Coordinated multivesicular release at a mammalian ribbon synapse

Traditional models of synaptic transmission hold that release sites within an active zone operate independently. Although the release of multiple vesicles (multivesicular release; MVR) from single active zones occurs at some central synapses, MVR is not thought to require coordination among release sites. Ribbon synapses seem to be optimized to release many vesicles over an extended period, but the dynamics of MVR at ribbon synapses is unknown. We examined MVR at a ribbon synapse in a retinal slice preparation using paired recordings from presynaptic rod bipolar and postsynaptic AII amacrine cells. When evoked release was highly desynchronized, discrete postsynaptic events were larger than quantal miniature excitatory postsynaptic currents (mEPSCs) but had the same time course. The amplitude of these multiquantal mEPSCs, which seem to arise from the essentially simultaneous release of multiple vesicles, was reduced by lowering release probability. The release synchrony reflected in these multivesicular events suggests that release within an active zone is coordinated during MVR.     

Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1−CD8+ Tumor-Infiltrating T Cells

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Comparison of Effects of Various Types of NA and 5-HT Agonists on Transmission from Group II Muscle Afferents in the Cat

A number of noradrenaline and serotonin agonists were tested to investigate which of them replicate the depressive actions of monoamines on transmission from group II muscle afferents in the cat spinal cord. The agonists were applied ionophoretically at the two sites at which maximal monosynaptic focal field potentials are evoked from group II afferents-in the intermediate zone and the dorsal horn of the 4th and 5th lumbar segments. Their effects were estimated from changes in the amplitude of the field potentials. The compounds tested fell into three categories according to the site at which they depressed transmission from group II afferents: one category with highly selective actions in the intermediate zone, a second category with similarly selective actions in the dorsal horn, and a third category with non-selective actions. Drugs in the first category included three noradrenaline agonists (tizanidine, B-HT 933 and clonidine), included in the second were five serotonin agonists (8-OH-DPAT, 5-methoxytryptamine, alpha-methyl serotonin, DOI and 2-methyl-serotonin), and in the third two noradrenaline agonists (phenylephrine and isoproterenol) and two serotonin agonists (RU 24969 and 5-carboxamidotryptamine). Field potentials evoked by group I afferents remained unaffected by all but one compound (8-OH-DPAT). Effects of one noradrenaline agonist and one serotonin agonist (tizanidine and 5-methoxytryptamine) were also tested on responses of single extracellularly recorded neurons. Tizanidine depressed responses induced by stimulation of group II afferents in intermediate zone interneurons, but not in dorsal horn neurons, while 5-methoxytryptamine depressed activation of the latter. Tizanidine had no effect on responses evoked by group I afferents, either in intermediate zone interneurons or in the dorsal spino-cerebellar tract neurons of Clarke's column. It is hypothesized that noradrenaline and serotonin released by descending monoaminergic neurons differ in the potency with which they depress transmission from group II afferents to different functional types of neuron. The results suggest that this depression may involve different membrane receptors at different locations, primarily alpha2 adrenoceptors in the intermediate zone/ventral horn and 5-HT1A serotonin receptors in the dorsal horn.     

Problem solving,sense of coherence and instrumental ADL of elderly people with depression and normal control group

The purpose of this study was first, to explore the separate contribution and interaction between verbal and performance based problem solving and sense of coherence; and second, to examine the association of these variables with Instrumental Activities of Daily Living (IADL) function among elderly people with depression living in the commuinity and a normal control group. The participants included elders receiving ambulatory care for depression (n=31; mean age=73, SD=9.3); and normal elders (n=30; mean age=78, SD=5.8). Screening for general cognitive ability and level of depression was done using the Mini Mental Status Examination (MMSE) and the Geriatric Depression Scale (GDS). All participants underwent evaluation using the Large Allen Cognitive Level Test (LACL) (a measure of performance based problem solving); the Problem Solving Verbal Reaction to everyday problematic situations (PSVR); the Sense of Coherence questionnaire (SOC) and the Routine Task Inventory (RTI) (a measure of IADL from the cognitive perspective). Wilcoxon statistical analysis indicated highly significant differences between the two groups for all of the study variables. In the depressive group, significant correlations were found between the components of problem solving (LACL and PSVR) and IADL (r=0.70 and r=0.53), while the SOC did not correlate with IADL in either group. Results of ANCOVA controlling for LACL showed that it has a significant effect (F=13.63, p=0.001); however, beyond it verbal problem solving still has a significant effect on IADL (F=4.77, p=0.02), and SOC in interaction with verbal problem solving was significant (F=3.97, p=0.035). The findings suggest that depression in elderly people is associated with lower functioning in problem solving and IADL function, and lower sense of coherence; hence, attention to these factors should be integral to intervention with elderly people. However, it is recommended that further study be made of the relationships of variables found in this study with the current instruments, and also with additional tools because of confounding effects, in order to further support and validate the findings. As the sample size was small compared with the number of measures, it is important to replicate the study with larger groups to have more power. Copyright © 1999 Whurr Publishers Ltd.     

A wearable sensor identifies alterations in community ambulation in multiple sclerosis: contributors to real-world gait quality and physical activity

Journal of Neurology - People with multiple sclerosis (pwMS) often suffer from gait impairments. These changes in gait have been well studied in laboratory and clinical settings. A thorough...     

The road not taken: Social vs. private comparisons in Asperger׳s syndrome and high functioning autism

Evaluation of the outcomes of our decisions may instigate comparisons of our actual outcome with those of others (social comparisons) or comparisons with alternative outcomes of choices not made (private comparisons). Previous research has suggested a deficit in attention to social information among individuals with autism spectrum disorders. As social comparison involves the processing of social information, here we investigated the orientation towards and sensitivity to social vs. private comparisons in individuals with autism spectrum disorders. We compared the sensitivity to social vs. private comparisons among individuals diagnosed with Asperger’s Syndrome (AS) or High Functioning Autism, using a task that entailed monetary rewards. Results showed that while individuals with AS generally demonstrate comparable sensitivity to absolute and relative rewards, they show less sensitivity to social comparison as compared to controls. Furthermore, they are characterized by a higher sensitivity to private rather than social comparison. These results suggest that low sensitivity to social comparisons is an important factor to consider in autism spectrum disorders.     

Timing abilities among children with developmental coordination disorders (DCD) in comparison to children with typical development

Timing ability is essential for common everyday performance. The aim of the study was to compare timing abilities and temporal aspects of handwriting performance and relationships between these two components among children with Developmental Coordination Disorders (DCD) and a control group. Forty two children, 21 diagnosed as DCD and 21 with typical development, aged 7–12, were matched for age, gender and school performed 14 tasks of the interactive metronome (IM) and three functional handwriting tasks on an electronic tablet that was part of a computerized system (ComPET – computerized penmanship evaluation tool). The IM supplies response time, while on-paper and in-air time per written stroke is received from the ComPET. Results indicated significant differences between the groups for both IM and handwriting tasks (ComPET). Linear regression indicated that the mean IM response time explained 37% of variance of the in-air time per stroke during a paragraph-copying task. Furthermore, based on one discriminate function including two measures reflected timing ability, 81% of all participants were correctly classified into groups. Study results strongly recommend consideration of the IM as an evaluation and intervention tool for children with DCD who are faced with timing deficits in their everyday functioning.     

Preliminary observation with dronabinol in patients with intractable pruritus secondary to cholestatic liver disease

Pruritus due to cholestatic liver disease can be particularly difficult to manage and frequently is intractable to a variety of medical therapies. The aim of our study is to evaluate the efficacy of delta-9-tetrahydrocannabinol (delta-9-THC) for intractable cholestatic related pruritus (ICRP) that has failed conventional (and unconventional) remedies. Three patients were evaluated for plasmapheresis because of ICRP. All 3 patients had previously been extensively treated with standard therapies for ICRP including: diphenhydramine, chlorpheniramine, cholestyramine, rifampicin, phenobarbital, doxepin, naltrexone, UV therapy, and topical lotions. Even multiple courses of plasmapheresis were performed without any benefit for the intractable pruritus. All patients reported significant decreases in their quality of life, including lack of sleep, depression, inability to work, and suicidal ideations. All patients were started on 5 mg of delta-9-THC (Marinol) at bedtime. All 3 patients reported a decrease in pruritus, marked improvement in sleep, and eventually were able to return to work. Resolution of depression occurred in two of three. Side effects related to the drug include one patient experiencing a disturbance in coordination. Marinol dosage was decreased to 2.5 mg in this patient with resolution of symptoms. The duration of antipruritic effect is approximately 4-6 hrs in all three patients suggesting the need for more frequent dosing. Delta-9-tetrahydrocannabinol may be an effective alternative in patients with intractable cholestatic pruritus.