The 6-minute mastication test: a unique test to assess endurance of continuous chewing; normal values, reliability, reproducibility and usability in patients with mitochondrial disease

Abstract

In patients with mitochondrial disease, fatigue and muscle problems are the most common complaints. They also experience these complaints during mastication. To measure endurance in continuous mastication in patients with mitochondrial diseases the 6-minute mastication test (6MMT) was developed. This study included the collection of normal data for the 6MMT in a healthy population (children and adults). During 6 minutes of continuous mastication on a chew tube chewing cycles per minute, total amount of chewing cycles and the difference between minute 1 (M₁) and minute 6 (M₂) were collected in 271 healthy participants (5 - 80 years old). These results were compared with those of 9 pediatric and 25 adult patients with a mitochondrial disease. Visual Analogue Scale (VAS) scores were collected directly after the test and after 5 minutes. A qualitative rating was made on masticatory movements. The reproducibility of the 6MMT in the healthy population with an interval of approximately two weeks was good. The interrater reliability for the observations was excellent. The patient group demonstrated lower total amount of chewing cycles or had greater differences between M₁ and M₆. The 6MMT is a reliable and objective test to assess endurance in continuous chewing. It demonstrates the ability of healthy children and adults to chew during 6 minutes with a highly stable frequency of mastication movements. The test may give an explanation for the masticatory problems in patient groups, who are complaining of pain and fatigue during mastication.

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The role of molecular pain biomarkers in temporomandibular joint internal derangement

Summary

There is evidence that low-grade inflammation may be responsible for pain and development of degenerative changes in temporomandibular joint internal derangement. This article reviews the current knowledge of the molecular mechanisms behind TMJ internal derangements. A non-systematic search was carried out in PubMed, Embase, and the Cochrane library for studies regarding pathophysiological mechanisms behind internal derangements focusing on pain mediating inflammatory and cartilage degrading molecules. Recent data suggests that release of cytokines may be the key event for pain and cartilage destruction in TMJ internal derangements. Cytokines promote the release of matrix metalloproteinases (MMPs) and due to hypoxia, vascular endothelial growth factor (VEGF) is released. This activates chondrocytes to produce MMPs and reduce their tissue inhibitors (TIMPs) as well as the recruitment of osteoclasts, ultimately leading to cartilage and bone resorption. Also proteoglycans have an important role in this process. Several cytokines, MMPs, TIMPs, and VEGF have been identified in higher concentrations in the TMJ synovial fluid of patients with painful internal derangements and shown to be associated with the degree of degeneration. Other molecules that show elevated levels include hyaluronic acid synthase, disintegrin, and metalloproteinase with thrombospondin motifs (ADAMTs), aggrecan, fibromodulin, biglycan, and lumican. Taken together more or less pronounced inflammation of TMJ structures with release of cytokines, MMPs and other molecular markers that interact in a complex manner may be responsible for tissue degeneration in internal derangements. As internal derangements may be symptom-free, the degree of inflammation, but also other mechanisms, may be important for pain development.

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Identification of novel candidate genes for the inverted teat defect in sows using a genome-wide marker panel

Abstract

The number of functional teats is an important selection criterion in pig breeding. Inherited defects of the udder, such as the inverted teat, do have a considerable negative impact on the nursing ability of the sow. To investigate the genetic background of this defect and the number of functional teats in Swedish maternal lines, samples from 230 Yorkshire pigs were selected for genotyping using the PorcineSNP60K BeadChip (Illumina Inc.), each pig with at least one inverted teat was matched with one non-affected pig (fullsib or pairs with matching herd and gender). A genome-wide association study on these 230 pigs was performed using the two-step approach implemented in GenABEL using 46,652 single nucleotide polymorphisms across all autosomes and the X chromosome. A number of significant regions were identified for the inverted teat defect on chromosomes 2, 10, and 18. Many of the regions associated with the number of functional teats were located in the same or close regions, except two associated markers on the X chromosome and one on chromosome 3. We identified some of the regions on chromosomes previously reported in one linkage and one gene expression study. We conclude, despite being able to suggest new candidate genes, that further studies are needed to better understand the biologic background of the teat development. Despite the in-depth comparison of identified regions for the inverted teat defect done here, more studies are required to allow a clear identification of genetic regions relevant for this defect across many pig populations.

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Broadened population-level frequency tuning in the auditory cortex of tinnitus patients

Tinnitus is a phantom auditory perception without an external sound source and is one of the most common public health concerns that impair the quality of life of many individuals. However, its neural mechanisms remain unclear. We herein examined population-level frequency tuning in the auditory cortex of unilateral tinnitus patients with similar hearing levels in both ears using magnetoencephalography. We compared auditory evoked neural activities elicited by a stimulation to the tinnitus and non-tinnitus ears. Objective magnetoencephalographic data suggested that population-level frequency tuning corresponding to the tinnitus ear was significantly broader than that corresponding to the non-tinnitus ear in the human auditory cortex. The results obtained support the hypothesis that pathological alterations in inhibitory neural networks play an important role in the perception of subjective tinnitus.

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Orientation selectivity in the visual cortex of the nine-banded armadillo

Orientation selectivity in primary visual cortex (V1) has been proposed to reflect a canonical computation performed by the neocortical circuitry.  While orientation selectivity has been reported in all mammals examined to date, the degree of selectivity and the functional organization of selectivity varies across clades. The differences in degree of orientation selectivity are large from reports in marsupials that only a small subset of neurons are selective to studies in carnivores in which it is rare to find a neuron lacking selectivity. Further, the functional organization in cortex varies in that the primate and carnivore V1 is characterized by an organization in which nearby neurons share orientation preference while other mammals such as rodents and lagomorphs either lack or have only extremely weak clustering. To gain insight into the evolutionary emergence of orientation selectivity we examined a member of Xenarthra, an early placental clade whose members are rod monochromats. Here, for the first time, we use a combination of neuroimaging, histological, and electrophysiological methods to identify the retinofugal pathways, locate V1, and examine the functional properties of V1 neurons in the armadillo (Dasypus novemcinctus) V1. Individual neurons were strongly sensitive to the orientation and often the direction of drifting gratings. We uncovered a wide range of orientation preferences, but found a bias for horizontal gratings. The presence of strong orientation selectivity in armadillo suggests that the circuitry responsible for this computation is common to placental mammals, and may reflect a difference in the cortical circuitry of marsupial and placental cohorts.

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Nitric oxide promotes GABA release by activating a voltage-independent Ca2+ influx pathway in retinal amacrine cells

Retinal amacrine cells express nitric oxide synthase and produce nitric oxide (NO), making NO available to regulate the function of amacrine cells. Here, we test the hypothesis that NO can alter the GABAergic synaptic output of amacrine cells. We investigate this using whole-cell voltage clamp recordings and Ca²⁺ imaging of cultured chick retinal amacrine cells. When recording from amacrine cells receiving synaptic input from other amacrine cells, we find that NO increases GABAergic spontaneous postsynaptic current (sPSC) frequency. This increase in sPSC frequency does not require the canonical NO receptor, soluble guanylate cyclase, or presynaptic action potentials. However, removal of extracellular Ca²⁺ and buffering of cytosolic Ca²⁺ both inhibit the response to NO. In Ca²⁺ imaging experiments, we confirm that NO increases cytosolic Ca²⁺ in amacrine cell processes by activating a Ca²⁺ influx pathway. Neither the increase in sPSC frequency nor the cytosolic Ca²⁺ elevations are dependent upon Ca²⁺ release from stores. NO also enhances evoked GABAergic responses. Because voltage-gated Ca²⁺ channel function is not altered by NO, the increased evoked response is likely due to the combined effect of voltage-dependent Ca²⁺ influx adding to the NO-dependent, voltage independent, Ca²⁺ influx. Insight into the identity of the Ca²⁺ influx pathway is provided by the transient receptor potential canonical (TRPC) channel inhibitor clemizole which prevents the NO-dependent increase in sPSC frequency and cytosolic Ca²⁺ elevations. These data suggest that NO production in the inner retina will enhance Ca²⁺-dependent GABA release from amacrine cells by activating TRPC channel(s).

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Synaptic control of the shape of the motoneuron pool input-output function

Although motoneurons have often been considered to be fairly linear transducers of synaptic input, recent evidence suggests that strong persistent inward currents (PICs) in motoneurons allow neuromodulatory and inhibitory synaptic inputs to induce large nonlinearities in the relation between the level of excitatory input and motor output. To try and estimate the possible extent of this nonlinearity, we developed a pool of model motoneurons designed to replicate the characteristics of motoneuron input-output properties measured in medial gastrocnemius motoneurons in the decerebrate cat using voltage-clamp and current-clamp techniques. We drove the model pool with a range of synaptic inputs consisting of various mixtures of excitation, inhibition and neuromodulation. We then looked at the relation between excitatory drive and total pool output. Our results revealed that the PICs not only enhance gain but also induce a strong nonlinearity in the relation between the average firing rate of the motoneuron pool and the level of excitatory input. The relation between the total simulated force output and input was somewhat more linear due to higher force outputs in later recruited units. We also found that the non-linearity can be increased by increasing neuromodulatory input and/or balanced inhibitory input and minimized by a reciprocal, push-pull pattern of inhibition. We consider the possibility that a flexible input-output function may allow motor output to be tuned to match the widely varying demands of the normal motor repertoire.

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