Ultrahigh nanostructured drug payloads from degradable mesoporous silicon aerocrystals.

Porous silicon has found increased attention as a drug delivery system due to its unique features such as high drug payloads, surface area and biodegradation. In this study supercritical fluid (SCF) assisted drying of ultrahigh porosity (>90%) silicon particles and flakes was shown to result in much higher mesopore volumes (~4.66 cm3/g) and surface areas (~680 m2/g) than with air-drying. The loading and physical state of the model drug (S)-(+)-Ibuprofen in SCF dried matrices was quantified and assessed using thermogravimetric analysis, differential scanning calorimetry, UV-Vis spectrophotometry, gravimetric analysis, gas adsorption and electron microscopy. Internal drug payloads of up to 72% were achieved which was substantially higher than values published for both conventionally dried porous silicon (17-51%) and other mesoporous materials (7-45%). In-vitro degradability kinetics of SCF-dried matrices in simulated media was also found to be faster than air-dried controls. The in-vitro release studies provided improved but sustained drug dissolution at both pH 2.0 and pH 7.4.

Electroencephalographic (EEG) features of encephalopathy in the setting of Covid-19: A case series.

OBJECTIVE: The Covid-19 pandemic is a global challenge presenting clinicians with an evolving diagnostic landscape. We sought to describe EEG findings observed from local experience in a typical case series of patients with severe Covid-19. METHODS: Ten cases of Covid-19 were identified in whom EEG recordings had been made during the course of admissions to Bristol hospitals which had required intensive care. Electro-clinical correlation between the EEG and available medical history, imaging and laboratory investigation results was explored. RESULTS: The predominant EEG features in severe Covid-19 are of generalised symmetrical slowing, consistent with encephalopathy. CONCLUSIONS: The presence of focal disturbances or irritative abnormalities may be a pointer away from a pure encephalopathy and warrant further investigation. SIGNIFICANCE: A growing range of neurological sequelae from Covid-19 are now recognised to be common amongst patients hospitalised by with this condition, being seen to affect approximately one third of such cases. Electroencephalography has a unique place in the diagnostic work-up of impaired consciousness, a frequent feature of severe Covid-19. However, there is currently a paucity of literature describing typical EEG findings in this setting.

Mortality from Listeria monocytogenes meningoencephalitis following escalation to alemtuzumab therapy for relapsing-remitting Multiple Sclerosis.

We report the case of a patient who died from the rare complication of Listeriosis in the immediate phase following alemtuzumab administration one month after discontinuing dimethyl fumarate (DMF). There is considerable overlap with typical post-infusion symptoms therefore high surveillance and low threshold for empirical or possible prophylactic antibiotic therapy is advocated.

Protocol for a randomized, double blind, placebo controlled, crossover trial of Melatonin for treatment of Nocturia in adults with Multiple Sclerosis (MeNiMS).

BACKGROUND: Nocturia (the symptom of needing to wake up to pass urine) is common in progressive Multiple Sclerosis (MS) patients. Moderate-to-severe nocturia affects quality of life, can exacerbate fatigue and may affect capacity to carry out daily activities. Melatonin is a natural hormone regulating circadian cycles, released by the pineal gland at night-time, and secretion is impaired in MS. Melatonin levels can be supplemented by administration in tablet form at bedtime. The aim of this study is to evaluate the effect of melatonin on mean number of nocturia episodes per night in MS patients. Secondary outcome measures will assess impact upon quality of life, urinated volumes, lower urinary tract symptoms (LUTS), cognition, sleep quality and sleep disturbance of partners. METHODS: A randomized, double blind, placebo controlled, crossover trial consisting of two, six week treatment phases (active drug melatonin 2 mg or placebo), with a 1 month wash-out period in between. The primary outcome (change in nocturia episodes per night) in this two arm, two treatment, two period crossover design, will be objectively measured using frequency volume charts (FVC) at baseline and following both treatment phases. Questionnaires will be used to assess quality of life, sleep quality, safety and urinary tract symptoms. Qualitative interviews of participants and partners will explore issues including quality of life, mechanisms of sleep disturbance and impact of nocturia on partners. DISCUSSION: This study will evaluate whether melatonin reduces the frequency of nocturia episodes in MS patients, and therefore whether 'Circadin' has the potential to reduce LUTS and fatigue, and improve cognition and overall quality of life. TRIAL REGISTRATION: (EudraCT reference) 2012-00418321 registered: 25/01/13. ISRCTN Registry: ISRCTN38687869.

Enhancement of Peroxidase Stability Against Oxidative Self-Inactivation by Co-immobilization with a Redox-Active Protein in Mesoporous Silicon and Silica Microparticles.

The study of the stability enhancement of a peroxidase immobilized onto mesoporous silicon/silica microparticles is presented. Peroxidases tend to get inactivated in the presence of hydrogen peroxide, their essential co-substrate, following an auto-inactivation mechanism. In order to minimize this inactivation, a second protein was co-immobilized to act as an electron acceptor and thus increase the stability against self-oxidation of peroxidase. Two heme proteins were immobilized into the microparticles: a fungal commercial peroxidase and cytochrome c from equine heart. Two types of biocatalysts were prepared: one with only covalently immobilized peroxidase (one-protein system) and another based on covalent co-immobilization of peroxidase and cytochrome c (two-protein system), both immobilized by using carbodiimide chemistry. The amount of immobilized protein was estimated spectrophotometrically, and the characterization of the biocatalyst support matrix was performed using Brunauer-Emmett-Teller (BET), scanning electron microscopy with energy-dispersive X-ray spectroscopy (SEM-EDX), and Fourier transform infrared (FTIR) analyses. Stability studies show that co-immobilization with the two-protein system enhances the oxidative stability of peroxidase almost four times with respect to the one-protein system. Thermal stability analysis shows that the immobilization of peroxidase in derivatized porous silicon microparticles does not protect the protein from thermal denaturation, whereas biogenic silica microparticles confer significant thermal stabilization.

Multimodal neurophysiological evaluation of primary progressive multiple sclerosis - An increasingly valid biomarker, with limits.

BACKGROUND: The promising utility of multi-modality evoked potential batteries to objectively measure multi-tract dysfunction has been evaluated by several groups using different methods. OBJECTIVE: To independently evaluate the use of multi-modality evoked potential batteries as surrogate biomarkers for both physical and cognitive status in a cohort of Primary Progressive Multiple Sclerosis patients and identify the most potentially useful scoring method of those described. METHODS: 28 Patients with Primary Progressive Multiple Sclerosis underwent clinical evaluation with Kurtzke's Modified EDSS and the Multiple Sclerosis Functional Composite (MSFC). 19 Participants also underwent the Minimal Assessment of Cognitive Function in Multiple Sclerosis. Visual, Brainstem Auditory, Somatosensory and Motor Evoked Potentials were recorded on all. Results were graded by variants of the Global Evoked Potential Score, Multiple Evoked Potential Score and Summation of Z transformed Evoked Potential Latencies for correlation against the clinical scores. CONCLUSIONS: Multi-modal evoked potential batteries generally show moderate and useful correlation with clinical status as measured by the regulatory standard of EDSS (r = .65 vs. mEPS p < .005) and MSFC (r = .39 vs. mEPS p < .05). The graded qualitative mEPS scoring system displayed the strongest relationship although the influence of scoring system applied appeared reassuringly minimal. Non-association with cognitive impairment is an important limitation however.

Silicon: the evolution of its use in biomaterials.

In the 1970s, several studies revealed the requirement for silicon in bone development, while bioactive silicate glasses simultaneously pioneered the current era of bioactive materials. Considerable research has subsequently focused on the chemistry and biological function of silicon in bone, demonstrating that the element has at least two separate effects in the extracellular matrix: (i) interacting with glycosaminoglycans and proteoglycans during their synthesis, and (ii) forming ionic substitutions in the crystal lattice structure of hydroxyapatite. In addition, the dissolution products of bioactive glass (predominantly silicic acids) have significant effects on the molecular biology of osteoblasts in vitro, regulating the expression of several genes including key osteoblastic markers, cell cycle regulators and extracellular matrix proteins. Researchers have sought to capitalize on these effects and have generated a diverse array of biomaterials, which include bioactive glasses, silicon-substituted hydroxyapatites and pure, porosified silicon, but all these materials share similarities in the mechanisms that result in their bioactivity. This review discusses the current data obtained from original research in biochemistry and biomaterials science supporting the role of silicon in bone, comparing both the biological function of the element and analysing the evolution of silicon-containing biomaterials.

Porous silicon confers bioactivity to polycaprolactone composites in vitro.

Silicon is an essential element for healthy bone development and supplementation with its bioavailable form (silicic acid) leads to enhancement of osteogenesis both in vivo and in vitro. Porous silicon (pSi) is a novel material with emerging applications in opto-electronics and drug delivery which dissolves to yield silicic acid as the sole degradation product, allowing the specific importance of soluble silicates for biomaterials to be investigated in isolation without the elution of other ionic species. Using polycaprolactone as a bioresorbable carrier for porous silicon microparticles, we found that composites containing pSi yielded more than twice the amount of bioavailable silicic acid than composites containing the same mass of 45S5 Bioglass. When incubated in a simulated body fluid, the addition of pSi to polycaprolactone significantly increased the deposition of calcium phosphate. Interestingly, the apatites formed had a Ca:P ratio directly proportional to the silicic acid concentration, indicating that silicon-substituted hydroxyapatites were being spontaneously formed as a first order reaction. Primary human osteoblasts cultured on the surface of the composite exhibited peak alkaline phosphatase activity at day 14, with a proportional relationship between pSi content and both osteoblast proliferation and collagen production over 4 weeks. Culturing the composite with J744A.1 murine macrophages demonstrated that porous silicon does not elicit an immune response and may even inhibit it. Porous silicon may therefore be an important next generation biomaterial with unique properties for applications in orthopaedic tissue engineering.

Morphological changes (including filamentation) in Escherichia coli grown under starvation conditions on silicon wafers and other surfaces.

Using a scanning electron microscope, pleomorphism (notably filamentation) was seen when Escherichia coli was grown under starvation conditions for 14 d on microporous silicon wafers, titanium, glass and plastic discs. Under these conditions, the 'standard', rod shaped cell (1-3 microns) failed to separate after division and filaments developed, some as long as 50 microns, with many showing bulbous tips. Filamentation began to occur 5 d after the imposition of starvation conditions. Dumbbell shaped cells were also observed, although apparent 'Y' and 'V'-shaped cells proved to be artefacts, caused by overlapping rods. The implications of the appearance of pleomorphism in E. coli, when grown under starvation conditions, is discussed in relation to its pathogenicity and growth in the environment.

Redundancy phenomena are affected by response requirements.

Results are reported for two go/no-go reaction time (RT) experiments, in which the redundant targets advantage was investigated. These experiments were replications of two earlier choice reaction time (CRT) experiments, in which letter stimuli were used. Important differences between the go/no-go RT experiments and the CRT experiments were obtained. Equal and significant redundancy advantages were obtained whether redundant targets were compared with a single target presented with a noise letter or without noise. In the CRT experiments, the advantage was not obtained in the comparison with a single target presented alone. Noise letters did not slow the RTs to single targets with which they were presented as was the case with CRT. Since the differing results of the two procedures depend on the response requirements, explanation of differing CRT data in terms of perceptual or attentional concepts is probably inappropriate. The presence and absence of response competition in the two situations may be the best interpretation. The results tend to support a conclusion of the parallel processing of two letter stimuli separated spatially by as much as 3 degrees.