Cold-Adapted Influenza and Recombinant Adenovirus Vaccines Induce Cross-Protective Immunity against pH1N1 Challenge in Mice

The rapid spread of the 2009 H1N1 pandemic influenza virus (pH1N1) highlighted problems associated with relying on strain-matched vaccines. A lengthy process of strain identification, manufacture, and testing is required for current strain-matched vaccines and delays vaccine availability. Vaccines inducing immunity to conserved viral proteins could be manufactured and tested in advance and provide cross-protection against novel influenza viruses until strain-matched vaccines became available. Here we test two prototype vaccines for cross-protection against the recent pandemic virus.BALB/c and C57BL/6 mice were intranasally immunized with a single dose of cold-adapted (ca) influenza viruses from 1977 or recombinant adenoviruses (rAd) expressing 1934 nucleoprotein (NP) and consensus matrix 2 (M2) (NP+M2-rAd). Antibodies against the M2 ectodomain (M2e) were seen in NP+M2-rAd immunized BALB/c but not C57BL/6 mice, and cross-reacted with pH1N1 M2e. The ca-immunized mice did not develop antibodies against M2e. Despite sequence differences between vaccine and challenge virus NP and M2e epitopes, extensive cross-reactivity of lung T cells with pH1N1 peptides was detected following immunization. Both ca and NP+M2-rAd immunization protected BALB/c and C57BL/6 mice against challenge with a mouse-adapted pH1N1 virus.Cross-protective vaccines such as NP+M2-rAd and ca virus are effective against pH1N1 challenge within 3 weeks of immunization. Protection was not dependent on recognition of the highly variable external viral proteins and could be achieved with a single vaccine dose. The rAd vaccine was superior to the ca vaccine by certain measures, justifying continued investigation of this experimental vaccine even though ca vaccine is already available. This study highlights the potential for cross-protective vaccines as a public health option early in an influenza pandemic

Tone burst-evoked otoacoustic emissions in neonates: normative data

<p>Abstract</p> <p>Background</p> <p>Tone-burst otoacoustic emissions (TBOAEs) have not been routinely studied in pediatric populations, although tone burst stimuli have greater frequency specificity compared with click sound stimuli. The present study aimed (1) to determine an appropriate stimulus level for neonatal TBOAE measurements when the stimulus center frequency was 1 kHz, (2) to explore the characteristics of 1 kHz TBOAEs in a neonatal population.</p> <p>Methods</p> <p>A total of 395 normal neonates (745 ears) were recruited. The study consisted of two parts, reflecting the two study aims. Part I included 40 normal neonatal ears, and TBOAE measurement was performed at five stimulus levels in the range 60–80 dB peSPL, with 5 dB incremental steps. Part II investigated the characteristics of the 1 kHz TBOAE response in a large group of 705 neonatal ears, and provided clinical reference criteria based on these characteristics.</p> <p>Results</p> <p>The study provided a series of reference parameters for 1 kHz TBOAE measurement in neonates. Based on the results, a suggested stimulus level and reference criteria for 1 kHz TBOAE measures with neonates were established. In addition, time-frequency analysis of the data gave new insight into the energy distribution of the neonatal TBOAE response.</p> <p>Conclusion</p> <p>TBOAE measures may be a useful method for investigating cochlear function at specific frequency ranges in neonates. However, further studies of both TBOAE time-frequency analysis and measurements in newborns are needed.</p

Effects of robotic-assisted laparoscopic prostatectomy on surgical pathology specimens

Background Robotic-assisted laparoscopic prostatectomy (RALP) has greatly changed clinical management of prostate cancer. It is important for pathologists and urologists to compare RALP with conventional open radical retropubic prostatectomy (RRP), and evaluate their effects on surgical pathology specimens. Methods We retrospectively reviewed and statistically analyzed 262 consecutive RALP (n = 182) and RRP (n = 80) procedures performed in our institution from 2007 to 2010. From these, 49 RALP and 33 RRP cases were randomly selected for additional microscopic examination to analyze the degree of capsular incision and the amount of residual prostate surface adipose tissue. Results Positive surgical margins were present in 28.6% RALP and 57.5% RRP cases, a statistically significant difference. In patients with stage T2c tumors, which represent 61.2% RALP and 63.8% RRP patients, the positive surgical margin rate was 24.1% in the RALP group and 58.8% in the RRP group (statistically significant difference). For other pathologic stages, the differences in positive margins between RALP and RRP groups were not statistically significant. The incidence of positive surgical margins after RALP was related to higher tumor stage, higher Gleason score, higher tumor volume and lower prostate weight, but was not related to the surgeons performing the procedure. When compared with RRP, RALP also caused less severe prostatic capsular incision and maintained larger amounts of residual surface adipose tissue in prostatectomy specimens. Conclusions In this study RALP showed a statistically significant lower positive surgical margin rate than RRP. Analysis of capsular incision and amount of prostatic surface residual adipose tissue suggested that RALP caused less prostatic capsular damage than RRP

Does the inclusion of 'professional development' teaching improve medical students' communication skills?

Background: This study investigated whether the introduction of professional development teaching in the first two years of a medical course improved students' observed communication skills with simulated patients. Students' observed communication skills were related to patient-centred attitudes, confidence in communicating with patients and performance in later clinical examinations.Methods: Eighty-two medical students from two consecutive cohorts at a UK medical school completed two videoed consultations with a simulated patient: one at the beginning of year 1 and one at the end of year 2. Group 1 (n = 35) received a traditional pre-clinical curriculum. Group 2 (n = 47) received a curriculum that included communication skills training integrated into a 'professional development' vertical module. Videoed consultations were rated using the Evans Interview Rating Scale by communication skills tutors. A subset of 27% were double-coded. Inter-rater reliability is reported.Results: Students who had received the professional development teaching achieved higher ratings for use of silence, not interrupting the patient, and keeping the discussion relevant compared to students receiving the traditional curriculum. Patient-centred attitudes were not related to observed communication. Students who were less nervous and felt they knew how to listen were rated as better communicators. Students receiving the traditional curriculum and who had been rated as better communicators when they entered medical school performed less well in the final year clinical examination.Conclusions: Students receiving the professional development training showed significant improvements in certain communication skills, but students in both cohorts improved over time. The lack of a relationship between observed communication skills and patient-centred attitudes may be a reflection of students' inexperience in working with patients, resulting in 'patient-centredness' being an abstract concept. Students in the early years of their medical course may benefit from further opportunities to practise basic communication skills on a one-to-one basis with patients

Activation of Cell Cycle Arrest and Apoptosis by the Proto-Oncogene Pim-2

Potent survival effects have been ascribed to the serine/threonine kinase proto-oncogene PIM-2. Elevated levels of PIM-2 are associated with various malignancies. In human cells, a single Pim-2 transcript gives rise mainly to two protein isoforms (34, 41 kDa) that share an identical catalytic site but differ at their N-terminus, due to in-frame alternative translation initiation sites. In this study we observed that the 34 kDa PIM-2 isoform has differential nuclear and cytoplasmic forms in all tested cell lines, suggesting a possible role for the balance between these forms for PIM-2's function. To further study the cellular role of the 34 kDa isoform of PIM-2, an N-terminally HA-tagged form of this isoform was transiently expressed in HeLa cells. Surprisingly, this resulted in increased level of G1 arrested cells, as well as of apoptotic cells. These effects could not be obtained by a Flag-tagged form of the 41 kDa isoform. The G1 arrest and apoptotic effects were associated with an increase in T14/Y15 phosphorylation of CDK2 and proteasom-dependent down-regulation of CDC25A, as well as with up-regulation of p57, E2F-1, and p73. No such effects were obtained upon over-expression of a kinase-dead form of the HA-tagged 34 kDa PIM-2. By either using a dominant negative form of p73, or by over-expressing the 34 kDa PIM-2 in p73-silenced cells, we demonstrated that these effects were p73-dependent. These results demonstrate that while PIM-2 can function as a potent survival factor, it can, under certain circumstances, exhibit pro-apoptotic effects as well

Genome Scan of M. tuberculosis Infection and Disease in Ugandans

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is an enduring public health problem globally, particularly in sub-Saharan Africa. Several studies have suggested a role for host genetic susceptibility in increased risk for TB but results across studies have been equivocal. As part of a household contact study of Mtb infection and disease in Kampala, Uganda, we have taken a unique approach to the study of genetic susceptibility to TB, by studying three phenotypes. First, we analyzed culture confirmed TB disease compared to latent Mtb infection (LTBI) or lack of Mtb infection. Second, we analyzed resistance to Mtb infection in the face of continuous exposure, defined by a persistently negative tuberculin skin test (PTST-); this outcome was contrasted to LTBI. Third, we analyzed an intermediate phenotype, tumor necrosis factor-alpha (TNFα) expression in response to soluble Mtb ligands enriched with molecules secreted from Mtb (culture filtrate). We conducted a full microsatellite genome scan, using genotypes generated by the Center for Medical Genetics at Marshfield. Multipoint model-free linkage analysis was conducted using an extension of the Haseman-Elston regression model that includes half sibling pairs, and HIV status was included as a covariate in the model. The analysis included 803 individuals from 193 pedigrees, comprising 258 full sibling pairs and 175 half sibling pairs. Suggestive linkage (p<10−3) was observed on chromosomes 2q21-2q24 and 5p13-5q22 for PTST-, and on chromosome 7p22-7p21 for TB; these findings for PTST- are novel and the chromosome 7 region contains the IL6 gene. In addition, we replicated recent linkage findings on chromosome 20q13 for TB (p = 0.002). We also observed linkage at the nominal α = 0.05 threshold to a number of promising candidate genes, SLC11A1 (PTST- p = 0.02), IL-1 complex (TB p = 0.01), IL12BR2 (TNFα p = 0.006), IL12A (TB p = 0.02) and IFNGR2 (TNFα p = 0.002). These results confirm not only that genetic factors influence the interaction between humans and Mtb but more importantly that they differ according to the outcome of that interaction: exposure but no infection, infection without progression to disease, or progression of infection to disease. Many of the genetic factors for each of these stages are part of the innate immune system