Attenuation of Sindbis virus variants incorporating uncleaved PE2 glycoprotein is correlated with attachment to cell-surface heparan sulfate

Sindbis virus virions incorporating uncleaved precursor envelope protein PE2 bind efficiently to cell-surface heparan sulfate (HS) because the furin cleavage site (a consensus HS-binding domain) is retained in the mature virus particle. However, they are essentially nonviable. Resuscitating mutations selected in the E3 or E2 protein preserve the PE2 noncleaving phenotype and HS binding, but facilitate fusion, and thereby restore wild-type infectivity on cultured cells. Here, we have demonstrated that the resuscitated PE2 noncleaving virus was almost avirulent in vivo, but mutated during the infection. Mutants had increased virulence and cleavage of PE2, with reduced HS binding capacity. We hypothesize that HS binding leads to sequestration of PE2 noncleaving virus particles and suppression of serum viremia, thereby selecting for evolution of the virus into a PE2-cleaving, low HS-binding phenotype

Attenuation of Sindbis virus variants incorporating uncleaved PE2 glycoprotein is correlated with attachment to cell-surface heparan sulfate

Sindbis virus virions incorporating uncleaved precursor envelope protein PE2 bind efficiently to cell-surface heparan sulfate (HS) because the furin cleavage site (a consensus HS-binding domain) is retained in the mature virus particle. However, they are essentially nonviable. Resuscitating mutations selected in the E3 or E2 protein preserve the PE2 noncleaving phenotype and HS binding, but facilitate fusion, and thereby restore wild-type infectivity on cultured cells. Here, we have demonstrated that the resuscitated PE2 noncleaving virus was almost avirulent in vivo, but mutated during the infection. Mutants had increased virulence and cleavage of PE2, with reduced HS binding capacity. We hypothesize that HS binding leads to sequestration of PE2 noncleaving virus particles and suppression of serum viremia, thereby selecting for evolution of the virus into a PE2-cleaving, low HS-binding phenotype

Updated analyses of the results from the Island Closure Feasibility Study for the Dassen/Robben and St Croix/Bird Island pairs given revised data and responses to matters raised in documents

Repetition of earlier analyses of the data from the island closure feasibility study, given some corrected and extended data series, makes little change to results for Robben and Dassen Islands, except that the estimated power of foraging–related response variables to achieve statistically significant results decreases appreciably. However for St Croix Island, the inference of a negative impact of fishing is strengthened. The rationales offered in MARAM/IWS/DEC14/Peng/A3 for using closure instead of catch as a covariate in the analysis, and for restricting data to the years from 2008 onwards, are questioned. Comparisons conducted by applying the MARAM/IWS/DEC14/Peng/B4 approach, which uses annual means of response variables, indicate that the use of closure rather than catch as the covariate generally results in poorer precision and fewer statistically significant estimates of the fishing effect parameter λ. Furthermore when catch is used as the covariate, appreciably better precision for estimates of λ is generally achieved by including all years in the analyses, rather than by restricting them to the period from 2008 onwards. Importantly comparative estimates of λ from the Peng/B4 approach are shown to achieve better precision generally than those from the more complex and data-intensive Peng/A3 approach, thus negating the assertions in Peng/A1 and Peng/A2 that estimates from the former are compromised by their dependence on response variable means alone. The failure of Peng/A3 to report the variance estimates needed for input to the power analysis required for the feasibility study is noted. Furthermore Peng/A3 offers no specification of the simulation studies necessary to carry out a power analysis for the estimators which it proposes, so that it has failed to address this key first step in this overall closure study process. Peng/A3 has prodived some strongish evidence that closures may benefit penguins, but for the Eastern Cape colonies only. However it has failed to address the primary aim of the feasibility study itself to ascertain for how long an experimental closures programme would need to continue for reliable determination of the impact of fishing in the near vicinity of island colonies on penguin reproductive success. Use of the Peng/B4 approach indicates that this period is appreciably lengthened if data for analyses are to be restricted to the years from 2008 onwards only, and particularly so if closure replaces catch as a covariate

Interleukin-15 Affects Patient Survival through Natural Killer Cell Recovery after Autologous Hematopoietic Stem Cell Transplantation for Non-Hodgkin Lymphomas

Natural killer cells at day 15 (NK-15), after autologous peripheral blood hematopoietic stem cell transplantation (APHSCT), is a prognostic factor for overall survival (OS) and progression-free survival (PFS) in non-Hodgkin lymphoma (NHL). The potential role of the immunologic (homeostatic) environment affecting NK-15 recovery and survival post-APHSCT has not been fully studied. Therefore, we evaluate prospectively the cytokine profile in 50 NHL patients treated with APHSCT. Patients with an interleukin-15 (IL-15) ≥ 76.5 pg/mL at day 15 post-APHSCT experienced superior OS and PFS compared with those who did not; median OS; not reached versus 19.2 months, P < .002; and median PFS; not reached versus 6.8 months, P < .002, respectively. IL-15 was found to correlate with (rs = 0.7, P < .0001) NK-15. Multivariate analysis showed only NK-15 as a prognostic factor for survival, suggesting that the survival benefit observed by IL-15 is most likely mediated by enhanced NK cell recovery post-APHSCT

A Multi-Institutional Study on the Safety and Efficacy of Specimen Morcellation After Laparoscopic Radical Nephrectomy for Clinical Stage T1 or T2 Renal Cell Carcinoma

Abstract Introduction and Objective: Specimen morcellation during laparoscopic radical nephrectomy (LRN) for renal cell carcinoma (RCC) is controversial. We seek to evaluate the safety and efficacy of specimen morcellation and LRN for treatment of presumed malignant renal lesions. Methods: We retrospectively reviewed all patients who underwent LRN at three academic institutions from 1996 to 2007. One hundred eighty-eight patients underwent specimen morcellation after LRN for enhancing solid or cystic renal masses. Results: LRN was successfully performed on all the patients. Patient age ranged from 36 to 94. One hundred sixty-seven patients were in clinical stage T1, 19 patients T2, and unknown in two. The specimen was manually morcellated within a Cook Lap Sac or Endocatch II bag under laparoscopic or direct observation. On histological review of morcellated specimens, 165 patients were confirmed to have RCC, 17 had an oncocytoma, and 2 had benign cysts. At least 13 patients with RCC were pathologically upgraded to stage T3. Mean operative time was 225 minutes (range 94-650). Mean hospital stay was 2.5 days (range 1-8). In patients with RCC, 11 developed recurrent disease with mean follow-up of 21 months (range 0.3-111). In one patient, a port site recurrence occurred in concert with renal fossa and lymph node metastases. Conclusions: Intracorporeal mechanical morcellation after LRN appears to be safe and effective in clinical stage T1 and T2 RCC. This supports the use of morcellation as an alternative for intact specimen removal in properly selected patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78157/1/end.2009.0387.pd

A Two Micron All-Sky Survey View of the Sagittarius Dwarf Galaxy: II. Swope Telescope Spectroscopy of M Giant Stars in the Dynamically Cold Sagittarius Tidal Stream

We present moderate resolution (~6 km/s) spectroscopy of 284 M giant candidates selected from the Two Micron All Sky Survey photometry. Radial velocities (RVs) are presented for stars mainly in the south, with a number having positions consistent with association to the trailing tidal tail of the Sagittarius (Sgr) dwarf galaxy. The latter show a clear RV trend with orbital longitude, as expected from models of the orbit and destruction of Sgr. A minimum 8 kpc width of the trailing stream about the Sgr orbital midplane is implied by verified RV members. The coldness of this stream (dispersion ~10 km/s) provides upper limits on the combined contributions of stream heating by a lumpy Galactic halo and the intrinsic dispersion of released stars, which is a function of the Sgr core mass. The Sgr trailing arm is consistent with a Galactic halo containing one dominant, LMC-like lump, however some lumpier halos are not ruled out. An upper limit to the total M/L of the Sgr core is 21 in solar units. A second structure that roughly mimics expectations for wrapped, leading Sgr arm debris crosses the trailing arm in the Southern Hemisphere; however, this may also be an unrelated tidal feature. Among the <13 kpc M giants toward the South Galactic Pole are some with large RVs that identify them as halo stars, perhaps part of the Sgr leading arm near the Sun. The positions and RVs of Southern Hemisphere M giants are compared with those of southern globular clusters potentially stripped from the Sgr system and support for association of Pal 2 and Pal 12 with Sgr debris is found. Our discussion includes description of a masked-filtered cross-correlation methodology that achieves better than 1/20 of a resolution element RVs in moderate resolution spectra.Comment: 41 pages, 6 figures, Astronomical Journal, in press (submitted Nov. 24, 2003; tentatively scheduled for July 2004 issue

Changes in undergraduate student alcohol consumption as they progress through university

BACKGROUND: Unhealthy alcohol use amongst university students is a major public health concern. Although previous studies suggest a raised level of consumption amongst the UK student population there is little consistent information available about the pattern of alcohol consumption as they progress through university. The aim of the current research was to describe drinking patterns of UK full-time undergraduate students as they progress through their degree course. METHOD: Data were collected over three years from 5895 undergraduate students who began their studies in either 2000 or 2001. Longitudinal data (i.e. Years 1–3) were available from 225 students. The remaining 5670 students all responded to at least one of the three surveys (Year 1 n = 2843; Year 2 n = 2219; Year 3 n = 1805). Results: Students reported consuming significantly more units of alcohol per week at Year 1 than at Years 2 or 3 of their degree. Male students reported a higher consumption of units of alcohol than their female peers. When alcohol intake was classified using the Royal College of Physicians guidelines [1] there was no difference between male and females students in terms of the percentage exceeding recommended limits. Compared to those who were low level consumers students who reported drinking above low levels at Year 1 had at least 10 times the odds of continuing to consume above low levels at year 3. Students who reported higher levels of drinking were more likely to report that alcohol had a negative impact on their studies, finances and physical health. Consistent with the reduction in units over time students reported lower levels of negative impact during Year 3 when compared to Year 1. CONCLUSION: The current findings suggest that student alcohol consumption declines over their undergraduate studies; however weekly levels of consumption at Year 3 remain high for a substantial number of students. The persistence of high levels of consumption in a large population of students suggests the need for effective preventative and treatment interventions for all year groups

Using geographically weighted regression to explore the spatially heterogeneous spread of bovine tuberculosis in England and Wales

An understanding of the factors that affect the spread of endemic bovine tuberculosis (bTB) is critical for the development of measures to stop and reverse this spread. Analyses of spatial data need to account for the inherent spatial heterogeneity within the data, or else spatial autocorrelation can lead to an overestimate of the significance of variables. This study used three methods of analysis—least-squares linear regression with a spatial autocorrelation term, geographically weighted regression (GWR) and boosted regression tree (BRT) analysis—to identify the factors that influence the spread of endemic bTB at a local level in England and Wales. The linear regression and GWR methods demonstrated the importance of accounting for spatial differences in risk factors for bTB, and showed some consistency in the identification of certain factors related to flooding, disease history and the presence of multiple genotypes of bTB. This is the first attempt to explore the factors associated with the spread of endemic bTB in England and Wales using GWR. This technique improves on least-squares linear regression approaches by identifying regional differences in the factors associated with bTB spread. However, interpretation of these complex regional differences is difficult and the approach does not lend itself to predictive models which are likely to be of more value to policy makers. Methods such as BRT may be more suited to such a task. Here we have demonstrated that GWR and BRT can produce comparable outputs