Neural activity states in different forms of physiological tremor. Facts and hypotheses

This paper attempts to combine (and thereby briefly review) various sets of physiological data in order to outline a qualitative model of the different states of stochastic neural activity underlying different forms of physiological tremor. Particular emphasis in put on spatial distributions of the properties of neural elements and their interconnexions, and on discharge characteristics of motor units and muscle spindle afferents including so-called early discharges and nonlinearities. It is argued that the wide variety of internal anatomical and functional structures of skeletal muscles and of their reflex organization must be considered when dealing with stability problems. Computer simulations of stochastic population models of the involved neuromuscular elements are advocated as means to investigate the relative importance of the many factors possibly contributing to stabilizing or de-stabilizing neuromuscular systems.     

The effects of recurrent inhibition on the cross-correlated firing patterns of motoneurones (and their relation to signal transmission in the spinal cord-muscle channel)

Cross-correlation histograms (CCH) were computed for discharge sequences of pairs of motoneurones which were excited by sinusoidal muscle stretches. These CCH's were compared before and after opening of the recurrent inhibitory loop by Renshaw cell blocking agents. Periodic patterns in the CCH's indicative of specifically timed phase relations between discharges of different motoneurones were enhanced after Renshaw cell blockage. This was confirmed by power spectra computed for the CCH's. They contained power peaks about 50Hz which tended to increase after depression of recurrent inhibition. The correlation was thus due predominantly to line current interference which seemed to act as a common entrainment input at the spinal level. It is concluded that Renshaw cells de-correlate discharge patterns of different motoneurones of the same pool by injecting uncorrelated signals into them. This de-correlation is an important prerequisite for distortion suppression of signal transmission in a multi-channel system, like that of stretch reflex, and for its linearization.     

Frequency response characteristics of a multi-loop representation of the segmental muscle stretch reflex

This paper continues the investigation of a three-loop representation of the segmental muscle stretch reflex system introduced in a preceding communication. Frequency response characteristics were computed for open-loop conditions, control and disturbance signal inputs under a variety of conditions: (i) in parallel and in series peripheral arrangements of muscle compartments, (ii) various patterns of central connectivity, (iii) various recruitment levels of motor units, (iv) various overall reflex gains, (v) absence or presence of muscle spindle accleration sensitivity. These computations disclosed a number of mechanisms by which the nervous system might improve system stability and behaviour. These mechanisms are discussed with regard to physiological data.     

Effect of Metalaxyl on the incidence and severity of Pearl millet downy mildew disease in Northern Nigeria

Pearl millet downy mildew (DM) incidence, severity and yield losses of two pearl millet varieties (local and improved) due to the disease were determined in the field. Significant differences in the disease incidence and severity were recorded in the plots sown with metalaxyl-treated seeds and those sown with non-treated seeds, indicating the efficacy of the fungicide on the fungus. Yield losses due to non-treatment of seeds with metalaxyl was 40.88 and 45.39% in a local variety and 43.00 and 18.60% in an improved variety in the 2000 and 2001 cropping seasons respectively. Significant differences between plots sown with metalaxyl-treated and those sown with non-treated seeds were obtained for other yield components such as 1000-grains weight, panicle length and weight.     

Identification of a new membrane-permeable inhibitor against inositol-1,4,5-trisphosphate-3-kinase A

Ectopic expression of the neuron-specific inositol-1,4,5-trisphosphate-3-kinase A (ITPKA) in lung cancer cells increases their metastatic potential because the protein exhibits two actin regulating activities; it bundles actin filaments and regulates inositol-1,4,5-trisphosphate (InsP₃)-mediated calcium signals by phosphorylating InsP₃. Thus, in order to inhibit the metastasis-promoting activity of ITPKA, both its actin bundling and its InsP₃kinase activity has to be blocked. In this study, we performed a high throughput screen in order to identify specific and membrane-permeable substances against the InsP₃kinase activity. Among 341,44 small molecules, 237 compounds (0.7%) were identified as potential InsP₃kinase inhibitors. After determination of IC₅₀-values, the three compounds with highest specificity and highest hydrophobicity (EPPC-3, BAMB-4, MEPTT-3) were further characterized. Only BAMB-4 was nearly completely taken up by H1299 cells and remained stable after cellular uptake, thus exhibiting a robust stability and a high membrane permeability. Determination of the inhibitor type revealed that BAMB-4 belongs to the group of mixed type inhibitors. Taken together, for the first time we identified a highly membrane-permeable inhibitor against the InsP₃kinase activity of ITPKA providing the possibility to partly inhibit the metastasis-promoting effect of ITPKA in lung tumor cells.     

Gene expression and the evolution of phenotypic diversity in social wasps

Background  

Organisms are capable of developing different phenotypes by altering the genes they express. This phenotypic plasticity provides a means for species to respond effectively to environmental conditions. One of the most dramatic examples of phenotypic plasticity occurs in the highly social hymenopteran insects (ants, social bees, and social wasps), where distinct castes and sexes all arise from the same genes. To elucidate how variation in patterns of gene expression affects phenotypic variation, we conducted a study to simultaneously address the influence of developmental stage, sex, and caste on patterns of gene expression in Vespula wasps. Furthermore, we compared the patterns found in this species to those found in other taxa in order to investigate how variation in gene expression leads to phenotypic evolution.     

Information-theoretic analysis of de-efferented single muscle spindles

 The information transmission properties of single, de-efferented primary muscle-spindle afferents from the hind limb of the cat were investigated. The gastrocnemius medialis muscle was stretched randomly while recording spike trains from several muscle-spindle afferents in the dorsal root. Two classes of input stimuli were used: (i) Gaussian noise with band-limited flat spectrum, and (ii) Gaussian noise with a more “naturalistic” 1/f ⁿ spectrum. The “reconstruction” method was used to calculate a lower bound to the information rate (in bits per second) between the muscle spindles and the spinal cord. Results show that in response to the flat-spectrum input, primary muscle-spindle afferents transfer information mainly about high frequencies, carrying 2.12 bits/spike. In response to naturalistic-spectrum inputs, primary muscle-spindle afferents transfer information about both low and high frequencies, with “spiking efficiency” increasing to 2.67 bits/spike. A simple muscle-spindle simulation model was analyzed with the same method, emphasizing the important part played by the intrafusal fiber mechanical properties in information transmission. Received: 22 January 2002 / Accepted in revised form: 17 June 2002 Correspondence to: Y. Tock (e-mail: ytock@tx.technion.ac.il, Fax: +972-4-8323041)     

Intracellular localization of human Ins(1,3,4,5,6)P5 2-kinase

InsP6 is an intracellular signal with several proposed functions that is synthesized by IP5K [Ins(1,3,4,5,6)P5 2-kinase]. In the present study, we overexpressed EGFP (enhanced green fluorescent protein)-IP5K fusion proteins in NRK (normal rat kidney), COS7 and H1299 cells. The results indicate that there is spatial microheterogeneity in the intracellular localization of IP5K that could also be confirmed for the endogenous enzyme. This may facilitate changes in InsP6 levels at its sites of action. For example, overexpressed IP5K showed a structured organization within the nucleus. The kinase was preferentially localized in euchromatin and nucleoli, and co-localized with mRNA. In the cytoplasm, the overexpressed IP5K showed locally high concentrations in discrete foci. The latter were attributed to stress granules by using mRNA, PABP [poly(A)-binding protein] and TIAR (TIA-1-related protein) as markers. The incidence of stress granules, in which IP5K remained highly concentrated, was further increased by puromycin treatment. Using FRAP (fluorescence recovery after photobleaching) we established that IP5K was actively transported into the nucleus. By site-directed mutagenesis we identified a nuclear import signal and a peptide segment mediating the nuclear export of IP5K.     

A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (the DART-AD trial)

Background

There have been increasing concerns regarding the safety and efficacy of neuroleptics in people with dementia, but there are very few long-term trials to inform clinical practice. The aim of this study was to determine the impact of long-term treatment with neuroleptic agents upon global cognitive decline and neuropsychiatric symptoms in patients with Alzheimer disease.

Methods and Findings

Design: Randomised, blinded, placebo-controlled parallel two-group treatment discontinuation trial.Setting: Oxfordshire, Newcastle and Gateshead, London and Edinburgh, United Kingdom.Participants: Patients currently prescribed the neuroleptics thioridazine, chlorpromazine, haloperidol trifluoperazine or risperidone for behavioural or psychiatric disturbance in dementia for at least 3 mo.Interventions: Continue neuroleptic treatment for 12 mo or switch to an identical placebo.Outcome measures: Primary outcome was total Severe Impairment Battery (SIB) score. Neuropsychiatric symptoms were evaluated with the Neuropsychiatric Inventory (NPI).Results: 165 patients were randomised (83 to continue treatment and 82 to placebo, i.e., discontinue treatment), of whom 128 (78%) commenced treatment (64 continue/64 placebo). Of those, 26 were lost to follow-up (13 per arm), resulting in 51 patients per arm analysed for the primary outcome. There was no significant difference between the continue treatment and placebo groups in the estimated mean change in SIB scores between baseline and 6 mo; estimated mean difference in deterioration (favouring placebo) −0.4 (95% confidence interval [CI] −6.4 to 5.5), adjusted for baseline value (p = 0.9). For neuropsychiatric symptoms, there was no significant difference between the continue treatment and placebo groups (n = 56 and 53, respectively) in the estimated mean change in NPI scores between baseline and 6 mo; estimated mean difference in deterioration (favouring continue treatment) −2.4 (95% CI −8.2 to 3.5), adjusted for baseline value (p = 0.4). Both results became more pronounced at 12 mo. There was some evidence to suggest that those patients with initial NPI ≥ 15 benefited on neuropsychiatric symptoms from continuing treatment.

Conclusions

For most patients with AD, withdrawal of neuroleptics had no overall detrimental effect on functional and cognitive status. Neuroleptics may have some value in the maintenance treatment of more severe neuropsychiatric symptoms, but this benefit must be weighed against the side effects of therapy.Trial registration: Cochrane Central Registry of Controlled Trials/National Research Register (#ISRCTN33368770).