We sought to measure the anatomic dimensions of the crista galli in a consecutive series of patients undergoing the endoscopic transcribriform approach for anterior skull base tumors at a tertiary academic university hospital. We performed a retrospective chart review of patients undergoing purely endoscopic transcribriform surgery for sinonasal and skull base lesions. Main outcome measures included radiological dimensions of the crista galli. A total of 12 patients were identified and treated by the senior authors at the University of Pennsylvania. The average crista galli dimensions were 12.7 ± 2.4 mm (anterior-posterior) and 12.9 ± 2.5 mm (cranial-caudal dimension). Knowledge of the dimensions of the crista galli is important in preoperative planning for both instrumentation and access.
Endoscopic skull base surgery; transcribriform; crista galli; radiology; anatomy
Purely endoscopic resections of transcranial/intracranial pathology represent an exciting minimally invasive option for some patients. There is an abundance of literature on surgical techniques, though very little deals with perioperative management, which is critical for good outcomes. We present a detailed case review and a perioperative management protocol with specific reference to skull base and neuroanatomy. We performed a retrospective chart review and analysis of outcomes and complications by approach and design and prospective employment of a perioperative management protocol in a major tertiary care referral hospital. We included patients undergoing endoscopic skull base approaches by the two senior surgeons from September 2005 to April 2009, selecting of transcranial/intracranial cases for detailed review. Our main outcome measures included perioperative morbidity, mortality, and complications; degree of resection; recurrence rate; and survival. Fifteen patients met study criteria. No perioperative mortality occurred. There were two major and four minor complications. Mean follow-up was 15 months; 11/13 patients with malignancies had no evidence of disease. A perioperative management protocol was designed from these data and has resulted in decreased lumbar drainage and increased fluid/electrolyte monitoring. Endoscopic transcranial/intracranial anterior skull base surgery is both safe and effective when a complete understanding of the surgery and perioperative management is achieved.
Extended endonasal approach; endoscopic; anterior skull base; skull base neoplasm
Typical measures for assessing the useful field (UFOV) of view involve many components of attention. The objective of the current experiment was to examine differences in visual search efficiency for older individuals with and without UFOV impairment.
The authors used a computerized screening instrument to assess the useful field of view and to characterize participants as having an impaired or normal UFOV. Participants also performed two visual search tasks, a feature search (e.g., search for a green target among red distractors) or a conjunction search (e.g., a green target with a gap on its left or right side among red distractors with gaps on the left or right and green distractors with gaps on the top or bottom).
Visual search performance did not differ between UFOV impaired and unimpaired individuals when searching for a basic feature. However, search efficiency was lower for impaired individuals than unimpaired individuals when searching for a conjunction of features.
The results suggest that UFOV decline in normal aging is associated with conjunction search. This finding suggests that the underlying cause of UFOV decline may arise from an overall decline in attentional efficiency. Because the useful field of view is a reliable predictor of driving safety, the results suggest that decline in the everyday visual behavior of older adults might arise from attentional declines.
Tumors of the olfactory groove may cause unilateral optic atrophy with contralateral papilledema and anosmia (Foster Kennedy syndrome). We describe a case of a young pregnant woman with Foster Kennedy syndrome due to an olfactory groove meningioma.
Foster Kennedy syndrome; meningioma; pregnancy; optic disk atrophy; papilledema; anosmia
To study the attitudes among general practitioners towards pneumococcal vaccination for middle-aged (50–64) and elderly population (over 65) in Hong Kong and the factors affecting their decision to advise pneumococcal vaccination for those age groups.
Cross-sectional study of general practitioners in private practice in Hong Kong.
Members of Hong Kong Medical Association delivering general practice services in private sector.
Main Outcome Measures
Intention to recommend pneumococcal vaccination, barriers against pneumococcal vaccination.
53.4% of the respondents would actively recommend pneumococcal vaccination to elderly patients but only 18.8% would recommend for middle-aged patients. Consultation not related to pneumococcal vaccine was the main reason for not recommending pneumococcal vaccine (43.6%). Rarity of pneumonia in their daily practice was another reason with 68.4% of respondents attending five or less patients with pneumonia each year. In multivariate analysis, factors such as respondents would get vaccination when reaching age 50 (ORm 10.1), and attending 6 pneumonia cases or more per year (ORm 2.28) were found to be associated with increasing likelihood for recommending vaccination to the middle-aged. While concerns of marketing a product (ORm 0.41), consultation not related to vaccination (ORm 0.45) and limited time (ORm 0.38) were factors that reduced the likelihood.
Public policy is needed to increase the awareness of impact of pneumococcal pneumonia and the availability of preventive measures.
There are no vaccines or therapeutics currently approved for the prevention or treatment of ebolavirus infection. Previously, a replicon vaccine based on Venezuelan equine encephalitis virus (VEEV) demonstrated protective efficacy against Marburg virus in nonhuman primates. Here, we report the protective efficacy of Sudan virus (SUDV)- and Ebola virus (EBOV)-specific VEEV replicon particle (VRP) vaccines in nonhuman primates. VRP vaccines were developed to express the glycoprotein (GP) of either SUDV or EBOV. A single intramuscular vaccination of cynomolgus macaques with VRP expressing SUDV GP provided complete protection against intramuscular challenge with SUDV. Vaccination against SUDV and subsequent survival of SUDV challenge did not fully protect cynomolgus macaques against intramuscular EBOV back-challenge. However, a single simultaneous intramuscular vaccination with VRP expressing SUDV GP combined with VRP expressing EBOV GP did provide complete protection against intramuscular challenge with either SUDV or EBOV in cynomolgus macaques. Finally, intramuscular vaccination with VRP expressing SUDV GP completely protected cynomolgus macaques when challenged with aerosolized SUDV, although complete protection against aerosol challenge required two vaccinations with this vaccine.
In the development of genetically inactivated bacterial vaccines, plasmid retention often requires the antibiotic resistance gene markers, the presence of which can cause the potential biosafety hazards such as the horizontal spread of resistance genes. The new lysis plasmid was constructed by utilizing the approach of balanced-lethal systems based on auxotrophic gene Aspartate semialdehyde dehydrogenase (asd). The PhiX174 lysis gene E and λPR37-cI857 temperature-sensitive regulatory system was cloned in the asd gene positive plasmid and this novel approach allowed the production of antibiotic resistance marker free Salmonella Enteritidis (S. Enteritidis) ghost. The immunogenic potential of the biosafety enhanced antibiotic resistance gene free S. Enteritidis ghost was evaluated in chickens by employing the prime-boost vaccination strategy using a combination of oral and intramuscular routes. A total of 75 two-week-old chickens were equally divided into five groups: group A (non-immunized control), group B (intramuscularly primed and boosted), group C (primed intramuscularly and boosted orally), group D (primed and boosted orally), and group E (primed orally and boosted intramuscularly). Chickens from all immunized groups demonstrated significant increases in plasma IgG, intestinal secretory IgA levels, and antigen-specific lymphocyte proliferative response. After a virulent S. Enteritidis challenge, all immunized groups showed fewer gross lesions and decreased bacterial recovery from organs in comparison with the non-immunized control group. Among the immunized chickens, groups B and D chickens showed optimized protection, indicating that the prime-booster immunization with the ghost via intramuscular or oral route is efficient. Taken together, our results demonstrate that an antibiotic resistance gene free lysis plasmid was successfully constructed and utilized for production of safety enhanced S. Enteritidis ghost, which can be used as a safe and effective vaccine against virulent S. Enteritidis infections.
Components of the innate immune complement system have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS); however, a comprehensive examination of complement expression in this disease has not been performed. This study therefore aimed to determine the expression of complement components (C1qB, C4, factor B, C3/C3b, C5 and CD88) and regulators (CD55 and CD59a) in the lumbar spinal cord of hSOD1G93A mice during defined disease stages.
hSOD1G93A and wild-type mice were examined at four different ages of disease progression. mRNA and protein expression of complement components and regulators were examined using quantitative PCR, western blotting and ELISA. Localisation of complement components within lumbar spinal cord was investigated using immunohistochemistry. Statistical differences between hSOD1G93A and wild-type mice were analysed using a two-tailed t-test at each stage of disease progression.
We found several early complement factors increased as disease progressed, whilst complement regulators decreased; suggesting overall increased complement activation through the classical or alternative pathways in hSOD1G93A mice. CD88 was also increased during disease progression, with immunolocalisation demonstrating expression on motor neurons and increasing expression on microglia surrounding the regions of motor neuron death.
These results indicate that local complement activation and increased expression of CD88 may contribute to motor neuron death and ALS pathology in the hSOD1G93A mouse. Hence, reducing complement-induced inflammation could be an important therapeutic strategy to treat ALS.
C1q; C4; Factor B; C3; C5; CD55; CD88; Motor neuron disease; Neuroinflammation
Primary upper endoscopy (EGD) and transabdominal US (TUS) are often performed in patients with upper abdominal pain.
Primary: Determine whether the combination of EGD and EUS was equivalent to EGD plus TUS in the diagnostic evaluation of upper abdominal pain. Secondary: Compare EUS versus TUS in detecting abdominal lesions, and compare EGD by using an oblique-viewing echoendoscope versus the standard, forward-viewing endoscope in detecting mucosal lesions.
Prospective, paired design.
Six academic endoscopy centers.
This study involved patients with upper abdominal pain referred for endoscopy.
All patients had EGD, EUS, and TUS. The EGD was done using both an oblique-viewing echoendoscope and the standard, forward-viewing endoscope (randomized order) by two separate endoscopists in a blinded fashion, followed by EUS. TUS was performed within 4 weeks of EGD/EUS, also in a blinded fashion. Follow-up: telephone interviews and chart reviews.
Main Outcome Measurements
Diagnose possible etiology of upper abdominal pain and detect clinically significant lesions.
A diagnosis of the etiology of upper abdominal pain was made in 66 of 172 patients (38%). The diagnostic rate was 42 of 66 patients (64%) for EGD plus EUS versus 41 of 66 patients (62%) for EGD plus TUS, which was statistically equivalent (McNemar test; P = .27). One hundred ninety-eight lesions were diagnosed with either EUS or TUS. EUS was superior to TUS for visualizing the pancreas (P < .0001) and for diagnosing chronic pancreatitis (P = .03). Two biliary stones were detected only by EUS. Two hundred fifty-one mucosal lesions were similarly diagnosed with EGD with either the standard, forward-viewing endoscope or the oblique-viewing echoendoscope (kappa = 0.48 [95% CI, .43-.54]). EGD with the standard, forward-viewing endoscope was preferred for biopsies.
No cost analysis.
The combination of EGD with EUS is equivalent to EGD plus TUS for diagnosing a potential etiology of upper abdominal pain. EUS is superior to TUS for detecting chronic pancreatitis. EGD combined with EUS should be considered in the first-line diagnostic evaluation of patients with upper abdominal pain.
Vasovagal syncope usually occurs during upright posture, but Jardine et al. have described a variant that occurs at night. During “sleep syncope”, patients are awakened from sleep with nausea, abdominal cramping or a sense of impending diarrhea, get up, and faint in the bathroom. We report on a patient with recurrent sleep syncope (with physical injury) in whom an asystolic pause was documented during one of her “sleep syncope” spells. Implantation of a dual chamber pacemaker (5 year follow-up) “cured” her of further syncope. This is the 1st report of pacemaker use for this unusual form of reflex syncope.
syncope; sleep; pacemaker
One of the most intriguing questions confronting the Bone Morphogenetic Protein family is the mechanism of ligand recognition, since there are more ligands than receptors. Crystal structures of two type II receptors ActR-II and BMPR-II are essentially identical, and a loop structure (A-loop) has been suggested to play a role in determining ligand specificity. Solution biophysical study showed mutations of several A-loop residues in these two receptors exert different ligand binding effects. Thus, the issues of mechanism of ligand recognition and specificity remain unresolved. We examined effects of mutations of residues Y40, G47, and S107 in BMPR-II receptor. These residues are not identified in contact with the ligand in the BMP-7-BMPR-II complex, but are found mutated in genetic diseases. They are likely to be useful in identifying their roles in differentiating the various BMP ligands. Spectroscopic probing revealed little mutation-induced structural change in BMPR-II. Ligand binding studies revealed that Y40 plays a significant role in differentiating three distinct ligands; G47 and S107 affect ligand binding to a lesser extent. The role of the A-loop in ActR-II or BMPR-II is dependent on the host sequence of the receptor extracellular domain (ECD) in which it is embedded, suggesting a host-guest relationship between the A-loop and the rest of the ECD. Computational analysis demonstrated a long-range connectivity between Y40, G47, and S107 and other locations in BMPR-II. An integration of these results on functional energetics and protein structures clearly demonstrate, for the first time, an intra-domain communication network within BMPR-II.
Background. Microvascular decompression (MVD) is a widely accepted treatment for neurovascular disorders associated with facial pain and spasm. The endoscope has rapidly become a standard tool in neurosurgical procedures; however, its adoption in lateral approaches to the posterior fossa has been slower. The endoscope is used primarily to assist conventional microscopic techniques. We are interested in developing fully endoscopic approaches to the cerebellopontine angle, and here, we describe our preliminary experience with this procedure for MVD. Methods. A retrospective review of our two-year experience from 2011 to 2012, transitioning from using conventional microscopic techniques to endoscope-assisted microsurgery to fully endoscopic MVD, is provided. We also reviewed our preliminary outcomes during this transition. Results. There was no difference in the surgical duration of these three procedures. In addition, the majority of procedures performed in 2012 were fully endoscopic, suggesting the ease of incorporating this solo tool into practice. Pain outcomes of fully endoscopic MVD appear to be very similar to those of both conventional and endoscope-assisted MVDs. Complications occurred in all groups at equally low rates. Conclusion. Fully endoscopic MVD is both safe and effective. By enhancing visualization of structures within the cerebellopontine angle, endoscopy may prove to be a valuable adjunct or alternative to conventional microscopic approaches.
Arthropod-borne viruses are important emerging pathogens world-wide. Viruses transmitted by mosquitoes, such as dengue, yellow fever, and Japanese encephalitis viruses, infect hundreds of millions of people and animals each year. Global surveillance of these viruses in mosquito vectors using molecular based assays is critical for prevention and control of the associated diseases. Here, we report an oligonucleotide DNA microarray design, termed ArboChip5.1, for multi-gene detection and identification of mosquito-borne RNA viruses from the genera Flavivirus (family Flaviviridae), Alphavirus (Togaviridae), Orthobunyavirus (Bunyaviridae), and Phlebovirus (Bunyaviridae).
The assay utilizes targeted PCR amplification of three genes from each virus genus for electrochemical detection on a portable, field-tested microarray platform. Fifty-two viruses propagated in cell-culture were used to evaluate the specificity of the PCR primer sets and the ArboChip5.1 microarray capture probes. The microarray detected all of the tested viruses and differentiated between many closely related viruses such as members of the dengue, Japanese encephalitis, and Semliki Forest virus clades. Laboratory infected mosquitoes were used to simulate field samples and to determine the limits of detection. Additionally, we identified dengue virus type 3, Japanese encephalitis virus, Tembusu virus, Culex flavivirus, and a Quang Binh-like virus from mosquitoes collected in Thailand in 2011 and 2012.
We demonstrated that the described assay can be utilized in a comprehensive field surveillance program by the broad-range amplification and specific identification of arboviruses from infected mosquitoes. Furthermore, the microarray platform can be deployed in the field and viral RNA extraction to data analysis can occur in as little as 12 h. The information derived from the ArboChip5.1 microarray can help to establish public health priorities, detect disease outbreaks, and evaluate control programs.
Approximately half of the world's population is at risk of viral, mosquito-borne illness such as dengue, yellow fever, Japanese encephalitis, Rift Valley fever, and chikungunya. In the past, these viruses have been regarded as pathogens of the tropics; however, they are emerging as global causes of illness. Very few effective drugs and vaccines have been developed for mosquito-borne viral infections and even less are available to people in resource-limited countries. An important aspect of disease prevention is mosquito surveillance to determine geographical range and seasonal prevalence of the associated viruses. However, there are hundreds of viruses transmitted by mosquitoes that are pathogenic to humans and animals. Using a portable microarray, we developed an assay with the ability to detect most of the known medically important viruses transmitted by mosquitoes. This assay was designed for use in conjunction with broad-range screening tools as a cost effective, rapid method to determine the identity of viruses from infected mosquitoes. To our knowledge, this is the most comprehensive assay to date for field surveillance of mosquito-borne viruses.
The singular value decomposition deconvolution of cerebral tissue concentration-time (C-T) curves with the arterial input function (AIF) is commonly used in dynamic susceptibility contrast (DSC) cerebral perfusion MR imaging. However, it is sensitive to the time discrepancy between the arrival of the bolus in the tissue C-T curve and the AIF signal. This normally causes inaccuracy in the quantitative perfusion maps due to delay and dispersion effects. A comprehensive correction algorithm has been achieved through slice-dependent time-shifting of the AIF, and a delay-dependent dispersion correction model. The correction algorithm was tested in 11 healthy subjects and 3 ischemic stroke patients scanned with a quantitative perfusion pulse sequence at 1.5T. A validation study was performed on 5 patients with confirmed cerebrovascular occlusive disease scanned with MRI and positron emission tomography (PET) at 3.0T. A significant effect (p<0.05) was reported on the quantitative cerebral blood flow and mean transit time measurements (up to 50%). There was no statistically significant effect on the quantitative cerebral blood volume values. The in vivo results were in agreement with the simulation results, as well as previous literature. This minimizes the bias in patient diagnosis due to the existing errors and artifacts in DSC imaging.
Quantitative cerebral perfusion; arterial-tissue delay and dispersion; singular value decomposition; ischemic stroke
Older adults are overrepresented in fatal crashes on a per mile basis. Those with useful field of view (UFOV) reductions show a particularly elevated crash risk that might be mitigated with vehicle-based warnings. To evaluate cross-modal cues that could be used in these warnings, we applied a variation of Posner‘s orienting of attention paradigm. Twenty-nine older drivers with UFOV impairments and 32 older drivers without impairments participated. Cues were presented in either a single modality or a combination of modalities (visual, auditory, haptic). Drivers experienced three cue types (valid spatial information, invalid spatial information, neutral) and an uncued baseline. Following each cue, drivers discriminated the direction of a target (a Landolt square with a gap facing up or down) in the visual panorama. Drivers with and without UFOV impairments showed comparable response times (RTs) across the different cue modalities and cue types. Both groups benefited most from auditory and auditory/haptic cues. Redundant visual cues, when paired with auditory cues, undermined performance rather than enhanced it. Overall, drivers responded faster to targets with valid spatial information followed by neutral, invalid, and uncued targets. Cues provide the greatest benefit in alerting rather than orienting the driver. The cue expected to be most effective at orienting attention—the extra-vehicular cue—performs most poorly when the spatial information is either invalid or neutral. Even when the spatial information is valid the extra-vehicular cue underperforms the auditory cues. The results suggest that temporal information dominates spatial information in the ability of cues to speed responses to targets. This study represents a first step in assessing whether combining a cognitive science paradigm and a driving simulator environment can quickly assess how different warning signals alert and orient drivers.
spatial attention; older drivers; useful field of view; driving; warning signal; interface design
Typical measures of the useful field of view (UFOV) involve many components of
attention. The objective of the current research was to examine the attentional
operations that might underlie declines in the UFOV.
Method and Results.
We used 2 basic attention tasks to characterize the profile of visual attention in
UFOV-impaired and -unimpaired observers. Our results suggested that declines in the UFOV
result from a deficit in attentional disengagement, not a decrease in attentional
breadth or scope.
The results suggested that UFOV decline in normal aging can be associated with a
specific attentional operation, namely attentional disengagement. These results suggest
that the underlying cause of UFOV decline may not be a restriction in the breadth or
scope of attention. Because the UFOV is a reliable predictor of driving safety, our
results point to attentional components that are critical for the visual behavior of
Aging; Attention; Attentional disengagement; Cognitive decline; Useful field of view
This study investigated the effects of long-term-enhanced UV-B, and combined UV-B with elevated CO2 on dwarf shrub berry characteristics in a sub-arctic heath community. Germination of Vaccinium myrtillus was enhanced in seeds produced at elevated UV-B, but seed numbers and berry size were unaffected. Elevated UV-B and CO2 stimulated the abundance of V. myrtillus berries, whilst UV-B alone stimulated the berry abundance of V. vitis-idaea and Empetrum hermaphroditum. Enhanced UV-B reduced concentrations of several polyphenolics in V. myrtillus berries, whilst elevated CO2 increased quercetin glycosides in V. myrtillus, and syringetin glycosides and anthocyanins in E. hermaphroditum berries. UV-B × CO2 interactions were found for total anthocyanins, delphinidin-3-hexoside and peonidin-3-pentosidein in V. myrtillus berries but not E. hermaphroditum. Results suggest positive impacts of UV-B on the germination of V. myrtillus and species-specific impacts of UV-B × elevated CO2 on berry abundance and quality. The findings have relevance and implications for human and animal consumers plus seed dispersal and seedling establishment.
Electronic supplementary material
The online version of this article (doi:10.1007/s13280-012-0311-4) contains supplementary material, which is available to authorized users.
CO2; Elevated; UV-B; Enhanced; Arctic; Reproduction; Berry; Abundance; Secondary metabolites
The number of visits to hospital emergency departments (EDs) in England has increased by 20% since 2007-08, placing unsustainable pressure on the National Health Service (NHS). Some patients attend EDs because they are unable to access primary care services. This study examined the association between access to primary care and ED visits in England.
A cross-sectional, population-based analysis of patients registered with 7,856 general practices in England was conducted, for the time period April 2010 to March 2011. The outcome measure was the number of self-referred discharged ED visits by the registered population of a general practice. The predictor variables were measures of patient-reported access to general practice services; these were entered into a negative binomial regression model with variables to control for the characteristics of patient populations, supply of general practitioners and travel times to health services.
Main Result and Conclusion
General practices providing more timely access to primary care had fewer self-referred discharged ED visits per registered patient (for the most accessible quintile of practices, RR = 0.898; P<0.001). Policy makers should consider improving timely access to primary care when developing plans to reduce ED utilisation.
We evaluated whether differences in treatment effectiveness or preference between languages emerged across Spanish and English during functional communication training (FCT) for young children with developmental disabilities exposed to Spanish and English in the home environment. Participants were 2 young children with developmental disabilities who displayed destructive behavior maintained by social contingencies and whose families spoke Spanish and English at home. All procedures were conducted in the participants’ homes by their mothers with coaching from the investigator. The effectiveness of FCT was evaluated within a reversal design across baseline, FCT, and extinction conditions. A multielement design across language type (Spanish and English) was embedded within the reversal design during the extinction and FCT conditions to evaluate differences in treatment effectiveness across type of language. Finally, during all FCT sessions, a concurrent schedules design was used to evaluate participant preference for type of language. Results suggested that FCT was effective in reducing destructive behavior, increasing manding, and/or increasing task completion for these 2 participants across Spanish and English treatment conditions. Preference for the type of language did not emerge for either participant during FCT. Results are discussed in terms of the merits of systematically evaluating language variables when working with culturally and linguistically diverse families and children.
Keywords Functional communication training; Language; Preference; Developmental disabilities; Culturally and linguistically diverse variables
Epithelial integrity in metazoan organs is maintained through the regulated proliferation and differentiation of organ-specific stem and progenitor cells. Although the epithelia of organs such as the intestine regenerate constantly and thus remain continuously proliferative1, other organs, such as the mammalian urinary bladder, shift from near-quiescence to a highly proliferative state in response to epithelial injury2–4. The cellular and molecular mechanisms underlying this injury-induced mode of regenerative response are poorly defined. Here we show in mice that the proliferative response to bacterial infection or chemical injury within the bladder is regulated by signal feedback between basal cells of the urothelium and the stromal cells that underlie them. We demonstrate that these basal cells include stem cells capable of regenerating all cell types within the urothelium, and are marked by expression of the secreted protein signal Sonic hedgehog (Shh). On injury, Shh expression in these basal cells increases and elicits increased stromal expression of Wnt protein signals, which in turn stimulate the proliferation of both urothelial and stromal cells. The heightened activity of this signal feedback circuit and the associated increase in cell proliferation appear to be required for restoration of urothelial function and, in the case of bacterial injury, may help clear and prevent further spread of infection. Our findings provide a conceptual framework for injury-induced epithelial regeneration in endodermal organs, and may provide a basis for understanding the roles of signalling pathways in cancer growth and metastasis.
Human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) incidence is increasing at a near epidemic rate. We investigated whether the mammalian (or mechanistic) target of rapamycin (mTOR) inhibitor, rapamycin, can be used as a concurrent agent to standard-of-care cisplatin/radiation therapy (CRT) to attenuate tumor lactate production, thus enhancing CRT-induced immune-mediated clearance of this antigenic tumor type. A C57Bl/6-derived mouse oropharyngeal epithelial cell line retrovirally transduced with HPV type 16 E6/E7 and human squamous cell carcinoma cell lines were evaluated for their response to rapamycin in vitro with proliferation assays, Western blots, and lactate assays. Clonogenic assays and a preclinical mouse model were used to assess rapamycin as a concurrent agent to CRT. The potential of rapamycin to enhance immune response through lactate attenuation was assessed using quantitative tumor lactate bioluminescence and assessment of cell-mediated immunity using E6/E7-vaccinated mouse splenocytes. Rapamycin alone inhibited mTOR signaling of all cancer cell lines tested in vitro and in vivo. Furthermore, rapamycin administered alone significantly prolonged survival in vivo but did not result in any long-term cures. Given concurrently, CRT/rapamycin significantly enhanced direct cell killing in clonogenic assays and prolonged survival in immunocompromised mice. However, in immunocompetent mice, concurrent CRT/rapamycin increased long-term cures by 21%. Preliminary findings suggest that improved survival involves increased cell killing and enhanced immune-mediated clearance in part due to decreased lactate production. The results may provide rationale for the clinical evaluation of mTOR inhibitors concurrent with standard-of-care CRT for treatment of HPV-positive HNSCC.
Pedunculated lipomas arising from the peritoneal wall are a rare finding during abdominal surgery. These benign tumours of mesenchymal origin can arise anywhere in the body and are usually asymptomatic. We present a case of a torted, pedunculated parietal wall lipoma in the right iliac fossa that gave rise to a clinical diagnosis of appendicitis. To our knowledge, such a case has never been reported in the literature previously. We suggest that torsion of a pedunculated parietal lipoma is a rare differential of acute abdominal pain.
The Salmonella Gallinarum (SG) lon/cpxR deletion mutant JOL916 was developed as a live vaccine candidate for fowl typhoid (FT), and a SG mutant secreting an Escherichia coli heat-labile enterotoxin B subunit (LTB), designated JOL1229, was recently constructed as an adjuvant strain for oral vaccination against FT. In this study, we evaluated the immunogenicity and protective properties of the SG mutant JOL916 and the LTB adjuvant strain JOL1229 in order to establish a prime and boost immunization strategy for each strain. In addition, we compared the increase in body weight, the immunogenicity, the egg production rates, and the bacteriological egg contamination of these strains with those of SG 9R, a widely used commercial vaccine.
Plasma IgG, intestinal secretory IgA (sIgA), and cell-mediated responses were significantly induced after a boost inoculation with a mixture of JOL916 and JOL1229, and significant reductions in the mortality of chickens challenged with a wild-type SG strain were observed in the immunized groups. There were no significant differences in increases in body weight, cell-mediated immune responses, or systemic IgG responses between our vaccine mixture and the SG 9R vaccine groups. However, there was a significant elevation in intestinal sIgA in chickens immunized with our mixture at 3 weeks post-prime-immunization and at 3 weeks post-boost-immunization, while sIgA levels in SG 9R-immunized chickens were not significantly elevated compared to the control. In addition, the SG strain was not detected in the eggs of chickens immunized with our mixture.
Our results suggest that immunization with the LTB-adjuvant strain JOL1229 can significantly increase the immune response, and provide efficient protection against FT with no side effects on body weight, egg production, or egg contamination.
Targeted intervention of the B-Raf V600E gene product that is prominent in melanoma has been met with modest success. Here, we characterize the pharmacological properties of PLX4032, a next-generation inhibitor with exquisite specificity against the V600E oncogene and striking anti-melanoma activity. PLX4032 induces potent cell cycle arrest, inhibits proliferation, and initiates apoptosis exclusively in V600E-positive cells in a variety of in vitro experimental systems; follow-up xenograft studies demonstrate extreme selectivity and efficacy against melanoma tumors bearing the V600E oncoproduct. The collective data support further exploration of PLX4032 as a candidate drug for patients with metastatic melanoma; accordingly, validation of PLX4032 as a therapeutic tool for melanoma patients is now underway in advanced human (Phase III) clinical trials.
Human papillomaviruses (HPVs) are the causative factor for greater than 90% of cervical cancers and 25% of head and neck cancers. The incidence of HPV positive (+) head and neck squamous cell carcinomas (HNSCCs) has greatly increased in the last 30 years. E6 and E7 are the two key viral oncoproteins that induce and propagate cellular transformation. An immune response generated during cisplatin/radiation therapy improves tumor clearance of HPV(+) cancers. Augmenting this induced response during therapy with an adenoviral HPV16 E6/E7 vaccine improves long term survival in preclinical models. Here we describe the generation of an HPV16 E6/E7 construct, which contains mutations that render E6/E7 non-oncogenic, while preserving antigenicity. These mutations do not allow E6/E7 to degrade p53, pRb, PTPN13, or activate telomerase. Non-oncogenic E6/E7 (E6Δ/E7Δ) expressed as a stable integrant, or in the [E1-, E2b-] adenovirus, lacks the ability to transform human cells while retaining the ability to induce an HPV specific immune response. Moreover, E6Δ/E7Δ plus chemotherapy/radiation statistically enhances clearance of established HPV(+) cancer in vivo.
HPV; E6; E7; Adenovirus; immunotherapy; head and neck cancer