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ObjectivesClinical trials of intracerebral cell replacement therapy (CRT) yield inconsistent results owing to poor graft survival and ectopic graft placement. A paucity of available CE marked specialised delivery systems and a lack of reliable delivery protocols could be major contributing factors to both phenomena. Here, we aimed to investigate current needle delivery strategies in-vitro and in a large animal model in pigs.Design In-vitro laboratory and in-vivo pigs experiments.SubjectsIn-vitroAgarose gel In-vivo: 4 white Landracer pigs.MethodsIn-vitro: Human Embryonic Kidney cells expressing luciferase and 0.6% agarose gel were used to test 3 delivery strategies:Bracelet deposit,Large deposit in a pre–formed tract,Multiple deposits in a pre–formed tract.In-vivo: Pigs underwent MRI- guided Human Foetal Luciferase-transduced cell transplantation into the putamen and thalamus. Post-operative MRI, Bioluminescence imaging (BLI) and histology were used to identify graft location and viability.ResultsUsing a commercially available needle delivery system, significant reflux of deposits was noted in all 3 delivery strategies during in-vitro testing. Depositing into a preformed tract yielded the best delivery, and was therefore used for in-vivo testing. Studies in pigs using MRI and BLI confirmed significant reflux and ectopic deposition of grafts.ConclusionsSimple needle delivery systems appear to suffer from significant reflux and ectopic cell deposition. This may adversely affect the outcomes of CRT trials in humans.

Diagnosis of internal external ventricular drain (EVD)-related infections (iERI) is an area of diagnostic difficulty. Empiric treatment is often initiated on clinical suspicion. There is limited guidance around antimicrobial management of confirmed versus suspected iERI.BackgroundDiagnosis of internal external ventricular drain (EVD)-related infections (iERI) is an area of diagnostic difficulty. Empiric treatment is often initiated on clinical suspicion. There is limited guidance around antimicrobial management of confirmed versus suspected iERI.Data on patients requiring EVD insertion were collected from 21 neurosurgical units in the United Kingdom from 2014 to 2015. Confirmed iERI was defined as clinical suspicion of infection with positive cerebrospinal fluid (CSF) culture and/or Gram stain. Cerebrospinal fluid, blood, and clinical parameters and antimicrobial management were compared between the 2 groups. Mortality and Modified Rankin Scores were compared at 30 days post-EVD insertion.MethodsData on patients requiring EVD insertion were collected from 21 neurosurgical units in the United Kingdom from 2014 to 2015. Confirmed iERI was defined as clinical suspicion of infection with positive cerebrospinal fluid (CSF) culture and/or Gram stain. Cerebrospinal fluid, blood, and clinical parameters and antimicrobial management were compared between the 2 groups. Mortality and Modified Rankin Scores were compared at 30 days post-EVD insertion.Internal EVD-related infection was suspected after 46 of 495 EVD insertions (9.3%), more common after an emergency insertion. Twenty-six of 46 were confirmed iERIs, mostly due to Staphylococci (16 of 26). When confirmed and suspected infections were compared, there were no differences in CSF white cell counts or glucose concentrations, nor peripheral blood white cell counts or C-reactive protein concentrations. The incidence of fever, meningism, and seizures was also similar, although altered consciousness was more common in people with confirmed iERI. Broad-spectrum antimicrobial usage was prevalent in both groups with no difference in median duration of therapy (10 days [interquartile range {IQR}, 7-24.5] for confirmed cases and 9.5 days [IQR, 5.75-14] for suspected, P = 0.3). Despite comparable baseline characteristics, suspected iERI was associated with lower mortality and better neurological outcomes.ResultsInternal EVD-related infection was suspected after 46 of 495 EVD insertions (9.3%), more common after an emergency insertion. Twenty-six of 46 were confirmed iERIs, mostly due to Staphylococci (16 of 26). When confirmed and suspected infections were compared, there were no differences in CSF white cell counts or glucose concentrations, nor peripheral blood white cell counts or C-reactive protein concentrations. The incidence of fever, meningism, and seizures was also similar, although altered consciousness was more common in people with confirmed iERI. Broad-spectrum antimicrobial usage was prevalent in both groups with no difference in median duration of therapy (10 days [interquartile range {IQR}, 7-24.5] for confirmed cases and 9.5 days [IQR, 5.75-14] for suspected, P = 0.3). Despite comparable baseline characteristics, suspected iERI was associated with lower mortality and better neurological outcomes.Suspected iERI could represent sterile inflammation or lower bacterial load leading to false-negative cultures. There is a need for improved microbiology diagnostics and biomarkers of bacterial infection to permit accurate discrimination and improve antimicrobial stewardship.ConclusionsSuspected iERI could represent sterile inflammation or lower bacterial load leading to false-negative cultures. There is a need for improved microbiology diagnostics and biomarkers of bacterial infection to permit accurate discrimination and improve antimicrobial stewardship.

BackgroundChronic subdural hematoma (CSDH) is a common neurological condition; surgical evacuation is the mainstay of treatment for symptomatic patients. No clear evidence exists regarding the impact of timing of surgery on outcomes. We investigated factors influencing time to surgery and its impact on outcomes of interest.MethodsPatients with CSDH who underwent burr-hole craniostomy were included. This is a subset of data from a prospective observational study conducted in the UK. Logistic mixed modelling was performed to examine the factors influencing time to surgery. The impact of time to surgery on discharge modified Rankin Scale (mRS), complications, recurrence, length of stay and survival was investigated with multivariable logistic regression analysis.Results656 patients were included. Time to surgery ranged from 0 to 44 days (median 1, IQR 1–3). Older age, more favorable mRS on admission, high preoperative Glasgow Coma Scale score, use of antiplatelet medications, comorbidities and bilateral hematomas were associated with increased time to surgery. Time to surgery showed a significant positive association with length of stay; it was not associated with outcome, complication rate, reoperation rate, or survival on multivariable analysis. There was a trend for patients with time to surgery of ≥7 days to have lower odds of favorable outcome at discharge (p=0.061).ConclusionsThis study provides evidence that time to surgery does not substantially impact on outcomes following CSDH. However, increasing time to surgery is associated with increasing length of stay. These results should not encourage delaying operations for patients when they are clinically indicated.

The dorsal hippocampal commissure (DHC) is a white matter tract that provides inter-hemispheric connections between temporal lobe brain regions. Despite the importance of these regions for learning and memory, there is scant evidence of a role for the DHC in successful memory performance. We used diffusion-weighted MRI (DW-MRI) and white matter tractography to reconstruct the DHC across both humans (in vivo) and nonhuman primates (ex vivo). Across species, our findings demonstrate close consistency between the known anatomy and tract reconstructions of the DHC. Anterograde tract-tracer techniques also highlighted the parahippocampal origins of DHC fibers in nonhuman primates. Finally, we derived Diffusion Tensor MRI (DT-MRI) metrics from the DHC in a large sample of human subjects to investigate whether inter-individual variation in DHC microstructure is predictive of memory performance. The mean diffusivity of the DHC was correlated with performance in a standardised episodic memory task; an effect that was not reproduced in a comparison commissure tract, the anterior commissure. These findings highlight a role for the DHC in episodic memory, and our tract reconstruction approach has the potential to generate further novel insights into the role of this previously understudied white matter tract in both health and disease.

Light intensity and atmospheric CO2 partial pressure are two environmental signals known to regulate stomatal numbers. It has previously been shown that if a mature Arabidopsis leaf is supplied with either elevated CO2 (750 ppm instead of ambient at 370 ppm) or reduced light levels (50 μmol m−2 s−1 instead of 250 μmol m−2 s−1), the young, developing leaves that are not receiving the treatment grow with a stomatal density as if they were exposed to the treatment. But the signal(s) that it is believed is generated in the mature leaves and transmitted to developing leaves are largely unknown. Photosynthetic rates of treated, mature Arabidopsis leaves increased in elevated CO2 and decreased when shaded, as would be expected. Similarly, the levels of sugars (glucose, fructose, and sucrose) in the treated mature leaves increased in elevated CO2 and decreased with shade treatment. The levels of sugar in developing leaves were also measured and it was found that they mirrored this result even though they were not receiving the shade or elevated CO2 treatment. To investigate the effect of these treatments on global gene expression patterns, transcriptomics analysis was carried out using Affymetrix, 22K, and ATH1 arrays. Total RNA was extracted from the developing leaves after the mature leaves had received either the ambient control treatment, the elevated CO2 treatment, or the shade treatment, or both elevated CO2 and shade treatments for 2, 4, 12, 24, 48, or 96 h. The experiment was replicated four times. Two other experiments were also conducted, one to compare and contrast gene expression in response to plants grown at elevated CO2 and the other to look at the effect of these treatments on the mature leaf. The data were analysed and 915 genes from the untreated, signalled leaves were identified as having expression levels affected by the shade treatment. These genes were then compared with those whose transcript abundance was affected by the shade treatment in the mature treated leaves (1181 genes) and with 220 putative ‘stomatal signalling’ genes previously identified from studies of the yoda mutant. The results of these experiments and how they relate to environmental signalling are discussed, as well as possible mechanisms for systemic signalling.

Women with breast cancer and at least 10 involved ipsilateral axillary lymph nodes were randomly assigned to receive postoperative (adjuvant) chemotherapy either alone or followed by high-dose chemotherapy plus hematopoietic stem-cell rescue. After six years, the outcome was the same in the two groups. The results of this trial support the use of conventional chemotherapy. Women with primary breast cancer and 10 or more involved ipsilateral axillary lymph nodes have a particularly poor prognosis. Only 20 to 30 percent of such patients who receive postoperative (adjuvant) chemotherapy with cyclophosphamide, methotrexate, and fluorouracil are disease-free at five years. 1 – 4 Among those given doxorubicin-containing adjuvant regimens, approximately 50 percent have not had a relapse at five years. 5 In the 1980s and 1990s, high-dose chemotherapy with autologous hematopoietic stem-cell transplantation was reported to be effective adjuvant therapy for patients with a high risk of relapse. Phase 2 trials and registry data suggested a three-year disease-free survival rate of . . .

Cloud-drift winds have been produced from geostationary satellite data in the Western Hemisphere since the early 1970s. During the early years, winds were used as an aid for the short-term forecaster in an era when numerical forecasts were often of questionable quality, especially over oceanic regions. Increased computing resources over the last two decades have led to significant advances in the performance of numerical forecast models. As a result, continental forecasts now stand to gain little from the inspection or assimilation of cloud-drift wind fields. However, the oceanic data void remains, and although numerical forecasts in such areas have improved, they still suffer from a lack of in situ observations. During the same two decades, the quality of geostationary satellite data has improved considerably, and the cloud-drift wind production process has also benefited from increased computing power. As a result, fully automated wind production is now possible, yielding cloud-drift winds whose quality and quantity is sufficient to add useful information to numerical model forecasts in oceanic and coastal regions. This article will detail the automated cloud-drift wind production process, as operated by the National Environmental Satellite Data and Information Service within the National Oceanic and Atmospheric Administration.

Mice lacking in CD8 were generated from homologous recombination in embryonal stem cells at the CD8 locus and bred with the experimental allergic encephalomyelitis (EAE)-susceptible PL/J H-2$^u$ through four backcross generations to investigate the role of CD8$^+$ T cells in this model of multiple sclerosis. The disease onset and susceptibility were similar to those of wild-type mice. However, the mutant mice had a milder acute EAE, reflected by fewer deaths, but more chronic EAE, reflected by a higher frequency of relapse. This suggests that CD8$^+$ T lymphocytes may participate as both effectors and regulators in this animal model.

Since April 1994 a new generation of geostationary sounders has been measuring atmospheric radiances in 18 infrared spectral bands and thus providing the capability for investigating oceanographic and meteorological phenomena that far exceed those available from the previous generation of Geostationary Operational Environmental Satellites(GOES). Menzel and Purdom foreshadowed many of the anticipated improvements from the GOES-8/9 sounders.

We have adapted the new MxA gene-induction bioassay to measure neutralizing antibodies to interferon- beta 1b (IFN- beta 1b, the active ingredient in Betaseron registered ) in sera from patients treated with Betaseron registered . This antibody assay has been validated to quantify neutralizing titers of 1:20 and above, with a precision of plus or minus 0.20 in log sub(10). We have used this MxA gene-induction antibody assay to reinvestigate serum samples from multiple sclerosis (MS) patients treated with Betaseron registered . The titers measured were closely comparable to those obtained in antiviral assays. Data obtained by both methods show that neutralizing antibodies may appear and subsequently disappear over time in the sera of some patients treated with Betaseron registered . Sera from some patients contain binding antibodies to IFN- beta 1b. It was shown that binding antibody titers do not correlate quantitatively or qualitatively with neutralizing antibody titers, and indeed, a number of patients develop high levels of binding antibodies but never form measurable levels of neutralizing antibodies.