A Preliminary Study of the Role of Gastrointestinal Endocrine Cells in the Maintenance of Villous Structure Following X-Irradiation

The mechanism of gastrointestinal villous damage following ionizing irradiation is complex. Various compartments within the gastrointestinal tract have in turn been considered important for the maintenance of normal villous structure. To date, however, evidence for a single overriding regulator of epithelial well-being is lacking. In this study, the role of the gastrointestinal (enteroendocrine) cells is explored and comparison made between endocrine cell number and villous structure. Experiments were organised using hath control and irradiated groups of mice. Two time points (1 and 3 days) and three radiation doses (6, 10 and 18Gy) were employed. A simple method for endocrine cell identification and subsequent quantification is described. Endocrine cell number was then compared with villous surface detail, as seen with a scanning electron microscope (SEM). Results indicated a decrease in the endocrine cell number at all three radiation doses. Whereas at low doses endocrine cell recovery occurred between 1 and 3 days, at medium and high doses further decline was noticed. A similar pattern was seen when considering villous surface structure. It is suggested that both scanning electron microscopy and endocrine cell number provide a more sensitive indicator of gastrointestinal radiation damage than do current crypt counting techniques. In addition, a link between endocrine cell number and villous structure is proposed

Structural Changes in Mouse Small Intestinal Villi Following Lower Body Hyperthermia

Heating an exteriorised loop of mouse small intestine resulted in marked changes in the shape of the villi as reported earlier. However, the exteriorisation techniques resulted in non-uniformity in both temperature and effect around circumference of intestine and, in addition, the extent to which handling contributed to the observed damage was not known. The work has therefore been extended using lower-body heating in the temperature range 37.5° - 43.0°C. Heating in the temperature range 37.5° to 41.0°C produced minimal to moderate structural changes, manifested as scattered, vertically collapsed villi amongst predominantly normal villi. No villi showed conical or rudimentary forms of collapse. Such villi were, however, seen after heating at 41.5°C and were greatly increased in number after heating at 42.0°C. The most severe damage was observed after heating at 43.0°C. Although the lower body heating method gave information which was less complicated by technical considerations, the hyperthermic damage observed was qualitatively similar to that previously seen following local administration of hyperthermia to an exteriorised loop of intestine. Direct quantitative comparisons between the two methods of heating are difficult because of differences in equilibration time and temperature. However, using a comparable heating time, less damage was scored following the exteriorisation technique compared with in situ heating

Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial

BACKGROUND: CDKL5 deficiency disorder (CDD) is a rare, X-linked, developmental and epileptic encephalopathy characterised by severe global developmental impairment and seizures that can begin in the first few months after birth and are often treatment refractory. Ganaxolone, an investigational neuroactive steroid, reduced seizure frequency in an open-label, phase 2 trial that included patients with CDD. We aimed to further assess the efficacy and safety of ganaxolone in patients with CDD-associated refractory epilepsy. METHODS: In the double-blind phase of this randomised, placebo-controlled, phase 3 trial, done at 39 outpatient clinics in eight countries (Australia, France, Israel, Italy, Poland, Russia, the UK, and the USA), patients were eligible if they were aged 2-21 years with a pathogenic or probably pathogenic CDKL5 variant and at least 16 major motor seizures (defined as bilateral tonic, generalised tonic-clonic, bilateral clonic, atonic, or focal to bilateral tonic-clonic) per 28 days in each 4-week period of an 8-week historical period. After a 6-week prospective baseline period, patients were randomly assigned (1:1) via an interactive web response system to receive either enteral adjunctive ganaxolone or matching enteral adjunctive placebo (maximum dose 63 mg/kg per day for patients weighing ≤28 kg or 1800 mg/day for patients weighing >28 kg) for 17 weeks. Patients, caregivers, investigators (including those analysing data), trial staff, and the sponsor (other than the investigational product manager) were masked to treatment allocation. The primary efficacy endpoint was percentage change in median 28-day major motor seizure frequency from the baseline period to the 17-week double-blind phase and was analysed (using a Wilcoxon-rank sum test) in all patients who received at least one dose of trial treatment and for whom baseline data were available. Safety (compared descriptively across groups) was analysed in all patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov, NCT03572933, and the open-label extension phase is ongoing. FINDINGS: Between June 25, 2018, and July 2, 2020, 114 patients were screened for eligibility, of whom 101 (median age 6 years [IQR 3 to 10]) were randomly assigned to receive either ganaxolone (n=50) or placebo (n=51). All patients received at least one dose of a study drug, but seizure frequency for one patient in the ganaxolone group was not recorded at baseline and so the primary endpoint was analysed in a population of 100 patients. There was a median percentage change in 28-day major motor seizure frequency of -30·7% (IQR -49·5 to -1·9) in the ganaxolone group and of -6·9% (-24·1 to 39·7) in the placebo group (p=0·0036). The Hodges-Lehmann estimate of median difference in responses to ganaxolone versus placebo was -27·1% (95% CI -47·9 to - 9·6). Treatment-emergent adverse events occurred in 43 (86%) of 50 patients in the ganaxolone group and in 45 (88%) of 51 patients in the placebo group. Somnolence, pyrexia, and upper respiratory tract infections occurred in at least 10% of patients in the ganaxolone group and more frequently than in the placebo group. Serious adverse events occurred in six (12%) patients in the ganaxolone group and in five (10%) patients in the placebo group. Two (4%) patients in the ganaxolone group and four (8%) patients in the placebo group discontinued the trial. There were no deaths in the double-blind phase. INTERPRETATION: Ganaxolone significantly reduced the frequency of CDD-associated seizures compared with placebo and was generally well tolerated. Results from what is, to our knowledge, the first controlled trial in CDD suggest a potential treatment benefit for ganaxolone. Long-term treatment is being assessed in the ongoing open-label extension phase of this trial. FUNDING: Marinus Pharmaceuticals

Isokinetic muscle function comparison of lower limbs among elderly fallers and non-fallers

O objetivo deste estudo foi identificar se há diferenças entre o desempenho muscular de tornozelo, joelho e quadril em idosos com e sem relato de queda nos últimos seis meses. Foram incluídos 81 idosos com 65 anos ou mais: 56 negaram quedas (G1) e 25 relataram quedas (G2). Utilizou-se o questionário perfil de atividade humana para medir o nível de atividade física, e o dinamômetro isocinético para mensurar os parâmetros físicos da função muscular. Os grupos não diferiram entre si em relação à idade (p=0,925), duração (p=0,065) e frequência (p=0,302) da prática do exercício físico, índice de massa corpórea (p=0,995) e nível de atividade física (p=0,561). O G2 apresentou menor desempenho para as variáveis pico de torque de flexão e extensão de joelho esquerdo (p=0,027 e p=0,030, respectivamente) e trabalho por peso corporal (p=0,040) de flexão de joelho esquerdo a 60°/s; pico de torque e trabalho por peso corporal de flexão e extensão de joelho a 180°/s bilateralmente (p<0,050); e potência média de flexão de joelhos direito e esquerdo (p=0,030). A maioria das variáveis do tornozelo e quadril não apresentou diferenças entre os grupos. Apenas a variável pico de torque de extensão de quadril esquerdo foi significativamente maior no G1 (p=0,035). É importante considerar a função muscular do joelho na avaliação clínica de idosos para direcionar a intervenção terapêutica e a prevenção de quedas.The aim of this study was to identify whether there are differences between the performance of muscular groups of ankle, knee and hip among elderly people who didn't have falls and individuals who reported falls in the last six months. The study included 81 elderly aged 65 or older: 56 non-faller subjects (G1) and 25 faaller subjects (G2). To obtain the level of physical activity, the questionnaire Human Activity Profile was used, and the muscle function of the lower limbs was assessed using isokinetic dynamometer. The groups did not differ regarding age (p=0.925), duration (p=0.065) and frequency (p=0.302) of the practice of physical exercise, body mass index (BMI) (p=0.995) and level of physical activity (p=0.561). The G2 showed a lower performance of peak torque of left knee flexion and extension (p=0.027 and p=0.030, respectively) and work proportional to body weight (p=0.040) of left knee flexion at 60°/s; peak torque and work proportional to body weight of bilaterally knee flexion and extension at 180°/s (p<0.05) and average power of right and left knee extension (p=0.03). Most variables of ankle and hip joints did not differ between groups. Only peak torque of left hip extension was significantly higher in the non-faller group (p=0.035). It is important to consider knee muscle function in the clinical evaluation of elderly in order to make the intervention more assertive and thus to prevent falls

Cerebral venous thrombosis after vaccination against COVID-19 in the UK: a multicentre cohort study.

BACKGROUND: A new syndrome of vaccine-induced immune thrombotic thrombocytopenia (VITT) has emerged as a rare side-effect of vaccination against COVID-19. Cerebral venous thrombosis is the most common manifestation of this syndrome but, to our knowledge, has not previously been described in detail. We aimed to document the features of post-vaccination cerebral venous thrombosis with and without VITT and to assess whether VITT is associated with poorer outcomes. METHODS: For this multicentre cohort study, clinicians were asked to submit all cases in which COVID-19 vaccination preceded the onset of cerebral venous thrombosis, regardless of the type of vaccine, interval between vaccine and onset of cerebral venous thrombosis symptoms, or blood test results. We collected clinical characteristics, laboratory results (including the results of tests for anti-platelet factor 4 antibodies where available), and radiological features at hospital admission of patients with cerebral venous thrombosis after vaccination against COVID-19, with no exclusion criteria. We defined cerebral venous thrombosis cases as VITT-associated if the lowest platelet count recorded during admission was below 150 × 109 per L and, if the D-dimer was measured, the highest value recorded was greater than 2000 μg/L. We compared the VITT and non-VITT groups for the proportion of patients who had died or were dependent on others to help them with their activities of daily living (modified Rankin score 3-6) at the end of hospital admission (the primary outcome of the study). The VITT group were also compared with a large cohort of patients with cerebral venous thrombosis described in the International Study on Cerebral Vein and Dural Sinus Thrombosis. FINDINGS: Between April 1 and May 20, 2021, we received data on 99 patients from collaborators in 43 hospitals across the UK. Four patients were excluded because they did not have definitive evidence of cerebral venous thrombosis on imaging. Of the remaining 95 patients, 70 had VITT and 25 did not. The median age of the VITT group (47 years, IQR 32-55) was lower than in the non-VITT group (57 years; 41-62; p=0·0045). Patients with VITT-associated cerebral venous thrombosis had more intracranial veins thrombosed (median three, IQR 2-4) than non-VITT patients (two, 2-3; p=0·041) and more frequently had extracranial thrombosis (31 [44%] of 70 patients) compared with non-VITT patients (one [4%] of 25 patients; p=0·0003). The primary outcome of death or dependency occurred more frequently in patients with VITT-associated cerebral venous thrombosis (33 [47%] of 70 patients) compared with the non-VITT control group (four [16%] of 25 patients; p=0·0061). This adverse outcome was less frequent in patients with VITT who received non-heparin anticoagulants (18 [36%] of 50 patients) compared with those who did not (15 [75%] of 20 patients; p=0·0031), and in those who received intravenous immunoglobulin (22 [40%] of 55 patients) compared with those who did not (11 [73%] of 15 patients; p=0·022). INTERPRETATION: Cerebral venous thrombosis is more severe in the context of VITT. Non-heparin anticoagulants and immunoglobulin treatment might improve outcomes of VITT-associated cerebral venous thrombosis. Since existing criteria excluded some patients with otherwise typical VITT-associated cerebral venous thrombosis, we propose new diagnostic criteria that are more appropriate. FUNDING: None

Mind your step: the effects of mobile phone use on gaze behavior in stair climbing

Stair walking is a hazardous activity and a common cause of fatal and non-fatal falls. Previous studies have assessed the role of eye movements in stair walking by asking people to repeatedly go up and down stairs in quiet and controlled conditions, while the role of peripheral vision was examined by giving participants specific fixation instructions or working memory tasks. We here extend this research to stair walking in a natural environment with other people present on the stairs and a now common secondary task: Using one's mobile phone. Results show that using the mobile phone strongly draws one's attention away from the stairs, but that the distribution of gaze locations away from the phone is little influenced by using one's phone. Phone use also increased the time needed to walk the stairs, but handrail use remained low. These results indicate that limited foveal vision suffices for adequate stair walking in normal environments, but that mobile phone use has a strong influence on attention, which may pose problems when unexpected obstacles are encountered

Keep looking ahead? Re-direction of visual fixation does not always occur during an unpredictable obstacle avoidance task

Visual information about the environment, especially fixation of key objects such as obstacles, is critical for safe locomotion. However, in unpredictable situations where an obstacle suddenly appears it is not known whether central vision of the obstacle and/or landing area is required or if peripheral vision is sufficient. We examined whether there is a re-direction of visual fixation from an object fixated ahead to a suddenly appearing obstacle during treadmill walking. Furthermore, we investigated the temporal relationship between the onset of muscle activity to avoid the obstacle and saccadic eye and head movements to shift fixation. Eight females (mean SD; age = 24.8 2.3 years) participated in this experiment. There were two visual conditions: a central vision condition where participants fixated on two obstacles attached to a bridge on the treadmill and a peripheral vision condition where participants fixated an object two steps ahead. There were two obstacle release conditions: only an obstacle in front of the left foot was released or an obstacle in front of either foot could be released. Only trials when the obstacle was released in front of the left foot were analyzed such that the difference in the two obstacle conditions was whether there was a choice of which foot to step over the obstacle. Obstacles were released randomly in one of three phases during the step cycle corresponding to available response times between 219 and 462 ms. We monitored eye and head movements along with muscle activity and spatial foot parameters. Performance on the task was not different between vision conditions. The results indicated that saccades are rarely made (< 18% of trials) and, when present, are initiated ∼ 350 ms after muscle activity for limb elevation, often accompanied by a downward head movement, and always directed to the landing area. Therefore, peripheral vision of a suddenly appearing obstacle in the travel path is sufficient for successful obstacle avoidance during locomotion: visual fixation is generally not re-directed to either the obstacle or landing area

When Is Visual Information Used to Control Locomotion When Descending a Kerb?

YesBackground: Descending kerbs during locomotion involves the regulation of appropriate foot placement before the kerb-edge and foot clearance over it. It also involves the modulation of gait output to ensure the body-mass is safely and smoothly lowered to the new level. Previous research has shown that vision is used in such adaptive gait tasks for feedforward planning, with vision from the lower visual field (lvf) used for online updating. The present study determined when lvf information is used to control/update locomotion when stepping from a kerb. Methodology/Principal Findings: 12 young adults stepped down a kerb during ongoing gait. Force sensitive resistors (attached to participants' feet) interfaced with an high-speed PDLC 'smart glass' sheet, allowed the lvf to be unpredictably occluded at either heel-contact of the penultimate or final step before the kerb-edge up to contact with the lower level. Analysis focussed on determining changes in foot placement distance before the kerb-edge, clearance over it, and in kinematic measures of the step down. Lvf occlusion from the instant of final step contact had no significant effect on any dependant variable (p>0.09). Occlusion of the lvf from the instant of penultimate step contact had a significant effect on foot clearance and on several kinematic measures, with findings consistent with participants becoming uncertain regarding relative horizontal location of the kerb-edge. Conclusion/Significance: These findings suggest concurrent feedback of the lower limb, kerb-edge, and/or floor area immediately in front/below the kerb is not used when stepping from a kerb during ongoing gait. Instead heel-clearance and pre-landing-kinematic parameters are determined/planned using lvf information acquired in the penultimate step during the approach to the kerb-edge, with information related to foot placement before the kerb-edge being the most salient

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy