Structural signature of sporadic Creutzfeldt-Jakob disease.

BACKGROUND AND PURPOSE: Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly progressive neurodegenerative disease caused by an abnormal isoform of the human prion protein. Structural magnetic resonance imaging in patients with pathologically confirmed sCJD was compared with cognitively normal individuals to identify a cortical thickness signature of sCJD. METHODS: This retrospective cross-sectional study compared patients with autopsy-confirmed sCJD with dementia (n = 11) with age- and sex-matched cognitively normal individuals (n = 22). We identified regions of interest (ROIs) in which cortical thickness was most affected by sCJD. Within patients with sCJD, the relationship between ROI cortical thickness and clinical measures (disease duration, cerebrospinal fluid tau and diffusion-weighted imaging abnormalities) was evaluated. RESULTS: Compared with cognitively normal individuals, patients with sCJD had significantly reduced cortical thickness in multiple ROIs, including the fusiform gyrus, precentral gyrus, precuneus and superior temporal gyrus bilaterally; the caudal middle frontal gyrus, superior frontal gyrus, postcentral gyrus, inferior temporal gyrus and transverse temporal gyrus in the left hemisphere; and the superior parietal lobule in the right hemisphere. Only one patient with sCJD had co-pathology consistent with Alzheimer's disease. Reduced cortical thickness did not correlate with disease duration, presence of diffusion restriction or elevated cerebrospinal fluid tau. CONCLUSION: Cortical signature changes in sCJD may reflect brain changes not captured by standard clinical measures. This information may be used with clinical measures to inform the progression of sCJD and patterns of prion protein spread throughout the brain. These results may have implications for prediction of symptomatic progression and plausibly for development of therapeutic strategies.

Axonal damage and astrocytosis are biological correlates of grey matter network integrity loss: a cohort study in autosomal dominant Alzheimer disease.

Brain development and maturation leads to grey matter networks that can be measured using magnetic resonance imaging. Network integrity is an indicator of information processing capacity which declines in neurodegenerative disorders such as Alzheimer disease (AD). The biological mechanisms causing this loss of network integrity remain unknown. Cerebrospinal fluid (CSF) protein biomarkers are available for studying diverse pathological mechanisms in humans and can provide insight into decline. We investigated the relationships between 10 CSF proteins and network integrity in mutation carriers (N=219) and noncarriers (N=136) of the Dominantly Inherited Alzheimer Network Observational study. Abnormalities in Aß, Tau, synaptic (SNAP-25, neurogranin) and neuronal calcium-sensor protein (VILIP-1) preceded grey matter network disruptions by several years, while inflammation related (YKL-40) and axonal injury (NfL) abnormalities co-occurred and correlated with network integrity. This suggests that axonal loss and inflammation play a role in structural grey matter network changes. Key points: Abnormal levels of fluid markers for neuronal damage and inflammatory processes in CSF are associated with grey matter network disruptions.The strongest association was with NfL, suggesting that axonal loss may contribute to disrupted network organization as observed in AD.Tracking biomarker trajectories over the disease course, changes in CSF biomarkers generally precede changes in brain networks by several years.

Net energy of cellulosic ethanol from switchgrass.

Perennial herbaceous plants such as switchgrass (Panicum virgatum L.) are being evaluated as cellulosic bioenergy crops. Two major concerns have been the net energy efficiency and economic feasibility of switchgrass and similar crops. All previous energy analyses have been based on data from research plots (<5 m2) and estimated inputs. We managed switchgrass as a biomass energy crop in field trials of 3-9 ha (1 ha = 10,000 m2) on marginal cropland on 10 farms across a wide precipitation and temperature gradient in the midcontinental U.S. to determine net energy and economic costs based on known farm inputs and harvested yields. In this report, we summarize the agricultural energy input costs, biomass yield, estimated ethanol output, greenhouse gas emissions, and net energy results. Annual biomass yields of established fields averaged 5.2-11.1 Mg x ha(-1) with a resulting average estimated net energy yield (NEY) of 60 GJ x ha(-1) x y(-1). Switchgrass produced 540% more renewable than nonrenewable energy consumed. Switchgrass monocultures managed for high yield produced 93% more biomass yield and an equivalent estimated NEY than previous estimates from human-made prairies that received low agricultural inputs. Estimated average greenhouse gas (GHG) emissions from cellulosic ethanol derived from switchgrass were 94% lower than estimated GHG from gasoline. This is a baseline study that represents the genetic material and agronomic technology available for switchgrass production in 2000 and 2001, when the fields were planted. Improved genetics and agronomics may further enhance energy sustainability and biofuel yield of switchgrass.

Antimicrobial stewardship programs in emergency departments: how do we measure antimicrobial use? A systematic review.

OBJECTIVE: The implementation of antimicrobial stewardship programs (ASPs) has become a usual practice in hospital settings. However, the method for monitoring antimicrobial use in accident and emergency departments (ED) is not yet adequately defined. Thus, the objective of this review is to describe antimicrobial use indicators used by ASPs implemented in ED. METHODS: A systematic review was performed based on studies found in the following academic research databases: MEDLINE, EMBASE, Web of Science, and Scopus (Period: January 2000 to December 2019). Controlled clinical trials, before-and-after studies, interrupted time series, and repeated measures studies assessing the impact of ASPs on antimicrobial use in ED were included; studies published in languages other than English or Spanish were excluded from this review. RESULTS: Twenty-six studies met the inclusion criteria and were included in this systematic review. In total, 15 (62.5%) studies described the ASP team members who collaborated with the ED staff. Most (21; 80.8%) studies used the percentage of patients with an antibiotic prescription as an indicator. Four (15.4%) studies included defined daily dose data. The antibiotic treatment duration was reported in four (15.4%) studies. Only two studies assessed the impact of the ASP using microbiological indicators, both of which used the incidence of infection with Clostridioides difficile as the indicator. CONCLUSIONS: The reports of experiences in implementing ASPs in ED show heterogeneous antimicrobial use indicators, which makes it difficult to compare results. Therefore, antimicrobial use indicators for ASPs must be standardised between hospital units.

The use of PET images for radiotherapy treatment planning: an error analysis using radiobiological endpoints.

PURPOSE: There is significant current interest in the use of biological image guidance in radiotherapy planning. In lung-cancer treatment, tumor motion due to respiration is known to be a limitation. This is particularly true in PET, where image data are collected over a number of minutes. An in-house-developed 4D PET acquisition mode is described and an analysis of the effects of acquisition parameters on the reconstructed image quality is presented. The potential impact of the resulting biological image quality on radiotherapy planning is then quantified in terms of tumor control probability (TCP). METHODS: Data were acquired using a human torso phantom comprised of a hot '8F-filled spheroidal "tumor" (40 mm in diameter) suspended in an air-filled "lung" cylinder and surrounded by a warm 18F-filled background. Two different sphere-to-background (S/B) ratios were used. The tumor was connected to a 3-axis computer-controlled motion stage and could be moved during PET data acquisition. Images were acquired with a range of count statistics, motion blurring, and CT attenuation correction (CTAC) misalignment. Four simple models were proposed for the assignment of clonogenic cell density according to the voxel value. The impact of image artifacts was then assessed by calculating the TCP, which is the probability that no clonogenic tumor cell remains after a given dose of radiation. TCP was calculated for a uniform dose distribution in the tumor. RESULTS: Reduced count statistics and misaligned CTAC images had the most detrimental impact on the image fidelity. It was found that in both cases the images became less intense, demonstrated by smaller number of voxels at the maximum values. The maximum TCP difference between images with the least and most noise was 3.4% (S/B=3), and with weakest and strongest CT misalignment artifacts, it was 3.2% (S/B = 10). Motion blurring only contributed weakly to the TCP imprecision at 1.7% (S/B=10) between best- and worst-case images. However, the model-calculated TCP showed increasing differences from the ground truth as the complexity of the model increased [maximum difference of approximately 8% (model 3)], which could be attributed to the partial volume effect. CONCLUSIONS: Based on the results of this study, it is believed that simple techniques of biologically guided radiotherapy planning for lung cancer should be feasible at intermediate contrast levels (tumor-to-background ratio of approximately 10) with the clinically achievable image quality.

COQ6 mutation in patients with nephrotic syndrome, sensorineural deafness, and optic atrophy.

INTRODUCTION: Primary coenzyme Q10 (CoQ10) deficiencies are a group of mitochondrial disorders that has proven responsiveness to replacement therapy. Mutations in enzymes involved in the biosynthesis of CoQ10 genes are associated with these deficits. The clinical presentation of this rare autosomal recessive disorder is heterogeneous and depends on the gene involved. Mutations in the COQ2, COQ6, PDSS2, and ADCK4 genes are responsible for steroid-resistant nephrotic syndrome (SRNS), which is associated with extra-renal symptoms. Previous studies have reported COQ6 mutations in 11 patients from five different families presenting with SRNS and sensorineural deafness. CASE REPORTS: Our study reports the cases of two brothers of Turkish origin with renal failure and sensorineural deafness associated with COQ6 mutations responsible of CoQ10 deficiency. Optical symptoms were present in the eldest, that improved with Idebenone. CONCLUSION/DISCUSSION: For the first time, COQ6 mutation with optical involvement is associated with renal and hearing impairment. Although the response to replacement CoQ10 therapy was difficult to evaluate, we think that this treatment was able to stop the disease progression in both patients, and even to prevent the occurrence/development of optical and neurological impairment in the younger brother. Mitochondrial dysfunction secondary to CoQ10 deficiency should always be suspected in patients with SRNS and extra-renal symptoms. Early recognition of this genetic SRNS is mandatory since SRNS can be avoided by adequate treatment based on CoQ10 supplement or an analogue. All cases of primary CoQ10 deficiency should be treated at an early stage to limit the progression of lesions and prevent the emergence of new symptoms.

Electroencephalographic and behavioral alterations produced by delta-1-tetrahydrocannabinol.

The administration of small doses of Delta(l)-tetrahydrocannabinol to cats with indwelling electrodes produced a disruption of both the electroencephalogram and behavior. Some of these alterations, including the appearance of a high-voltage slow wave electroencephalogram in the awake and moving animal, have been observed in cats that had been administered other drugs known to cause hallucinogenic states in man.

Xyloglucan fucosyltransferase, an enzyme involved in plant cell wall biosynthesis.

Cell walls are crucial for development, signal transduction, and disease resistance in plants. Cell walls are made of cellulose, hemicelluloses, and pectins. Xyloglucan (XG), the principal load-bearing hemicellulose of dicotyledonous plants, has a terminal fucosyl residue. A 60-kilodalton fucosyltransferase (FTase) that adds this residue was purified from pea epicotyls. Peptide sequence information from the pea FTase allowed the cloning of a homologous gene, AtFT1, from Arabidopsis. Antibodies raised against recombinant AtFTase immunoprecipitate FTase enzyme activity from solubilized Arabidopsis membrane proteins, and AtFT1 expressed in mammalian COS cells results in the presence of XG FTase activity in these cells.

Multicentre experience with a simple blood salvage technique in patients with ruptured ectopic pregnancy in sub-Sahelian West Africa.

BACKGROUND AND OBJECTIVE: Haemorrhage from ruptured ectopic pregnancy is a major cause of maternal death in Africa. The experience in three hospitals in salvaging intraperitoneal blood with a perforated metallic conical funnel is reported. METHOD: The blood was transfused back to the patient immediately after salvaging. Data were collected concerning the patient, her clinical state and haemoglobin levels throughout her stay in hospital, the diagnosis, the transfusion, and the complications encountered. RESULTS: Two hundred and twelve patients were reported prospectively. The preoperative haemoglobin level was 70.6 +/- 18.7 g/l (n = 132). After transfusion of 681 +/- 389 ml (n = 212) of salvaged blood, haemoglobin levels reached 84.7 +/- 10.5 g/l (n = 23) 6 days postoperatively. Twenty-two patients, half of whom had a life-threatening haemodynamic state, were also given donor blood. Twenty patients still had severe anaemia on leaving hospital (blood haemoglobin < 70 g/l). No untoward outcomes attributable to the reinfusion were seen. CONCLUSION: The surgical treatment of ruptured ectopic pregnancy with intraperitoneal haemorrhage was rendered safe and efficient with this new salvaging equipment.

The efficacy of a medication review programme conducted in an emergency department.

Background Older age and inappropriate prescribing is related to a greater rate of emergency department visits and hospitalisations. Objective To assess the efficacy of an interprofessional collaboration programme in which a review of the medication of older patients seen in the emergency observation unit was carried out. Setting Emergency departments at four Spanish hospitals. Method Randomised, controlled study. Patients over 65 years of age presenting to the emergency department were randomised to a control or an intervention group. In the intervention group, a pharmacist reviewed the patients' chronic medication and identified any potentially inappropriate prescriptions based on the STOPP/START criteria. Each case was discussed with the emergency specialist and a recommendation to modify the treatment was sent to the general practitioner. Main outcome measure Rate of emergency visits and hospital admissions. Results The adjusted rate ratio of emergency visits and hospital admissions was 0.808 (95% CI 0.617 to 1.059) at 3 months, 0.888 (95% CI 0.696 to 1.134) at 6 months and 0.954 (95% CI 0.772 to 1.179) at 12 months. There was a statistically significant reduction at 3 months in two of the hospitals that participated in the study [adjusted rate ratio at 3 months was 0.452 (95% CI 0.222 to 0.923) in hospital 3 and 0.567 (95% CI 0.328 to 0.983) in hospital 4]. Conclusion Overall, the intervention did not reduce the number of emergency visits and hospital admissions. However, a significant effect was observed in centres were a high acceptance rate of treatment recommendations was achieved.

VEGF 165 b, an antiangiogenic VEGF-A isoform, binds and inhibits bevacizumab treatment in experimental colorectal carcinoma: balance of pro- and antiangiogenic VEGF-A isoforms has implications for therapy.

Bevacizumab, an anti-vascular endothelial growth factor (VEGF-A) antibody, is used in metastatic colorectal carcinoma (CRC) treatment, but responses are unpredictable. Vascular endothelial growth factor is alternatively spliced to form proangiogenic VEGF(165) and antiangiogenic VEGF(165)b. Using isoform-specific enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, we found that over 90% of the VEGF in normal colonic tissue was VEGF(xxx)b, but there was a variable upregulation of VEGF(xxx) and downregulation of VEGF(xxx)b in paired human CRC samples. Furthermore, cultured colonic adenoma cells expressed predominantly VEGF(xxx)b, whereas colonic carcinoma cells expressed predominantly VEGF(xxx). However, adenoma cells exposed to hypoxia switched their expression from predominantly VEGF(xxx)b to predominantly VEGF(xxx). VEGF(165)b overexpression in LS174t colon cancer cells inhibited colon carcinoma growth in mouse xenograft models. Western blotting and surface plasmon resonance showed that VEGF(165)b bound to bevacizumab with similar affinity as VEGF(165). However, although bevacizumab effectively inhibited the rapid growth of colon carcinomas expressing VEGF(165), it did not affect the slower growth of tumours from colonic carcinoma cells expressing VEGF(165)b. Both bevacizumab and anti-VEGF(165)b-specific antibodies were cytotoxic to colonic epithelial cells, but less so to colonic carcinoma cells. These results show that the balance of antiangiogenic to proangiogenic isoforms switches to a variable extent in CRC, regulates tumour growth rates and affects the sensitivity of tumours to bevacizumab by competitive binding. Together with the identification of an autocrine cytoprotective role for VEGF(165)b in colonic epithelial cells, these results indicate that bevacizumab treatment of human CRC may depend upon this balance of VEGF isoforms.

Cellulose: how many cellulose synthases to make a plant?

Many questions remain about the biosynthesis of cellulose, the major plant cell wall component, not least of which is why plants have so many genes for the cellulose synthase catalytic subunit. Perhaps multiple isoforms of cellulose synthase are needed in the same cell for the formation of functional dimeric complexes.

Augmentation of lung liquid clearance via adenovirus-mediated transfer of a Na,K-ATPase beta1 subunit gene.

Previous studies have suggested that alveolar Na,K-ATPases play an important role in active Na+ transport and lung edema clearance. We reasoned that overexpression of Na,K-ATPase subunit genes could increase Na,K-ATPase function in lung epithelial cells and edema clearance in rat lungs. To test this hypothesis we produced replication deficient human type 5 adenoviruses containing cDNAs for the rat alpha1 and beta1 Na,K-ATPase subunits (adMRCMValpha1 and adMRCMVbeta1, respectively). As compared to controls, adMRCMVbeta1 increased beta1 subunit expression and Na,K-ATPase function by 2. 5-fold in alveolar type 2 epithelial cells and rat airway epithelial cell monolayers. No change in Na,K-ATPase function was noted after infection with adMRCMValpha1. Rat lungs infected with adMRCMVbeta1, but not adMRCMValpha1, had increased beta1 protein levels and lung liquid clearance 7 d after tracheal instillation. Alveolar epithelial permeability to Na+ and mannitol was mildly increased in animals infected with adMRCMVbeta1 and a similar Escherichia coli lacZ-expressing virus. Our data shows, for the first time, that transfer of the beta1 Na,K-ATPase subunit gene augments Na,K-ATPase function in epithelial cells and liquid clearance in rat lungs. Conceivably, overexpression of Na,K-ATPases could be used as a strategy to augment lung liquid clearance in patients with pulmonary edema.

Neuropathology for the neuroradiologist: Antoni A and Antoni B tissue patterns.

Histologic patterns of cellular architecture often suggest a tissue diagnosis. Distinctive histologic patterns seen within the peripheral nerve sheath tumor schwannoma include the Antoni A and Antoni B regions. The purpose of this report is to review the significance of Antoni regions in the context of schwannomas.

Pre- and Post-Transfusion Alloimmunization in Dogs Characterized by 2 Antiglobulin-Enhanced Cross-match Tests.

BACKGROUND: When dogs are transfused, blood compatibility testing varies widely but may include dog erythrocyte antigen (DEA) 1 typing and rarely cross-matching. OBJECTIVES: Prospective study to examine naturally occurring alloantibodies against red blood cells (RBCs) and alloimmunization by transfusion using 2 antiglobulin-enhanced cross-match tests. ANIMALS: Eighty client-owned anemic, 72 donor, and 7 control dogs. METHODS: All dogs were typed for DEA 1 and some also for DEA 4 and DEA 7. Major cross-match tests with canine antiglobulin-enhanced immunochromatographic strip and gel columns were performed 26-129 days post-transfusion (median, 39 days); some dogs had an additional early evaluation 11-22 days post-transfusion (median, 16 days). Plasma from alloimmunized recipients was cross-matched against RBCs from 34 donor and control dogs. RESULTS: The 2 cross-match methods gave entirely concordant results. All 126 pretransfusion cross-match results for the 80 anemic recipients were compatible, but 54 dogs died or were lost to follow up. Among the 26 recipients with follow-up, 1 dog accidently received DEA 1-mismatched blood and became cross-match-incompatible post-transfusion. Eleven of the 25 DEA 1-matched recipients (44%) became incompatible against other RBC antigens. No naturally occurring anti-DEA 7 alloantibodies were detected in DEA 7- dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: The antiglobulin-enhanced immunochromatographic strip cross-match and laboratory gel column techniques identified no naturally occurring alloantibodies against RBC antigens, but a high degree of post-transfusion alloimmunization in dogs. Cross-matching is warranted in any dog that has been previously transfused independent of initial DEA 1 typing and cross-matching results before the first transfusion event.

An anthropomorphic breathing phantom of the thorax for testing new motion mitigation techniques for pencil beam scanning proton therapy.

Motion-induced range changes and incorrectly placed dose spots strongly affect the quality of pencil-beam-scanned (PBS) proton therapy, especially in thoracic tumour sites, where density changes are large. Thus motion-mitigation techniques are necessary, which must be validated in a realistic patient-like geometry. We report on the development and characterisation of a dynamic, anthropomorphic, thorax phantom that can realistically mimic thoracic motions and anatomical features for verifications of proton and photon 4D treatments. The presented phantom is of an average thorax size, and consists of inflatable, deformable lungs surrounded by a skeleton and skin. A mobile 'tumour' is embedded in the lungs in which dosimetry devices (such as radiochromic films) can be inserted. Motion of the tumour and deformation of the thorax is controlled via a custom made pump system driving air into and out of the lungs. Comprehensive commissioning tests have been performed to evaluate the mechanical performance of the phantom, its visibility on CT and MR imaging and its feasibility for dosimetric validation of 4D proton treatments. The phantom performed well on both regular and irregular pre-programmed breathing curves, reaching peak-to-peak amplitudes in the tumour of <20 mm. Some hysteresis in the inflation versus deflation phases was seen. All materials were clearly visualised in CT scans, and all, except the bone and lung components, were MRI visible. Radiochromic film measurements in the phantom showed that imaging for repositioning was required (as for a patient treatment). Dosimetry was feasible with Gamma Index agreements (4%/4 mm) between film dose and planned dose >90% in the central planes of the target. The results of this study demonstrate that this anthropomorphic thorax phantom is suitable for imaging and dosimetric studies in a thoracic geometry closely-matched to lung cancer patients under realistic motion conditions.

Ex Vivo Assessment of an Ultrasound-Guided Injection Technique of the Navicular Bursa in the Horse.

Synovitis of the navicular bursa is common in performance horses. The objective of this study was to describe an ultrasound-guided technique to inject a distended navicular bursa and to evaluate its feasibility for use by a clinician not trained in the technique. Twenty distal limbs of horses of various breeds and sizes were used. To produce synovial distension, the navicular bursa of each limb was injected with contrast medium using a lateral approach and radiography was performed to confirm that the contrast medium was distending the bursa. The digit was positioned with the distal interphalangeal joint in hyperextension. A microconvex ultrasound probe was placed in the hollow of the pastern, palmar to the middle phalanx and the region was assessed in a transverse plane slightly oblique to the horizontal plane. The ultrasound probe was rotated to visualize both the lateral and medial recesses and to select which side was more distended to inject. A 21G 0.8 × 50 mm needle was inserted abaxially to the probe in the plane of the ultrasound beam into the proximal recess of this navicular bursa and a methylene blue solution was injected. Following injection, dissection was performed to assess whether the navicular bursa had been successfully injected. This ultrasound-guided technique was reliably performed with a success rate of 68%. The success of injection is influenced by hyperextension of the foot, quality of ultrasound images and degree of distension of the bursa.

Herniated lumbar disc disease in patients with malignancy.

Six patients with cancer presented with signs and symptoms of a lumbar herniated disc syndrome due to a herniated lumbar disc. The differential diagnosis and literature are reviewed. In four of the six, the patients' complaints were attributed to the malignancy, with delay in diagnosis and institution of appropriate therapy. In two of the patients, treatment was administered for presumed spinal metastasis with radiation therapy and/or chemotherapy with castration before the correct diagnosis was made. Surgery was performed on all six patients confirming the diagnosis of a herniated lumbar disc at the involved level and relieving the patients' pain.

Intramedullary spinal cord metastases from small cell carcinoma of the lung.

Four patients with intramedullary spinal cord metastases from small cell carcinoma of the lung (SCCL) are described, with emphasis on clinical presentation and treatment. All patients developed the Brown-Séquard syndrome due to intramedullary tumor in the cervical spinal cord, three within 2 mo after combined modality treatment using chemotherapy and radiotherapy. One patient presented with a Brown-Séquard syndrome and an extradural spinal cord compression from tumor. The radiological and cerebrospinal fluid findings are presented and discussed. Radiation treatment was administered to the involved segments of spinal cord in each patient. All patients responded; two for 3 and 7 mo, two for 3 and 4 wk, respectively. There was significant improvement in the quality of life for three of the four patients.