Enhanced immunity in a mouse model of malignant glioma is mediated by a therapeutic ketogenic diet.

BACKGROUND: Glioblastoma multiforme is a highly aggressive brain tumor with a poor prognosis, and advances in treatment have led to only marginal increases in overall survival. We and others have shown previously that the therapeutic ketogenic diet (KD) prolongs survival in mouse models of glioma, explained by both direct tumor growth inhibition and suppression of pro-inflammatory microenvironment conditions. The aim of this study is to assess the effects of the KD on the glioma reactive immune response. METHODS: The GL261-Luc2 intracranial mouse model of glioma was used to investigate the effects of the KD on the tumor-specific immune response. Tumor-infiltrating CD8+ T cells, CD4+ T cells and natural killer (NK) cells were analyzed by flow cytometry. The expression of immune inhibitory receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) on CD8+ T cells were also analyzed by flow cytometry. Analysis of intracellular cytokine production was used to determine production of IFN, IL-2 and IFN- in tumor-infiltrating CD8+ T and natural killer (NK) cells and IL-10 production by T regulatory cells. RESULTS: We demonstrate that mice fed the KD had increased tumor-reactive innate and adaptive immune responses, including increased cytokine production and cytolysis via tumor-reactive CD8+ T cells. Additionally, we saw that mice maintained on the KD had increased CD4 infiltration, while T regulatory cell numbers stayed consistent. Lastly, mice fed the KD had a significant reduction in immune inhibitory receptor expression as well as decreased inhibitory ligand expression on glioma cells. CONCLUSIONS: The KD may work in part as an immune adjuvant, boosting tumor-reactive immune responses in the microenvironment by alleviating immune suppression. This evidence suggests that the KD increases tumor-reactive immune responses, and may have implications in combinational treatment approaches.

Flexible software platform for fast-scan cyclic voltammetry data acquisition and analysis.

Over the last several decades, fast-scan cyclic voltammetry (FSCV) has proved to be a valuable analytical tool for the real-time measurement of neurotransmitter dynamics in vitro and in vivo. Indeed, FSCV has found application in a wide variety of disciplines including electrochemistry, neurobiology, and behavioral psychology. The maturation of FSCV as an in vivo technique led users to pose increasingly complex questions that require a more sophisticated experimental design. To accommodate recent and future advances in FSCV application, our lab has developed High Definition Cyclic Voltammetry (HDCV). HDCV is an electrochemical software suite that includes data acquisition and analysis programs. The data collection program delivers greater experimental flexibility and better user feedback through live displays. It supports experiments involving multiple electrodes with customized waveforms. It is compatible with transistor-transistor logic-based systems that are used for monitoring animal behavior, and it enables simultaneous recording of electrochemical and electrophysiological data. HDCV analysis streamlines data processing with superior filtering options, seamlessly manages behavioral events, and integrates chemometric processing. Furthermore, analysis is capable of handling single files collected over extended periods of time, allowing the user to consider biological events on both subsecond and multiminute time scales. Here we describe and demonstrate the utility of HDCV for in vivo experiments.

Spatial and temporal variation in suspended sediment, organic matter, and turbidity in a Minnesota prairie river: implications for TMDLs.

The Minnesota River Basin (MRB), situated in the prairie pothole region of the Upper Midwest, contributes excessive sediment and nutrient loads to the Upper Mississippi River. Over 330 stream channels in the MRB are listed as impaired by the Minnesota Pollution Control Agency, with turbidity levels exceeding water quality standards in much of the basin. Addressing turbidity impairment requires an understanding of pollutant sources that drive turbidity, which was the focus of this study. Suspended volatile solids (SVS), total suspended solids (TSS), and turbidity were measured over two sampling seasons at ten monitoring stations in Elm Creek, a turbidity impaired tributary in the MRB. Turbidity levels exceeded the Minnesota standard of 25 nephelometric units in 73% of Elm Creek samples. Turbidity and TSS were correlated (r (2) = 0.76), yet they varied with discharge and season. High levels of turbidity occurred during periods of high stream flow (May-June) because of excessive suspended inorganic sediment from watershed runoff, stream bank, and channel contributions. Both turbidity and TSS increased exponentially downstream with increasing stream power, bank height, and bluff erosion. However, organic matter discharged from wetlands and eutrophic lakes elevated SVS levels and stream turbidity in late summer when flows were low. SVS concentrations reached maxima at lake outlets (50 mg/l) in August. Relying on turbidity measurements alone fails to identify the cause of water quality impairment whether from suspended inorganic sediment or organic matter. Therefore, developing mitigation measures requires monitoring of both TSS and SVS from upstream to downstream reaches.

MCA-to-MCA Bypass with Interposition Graft for Ruptured Mycotic Middle Cerebral Artery Aneurysm.

Mycotic aneurysm, also referred to as infected aneurysm, is a rare entity that may result from the bacterial infection or infective endocarditis.1-3 The treatment options include conservative medication and endovascular or direct microsurgical intervention.1,4,5 However, the optimal strategy remains unknown and cerebral revascularization may be required in some rare cases.6 In this surgical video, we demonstrate a distal middle cerebral artery (MCA) mycotic aneurysm that we treated by intracranial-intracranial bypass with an interpositional graft. Our patient is a 53-year-old male who presented with a 6-day history of severe headache. He was subsequently admitted to our institution. Preoperative computed tomography angiography showed a left temporal hematoma (>30 mL) and an opercular segment of the MCA (M3) aneurysm, which was highly suspicious for mycotic origin. A standard frontotemporal craniotomy was carried out with preservation of superficial temporal artery (STA). Following the sylvian fissure dissection, the aneurysm was exposed with the characteristics of a thick wall and an undefinable neck, which made direct clip application difficult. The aneurysm was resected initially, and 2 cut ends were reconnected by an STA graft. Following arterial reconstruction, intraoperative Doppler revealed a patent status of the interpositional graft vessel. Postoperatively, no neurologic deficit was observed and computed tomography angiography demonstrated total elimination of the aneurysm without stenosis of the graft vessel. Low-molecular dextran was prescribed rather than aspirin, as there was concern for hemorrhage. Antibiotic treatment was used for at least 4 weeks, and the patient was transferred to the inpatient cardiology team for management of endocarditis. A 4-month follow-up angiogram showed a patent STA and excellent left distal MCA blood flow (Video 1). The favorable outcome of this case revealed that MCA-to-MCA bypass with interpositional graft is a safe, effective method for the unclippable cerebral aneurysm. As other authors have asserted, a full dose of long-term antibiotic therapy remains essential following intervention.7 Meanwhile, dextran has proved to be a viable alternative for anticoagulation during perioperative management of bypass surgery.8,9.

Intraoperative Finding of an Anterior Communicating Artery Blister-Like Aneurysm During a Primary Craniopharyngioma Resection: Accidental or Incidental?

BACKGROUND: The presence of an anterior communicating artery blister-like aneurysm in the setting of a craniopharyngioma has never been reported to our knowledge. CASE DESCRIPTION: This patient was admitted to our service for an untreated craniopharyngioma resection. An anterior interhemispheric approach with right frontal craniotomy was performed and a blister-like aneurysm of the anterior communicating artery was found during the surgery. After the tumor was completely resected, a suturing technique was used for the aneurysm. In this article, we are going to present this rare case and discuss the potential pathogeny of the aneurysm. CONCLUSIONS: We hypothesized that cystic craniopharyngioma may rupture spontaneously. The cystic fluid accumulated in the lower subarachnoid space due to gravity, and it may lead to local vascular cytotoxic and inflammatory reactions which may result in the vascular wall remodeling and lead to the reconstructed vascular wall weakness.

Vertical Lasso and Horizontal Lasso Sutures for Repair of Horizontal Cleavage and Horizontal Oblique Meniscal Tears: Surgical Technique and Indications.

Horizontal cleavage and horizontal oblique meniscal tears have traditionally been treated with partial meniscectomy. Recent research has shown the deleterious long-term effects of meniscectomy in these patients regarding the development of osteoarthritis. Meniscal preservation is thus the preferred method of surgical treatment in patients with these tears. However, traditional repair techniques using inside-out sutures or suture anchor-based devices do not address the horizontally aligned nature of these particular tears and thus do not compress the meniscal tissue in the correct plane. The recent development of an arthroscopic suture-passing system now allows surgeons to place arthroscopic sutures in any pattern or direction. This allows surgeons to treat tears of any type with sutures ideally placed to repair the given tears. This Technical Note describes and demonstrates 2 all-suture, all-inside, arthroscopic meniscus repair techniques to treat these challenging horizontal tear types. The repair techniques are named the vertical lasso and horizontal lasso.

Tissue Expanders and Proton Beam Radiotherapy: What You Need to Know.

Proton beam radiotherapy (PBR) has gained acceptance for the treatment of breast cancer because of unique beam characteristics that allow superior dose distributions with optimal dose to the target and limited collateral damage to adjacent normal tissue, especially to the heart and lungs. To determine the compatibility of breast tissue expanders (TEs) with PBR, we evaluated the structural and dosimetric properties of 2 ex vivo models: 1 model with internal struts and another model without an internal structure. Although the struts appeared to have minimal impact, we found that the metal TE port alters PBR dynamics, which may increase proton beam range uncertainty. Therefore, submuscular TE placement may be preferable to subcutaneous TE placement to reduce the interaction of the TE and proton beam. This will reduce range uncertainty and allow for more ideal radiation dose distribution.

Incidence, etiology, and impact of diarrhea among deployed US military personnel in support of Operation Iraqi Freedom and Operation Enduring Freedom.

A health assessment survey was collected from US military personnel deployed to the Middle East taking part in the "Rest and Recuperation" program or on temporary assignment to Camp As Sayliyah Doha, Qatar, from January to December 2004. In addition, a concurrent clinic-based observational study was conducted to determine pathogen etiology and potential risk factors. From 28,322 health assessment surveys, overall self-reported incidence of diarrhea was 4.9 cases per 100 person-months. Disease incidence increased with rank and was higher in Iraq compared with Afghanistan. During this period, 109 US military personnel with acute diarrhea and 85 asymptomatic personnel were enrolled in the observational study. Enterotoxigenic E. coli (ETEC) was the predominant pathogen (32%), followed by enteroaggregative E. coli (12%) and Salmonella spp. (6%). These data are consistent with previous reports implicating ETEC as the primary cause of acute diarrhea for military personnel deployed to this region.

Efficacy and safety of firocoxib in the management of canine osteoarthritis under field conditions.

A total of 249 client-owned dogs with osteoarthritis were treated with firocoxib (5 mg/kg/day) or a positive control, etodolac (10-15 mg/kg/day), for 30 days. Veterinary examinations were performed on approximately days 0 (visit 1), 14 (visit 2), and 29 (visit 3). Based on defined noninferiority criteria, firocoxib and etodolac were comparable. Based on the magnitude of the change from baseline, improvement with firocoxib was significantly greater than with etodolac for lameness at a trot (visits 2 and 3) and for lameness at a walk, pain on manipulation, and range of motion (visit 3) (P < .05). In weekly owner evaluations, firocoxib provided significantly greater improvement than etodolac (P < .05) at each scoring.

Gardnerella vaginalis triggers NLRP3 inflammasome recruitment in THP-1 monocytes.

Gardnerella vaginalis is a Gram-positive bacterium associated with bacterial vaginosis (BV), pelvic inflammatory disease, and preterm birth. BV is the most prevalent vaginal dysbiosis in women of childbearing age characterized by the absence of normal lactobacilli and an overgrowth of G. vaginalis and other bacteria. Although mucosal fluids from BV patients exhibit increases in proinflammatory cytokines and Toll-like receptor 2 and 4 mRNA, G. vaginalis has not been demonstrated to directly induce an inflammatory response. This study tested the hypothesis that G. vaginalis induces an inflammatory response in the human monocyte cell line, THP-1. The objectives of the study were to measure proinflammatory cytokine production, molecular mechanisms by which cytokines are produced, and whether G. vaginalis results in death of the monocytic cells. We found that G. vaginalis induced significant increases in the inflammasome-dependent cytokines IL-1ß, IL-18, as well as TNF-α in treated cells. G. vaginalis caused significant cell death by 24h post-treatment compared with untreated controls, but cells remained 66% viable. Caspase-1 cleavage in treated cells confirmed the inflammatory cell death, and NLRP3 knockdown confirmed its involvement through reduction of IL-1ß secretion. Using a stably expressing YFP-ASC THP-1 cell model with immunofluorescent staining, YFP-ASC colocalized with NLRP3 in G. vaginalis-treated cells and the addition of a caspase-1 inhibitor wholly ameliorated IL-1ß secretion. Our study provides new insight into the role of G. vaginalis in inflammatory conditions in the genital tract.

Biomechanical stability of four fixation constructs for distal radius fractures.

Implants available for distal radius fracture fixation include dorsal nonlocked plating (DNLP), volar locked plating (VLP), radial-ulnar dual-column locked plating (DCPs), and locked intramedullary fixation (IMN). This study examines the biomechanical properties of these four different fixation constructs. In 28 fresh-frozen radii, a wedge osteotomy was performed, creating an unstable fracture model and the four fixation constructs employed (DNLP, VLP, DCPs, and IMN). Dorsal bending loads were applied and bending stiffness, load to yield 5 mm displacement, and ultimate failure were measured. Bending stiffness for VLP (16.7 N/mm) was significantly higher than for DNLP (6.8 N/mm), while IMN (12.6 N/mm) and DCPs (11.8 N/mm) were similar. Ultimate load to failure occurred at 278.2 N for the VLP, 245.7 N for the IMN, and 52.0 N for the DNLP. The VLP was significantly stronger than the DNLP and DCPs, and the IMN and DCPs were stronger than the DNLP. The VLP has higher average bending stiffness, ultimate bending strength, and resistance to 5 mm displacement than the other constructs and significantly higher ultimate bending strength than the DCPs and DNLP. There was no statistically significant difference between the VLP and IMN. VLP and IMN fixation of distal radius fractures can achieve comparable stability.

Grazed riparian management and stream channel response in southeastern Minnesota (USA) streams.

The U.S. Department of Agriculture-Natural Resources Conservation Service has recommended domestic cattle grazing exclusion from riparian corridors for decades. This recommendation was based on a belief that domestic cattle grazing would typically destroy stream bank vegetation and in-channel habitat. Continuous grazing (CG) has caused adverse environmental damage, but along cohesive-sediment stream banks of disturbed catchments in southeastern Minnesota, short-duration grazing (SDG), a rotational grazing system, may offer a better riparian management practice than CG. Over 30 physical and biological metrics were gathered at 26 sites to evaluate differences between SDG, CG, and nongrazed sites (NG). Ordinations produced with nonmetric multidimensional scaling (NMS) indicated a gradient with a benthic macroinvertebrate index of biotic integrity (IBI) and riparian site management; low IBI scores associated with CG sites and higher IBI scores associated with NG sites. Nongrazed sites were associated with reduced soil compaction and higher bank stability, as measured by the Pfankuch stability index; whereas CG sites were associated with increased soil compaction and lower bank stability, SDG sites were intermediate. Bedrock geology influenced NMS results: sites with carbonate derived cobble were associated with more stable channels and higher IBI scores. Though current riparian grazing practices in southeastern Minnesota present pollution problems, short duration grazing could reduce sediment pollution if managed in an environmentally sustainable fashion that considers stream channel response.

Internal fixation of distal radius fractures with novel intramedullary implants.

UNLABELLED: Fracture of the distal radius is a common injury and treatment varies depending on the fracture, patient factors, and surgeon preference. Internal fixation has grown in popularity because it affords increased stability and early motion of the extremity. The desire to provide stable fracture support while minimizing soft tissue dissection and complications has led to the development of new intramedullary implants. These implants use distal screw divergence for subchondral support, fixed-angle screws locked to the implant, and minimally invasive technique to allow early patient rehabilitation. Early results of these intramedullary devices are promising but require longer followup. LEVEL OF EVIDENCE: Level IV (expert opinion).

Impacts of land use conversion on bankfull discharge and mass wasting.

Mass wasting and channel incision are widespread in the Nemadji River watershed of eastern Minnesota and northwestern Wisconsin. While much of this is a natural response to glacial rebound, sediment coring and tree ring data suggest that land use has also influenced these erosional processes. We characterized land use, inventoried mass wasting, surveyed stream channels and collected discharge data along segments of five streams in the Nemadji River watershed. Due to natural relief in this region, wetlands and agricultural lands are concentrated in the flatter terrain of the uplands of the Nemadji watershed, while forestland (coniferous or deciduous) is concentrated in the deeply incised (50-200% slope) stream valleys. Bankfull discharge was higher where forests had been converted from coniferous to deciduous forests and where there were fewer wetlands. Mass wasting increased exponentially with bankfull flows. While mass wasting was not correlated with forest type conversion and agricultural land use, it was negatively dependent upon wetland extent in headwater areas. Interactions between the spatial distribution of land use and terrain obfuscate any clear cause-and-effect relationships between land use, hydrology and fluvial processes.