Bacteriophage is known to infect motile strains of enteric bacteria by adsorbing randomly along the length of a f lagellar filament and then injecting its DNA into the bacterial cell at the filament base. Here, we provide evidence for a ''nut and bolt'' model for translocation of phage along the filament: the tail fiber of fits the grooves formed by helical rows of f lagellin monomers, and active f lagellar rotation forces the phage to follow the grooves as a nut follows the threads of a bolt.Bacteriophage infects motile strains of the genera Escherichia, Salmonella, and Serratia (1-3). Schade et al. (4) demonstrated translocation of phage along flagellar filaments by electron microscopy: phage heads tended to be full when attached to a filament but empty when attached to its base. When it was realized that flagellar filaments rotate, the suggestion was made that a phage moves along the filament ''like a nut on a bolt'' (5). This observation was consistent with the finding that mutants with straight filaments, while nonmotile, remain fully sensitive to (6). Ravid and Eisenbach (7) found that the number of phage particles adsorbed by cells, i.e., removed from the supernatant fraction, correlated only with the fraction of the population of cells whose flagella rotated incessantly; it did not correlate with the direction of rotation. This finding was not consistent with a nut and bolt model. Yamaguchi et al. (8) found conditions in which unflagellated bacteria are sensitive to -phage: drops of concentrated phage cleared spots on the surfaces of hard agar plates. However, this sensitivity might have resulted simply from the large multiplicity of phage. Attempts to visualize phage translocation by dark-field or differential-interference-contrast microscopy have not been successful: one can see -phage attached to filaments but not their travel in either direction (R.M. Macnab, personal communication; ref. 9). However, these experiments required low flagellar rotation rates. The prevailing view seems to be that phage particles adsorb and desorb, stepping along the filament in a one-dimensional random walk.If flagellar rotation drives translocation in the manner of a nut on a bolt, then a bacterial strain's sensitivity to -phage has three mechanical requirements: flagellar rotation, the correct direction of flagellar rotation, and the correct pattern of grooves on the surface of the flagellar filament. By measuring infectivity directly, we asked whether these mechanical constraints are determinants of sensitivity to -phage.
Our objective was to assess the ability of a smartphone-based electroencephalography (EEG) application, the Smartphone Brain Scanner-2 (SBS2), to detect epileptiform abnormalities compared to standard clinical EEG. The SBS2 system consists of an Android tablet wirelessly connected to a 14-electrode EasyCap headset (cost ~ 300 USD). SBS2 and standard EEG were performed in people with suspected epilepsy in Bhutan (2014–2015), and recordings were interpreted by neurologists. Among 205 participants (54% female, median age 24 years), epileptiform discharges were detected on 14% of SBS2 and 25% of standard EEGs. The SBS2 had 39.2% sensitivity (95% confidence interval (CI) 25.8%, 53.9%) and 94.8% specificity (95% CI 90.0%, 97.7%) for epileptiform discharges with positive and negative predictive values of 0.71 (95% CI 0.51, 0.87) and 0.82 (95% CI 0.76, 0.89) respectively. 31% of focal and 82% of generalized abnormalities were identified on SBS2 recordings. Cohen’s kappa (κ) for the SBS2 EEG and standard EEG for the epileptiform versus non-epileptiform outcome was κ = 0.40 (95% CI 0.25, 0.55). No safety or tolerability concerns were reported. Despite limitations in sensitivity, the SBS2 may become a viable supportive test for the capture of epileptiform abnormalities, and extend EEG access to new, especially resource-limited, populations at a reduced cost.
on behalf of the Study 011-10 Investigators* Objective To report clinical characteristics and medical history data obtained retrospectively for a large cohort of pediatric patients with perinatal and infantile hypophosphatasia. Study design Medical records from academic medical centers known to diagnose and/or treat hypophosphatasia were reviewed. Patients born between 1970 and 2011 with hypophosphatasia and any of the following signs/ symptoms at age <6 months were eligible: vitamin B6-dependent seizures, respiratory compromise, or rachitic chest deformity (NCT01419028). Patient demographics and characteristics, respiratory support requirements, invasive ventilator-free survival, and further complications of hypophosphatasia were followed for up to the first 5 years of life. Results Forty-eight patients represented 12 study sites in 7 countries; 13 patients were alive, and 35 were dead (including 1 stillborn). Chest deformity, respiratory distress, respiratory failure (as conditioned by the eligibility criteria), failure to thrive, and elevated calcium levels were present in >70% of patients between birth and age 5 years. Vitamin B6-dependent seizures and respiratory distress and failure were associated significantly (P < .05) with the risk of early death. Serum alkaline phosphatase activity in all 41 patients tested (mean [SD]: 18.1 [15.4] U/L) was below the mean lower limit of normal of the reference ranges of the various laboratories (88.2 U/L). Among the 45 patients with relevant data, 29 had received respiratory support, of whom 26 had died at the time of data collection. The likelihood of invasive ventilator-free survival for this cohort decreased to 63% at 3 months, 54% at 6 months, 31% at 12 months, and 25% at 5 years. Conclusions Patients with perinatal or infantile hypophosphatasia and vitamin B6-dependent seizures, with or without significant respiratory distress or chest deformities, have high morbidity and mortality in the first 5 years of life.
Purpose: There is uncertainty regarding the appropriate dose of Cannabidiol (CBD) for childhood epilepsy. We present the preliminary data of seven participants from the Cannabidiol in Children with Refractory Epileptic Encephalopathy (CARE-E) study. Methods: The study is an open-label, prospective, dose-escalation trial. Participants received escalating doses of a Cannabis Herbal Extract (CHE) preparation of 1:20 Δ 9 -tetrahydrocannabinol (THC): CBD up to 10–12 mg CBD/kg/day. Seizure frequency was monitored in daily logs, participants underwent regular electroencephalograms, and parents filled out modified Quality of Life in Childhood Epilepsy (QOLCE) and Side Effect rating scale questionnaires. Steady-state trough levels (C ss, Min ) of selected cannabinoids were quantified. Results: All seven participants tolerated the CHE up to 10–12 mg CBD/kg/day and had improvements in seizure frequency and QOLCE scores. C SS, Min plasma levels for CBD, THC, and cannabichromene (CBC) showed dose-independent pharmacokinetics in all but one participant. C SS, Min CBD levels associated with a >50% reduction in seizures and seizure freedom were lower than those reported previously with purified CBD. In most patients, C SS, Min levels of THC remained lower than what would be expected to cause intoxication. Conclusion: The preliminary data suggest an initial CBD target dose of 5–6 mg/kg/day when a 1:20 THC:CBD CHE is used. Possible non-linear pharmacokinetics of CBD and CBC needs investigation. The reduction in seizure frequency seen suggests improved seizure control when a whole plant CHE is used. Plasma THC levels suggest a low risk of THC intoxication when a 1:20 THC:CBD CHE is used in doses up to 12 mg/kg CBD/kg/day.
Hypophosphatasia (HPP) is the metabolic bone disease caused by loss-of-function mutation within the gene that encodes the "tissue nonspecific" isoenzyme of alkaline phosphatase (TNSALP). Perinatal HPP is usually fatal due to respiratory insufficiency, and infantile HPP often has a similar outcome although no formal study into the natural history of these severe forms of HPP has been undertaken. We reviewed our 80-year (1927-
Children with epilepsy in low-income countries often go undiagnosed and untreated. We examine a portable, low-cost smartphone-based EEG technology in a heterogeneous pediatric epilepsy cohort in the West African Republic of Guinea. Methods: : Children with epilepsy were recruited at the Ignace Deen Hospital in Conakry, 2017. Participants underwent sequential EEG recordings with an app-based EEG, the Smartphone Brain Scanner-2 (SBS2) and a standard Xltek EEG. Raw EEG data were transmitted via Bluetooth ™ connection to an Android ™ tablet and uploaded for remote EEG specialist review and reporting via a new, secure web-based reading platform, crowdEEG. The results were compared to same-visit Xltek 10-20 EEG recordings for identification of epileptiform and nonepileptiform abnormalities. Results: : 97 children meeting the International League Against Epilepsy's definition of epilepsy (49 male; mean age 10.3 years, 29 untreated with an antiepileptic drug; 0 with a prior EEG) were enrolled. Epileptiform discharges were detected on 21 (25.3%) SBS2 and 31 (37.3%) standard EEG recordings. The SBS2 had a sensitivity of 51.6% (95%CI 32.4%, 70.8%) and a specificity of 90.4% (95%CI 81.4%, 94.4%) for all types of epileptiform discharges, with positive and negative predictive values of 76.2% and 75.8% respectively. For generalized discharges, the SBS2 had a sensitivity of 43.5% with a specificity of 96.2%. Conclusions: : The SBS2 has a moderate sensitivity and high specificity for the detection of epileptiform abnormalities in children with epilepsy in this low-income setting. Use of the SBS2+crowdEEG platform permits specialist input for patients with previously poor access to clinical neurophysiology expertise.
BackgroundInitial studies suggest pharmaceutical grade cannabidiol (CBD) can reduce the frequency of convulsive seizures and lead to improvements in quality of life in children affected by epileptic encephalopathies. With limited access to pharmaceutical CBD, Cannabis extracts in oil are becoming increasingly available. Physicians show reluctance to recommend Cannabis extracts given the lack of high quality safety data especially regarding the potential for harm caused by other cannabinoids, such as Δ9-tetrahydrocannabinol (Δ9-THC). The primary aims of the study presented in this protocol are (i) To determine whether CBD enriched Cannabis extract is safe and well-tolerated for pediatric patients with refractory epilepsy, (ii) To monitor the effects of CBD-enriched Cannabis extract on the frequency and duration of seizure types and on quality of life.MethodsTwenty-eight children with treatment resistant epileptic encephalopathy ranging in age from 1 to 10 years will be recruited in four Canadian cities into an open-label, dose-escalation phase 1 trial. The primary objectives for the study are (i) To determine if the CBD-enriched Cannabis herbal extract is safe and well-tolerated for pediatric patients with treatment resistant epileptic encephalopathy and (ii) To determine the effect of CBD-enriched Cannabis herbal extract on the frequency and duration of seizures. Secondary objectives include (i) To determine if CBD-enriched Cannabis herbal extracts alter steady-state levels of co-administered anticonvulsant medications. (ii) To assess the relation between dose escalation and quality of life measures, (iii) To determine the relation between dose escalation and steady state trough levels of bioactive cannabinoids. (iv) To determine the relation between dose escalation and incidence of adverse effects.DiscussionThis paper describes the study design of a phase 1 trial of CBD-enriched Cannabis herbal extract in children with treatment-resistant epileptic encephalopathy. This study will provide the first high quality analysis of safety of CBD-enriched Cannabis herbal extract in pediatric patients in relation to dosage and pharmacokinetics of the active cannabinoids.Trial registrationhttp://clinicaltrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2016 Dec 16. Identifier NCT03024827, Cannabidiol in Children with Refractory Epileptic Encephalopathy: CARE-E; 2017 Jan 19 [cited 2017 Oct]; Available from: http://clinicaltrials.gov/ct2/show/NCT03024827
Background and purpose Epilepsy is most common in lower‐income settings where access to electroencephalography (EEG) is generally poor. A low‐cost tablet‐based EEG device may be valuable, but the quality and reproducibility of the EEG output are not established. Methods Tablet‐based EEG was deployed in a heterogeneous epilepsy cohort in the Republic of Guinea (2018–2019), consisting of a tablet wirelessly connected to a 14‐electrode cap. Participants underwent EEG twice (EEG1 and EEG2), separated by a variable time interval. Recordings were scored remotely by experts in clinical neurophysiology as to data quality and clinical utility. Results There were 149 participants (41% female; median age 17.9 years; 66.6% ≤21 years of age; mean seizures per month 5.7 ± SD 15.5). The mean duration of EEG1 was 53 ± 12.3 min and that of EEG2 was 29.6 ± 12.8 min. The mean quality scores of EEG1 and EEG2 were 6.4 [range, 1 (low) to 10 (high); both medians 7.0]. A total of 44 (29.5%) participants had epileptiform discharges (EDs) at EEG1 and 25 (16.8%) had EDs at EEG2. EDs were focal/multifocal (rather than generalized) in 70.1% of EEG1 and 72.5% of EEG2 interpretations. A total of 39 (26.2%) were recommended for neuroimaging after EEG1 and 22 (14.8%) after EEG2. Of participants without EDs at EEG1 (n = 53, 55.8%), seven (13.2%) had EDs at EEG2. Of participants with detectable EDs on EEG1 (n = 23, 24.2%), 12 (52.1%) did not have EDs at EEG2. Conclusions Tablet‐based EEG had a reproducible quality level on repeat testing and was useful for the detection of EDs. The incremental yield of a second EEG in this setting was ~13%. The need for neuroimaging access was evident.
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