were entered into the study. The most remarkable lowering of the NK activity was seen in patients aged 41 to 50 years. In patients aged 51 to 59 years, the NK activity was not different from that in a group of healthy donors. The most pronounced increase of the variability index (VI) was recorded in patients aged 41 to 50 years. In the senior age group (from 51 to 59 years), the VI of the NK activity was 1.7 to 2.8 times as reduced as compared to the healthy control. It has been revealed that the changes in the NK activity and its variability in the respective patients' groups are of concomitant nature and that the estimates undergo fluctuations in the counterphase. During studies of the NK activity as dependent on the disease standing, NK deficiency was found to be associated with the gravity of the patient's clinical status and long disease standing. A possible relation of the changes in the NK activity and its variability to the disease pathogenesis is under discussion as are the compensation mechanisms that get triggered during depletion of the system according to the secondary deficiency type.


Cutoff Pepsinogen Level for Predicting Unintendedly Eradicated Cases of Helicobacter pylori Infection in Subjects with Seemingly Normal Pepsinogen Levels.
In the ABC method, which is a method for risk stratification of gastric cancer using serum anti-Helicobacter pylori antibody and pepsinogen (PG) test, subjects with normal PG and seronegative for H. pylori are named as "Group A" and are regarded as having a low risk of gastric cancer. These "Group A" subjects include unintentionally eradicated cases at relatively high risk, and this study aimed to identify these subjects. Of the 109 subjects, 76 were classified as uninfected Group A subjects with negative histologic H. pylori infection and no histologic and endoscopic atrophy, and 33 subjects were classified serologically as Group A after successful eradication, which are serologically equal to the unintendedly eradicated cases in Group A. The usefulness of measuring PG levels to detect post-eradication cases was validated by using a receiver operating characteristic (ROC) curve analysis. The area under the ROC curve for PGI level was 0.736 ± 0.06 (p < 0.01; cutoff value, 37.0 ng/mL; sensitivity, 77.6%; specificity, 72.7%), and that for the PGI/II ratio was 0.660 ± 0.06 (p < 0.01; cutoff value, 5.1; sensitivity, 84.2%; specificity, 43.4%). PGI levels of ≤37 ng/mL and PGI/II ratios of ≤5.1 effectively identified unintendedly eradicated cases in Group A.


Can the methanolic extract of Andrographis paniculata be used as a supplement to anti-snake venom to normalize hemostatic parameters: A thromboelastographic study.
The whole plant (including leaves and roots) is used in traditional Ayurveda and Siddha medicine to treat various clinical conditions such as fever, respiratory tract infections, colic pain, liver disorders, diabetes, hypertension, and inflammation. It is also used as an antidote for snake-bite, poisonous bites of insects and recommended as a dietary supplement to boost immunity. In-vitro thromboelastographic evaluation of the efficacy of methanolic extract of Andrographis paniculata (MAP) and polyvalent anti-snake venom (ASV) in neutralizing the Naja naja (N.N) venom-induced changes in hemostatic parameters. Thromboelastographic evaluation of hemostatic parameters was initiated by adding 3μg N.N venom to citrated whole blood from healthy volunteers. The effect of different concentrations of ASV and MAP in neutralizing the toxicity of N.N venom were studied in two groups. In group 1 experiments, citrated whole blood (340μl) was mixed with N.N venom (3μg), immediately followed by successive addition of ASV (5μl, 8μl and 15μl) or MAP (15μg, 30μg, 60μg and 120 μg) or combination of ASV and MAP (3μl ASV+30μg MAP and 3μl ASV+60μg MAP). In group 2 experiments, N.N venom was incubated with whole blood for 90 minutes at 37°C, followed by successive addition of ASV (5μl, 10μl, and 15μl) or MAP (30μg and 60μg) or combination of ASV and MAP (5μl ASV+30μg MAP and 5μl ASV+60μg MAP). In Group 1 experiments, N.N venom caused significant (p<0.05) increase in R-time, K-time, LY30% and a decrease in angle and MA. Optimum effect on hemostatic parameters was observed at a concentration of 8μl ASV, where all the deleterious effects of the venom were completely reversed. Similarly, the addition of MAP to the assay system could reproduce results as ASV, in reversing the deleterious effects of the venom. This occurred in a concentration-dependent manner, from 15μg-60μg, with the optimum results at 60μg. When ASV concentration was reduced to 3μl and supplemented with MAP (30μg or 60μg), the positive supplementary effect of MAP was demonstrated. In Group 2 experiments, N.N venom caused significant (p<0.05) changes in all TEG parameters, with most deleterious changes observed in MA and LY30% compared to Group 1 experiments. ASV when added in increasing concentrations (5-15μl), had beneficial effects only on K-time, angle, and MA. When added together with ASV, MAP (30μg or 60μg) could significantly (p<0.05) supplement the effect of ASV (5μl) in improving R-time, K-time, and angle. This in-vitro study demonstrates the effectiveness of MAP as a supplement to ASV in combating the deleterious effects of N.N venom on hemostasis. However, further in-vivo experiments in animal models are required to substantiate these effects.


The Association between Prefrontal Cortex Activity and Turning Behavior in People with and without Freezing of Gait.
Turning elicits Freezing of Gait (FoG) episodes in people with Parkinson's disease (PD) and is thought to require higher cortical control compared to straight ahead gait. Functional near infrared spectroscopy (fNIRS) has been used to examine prefrontal cortex (PFC) activity while walking, but the relationship between PFC activity and turn performance remains unclear. The aim of this pilot study was to examine PFC activity during turning in PD and healthy controls, and to investigate the association between PFC activity and turning. Thirty-two subjects, 15 freezers (PD + FoG) and 17 non-freezers (PD - FoG), and 8 controls were asked to perform a 2-min turning-in-place test under single-task (ST) and dual-task (DT) conditions. Each participant wore an fNIRS system to measure changes in oxyhemoglobin, as measure of PFC activity, and inertial sensors to quantify turning. Our results show a significant group (p = .050), task (p = .039), and interaction (p = .047) for the PFC activity during turning. Specifically, PD + FoG show higher PFC during turning compared to the other groups; PFC activity during DT is overall different compared to ST with an opposite trend in PD + FoG compared to controls and PD - FoG. In addition, higher PFC is associated with worse FoG in PD + FoG (r = 0.57, p = .048) and with lower number of turns in PD - FoG (r = -0.70, p = .002). The increased PFC activity in PD and the association between higher PFC activity and poorer turning performance may be a sign of poor movement automaticity in PD. Although further investigations are required, these pilot findings may guide development of personalized treatments to improve motor automaticity in PD.


Oxaliplatin complexes with carnosine and its derivatives: in vitro cytotoxicity, mass spectrometric and computational studies with a focus on complex fragmentation.
The complexation of the Pt-based anti-cancer drug oxaliplatin (OxPt) with biological ligands other than DNA is believed to be a major cellular sink for the drug reducing its therapeutic potential and acting as a potential cause of toxicity. In this paper, the very first hypothesis driven investigation of the role of the naturally abundant cytoplasmic dipeptide ligand β-alanyl-l-histidine dipeptide (carnosine) in OxPt detoxification is presented. In vitro studies on hepatocellular carcinoma HepG2 cells suggest that carnosine may inhibit the cytotoxic action of OxPt most likely through the formation of complexes that are less cytotoxic than OxPt alone. Evidence is provided to suggest that pre-exposure of HepG2 cells to elevated levels of carnosine appears to have a lasting effect on reducing the cytotoxicity of OxPt even after the removal of the externally added carnosine. This effect, however, is likely under kinetic control as its magnitude was shown not to vary significantly with the level of carnosine exposure within the concentration range used in this study. Various mass spectrometry techniques employing electrospray ionization and chip nanospray were employed to study the interaction of oxaliplatin with carnosine as well as two of its derivatives β-alanyl-N-methylhistidine (anserine) and N-acetylcarnosine (NAC). Evidence of complexation between OxPt and each of the three ligands examined is presented. Most species observed were unambiguously assigned and compared to their theoretical isotopic patterns. Common fragmentation products due to the collisionally-activated protonated complexes of each of the ligands examined with OxPt, [M + OxPt + H](+), where M = carnosine, anserine or NAC, were reported. Density functional calculations at the B3LYP/LANL2DZ level were used to obtain structural information and relative free energies of different isomers of the observed precursor [Carnosine + OxPt + H](+) both in the gas phase and in solution as well as to probe its fragmentation, highlighting plausible fragmentation mechanisms that account for all the experimental results. Data are presented to show several binding modes between electron rich sites such as N and O centers of carnosine and the Pt metal of OxPt. Calculations were also employed to obtain proton affinities and free energies of key reactions. The proton affinities of carnosine, anserine and NAC at 298 K were calculated to be 254.4, 255.9 and 250.2 kcal mol(-1) respectively. To the best of our knowledge the proton affinities of anserine and N-acetyl-carnosine are the first reported values in the literature.


Glutamine protects Chinese hamster ovary cells from radiation killing.
Chinese Hamster Ovary (CHO) cells were propagated in vitro and exposed to varying doses of ionizing radiation. The surviving fraction of cells was determined, being found to be a function of the radiation dose. The cell survival curves obtained as a function of radiation dose were modified by the inclusion of varying doses of glutamine in the medium with glutamine demonstrating a radioprotective effect. The radioprotectant effect of glutamine for CHO cells was more pronounced at higher radiation doses. Glutamine has been categorized as a non-essential amino acid in that it can be synthesized in some tissues; however, a number of cell lines require glutamine to survive and grow in vitro and supplementation of glutamine has been found to ameliorate the stress of surgery or irradiation to the gastrointestinal tract. It may be appropriate to consider glutamine as a conditionally essential amino acid.


Linear mixed models with endogenous covariates: modeling sequential treatment effects with application to a mobile health study.
Mobile health is a rapidly developing field in which behavioral treatments are delivered to individuals via wearables or smartphones to facilitate health-related behavior change. Micro-randomized trials (MRT) are an experimental design for developing mobile health interventions. In an MRT the treatments are randomized numerous times for each individual over course of the trial. Along with assessing treatment effects, behavioral scientists aim to understand between-person heterogeneity in the treatment effect. A natural approach is the familiar linear mixed model. However, directly applying linear mixed models is problematic because potential moderators of the treatment effect are frequently endogenous-that is, may depend on prior treatment. We discuss model interpretation and biases that arise in the absence of additional assumptions when endogenous covariates are included in a linear mixed model. In particular, when there are endogenous covariates, the coefficients no longer have the customary marginal interpretation. However, these coefficients still have a conditional-on-the-random-effect interpretation. We provide an additional assumption that, if true, allows scientists to use standard software to fit linear mixed model with endogenous covariates, and person-specific predictions of effects can be provided. As an illustration, we assess the effect of activity suggestion in the HeartSteps MRT and analyze the between-person treatment effect heterogeneity.


Bee Venom Phospholipase A2 Ameliorates House Dust Mite Extract Induced Atopic Dermatitis Like Skin Lesions in Mice.
Atopic dermatitis (AD) is a biphasic inflammatory skin disease that is provoked by epidermal barrier defects, immune dysregulation, and increased skin infections. Previously, we have demonstrated that bvPLA2 evoked immune tolerance by inducing regulatory T cells (Treg), and thus alleviated Th2 dominant allergic asthma in mice. Here, we would like to determine whether treatment with bvPLA2 exacerbates the AD-like allergic inflammations induced by house dust mite extract (DFE) in a murine model. Epidermal thickness, immune cell infiltration, serum immunoglobulin, and cytokines were measured. Ear swelling, skin lesions, and the levels of total serum IgE and Th1/Th2 cytokines were elevated in DFE/DNCB-induced AD mice. Topical application of bvPLA2 elicited significant suppression of the increased AD symptoms, including ear thickness, serum IgE concentration, inflammatory cytokines, and histological changes. Furthermore, bvPLA2 treatment inhibited mast cell infiltration into the ear. On the other hand, Treg cell depletion abolished the anti-atopic effects of bvPLA2, suggesting that the effects of bvPLA2 depend on the existence of Tregs. Taken together, the results revealed that topical exposure to bvPLA2 aggravated atopic skin inflammation, suggesting that bvPLA2 might be a candidate for the treatment of AD.


Distractor Effect of Auditory Rhythms on Self-Paced Tapping in Chimpanzees and Humans.
Humans tend to spontaneously align their movements in response to visual (e.g., swinging pendulum) and auditory rhythms (e.g., hearing music while walking). Particularly in the case of the response to auditory rhythms, neuroscientific research has indicated that motor resources are also recruited while perceiving an auditory rhythm (or regular pulse), suggesting a tight link between the auditory and motor systems in the human brain. However, the evolutionary origin of spontaneous responses to auditory rhythms is unclear. Here, we report that chimpanzees and humans show a similar distractor effect in perceiving isochronous rhythms during rhythmic movement. We used isochronous auditory rhythms as distractor stimuli during self-paced alternate tapping of two keys of an electronic keyboard by humans and chimpanzees. When the tempo was similar to their spontaneous motor tempo, tapping onset was influenced by intermittent entrainment to auditory rhythms. Although this effect itself is not an advanced rhythmic ability such as dancing or singing, our results suggest that, to some extent, the biological foundation for spontaneous responses to auditory rhythms was already deeply rooted in the common ancestor of chimpanzees and humans, 6 million years ago. This also suggests the possibility of a common attentional mechanism, as proposed by the dynamic attending theory, underlying the effect of perceiving external rhythms on motor movement.


The antiangiogenic agents SU5416 and SU6668 increase the antitumor effects of fractionated irradiation.
Angiogenesis is critical for tumor development, growth and metastasis. The vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) and their tyrosine kinase receptors are major regulators of angiogenesis. Radiation induces the production of VEGF, FGF and PDGF in many tumor cells. We hypothesized that inhibition of the function of these growth factors could inhibit tumor angiogenesis and thereby enhance the efficacy of radiation therapy. To test this hypothesis, we used the small molecule inhibitors SU5416 (an inhibitor for Vegf receptor) and SU6668 (an inhibitor for Vegf, Fgf and Pdgf receptors) alone and in combination with fractionated irradiation to treat C3H mice bearing SCC VII carcinomas. The SCC VII tumors express Vegf, Fgf2 (also known as bFGF), Pdgf and their associated receptors. Animals were given either SU5416 or SU6668 daily before or after irradiation (2 Gy per fraction per day for 5 days). The results from these experiments demonstrate that administration of either SU5416 or SU6668 without radiation delayed tumor growth. Administration of SU5416 at a dose of 25 mg/kg per day (the maximum tolerated effective dose) inhibited tumor growth by 17.9% on day 7 (P < 0.05 compared to untreated control mice) and produced an average tumor growth delay time of 0.5-2.0 days. When combined with fractionated irradiation, administration of SU5416 increased the inhibition of tumor growth to 50-53% on day 7 and the tumor growth delay time to 5.7-6.5 days (P < 0.001 compared with SU5416 alone; P < or = 0.05 compared with radiation alone). SU6668 alone inhibited tumor growth in a dose-dependent manner. Administration of SU6668 at a dose of 75 mg/kg per day (a suboptimal dose) inhibited tumor growth by 36% on day 7 and produced an average tumor growth delay time of 3.3 +/- 1.4 days. The combination of SU6668 with fractionated radiation increased inhibition of tumor growth to 66-70% and the tumor growth delay time from 3.3 days to 11.9 days (P < or = 0.001 compared with either radiation alone or SU6668 alone). Administration of these agents before or after irradiation produced similar results (P = 0.40 for SU5416; P = 0.98 for SU6668). SU5416 or SU6668 alone or in combination with radiation was very well tolerated with little or no toxicity. These results suggest that inhibition of Vegf, Fgf and Pdgf receptor function by SU5416 and SU6668 can enhance the efficacy of irradiation. The targeting of multiple tyrosine kinase receptors by SU6668 is more effective than inhibition of the Vegf receptor alone by SU5416 for the enhancement of tumor cell killing by fractionated irradiation.


Heater probe thermocoagulation for high-risk patients who show rebleeding from peptic ulcers.
To investigate whether heater probe therapy is effective for patients showing rebleeding from peptic ulcers. We retrospectively reviewed the case profiles in our previous studies on endoscopic therapy for high-risk patients with peptic ulcer bleeding in the past two decades. We analysed the outcomes of 191 patients who showed rebleeding after initial endoscopic haemostasis and received endoscopic therapy with heater probe thermocoagulation. . A total of 191 patients showing rebleeding received heater probe thermocoagulation. After re-therapy, 158 patients (82.7%) achieved ultimate haemostasis. Twenty-five of the 33 patients who failed to achieve haemostasis received surgical intervention. Ten patients (5.2%) died within 1 month after re-therapy. Heater probe thermocoagulation can be used as the first choice for management of patients showing rebleeding after initial endoscopic therapy.


DNA repair mechanisms and the bypass of DNA damage in Saccharomyces cerevisiae.
DNA repair mechanisms are critical for maintaining the integrity of genomic DNA, and their loss is associated with cancer predisposition syndromes. Studies in Saccharomyces cerevisiae have played a central role in elucidating the highly conserved mechanisms that promote eukaryotic genome stability. This review will focus on repair mechanisms that involve excision of a single strand from duplex DNA with the intact, complementary strand serving as a template to fill the resulting gap. These mechanisms are of two general types: those that remove damage from DNA and those that repair errors made during DNA synthesis. The major DNA-damage repair pathways are base excision repair and nucleotide excision repair, which, in the most simple terms, are distinguished by the extent of single-strand DNA removed together with the lesion. Mistakes made by DNA polymerases are corrected by the mismatch repair pathway, which also corrects mismatches generated when single strands of non-identical duplexes are exchanged during homologous recombination. In addition to the true repair pathways, the postreplication repair pathway allows lesions or structural aberrations that block replicative DNA polymerases to be tolerated. There are two bypass mechanisms: an error-free mechanism that involves a switch to an undamaged template for synthesis past the lesion and an error-prone mechanism that utilizes specialized translesion synthesis DNA polymerases to directly synthesize DNA across the lesion. A high level of functional redundancy exists among the pathways that deal with lesions, which minimizes the detrimental effects of endogenous and exogenous DNA damage.


In vivo imaging of disease-related mitochondrial dynamics in a vertebrate model system.
Mitochondria provide ATP, maintain calcium homeostasis, and regulate apoptosis. Neurons, due to their size and complex geometry, are particularly dependent on the proper functioning and distribution of mitochondria. Thus disruptions of these organelles and their transport play a central role in a broad range of neurodegenerative diseases. While in vitro studies have greatly expanded our knowledge of mitochondrial dynamics, our understanding in vivo remains limited. To address this shortcoming, we developed tools to study mitochondrial dynamics in vivo in optically accessible zebrafish. We demonstrate here that our newly generated tools, including transgenic "MitoFish," can be used to study the in vivo "life cycle" of mitochondria and allows identifying pharmacological and genetic modulators of mitochondrial dynamics. Furthermore we observed profound mitochondrial transport deficits in real time in a zebrafish tauopathy model. By rescuing this phenotype using MARK2 (microtubule-affinity regulating kinase 2), we provide direct in vivo evidence that this kinase regulates axonal transport in a Tau-dependent manner. Thus, our approach allows detailed studies of the dynamics of mitochondria in their natural environment under normal and disease conditions.


MicroRNAs in colorectal cancer: from diagnosis to targeted therapy.
Colorectal cancer (CRC) is one of the major healthcare problems worldwide and its processes of genesis include a sequence of molecular pathways from adenoma to carcinoma. The discovery of microRNAs, a subset of regulatory non-coding RNAs, has added new insights into CRC diagnosis and management. Together with several causes of colorectal neoplasia, aberrant expression of oncomiRs (oncogenic and tumor suppressor miRNAs) in cancer cells was found to be indirectly result in up- or down-regulation of targeted mRNAs specific to tumor promoter or inhibitor genes. The study of miRNAs as CRC biomarkers utilizes expression profiling methods from traditional tissue samples along with newly introduced non-invasive samples of faeces and body fluids. In addition, miRNAs could be employed to predict chemo- and radio-therapy responses and be manipulated in order to alleviate CRC characteristics. The scope of this article is to provide a comprehensive review of scientific literature describing aberrantly expressed miRNAs, and consequently dysregulation of targeted mRNAs along with the potential role of miRNAs in CRC diagnosis and prognosis, as well as to summarize the recent findings on miRNA-based manipulation methods with the aim of advancing in anti-CRC therapies.


Deterioration of renal function at stent implantation can predict long-term outcome after stent thrombosis.
The aim of the study was to examine the possible influence of minor deterioration of the renal function after stent implantation not fulfilling the criteria for acute kidney injury on long-term outcomes after stent thrombosis (ST). Decreased renal function (DRF) is associated with an increased risk for worse outcome after percutaneous coronary intervention. There is no data if the deterioration of renal function after stent implantation influences the prognosis after ST. If so patients with a higher risk for worse outcome after ST could be identified already at the time of stent implantation. Data from 4824 consecutive patients treated with percutaneous coronary intervention in our center was recorded from March 2004 to April 2010. We excluded patients with acute kidney injury at stent implantation and 86 of them with ST without acute kidney injury at stent implantation were involved in the study. They were prospectively followed until December 2012 for 50.2 ± 28.1 months. Only patients with definite ST were included in the study. The Academic Research Consortium definition of ST was used. Data on death, myocardial infarction, and repeated percutaneous or operative revascularization after ST were ascertained from the hospital database, by phone or with clinical examinations. The outcomes after definite ST were compared in patients with and without deterioration of renal function after stent implantation (DRFafterSI). During the observational period patients with DRFafterSI had a higher mortality rate after ST than patients without DRFafterSI (35.1 vs. 10.3 %; p <0.019). The incidence of major adverse cardiac events (major adverse coronary event (MACE)-death, myocardial infarction, repeated revascularization) rate after ST was similar in both groups (66.1 % with DRFafterSI vs. 55.2 % without DRFafterSI). The prevalence of myocardial infarction was also similar in both groups (31.6 vs. 34.5 %) as was the revascularizations rate (43.9 vs. 48.3 %). Death was predicted by DRFafterSI (adjusted hazard ratio (HR) 3.96; 95 % confidence interval (CI) 1.11 to 14.10; p <0.034) and age > 75 years (adjusted HR 2.85: 95 % CI 1.12-7.30; p = 0.029). We could not find any predictor for MACE. Even more subtle DRFafterSI (not fulfilling the criteria for acute kidney injury) at stent implantation were associated with higher long-term mortality after ST. Especially at risk were patients older than 75 years at stent implantation. DRFafterSI and age more than 75 years pointed out the group of patients with a high risk for death after ST already at the time of stent implantation. The best treatment option for preventing ST in these patients is still to be determined. Until then, we must pay a special attention to proper patients' preparation and hydration to avoid DRFafterSI.


Maturity ogives for South Pacific albacore tuna (Thunnus alalunga) that account for spatial and seasonal variation in the distributions of mature and immature fish.
Length and age at maturity are important life history parameters for estimating spawning stock biomass and reproductive potential of fish stocks. Bias in estimates of size and age at maturity can arise when disparate distributions of mature and immature fish within a population are not accounted for in the analysis. Here we investigate the spatial and temporal variability in observed size and age at maturity of female albacore tuna, Thunnus alalunga, using samples collected across the South Pacific. Maturity status was identified using consistent histological criteria that were precise enough to allow for mature but regenerating females to be distinguished from immature females during the non-spawning season, permitting year-round sampling for maturity estimation in albacore. Using generalised linear mixed models, we found that the proportion of mature females at length varied significantly with latitude and time of year. Specifically, females at northern latitudes (∼10-20°S, where spawning occurs) were mature at significantly smaller lengths and ages than females at southern latitudes (∼20-40°S), particularly during the spawning season (October-March). This variation was due to different geographic distributions of mature and immature fish during the year. We present a method for estimating an unbiased maturity ogive that takes into account the latitudinal variation in proportion mature at length during a given season (spawning or non-spawning). Applying this method to albacore samples from the western region of the South Pacific gave a predicted length at 50% mature of ∼87 cm fork length (4.5 years).


Effect of repaglinide on cloned beta cell, cardiac and smooth muscle types of ATP-sensitive potassium channels.
The carbamoylbenzoic acid derivative repaglinide is a potent short-acting insulin secretagogue that acts by closing ATP-sensitive potassium (KATP) channels in the plasma membrane of the pancreatic beta cell. In this paper we investigated. the specificity of repaglinide for three types of cloned (KATP) channel composed of the inwardly rectifying potassium channel Kir6.2 and either the sulphonylurea receptor SUR1, SUR2A or SUR2B, corresponding to the beta cell, cardiac and either smooth muscle types of KATP channel, respectively. The action of the drug was studied by whole-cell current recordings of KATP channels expressed either in Xenopus oocytes or mammalian cells (HEK293). We also used inside-out macropatches excised from Xenopus oocytes for detailed analysis of repaglinide action. The drug blocked all three types of KATP channel with similar potency, by interacting with a low-affinity site on the pore-forming subunit of the channel (Kir6.2: half-maximal inhibition 230 micromol/l) and with a high-affinity site on the regulatory subunit, the sulphonylurea receptor (SUR: half-maximal inhibition 2-8 nmol/l). There was no difference in potency between channels containing SUR1, SUR2A or SUR2B. MgADP potentiated the inhibitory effect of repaglinide on Kir6.2/SUR1 and (to a lesser extent) Kir6.2/SUR2B, but not on Kir6.2/SUR2A. Repaglinide interacts with a site common to all three types of sulphonylurea receptor leading to inhibition of the KATP channel. The fact that MgADP potentiated this effect in the case of the beta cell, but not cardiac, type of channel could help explain why the drug shows no adverse cardiovascular side-effects in vivo.


Using Machine Learning Methods Incorporating Individual Reader Annotations to Classify Paediatric Chest Radiographs in Epidemiological Studies.
Introduction: Epidemiological studies that involve interpretation of chest radiographs (CXRs) suffer from inter-reader and intra-reader variability. Inter-reader and intra-reader variability hinder comparison of results from different studies or centres, which negatively affects efforts to track the burden of chest diseases or evaluate the efficacy of interventions such as vaccines. This study explores machine learning models that could standardize interpretation of CXR across studies and the utility of incorporating individual reader annotations when training models using CXR data sets annotated by multiple readers. Methods: Convolutional neural networks were used to classify CXRs from seven low to middle-income countries into five categories according to the World Health Organization's standardized methodology for interpreting paediatric CXRs. We compared models trained to predict the final/aggregate classification with models trained to predict how each reader would classify an image and then aggregate predictions for all readers using unweighted mean. Results: Incorporating individual reader's annotations during model training improved classification accuracy by 3.4% (multi-class accuracy 61% vs 59%). Model accuracy was higher for children above 12 months of age (68% vs 58%). The accuracy of the models in different countries ranged between 45% and 71%. Conclusions: Machine learning models can annotate CXRs in epidemiological studies reducing inter-reader and intra-reader variability. In addition, incorporating individual reader annotations can improve the performance of machine learning models trained using CXRs annotated by multiple readers.


Daclatasvir plus peginterferon and ribavirin is noninferior to peginterferon and ribavirin alone, and reduces the duration of treatment for HCV genotype 2 or 3 infection.
Twenty-four weeks of treatment with peginterferon and ribavirin for chronic hepatitis C virus (HCV) genotype 2 or 3 infection produces a sustained virologic response (SVR) in 70%-80% of patients. We performed a randomized, double-blind, phase 2b study to assess whether adding daclatasvir, a nonstructural protein 5A (NS5A) inhibitor that is active against these genotypes, improves efficacy and shortens therapy. Patients with HCV genotype 2 or 3 infection (n = 151), enrolled at research centers in North America, Europe, or Australia, were assigned randomly to groups given 12 or 16 weeks of daclatasvir (60 mg once daily), or 24 weeks of placebo, each combined with peginterferon alfa-2a and ribavirin. Treatment was extended to 24 weeks for recipients of daclatasvir who did not meet the criteria for early virologic response. The primary end point was SVR at 24 weeks after treatment (SVR24). Baseline characteristics were similar among patients within each HCV genotype group. However, the 80 patients with HCV genotype 3, compared with the 71 patients with HCV genotype 2, were younger (mean age, 45 vs 53 y, respectively), and a larger proportion had cirrhosis (23% vs 1%, respectively). Among patients with HCV genotype 2 infection, an SVR24 was achieved by 83%, 83%, and 63% of those in the daclatasvir 12-week group, the daclatasvir 16-week group, or the placebo group, respectively; among patients with HCV genotype 3 infection, an SVR24 was achieved by 69%, 67%, and 59% of patients in these groups, respectively. Differences between genotypes largely were attributable to the higher frequency of post-treatment relapse among patients infected with HCV genotype 3. In both daclatasvir arms for both HCV genotypes, the lower bound of the 80% confidence interval of the difference in SVR24 rates between the daclatasvir and placebo arms was above -20%, establishing noninferiority. Safety findings were similar among groups, and were typical of those expected from peginterferon alfa and ribavirin therapy. Twelve or 16 weeks of treatment with daclatasvir, in combination with peginterferon alfa-2a and ribavirin, is a well tolerated and effective therapy for patients with HCV genotype 2 or 3 infections. Daclatasvir-containing regimens could reduce the duration of therapy for these patients. Clinicaltrials.gov number: NCT01257204.


Macronutrient and energy contents of human milk fractions during the first six months of lactation.
To study the macronutrient and energy contents of human milk fractions during the first 6 mo of lactation. A total of 483 milk samples, including 52 pairs of fore- and hindmilk samples from 20 mothers, 253 samples from 53 donor mothers and 126 samples from 36 mothers of preterm infants, were collected longitudinally, starting at 1 wk postpartum and continuing monthly up to 6 mo. Protein, lactose and fat contents were measured and energy density estimated. The protein content was significantly lower in fore- and hindmilk than in donor or preterm milk during the first months of lactation. In donor and preterm milk, the protein content declined consistently from 2.0 g/100 ml at 1 wk to half of that at 6 mo, and a similar trend was observed in fore- and hindmilk. Lactose content showed no significant changes between the groups or in the course of lactation. The fat content was highest in hindmilk, being approximately two- to threefold that of foremilk. Accordingly, hindmilk included 25-35 kcal/100 ml more energy on average than foremilk. The fat content of human milk increases in relation to breast emptying, while the other macronutritients of milk show only slight changes. When enteral feeding with high-energy human milk is preferred, as in the case of very preterm infants, hind milk, with its higher fat content, would be a natural choice.


The preimaginal stages and development of Spalangia cameroni Perkins (Hymenoptera: Pteromalidae) on Ceratitis capitata (Wiedemann) (Diptera: Tephritidae).
The development and morphology of the immature phases of Spalangia cameroni Perkins, 1910 (Hymenoptera, Pteromalidae) are described from a laboratory rearing culture maintained on Ceratitis capitata (Wiedemann, 1824) (Diptera, Tephritidae), using microscopic techniques, including light and scanning electron microscopy. The surface of the chorion of the egg is smooth and the micropyle occurs at the anterior end. The immature larvae are similar to the mature larva, differing mainly in the size of the head capsule and mandibles. The mature larva displays tubercules on the body segments as well as a pleurostoma and superior and inferior mandibular processes. On completion of its larval development, an adecticous and exarate pupa is produced. The mandibles of the pupa, as for the adult, are toothed. Three larval instars are recorded based on statistical analyses of the sizes of the larval mandibles and head capsules, in combination with such characters as the number of exuviae and excretion of the meconium. There are significant positive correlations between mandible length and width of larval head capsule with the number of instars, thus indicating that the mandible length and width of larval capsule are good predictors of the number of instars in this parasitoid. Developmental time from egg to adult emergence was approximately 33-34 days for females and approximately 28-29 days for males at 21-26 degrees C, 55-85 RH and a L16:D8 photoperiod. Our results show that the eggs and different instars of S. cameroni can be unambiguously identified only by SEM. Therefore, characterization of the immature stages of Spalangia species using SEM should be done before subsequent routine identifications using a binocular microscope or stereomicroscope.


Uptake and retrograde transport of [3H]GABA from the cochlear nucleus to the superior olive in the guinea pig.
The purpose of the present study is to determine which descending projections to the cochlear nucleus may use gamma-aminobutyric acid (GABA) as a neurotransmitter. [3H]GABA (120 microM) was injected into the cochlear nucleus of albino and pigmented guinea pigs. After survival times between 0.25 and 16 h, the brain stems were prepared for light microscopic autoradiography. After 2 h survival there was a pulse of label, which progressed through the fibres from the cochlear nucleus to the ipsilateral superior olive. After 5 h, retrogradely labelled neuronal cell bodies and fibres were located in the superior olivary complex bilaterally. In the trapezoid body, clusters of labelled cells were seen in the lateral nucleus, ipsilaterally, and in the ventral nucleus, bilaterally. Also there were labelled cells in the ipsilateral dorsal and anterolateral periolivary nucleus. Large and small cells of several types were labelled. Survival times of 10 h or more resulted in very light, diffuse labelling. Projections to the cochlear nucleus labelled by retrograde transport of horseradish peroxidase that did not take up [3H]GABA included the inferior colliculus, bilaterally, and the cochlear nucleus and periolivary nuclei (other than ventral trapezoid nucleus), contralaterally. The selective labelling of cell groups in the superior olive with the moderately low concentration of [3H]GABA used is consistent with the high-affinity uptake of [3H]GABA by synaptic endings in the cochlear nucleus and its retrograde by transport GABA-ergic neurons. This provides evidence for a descending projection system for inhibitory feedback from the superior olive to the cochlear nucleus.


Bag-Mask Ventilation during Tracheal Intubation of Critically Ill Adults.
Hypoxemia is the most common complication during tracheal intubation of critically ill adults and may increase the risk of cardiac arrest and death. Whether positive-pressure ventilation with a bag-mask device (bag-mask ventilation) during tracheal intubation of critically ill adults prevents hypoxemia without increasing the risk of aspiration remains controversial. In a multicenter, randomized trial conducted in seven intensive care units in the United States, we randomly assigned adults undergoing tracheal intubation to receive either ventilation with a bag-mask device or no ventilation between induction and laryngoscopy. The primary outcome was the lowest oxygen saturation observed during the interval between induction and 2 minutes after tracheal intubation. The secondary outcome was the incidence of severe hypoxemia, defined as an oxygen saturation of less than 80%. Among the 401 patients enrolled, the median lowest oxygen saturation was 96% (interquartile range, 87 to 99) in the bag-mask ventilation group and 93% (interquartile range, 81 to 99) in the no-ventilation group (P = 0.01). A total of 21 patients (10.9%) in the bag-mask ventilation group had severe hypoxemia, as compared with 45 patients (22.8%) in the no-ventilation group (relative risk, 0.48; 95% confidence interval [CI], 0.30 to 0.77). Operator-reported aspiration occurred during 2.5% of intubations in the bag-mask ventilation group and during 4.0% in the no-ventilation group (P = 0.41). The incidence of new opacity on chest radiography in the 48 hours after tracheal intubation was 16.4% and 14.8%, respectively (P = 0.73). Among critically ill adults undergoing tracheal intubation, patients receiving bag-mask ventilation had higher oxygen saturations and a lower incidence of severe hypoxemia than those receiving no ventilation. (Funded by Vanderbilt Institute for Clinical and Translational Research and others; PreVent ClinicalTrials.gov number, NCT03026322.).


Digestive involvement in COVID-19: what we have learned in the past 12 months.
The year 2020 will remain in the medical history as the year of COVID-19 pandemic. Although COVID-19 is considered mainly a respiratory disease, it is well known now that SARS-CoV-2 can affect major organs including the digestive system. This is a comprehensive review on gastrointestinal involvement in the SARS-CoV-2 infection, also the digestive damage due to COVID-19. A literature search was undertaken in main databases of medical publications following the search items digestive or gastrointestinal or gastric or enteral and SARS-CoV-2 or COVID-19. Data on gastrointestinal symptoms and alterations in this viral condition were collected and presented. Only observational studies were included. In this review we discuss the recent information on the relationship between COVID-19 and the digestive system. The putative underlying pathogenic mechanisms of COVID-19 as well as the clinical findings in relation to gastrointestinal changes are presented. SARS-CoV-2 virus can affect any part of the digestive system. Patients with chronic diseases are at greatest risk of adverse out-comes. There is a considerable risk for drug-drug interactions in patients who require a large treatment schedule.


Covalent coupling of gum arabic onto superparamagnetic iron oxide nanoparticles for MRI cell labeling: physicochemical and in vitro characterization.
Gum arabic (GA) is a hydrophilic composite polysaccharide derived from exudates of Acacia senegal and Acacia seyal trees. It is biocompatible, possesses emulsifying and stabilizing properties and has been explored as coating agent of nanomaterials for biomedical applications, namely magnetic nanoparticles (MNPs). Previous studies focused on the adsorption of GA onto MNPs produced by co-precipitation methods. In this work, MNPs produced by a thermal decomposition method, known to produce uniform particles with better crystalline properties, were used for the covalent coupling of GA through its free amine groups, which increases the stability of the coating layer. The MNPs were produced by thermal decomposition of Fe(acac)3 in organic solvent and, after ligand-exchange with meso-2,3-dimercaptosuccinic acid (DMSA), GA coating was achieved by the establishment of a covalent bond between DMSA and GA moieties. Clusters of several magnetic cores entrapped in a shell of GA were obtained, with good colloidal stability and promising magnetic relaxation properties (r2 /r1 ratio of 350). HCT116 colorectal carcinoma cell line was used for in vitro cytotoxicity evaluation and cell-labeling efficiency studies. We show that, upon administration at the respective IC50 , GA coating enhances MNP cellular uptake by 19 times compared to particles bearing only DMSA moieties. Accordingly, in vitro MR images of cells incubated with increasing concentrations of GA-coated MNP present dose-dependent contrast enhancement. The obtained results suggest that the GA magnetic nanosystem could be used as a MRI contrast agent for cell-labeling applications.


Functional brain mapping using specific sensory-circuit stimulation and a theoretical graph network analysis in mice with neuropathic allodynia.
Allodynia, a form of neuropathic pain, is defined as pain in response to a non-nociceptive stimulus. The brain regions responsible for pain, which are not normally activated, can be activated in allodynic mice by providing a suitable stimulus to Aβ-fibers, which transmit signals from tactile sensory fibers. Functional MRI (fMRI) can be used to objectively observe abnormal brain activation. In the present study, fMRI was conducted to investigate allodynia in mice; allodynia was generated by surgical injury at the L4 spinal nerve root, thus selectively stimulating sensory nerve fibers. In intact mice, only the primary somatosensory cortex (S1) was activated by stimulation of Aβ-fibers. Meanwhile, allodynic mice showed significantly higher BOLD signals in the anterior cingulate area (ACA) and thalamus. Using resting state fMRI, both degree and eigenvector centrality were significantly decreased in the contralateral S1, clustering coefficient and local efficiency were significantly increased in the ACA, and betweenness centrality was significantly higher in the ventral posterolateral nucleus of the thalamus. These results suggest that the observed abnormal BOLD activation is associated with defects in Aβ-fibers when Aβ-fibers in allodynic mice are selectively stimulated. The objective approach enabled by fMRI can improve our understanding of pathophysiological mechanisms and therapeutic efficacy.


Incidence of acute injuries, active component, U.S. Armed Forces, 2008-2017.
Injuries have consistently ranked among the top morbidity burdens among U.S. military service members. This report describes the incidence, trends, types, causes, and dispositions of acute injuries among active component service members by anatomic region. From 2008 through 2017, there were more than 3.6 million acute incident injuries among more than 1.6 million individuals. The highest rates were for injuries to the foot/ankle, head/neck, and hand/wrist. Injury incidence decreased during the surveillance period for all anatomic sites except for the leg and knee. In addition, incidence varied by military/demographic characteristics and anatomic site. Overall, service members in the Army and service members in motor transport and/or combat-related occupations tended to have higher incidence rates than their respective counterparts. "Sprains and strains" was the most common type of injury (48.5%), and most injuries were due to undocumented or undetermined causes (69.7%). The most common disposition was "returned to duty with no limitations" (69.8%). Findings suggest that injury prevention strategies should be tailored to different populations with different risk factors. Future analyses will describe the epidemiology of cumulative traumatic injuries.


Relationship between fasting plasma glucose and glycosylated hemoglobin: potential for false-positive diagnoses of type 2 diabetes using new diagnostic criteria.
New criteria for the diagnosis of type 2 diabetes mellitus have recently been introduced that lowered the diagnostic fasting plasma glucose (FPG) concentration from 7.8 to 7.0 mmol/L (140 to 126 mg/dL). To determine if individuals with diabetes diagnosed by the new FPG concentration criterion would have excessive glycosylation (elevated hemoglobin [HbA1c] levels). We determined the distribution of HbA1c levels in individuals using 4 classifications: (1) normal by the new criterion (FPG concentration <6.1 mmol/L [110 mg/dL]); (2) impaired fasting glucose by the new criterion (FPG concentration of 6.1-6.9 mmol/L [110-125 mg/dL]); (3) diabetes diagnosed solely by the new FPG concentration criterion of 7.0 through 7.7 mmol/L (126-139 mg/dL); and (4) diabetes diagnosed by the previous FPG concentration criterion of 7.8 mmol/L (140 mg/dL) or higher. Cross-sectional analysis of 2 large data sets (NHANES III and Meta-Analysis Research Group [MRG] on the Diagnosis of Diabetes Using Glycated Hemoglobin) that contained individuals in whom FPG concentrations, 2-hour glucose concentrations using an oral glucose tolerance test, and an HbA1c level were simultaneously measured. We cross-tabulated FPG concentrations (<6.1 mmol/L [110 mg/dL], 6.1-6.9 mmol/L [110-125 mg/dL], 7.0-7.7 mmol/L [126-139 mg/dL], and > or =7.8 mmol/L [140 mg/dL]) and HbA1c levels separated into 3 intervals: normal, less than the upper limit of normal (ULN); slightly elevated, ULN to ULN plus 1%; and high, higher than ULN plus 1%. Among subjects with normal FPG concentrations, HbA1c levels in the NHANES III (and the MRG) data sets were normal in 97.3% (96.2%), slightly elevated in 2.7% (3.6%), and high in 0.1% (0.2%). Among individuals with impaired fasting glucose, HbA1c concentrations were normal in 86.7% (81.4%), slightly elevated in 13.1% (16.4%), and high in 0.2% (2.2%). Among diabetic patients diagnosed by the new FPG criterion only, HbA1c levels were normal in 60.9% (59.6%), slightly elevated in 35.8% (32.8%), and high in 3.4% (7.6%). In diabetic patients diagnosed by the former FPG criterion, HbA1c levels were normal in 18.6% (16.7%), slightly elevated in 32.5% (21.0%), and high in 48.9% (62.3%). About 60% of the new cohort of diabetic patients in both data sets have normal HbA1c levels. We believe that diabetes should not be diagnosed in those with FPG concentrations less than 7.8 mmol/L (140 mg/dL) unless excessive glycosylation is evident. Individuals without excessive glycosylation but with moderate elevations of FPG concentrations (6.1-7.7 mmol/L [110-139 mg/dL]) should be diagnosed as having impaired fasting glucose and treated with an appropriate diet and exercise. This diagnostic labeling achieves the goal of early intervention without subjecting these persons to the potentially negative insurance, employment, social, and psychological consequences of a diagnosis of diabetes mellitus.


Assessment of freeze damage in fruits and vegetables.
Freezing is an efficient and widely used method of food preservation. However, it can also cause irreversible damages at cellular level which in turn degrade the overall quality of the frozen food products. Therefore, qualitative and quantitative methods and technologies that will be able to evaluate with accuracy the freeze damage are of great importance. This review paper provides a comprehensive study of the methods that have been used to evaluate the freeze damage in fruits and vegetables. Further than the principles and the applications of those methods, the advantages and the limitations are also being discussed.


Calcified neurocysticercosis associates with hippocampal atrophy: a population-based study.
Calcified neurocysticercosis has been associated with hippocampal atrophy in patients with refractory epilepsy, but the relevance of this association in the population at large is unknown. We assessed calcified cysticerci and its association with hippocampal atrophy in elderly persons living in Atahualpa, an Ecuadorian village endemic for neurocysticercosis. All Atahualpa residents ≥ 60 years of age were invited to undergo computed tomography/magnetic resonance imaging for neurocysticercosis detection. Twenty-eight (11%) out of 248 enrolled persons had calcified cysticerci (case-patients) and were matched 1:1 by age, sex, and years of education to individuals without neurocysticercosis on computed tomography/magnetic resonance imaging (controls). Four case-patients and none of the controls had epilepsy (P = 0.134). Cognitive performance was similar across both groups. The Scheltens' medial temporal atrophy scale was used for hippocampal rating in case-patients and matched controls without neurocysticercosis. Mean score in the Scheltens' scale was higher in case-patients than in controls (P < 0.001). Atrophic hippocampi were noticed in 19 case-patients and five controls (P = 0.003). Atrophy was bilateral in 11 case-patients and unilateral in eight. All case-patients with unilateral hippocampal atrophy had at least one ipsilateral calcification. This study shows an association between calcified cysticerci and hippocampal atrophy and raises the possibility of an inflammation-mediated hippocampal damage as the responsible mechanism for these findings.


Regulatory T cells: the ultimate HIV reservoir?
Despite significant advances in the understanding of HIV-1 infection, a cure remains out of reach. This is, in part, due to a long-lived HIV-1 reservoir in resting CD4+ T cells, which do not express viral antigens, and thus are invisible to the immune system. These latently infected cells carry replication-competent proviruses and can cause rebound viraemia if antiretrovirals are interrupted. Characterising this HIV-1 reservoir is a challenging task, requiring identification of CD4+ T cell subsets carrying intact proviruses, as well as defining their distribution within the body. Regulatory T cells (Tregs) comprise a subset of CD4+ T cells that are essential for maintaining immune tolerance. HIV-1 is known to infect Tregs in vivo but there is limited understanding of their role in HIV-1 persistence. Recent studies of well-controlled HIV-1 infection on antiretroviral therapy (ART) have shown higher frequencies of inducible, intact proviruses in Tregs compared to other CD4+ T cells, and provirus-containing Tregs have been found in lymphoid tissues at substantial frequencies. This evidence is supportive of a latent HIV-1 reservoir in Tregs, but greater detail is needed, including tissue distribution. An HIV-1 reservoir in Tregs could pose a significant barrier to HIV-1 eradication because Tregs are known to be long lived and resistant to apoptosis. Tregs are also immunosuppressive, and can inhibit cell-mediated immunity through multiple mechanisms. Non-specific depletion of Tregs would be likely to result in severe autoimmunity. Additional research is needed to further characterise regulatory T cells as a reservoir of HIV-1 and as an obstacle to eradication, or immune control, of HIV-1 infection.


Cumulative risk effects in the bullying of children and young people with autism spectrum conditions.
Students with autism are more likely to be bullied than their typically developing peers. However, several studies have shown that their likelihood of being bullied increases in the context of exposure to certain risk factors (e.g. behaviour difficulties and poor peer relationships). This study explores vulnerability to bullying from a cumulative risk perspective, where the number of risks rather than their nature is considered. A total of 722 teachers and 119 parents of young people with autism spectrum conditions participated in the study. Established risk factors were summed to form a cumulative risk score in teacher and parent models. There was evidence of a cumulative risk effect in both models, suggesting that as the number of risks increased, so did exposure to bullying. A quadratic effect was found in the teacher model, indicating that there was a disproportionate increase in the likelihood of being bullied in relation to the number of risk factors to which a young person was exposed. In light of these findings, it is proposed that more attention needs to be given to the number of risks to which children and young people with autism spectrum conditions are exposed when planning interventions and providing a suitable educational environment.


Semi-parametric inferences for association with semi-competing risks data.
In many biomedical studies, it is of interest to assess dependence between bivariate failure time data. We focus here on a special type of such data, referred to as semi-competing risks data. In this article, we develop methods for making inferences regarding dependence of semi-competing risks data across strata of a discrete covariate Z. A class of rank statistics for testing constancy of association across strata are proposed; its asymptotic properties are also derived. We develop a novel re-sampling-based technique for calculating the variances of the proposed test statistics. In addition, we develop methods for combining test statistics for assessing marginal effects of Z on the dependent censoring variable as well as its effects on association. The finite-sample properties of the proposed methodology are assessed using simulation studies, and they are applied to data from a leukaemia transplantation study.


Subsequent reproductive experience after treatment for gestational trophoblastic disease.
The purpose of this study was to evaluate reproductive performance of patients with gestational trophoblastic disease (GTD) after completion of treatment and follow-up periods. Subjects comprised 115 patients who became pregnant after having been judged completely cured after a follow-up period of at least 1 year. There were 77 hydatidiform-mole patients who had a natural cure and 38 gestational trophoblastic tumor patients who were cured after chemotherapy. We studied these patients with respect to parameters concerning pregnancy outcome. Average age at first pregnancy was 28.0 and average number of past deliveries was 1.3. After a 1-year contraception period, the average time to the next pregnancy was 0.8 year, with 59 of 115 (51.3%) women becoming pregnant within 1 year after pregnancy was permitted and 98 women (85.2%) conceiving within 3 years. Results of the pregnancies after cure of GTD did not deviate from normal ranges in separated analyses of complete mole (CM), partial mole (PM), and gestational trophoblastic tumor. Rate of repeat mole was found to be high, occurring in 5 of 115 (4.3%) cases. Rates of antepartum and postpartum complications did not deviate from normal ranges, and there was nothing peculiar about the neonatal sex and weight. GTD and chemotherapy rarely affect later pregnancies; however, the rate of repeat mole is relatively high.


Experimental porcine cysticercosis using infected beetles with Taenia solium eggs.
Beetles are intermediate hosts for human and animal parasites, and several beetle species have been shown to carry Taenia eggs. An experimental porcine cysticercosis infection model was developed using beetles (Ammophorus rubripes) infected with Taenia solium eggs and then using these beetles for oral pig challenge. A total of 18 three months-old Landrace pigs were divided in four groups. Pigs from groups 1, 2, and 3 (n = 6 pigs per group) were challenged with one, three, and six beetles infected with T. solium eggs, containing approximately 52, 156 or 312 eggs respectively. Pigs were necropsied 12 weeks after infection to assess the presence of T. solium metacestode. Porcine cysticercosis by T. solium was produced in 17 out of 18 pigs (94.4%) challenged with infected beetles, all infected pigs had viable cysts. Only one pig from group 1 was negative to the presence of cysts. The median number of metacestodes per pig in groups 1, 2, and 3 were 2 (range 0-71), 26 (range 5-33) and 40 cysts (range 4-111), respectively. Experimental porcine cysticercosis infection is consistently obtained using beetles as mechanical vectors for T. solium eggs.


Computed tomographic evaluation of abdominal fat in minipigs.
Computed tomography (CT) exams were conducted to determine the distribution of abdominal fat identified based on the CT number measured in Hounsfield Units (HU) and to measure the volume of the abdominal visceral and subcutaneous fat in minipigs. The relationship between the CT-based fat volumes of several vertebral levels and the entire abdomen and anthropometric data including the sagittal abdominal diameter and waist circumference were evaluated. Moreover, the total fat volumes at the T11, T13, L3, and L5 levels were compared with the total fat volume of the entire abdomen to define the landmark of abdominal fat distribution. Using a single-detector CT, six 6-month-old male minipigs were scanned under general anesthesia. Three radiologists then assessed the HU value of visceral and subcutaneous abdominal fat by drawing the region of interest manually at the T11, T13, L1, L3, and L5 levels. The CT number and abdominal fat determined in this way by the three radiologists was found to be correlated (intra-class coefficient = 0.9). The overall HU ranges for the visceral and subcutaneous fat depots were -147.47 to -83.46 and -131.62 to -90.97, respectively. The total fat volume of the entire abdomen was highly correlated with the volume of abdominal fat at the T13 level (r = 0.97, p < 0.0001). These findings demonstrate that the volume of abdominal adipose tissue measured at the T13 level using CT is a strong and reliable predictor of total abdominal adipose volume.


Endocytosis of chimeric influenza virus hemagglutinin proteins that lack a cytoplasmic recognition feature for coated pits.
The influenza virus A/Japan/305/57 hemagglutinin (HA) can be converted from a protein that is essentially excluded from coated pits into one that is internalized at approximately the rate of uptake of bulk membrane by replacing the HA transmembrane and cytoplasmic sequences with those of either of two other glycoproteins (Roth et al., 1986. J. Cell Biol. 102:1271-1283). To identify more precisely the foreign amino acid sequences responsible for this change in HA traffic, DNA sequences encoding the transmembrane (TM) or cytoplasmic (CD) domains of either the G glycoprotein of vesicular stomatitis virus (VSV) or the gC glycoprotein of herpes simplex virus were exchanged for those encoding the analogous regions of wild type HA (HA wt). HA-HA-G and HA-HA-gC, chimeras that contain only a foreign CD, resembled HA wt in having a long residence on the cell surface and were internalized very slowly. HA-HA-gC was indistinguishable from HA in our assays, whereas twice as much HA-HA-G was internalized as was HA wt. However, HA-G-HA, containing only a foreign TM, was internalized as efficiently as was HA-G-G, a chimeric protein with transmembrane and cytoplasmic sequences of VSV G protein. Conditions that blocked internalization through coated pits also inhibited endocytosis of the chimeric proteins. Although the external domains of the chimeras were less well folded than that of the wild type HA, denaturation of the wild type HA external domain by treatment with low pH did not increase the interaction of HA with coated pits. However, mutation of four amino acids in the TM of HA allowed the protein to be internalized, indicating that the property that allows HA to escape endocytosis resides in its TM. These results indicate that possession of a cytoplasmic recognition feature is not required for the internalization of all cell surface proteins and suggest that multiple mechanisms for internalization exist that operate at distinctly different rates.


A phase III, randomized, double-blind, multicenter study to compare the efficacy, safety, pharmacokinetics, and immunogenicity between SB8 (proposed bevacizumab biosimilar) and reference bevacizumab in patients with metastatic or recurrent nonsquamous non-small cell lung cancer.
Efficacy, safety, pharmacokinetics (PK), and immunogenicity of the biosimilar candidate SB8 was compared to its reference product bevacizumab (BEV) in patients with metastatic or recurrent nonsquamous non-small cell lung cancer. Patients were randomized (1:1) in a phase III, double-blind study to receive intravenous SB8 or BEV 15 mg/kg with paclitaxel/carboplatin every 3 weeks for 24 weeks, followed by SB8 or BEV maintenance monotherapy. The primary endpoint was best overall response rate (ORR) by 24 weeks. Secondary endpoints included survival outcomes, safety, PK, and immunogenicity. 763 patients (SB8, n = 379; BEV, n = 384) were randomized; baseline characteristics were well balanced. Best ORR in the FAS was 47.6% and 42.8%, and best ORR in the PPS was 50.1% and 44.8% for SB8 and BEV, respectively. The risk ratio of best ORR was 1.11 (90% CI, 0.975-1.269), and the risk difference in best ORR was 5.3% (95% CI, -2.2%-12.9%). Median survival outcomes were comparable between SB8 and BEV: progression-free survival was 8.50 vs 7.90 months, respectively (HR [95% CI], 0.99 [0.83-1.18]; p = 0.9338); overall survival was 14.90 vs 15.80 months, respectively (HR [95% CI], 1.03 [0.83-1.28]; p = 0.7713); and duration of response was 7.70 vs 7.00 months, respectively (HR [95% CI], 1.05 [0.81-1.37]; p = 0.6928). Severity and incidence of treatment-emergent adverse events, PK, and immunogenicity were comparable between SB8 and BEV. This study demonstrated equivalence between SB8 and BEV in terms of best ORR risk ratio, with comparable safety, PK, and immunogenicity.


Willingness to pay for a new drug delivery in Parkinson patients.
The Swedish reimbursement system operates a system where prices are set based on the expected value to the consumer. This value can be measured using willingness to pay (WTP). To assess Parkinson's disease (PD) patients' WTP for newly developed microtablets of levodopa in combination with a drug-delivering electronic device (M/E) compared to standard treatment with levodopa in combination with the COMT (catechol-O-methyl transferase)-inhibitor entacapone (L/e). A total of 2,000 randomly included PD patients had a postal questionnaire covering demographics, disease-specific issues, views on medication and WTP in different hypothetical scenarios. The first scenario was M/E with no change in effects or side effects; the second scenario was M/E with same effect and less side effects; and the third scenario was M/E with improved effect and less side effects. These scenarios were coupled to different costs to choose from. A total of 999 patients (50%) responded, mean age of 71 years and a mean PD duration of 9 years. Of all respondents, 50% preferred M/E before L/e in scenario one with increasing preference to scenario three. The average monthly WTP among all respondents in scenario one was SEK 230 and SEK 226 in L/e, both with an almost longitudinal doubling up to scenario three. Duration of PD-related symptoms, high education, and high medication intake implied a higher WTP in all scenarios in contrast to age, sex, and extra doses of levodopa. WTP for M/E increased gradually with high medication intake and education as well as with expected increased reduction of PD symptoms.


Which anthropometric measures best reflect neonatal adiposity?
Studying the determinants and the long-term consequences of fetal adipose accretion requires accurate assessment of neonatal body composition. In large epidemiological studies, in-depth body composition measurement methods are usually not feasible for cost and logistical reasons, and there is a need to identify anthropometric measures that adequately reflect neonatal adiposity. In a multiethnic Asian mother-offspring cohort in Singapore, anthropometric measures (weight, length, abdominal circumference, skinfold thicknesses) were measured using standardized protocols in newborn infants, and anthropometric indices (weight/length, weight/length2 (body mass index, BMI), weight/length3 (ponderal index, PI)) derived. Neonatal total adiposity was measured using air displacement plethysmography (ADP) and abdominal adiposity using magnetic resonance imaging (MRI). Correlations of the anthropometric measures with ADP- and MRI-based adiposity were assessed using Pearson's correlation coefficients (rp), including in subsamples stratified by sex and ethnicity. Study neonates (n=251) had a mean (s.d.) age of 10.2 (2.5) days. Correlations between ADP-based fat mass (ADPFM) and anthropometric measures were moderate (rp range: 0.44-0.67), with the strongest being with weight/length, weight, BMI and sum of skinfolds (rp=0.67, 0.66, 0.62, 0.62, respectively, all P<0.01). All anthropometric measures except skinfold thicknesses correlated more strongly with ADP-based fat-free mass than ADPFM, indicating that skinfold measures may have more discriminative power in terms of neonatal total body adiposity. For MRI-based measures, weight and weight/length consistently showed strong positive correlations (rp⩾0.7) with abdominal adipose tissue compartments. These correlations were consistent in boys and girls, across different ethnic groups, and when conventional determinants of neonatal adiposity were adjusted for potential confounding. Abdominal circumference was not strongly associated with ADPFM or abdominal fat mass. Simple anthropometric measures (weight and weight/length) correlated strongly with neonatal adiposity, with some evidence for greater discriminative power for skinfold measures. These simple measures could be of value in large epidemiological studies.


Identification of phosphatidylinositol-specific phospholipase C activity in Listeria monocytogenes: a novel type of virulence factor?
A phospholipase C which cleaves phosphatidylinositol and glycosylphosphatidylinositol (GPI) anchors was identified in Listeria monocytogenes. This 36 kDa protein is encoded by the gene plcA, and is homologous to the Bacillus cereus, Bacillus thuringiensis and eukaryotic phosphatidylinositol-specific phospholipases C (PI-PLC). Expression of the plcA gene in Escherichia coli correlates with the appearance of PI-PLC activity in the cells. In Listeria monocytogenes, the activity is secreted to the culture medium. PI-PLC activity was only found in the two pathogenic species of the genus Listeria, namely L. monocytogenes and L. ivanovii. PI-PLC activity was lost and virulence decreased when the plcA gene was disrupted in the chromosome. This suggests that the PI-PLC of L. monocytogenes might be involved in virulence.


Factors predictive of long-term visual outcomes of Group D eyes treated with chemoreduction and low-dose IMRT salvage: the Children's Hospital Los Angeles experience.
To evaluate clinical factors predictive of visual outcomes in Group D retinoblastoma eyes. Retrospective chart review of patients with Group D retinoblastoma from January 2000 to December 2009. All patients were treated with systemic chemoreduction and external beam radiation as salvage therapy when indicated. Primary outcome measure was visual acuity. Clinical factors evaluated include quadrants of subretinal fluid, extent of vitreous seeding, involvement of more/less than 50% of the macula, endophytic/exophytic tumour classification, and presence of tumour behind the lens at diagnosis. Fifty-two Group D eyes of 41 patients were included; 10 eyes with visual acuity better than 20/80, 32 eyes with vision worse than 20/100 and 10 eyes with indeterminate vision (fix and follow). Complete retinal detachment (p=0.002), involvement of >50% of the macula (p=0.01), and seeding >3 quadrants (p=0.05) were associated with worse visual outcome. Average follow-up was 50.0 months (range: 10-118 months). At presentation, it is difficult to predict which Group D eyes will be salvaged with useful vision following systemic chemotherapy. The presence of complete retinal detachment, macular involvement and extensive seeding on presentation were factors associated with a worse visual prognosis in this study. These findings can guide the ophthalmologist in clinical decision making, as well as in counselling parents.


Chemoprophylaxis in cardiac and orthopedic surgery: comparison of cephalothin and cephapirin.
In a retrospective sequential study we determined the rate of infection occurring despite cephalothin or cephapirin chemoprophylaxis in orthopedic and cardiac surgery done from 1973 to 1977. The incidence of infection after prosthetic hip placement or open reduction of hip fracture was 3.4% and 1.0% in patients receiving cephalothin or cephapirin, respectively. The infection rate after prosthetic heart valve implantation was 3.5% in those receiving cephalothin and 1.6% in those receiving cephapirin. There was no significant difference in infection rate, duration of fever greater than or equal to 38.0 C, or length of postoperative hospitalization. The efficacy of selected antistaphylococcal antibiotics in preventing colonization of human fibrin clots by staphylococci was studied. Although cephapirin was effective at lower concentration, the activity of cephalothin and cephapirin was comparable. Cephalothin and cephapirin have equivalent chemoprophylactic activity by clinical and microbiological criteria, permitting cost to be used as a basis for choosing between these antibiotics.


Content validity and electronic PRO (ePRO) usability of the Lung Cancer Symptom Scale-Mesothelioma (LCSS-Meso) in mesothelioma patients.
Obtaining qualitative data directly from the patient perspective enhances the content validity of patient-reported outcome (PRO) instruments. The objective of this qualitative study was to evaluate the content validity of the Lung Cancer Symptom Scale for Mesothelioma (LCSS-Meso) and its usability on an electronic device. A cross-sectional methodological study, using a qualitative approach, was conducted among patients recruited from four clinical sites. The primary target population included patients with pleural mesothelioma; data were also collected from patients with peritoneal mesothelioma on an exploratory basis. Semi-structured interviews were conducted consisting of concept elicitation, cognitive interviewing, and evaluation of electronic patient-reported outcome (ePRO) usability. Participants (n = 21) were interviewed in person (n = 9) or by telephone (n = 12); 71% were male with a mean age of 69 years (SD = 14). The most common signs and symptoms experienced by participants with pleural mesothelioma (n = 18) were shortness of breath, fluid build-up, pain, fatigue, coughing, and appetite loss. The most commonly described symptoms for those with peritoneal mesothelioma (n = 4) were bloating, changes in appetite, fatigue, fluid build-up, shortness of breath, and pain. Participants with pleural mesothelioma commonly described symptoms assessed by the LCSS-Meso in language consistent with the questionnaire and a majority understood and easily completed each of the items. The ePRO version was easy to use, and there was no evidence that the electronic formatting changed the way participants responded to the questions. Results support the content validity of the LCSS-Meso and the usability of the electronic format for use in assessing symptoms among patients with pleural mesothelioma.


Conservative management of breast cancer in the elderly in a developing country.
The cost effective treatment of cancer in developing countries remains challenging. In the elderly with possible limited life expectancy, the health expenditure associated with standard treatment regimes should be carefully considered. We present the results of conservative management of breast cancer in the aged in a resource-limited environment. Patients aged 70 or older with early breast cancer were treated with tumour excision or simple mastectomy and adjuvant tamoxifen. The records of patients presenting to the Breast Unit between January 1990 and December 2004 were retrieved and demographic, clinical, pathological and oncological data were reviewed. Survival statistics were calculated using the life table method. A total of 483 patients above 70 years of age were identified. One hundred and eighty eight patients were managed according to the conservative protocol. Forty-one had a simple mastectomy and 147 tumour excision. Their mean age was 77.3 years. The mean follow-up is 62 months. Thirty-one patients (16.4%) were not compliant with tamoxifen use. TNM staging was 0 in 4 patients, I in 42 patients, II in 116 patients and III in 26 patients. There was no 30-day mortality. The cumulative incidence of local recurrence was 3.3% at 5 and 10 years. The cumulative incidence of regional recurrence was 3.3% at 5 years and 4.5% at 10 years. The cumulative incidence of distant recurrence was 6.2% at 5 years and 12.2% at 10 years. The cumulative overall, disease specific and disease free survival at 10 years was 59%, 88% and 81% respectively. Limited surgery and tamoxifen provide excellent control of breast cancer in the elderly in a resource restricted environment. Radiotherapy and axillary dissection and can be safely omitted thereby reducing health care resource utilization.


Multifocal motor neuropathy: clinical and immunological features and response to IVIg in relation to the presence and degree of motor conduction block.
To determine whether patients with clinically typical multifocal motor neuropathy (MMN) with or without definite or probable conduction block (CB) differ in terms of clinical presentation, immunological findings, or response to treatment with intravenous immunoglobulin (IVIg). 23 consecutive patients were studied with the typical clinical features of MMN, consisting of a progressive multineuropathic motor impairment with minimal or no sensory loss. In 14 patients, electrophysiological studies disclosed the presence of a definite or probable CB according to the criteria proposed by the American Association of Electrodiagnostic Medicine (AAEM) in at least one motor nerve. Six patients had possible CB, defined as a degree of CB 10% less than that required by the AAEM for probable CB, while no CB was detected in three patients. Patients with possible CB did not differ from those with a definite or probable CB in terms of age at disease onset (mean 38.8 v 38.2 years, respectively), distribution and severity of limb weakness, clinical impairment (mean Rankin score 2.2 in both), and frequency of antiganglioside antibodies (33% v 29%). Patients with possible CB had a longer mean disease duration (9 v 5.9 years, p < 0.05) and a less frequent consistent response to IVIg (67% v 86%) than those with a definite or probable CB. Patients without a detectable CB had a similar frequency of antiganglioside antibodies (33%) but had a longer disease duration (20.3 years), greater impairment (Rankin score 2.7), and more frequent signs of axonal degeneration (41% of examined motor nerves) than patients with CB (13-15%, p < 0.005). Only one patient without detectable CB (33%) consistently improved with IVIg. Patients with possible CB were clinically and immunologically indistinguishable from those with definite or probable CB, albeit with a slightly less frequent response to IVIg. This finding suggests that failure to fulfil AAEM criteria for CB in patients with otherwise clinically typical MMN should not preclude this diagnosis and consequently a treatment trial with IVIg. Whether the longer duration and greater severity of the disease and more frequent axonal impairment in patients without detectable CB than in those with CB explain their lower response to IVIg remains to be established.