Regulation Of Muscle Tone Research Articles

Neurophysiology of gait: From the spinal cord to the frontal lobe

Locomotion is a purposeful, goal-directed behavior initiated by signals arising from either volitional processing in the cerebral cortex or emotional processing in the limbic system. Regardless of whether the locomotion initiation is volitional or emotional, locomotion is accompanied by automatic controlled movement processes, such as the adjustment of postural muscle tone and rhythmic limb movements. Sensori-motor integration in the brainstem and the spinal cord plays crucial roles in this process. The basic locomotor motor pattern is generated by spinal interneuronal networks, termed central pattern generators (CPGs). Responding to signals in proprioceptive and skin afferents, the spinal interneuronal networks modify the locomotor pattern in cooperation with descending signals from the brainstem structures and the cerebral cortex. Information processing between the basal ganglia, the cerebellum, and the brainstem may enable automatic regulation of muscle tone and rhythmic limb movements in the absence of conscious awareness. However, when a locomoting subject encounters obstacles, the subject has to intentionally adjust bodily alignment to guide limb movements. Such an intentional gait modification requires motor programming in the premotor cortices. The motor programs utilize one's bodily information, such as the body schema, which is preserved and updated in the temporoparietal cortex. The motor programs are transmitted to the brainstem by the corticoreticulospinal system, so that one's posture is anticipatorily controlled. These processes enable the corticospinal system to generate limb trajectory and achieve accurate foot placement. Loops from the motor cortical areas to the basal ganglia and the cerebellum can serve this purpose.

The cuneiform nucleus may be involved in the regulation of skeletal muscle tone by motor pathway: a virally mediated trans-synaptic tracing study in surgically sympathectomized mice

ARTICLE Sir, The review article entitled ‘The pedunculopontine nucleus area: critical evaluation of interspecies differences relevant for its use as a target for deep brain stimulation’ by Alam et al. (2011), addressed that the cuneiform nucleus, an adjacent region of the pedunculopontine nucleus, was the important area of the mesencephalic locomotor region and played a major role in the initiation of gait. It has been suggested by many studies that neurons in the cuneiform nucleus are involved in the generation of locomotion, and signals from the cuneiform nucleus activate central pattern generators in the spinal cord, mainly through the medullary reticulospinal tract (Takakusaki et al. , 2003). The understanding of neuroanatomical motor circuitry and neuronal connections from cuneiform nucleus to skeletal muscle is important for studying the possible mechanism of cuneiform nucleus involved in the regulation of skeletal muscle tone by motor pathway. We would like to further complete the discussion of Alam et al. (2011) by introducing a virally-mediated trans-synaptic tracing study. Deep brain stimulation has become a remarkable treatment option for several different movement disorders, such as neuropsychiatric disorders, intractable pain, epilepsy, restless legs syndrome, Parkinson’s disease, and Alzheimer’s disease (Wichmann and Delong, 2006; Halpern et al. , 2007; Lyons, 2011; Thevathasan et al. , 2011). The mesencephalic pedunculopontine tegmental nucleus has been suggested as a target for deep brain stimulation, but the exact mechanism of deep brain stimulation in the pedunculopontine tegmental nucleus area is not fully understood. Because clinical data have demonstrated that the outcome of deep brain stimulation in the pedunculopontine nucleus area can be quite variable, there is great controversy about the …

Reply: The cuneiform nucleus may be involved in the regulation of skeletal muscle tone by motor pathway: a virally mediated trans-synaptic tracing study in surgically sympathectomized mice

Sir, We appreciate the opportunity to respond to the comment by Xiang et al. (2013) on our review on interspecies differences in the pedunculopontine nucleus area. As exemplified by the data of Xiang et al. (2013) it is evident that the mesencephalic locomotor region compromises several distinct structures that are involved in initiation and inhibition of gait, and certainly the implications of both the cuneiform nucleus and the subcuneiform nucleus need to be studied in more detail. Also, as mentioned in our review, there is a paucity of data on the downstream mechanisms mediating neuronal activity in the mesencephalic locomotor region. The role of the pedunculopontine nucleus area as a target site for deep brain stimulation for treatment of medically refractory gait and postural abnormalities in late stage Parkinson’s disease and progressive supranuclear palsy still needs further clarification. Because post-mortem studies in Parkinson’s disease and progressive supranuclear palsy show ∼60% loss of cholinergic neurons in the pedunculopontine nucleus (Jellinger, 1988) it should also …

Brain Regulation of Muscle Tone in Healthy and Functionally Unstable Ankles

Current research into the etiology of joint instability has yielded inconsistent results, limiting our understanding of how to prevent and treat ligamentous injury effectively. Recently, cortical reorganization was demonstrated in patients with ligamentous injury; however, these neural changes have not been assessed relative to joint laxity. The purpose of the current study was to determine if changes in cortical excitability and inhibition occur in subjects with functional ankle instability, as well as to investigate the relationship between these measures and joint laxity. Posttest only with control group. University laboratory. 12 subjects with no history of ankle sprain (CON) and 12 subjects with a history of unilateral functional ankle instability (UNS). Subjects were tested for joint laxity using an instrumented ankle arthrometer. Cortical excitability and inhibition were assessed using transcranial magnetic stimulation (TMS) to obtain motor-evoked potentials and the cortical silent period from the lower leg muscles. Joint laxity was quantified as peak anterior displacement and inversion rotation. Active motor threshold, slope, and intensity at 50% of peak slope of TMS-derived recruitment curves were used to quantify cortical excitability from lower leg muscles, while the cortical silent period from the peroneus longus was used to represent intracortical inhibition. No significant differences were observed between groups for laxity or cortical measures. CON demonstrated a significant relationship between laxity and tibialis anterior excitability, as well as laxity and silent period, while UNS ankles demonstrated significant relationships between peroneal and soleus excitability and laxity measures. Our results support relationships between laxity and measures of excitability and inhibition that differ between healthy and unstable subjects. Future research should further investigate the mechanisms behind these findings and consider cortical influences when investigating altered joint laxity.

Effects of orexin gene transfer in the dorsolateral pons in orexin knockout mice.

Narcolepsy is a sleep disorder characterized by loss of orexin neurons. Previously, our group demonstrated that transfer of the orexin gene into surrogate neurons in the lateral hypothalamus and the zona incerta significantly reduced cataplexy bouts in the orexin-ataxin-3 mice model of narcolepsy. The current study determined the effects of orexin gene transfer into the dorsolateral pontine neurons in the orexin knockout (KO) mice model of narcolepsy. The dorsolateral pons was chosen because it plays a critical role in regulating muscle tone and thus it is conceivable to be involved in cataplexy as well. Cataplexy is the pathognomonic symptom in narcolepsy. Independent groups of orexin KO mice were given bilateral microinjections (0.75 μL each side) of either recombinant adenoassociated virus-orexin (rAAV-orexin; n = 7), or rAAV-green fluorescent protein (rAAV-GFP; n = 7) into the dorsolateral pons. A group of orexin KO mice that did not receive rAAV (n = 7) and a group of wild-type mice (C57BL/J6; n = 5) were used as controls. Three weeks after rAAV-mediated gene transfer narcolepsy symptoms were examined using sleep and behavioral recordings. Number, location of the orexin-immunoreactive neurons, and relative density of orexin immunoreactive fibers were determined. Orexin gene transfer into the dorsolateral pons significantly decreased cataplexy and modestly improved wake maintenance compared to the orexin KO mice that did not receive rAAV. In contrast, GFP gene transfer worsened narcoleptic symptoms compared to the no-rAAV orexin KO group. Orexin gene transfer into the dorsolateral pontine neurons can control cataplexy attacks and modestly improve wake maintenance.

Rho Kinase (ROK)‐Related Proteins in Human Cavernous Arteries: An Immunohistochemical and Functional Approach

Rho kinases (ROKs) cause calcium-independent modulation of smooth muscle contraction. A significant role for the RhoA/ROK pathway in mediating the contraction of the penile erectile tissue has been suggested. Moreover, it has been postulated that ROK activity might represent a key factor in the pathophysiology of erectile dysfunction. Up until today, little is known on the significance of ROK and related proteins in the control of blood flow in the corpus cavernosum. To investigate by means of immunohistochemistry and organ bath studies the significance of the Rho pathway in human cavernous arteries. The expression of ROK1, ROK2, RhoA, and RhoGDI in human cavernous arteries was investigated by means of immunohistochemistry; myographic studies were conducted in order to characterize the effects of the ROK inhibitor Y27632 on isolated cavernous arteries. Specimens of human cavernous arteries were processed for immunohistochemistry for ROK1, ROK2, RhoA, and RhoGDI. Circular penile vascular segments were mounted in a tissue bath and the effects of increasing concentrations of the ROK inhibitor Y27632 on the tension induced by norepinephrine (NE, 1 µM) were investigated. Alpha-actin immunoreactive cavernous arterioles also presented abundant staining specific for ROK1, ROK2, RhoA, and RhoGDI in the smooth musculature of the vascular wall. Cumulative addition of Y27632 dose-dependently reversed the tension induced by NE of isolated arterial segments. Y27632 produced relaxant responses with a reversion of tension of 34.3 ± 11.8% at a concentration of 1 µM. The findings are in support for a role of the Rho/ROK-mediated signaling in the regulation of muscle tone of human cavernous arteries.

Narcolepsy–cataplexy: deficient prepulse inhibition of blink reflex suggests pedunculopontine involvement

Hypocretin (orexin) deficiency plays a major role in the pathophysiology of narcolepsy-cataplexy. In animal models, hypocretinergic projections to the pedunculopontine nucleus are directly involved in muscle tone regulation mediating muscle atonia - a hallmark of cataplexy. We hypothesized that pedunculopontine nucleus function, tested with prepulse inhibition of the blink reflex, is altered in human narcolepsy-cataplexy. Twenty patients with narcolepsy-cataplexy and 20 healthy controls underwent a neurophysiological study of pedunculopontine nucleus function. Blink reflex, prepulse inhibition of the blink reflex and blink reflex excitability recovery were measured. Blink reflex characteristics (R1 latency and amplitude, and R2 and R2c latency and area under the curve) did not differ between patients and controls (P > 0.05). Prepulse stimulation significantly increased R2 and R2c latencies and reduced R2 and R2c areas in patients and controls. However, the R2 and R2c area suppression was significantly less in patients than in controls (to 69.8 ± 14.4 and 74.9 ± 12.6%, respectively, versus 34.5 ± 28.6 and 43.3 ± 29.5%, respectively; each P < 0.001). Blink reflex excitability recovery, as measured by paired-pulse stimulation, which is not mediated via the pedunculopontine nucleus, did not differ between patients and controls (P > 0.05). Our data showed that prepulse inhibition is reduced in narcolepsy-cataplexy, whereas unconditioned blink reflex and its excitability recovery are normal. Because the pedunculopontine nucleus is important for prepulse inhibition, these results suggest its functional involvement in narcolepsy-cataplexy.

Muscle tone regulation during REM sleep: neural circuitry and clinical significance.

Rapid eye movement (REM) sleep is a distinct behavioral state characterized by an activated cortical and hippocampal electroencephalogram (EEG) and concurrent muscle atonia. Research conducted over the past 50 years has revealed the neuronal circuits responsible for the generation and maintenance of REM sleep, as well as the pathways involved in generating the cardinal signs of REM sleep such as cortical activation and muscle atonia. The generation and maintenance of REM sleep appear to involve a widespread network in the pons and medulla. The caudal laterodorsal tegmental nucleus (cLDT) and sublaterodorsal nucleus (SLD) within the dorsolateral pons contain REM-on neurons, and the ventrolateral periaqueductal grey (vlPAG) contains REM-off neurons. The interaction between these structures is proposed to regulate REM sleep amounts. The cLDT-SLD neurons project to the basal forebrain via the parabrachial-precoeruleus (PB-PC) complex, and this pathway may be critical for the EEG activation seen during REM sleep. Descending SLD glutamatergic projections activate the ventromedial medulla, and spinal cord interneurons mediate muscle atonia and suppress phasic muscle twitches in spinal musculature. In contrast, phasic muscle twitches in the masseter muscles may be driven by glutamatergic neurons in the rostral parvicellular reticular nucleus (PCRt); however, the brain region responsible for generating phasic twitches in the other cranial muscles including facial muscles and tongue are not clear.

Silencing MaxiK Activity in Corporal Smooth Muscle Cells Initiates Compensatory Mechanisms to Maintain Calcium Homeostasis

The MaxiK potassium channel is regulated by voltage and intracellular calcium, and plays a critical role in regulating intracellular calcium concentration ([Ca(2+) ](i)), which is the ultimate determinant of smooth muscle tone. Tight control of corpus cavernosum smooth muscle (CCSM) tone is critically important and misregulation can result in erectile dysfunction. Because of the tight functional linkage of MaxiK and calcium channel activity, the aim of this study was to determine the effects of silencing and pharmacological inhibition of MaxiK on calcium homeostasis and intercellular calcium signaling in CCSM cells. We compared changes in the basal intracellular [Ca(2+) ](i) and parameters defining intercellular calcium wave (ICW) spread in 48 hours MaxiK silenced CCSM cells vs. acute blockade of the channel with iberiotoxin. To analyze changes occurring in gene expression we performed micro-array analysis following MaxiK silencing for 48 hours. Changes in Fura-2 fluorescence intensities were measured to evaluate basal [Ca(2+) ](i) levels and ICW parameters. Microarray analysis of global gene expression was performed. Forty-eight hours after MaxiK silencing the basal [Ca(2+) ](i) , the ICW amplitude and spread among CCSM cells were not markedly different in silenced compared to mock transfected controls, whereas short-term blockade significantly increased basal [Ca(2+) ](i) level and amplified Ca(2+) signaling among CCSM cells. Micro-array analysis showed that several genes within Ca(2+) homeostasis and smooth muscle tone regulation pathways had significantly altered expression. Our results indicate that while short-term blockade of the MaxiK channel is associated with an increase in basal [Ca(2+) ](i), Ca(2+) homeostasis is restored during the 48 hours period following silencing. We hypothesize that the different pathways regulating [Ca(2+) ](i) and CCSM tone are linked through molecular crosstalk and that their coordinated regulation is part of a compensatory mechanism aimed to maintain Ca(2+) homeostasis and CCSM tone.

REM sleep behavior disorder in a patient with frontotemporal dementia

We describe a patient with frontotemporal dementia (FTD), a tauopathy, who also showed clinical and polysomnographic features of REM sleep behavior disorder (RBD). The patient is a 78-year-old male with a 1 year history of behavioral dysfunction involving emotion, character and social functioning. Brain imaging and the results of neuropsychological testing were consistent with a diagnosis of FTD. Sleep symptom onset occurred some years before the behavioral changes, and consisted of unpleasant dreams, vocalization, and prominent motor behaviors. A polysomnography confirmed the diagnosis of RBD. Our findings support the hypothesis that RBD, although more frequent in synucleinopathies, might be a pathological stage in the development of almost every neurodegenerative disorder in which the pathological process involves the cerebral structures that regulate muscle tone during REM sleep.

K V7 channels regulate muscle tone and nonadrenergic noncholinergic relaxation of the rat gastric fundus

Voltage-dependent type 7 K + (K V7) channels play important physiological roles in neurons and muscle cells. The aims of the present study were to investigate the motor effects of K V7 channel modulators in the rat gastric fundus and the expression of K V7 channels in this tissue. Muscle tone and electrical field stimulation (EFS)-evoked relaxations of precontracted longitudinal muscle strips of the rat gastric fundus were investigated under nonadrenergic noncholinergic conditions by organ bath studies. Gene expression was studied by real-time PCR and tissue localization of channels was investigated by immunohistochemistry. The K V7 channel blocker XE-991 induced concentration-dependent contractions, with mean pD 2 and E max of 5.4 and 48% of the maximal U46619-induced contraction, respectively. The K V7 channel activators retigabine and flupirtine concentration-dependently relaxed U46619-precontracted strips, with pD 2s of 4.7 and 4.4 and E max of 93% and 91% of the maximal relaxation induced by papaverine, respectively. XE-991 concentration-dependently inhibited retigabine-induced relaxation with a pIC 50 of 6.2. XE-991 and DMP-543, another K V7 channel blocker, increased by 13–25% or reduced by 11–21% the relaxations evoked by low- or high-frequency EFS, respectively. XE-991 also reduced the relaxation induced by vasoactive intestinal polypeptide (VIP) by 33% of controls. Transcripts encoded by all K V7 genes were detected in the fundus, with 7.4 and 7.5 showing the highest expression levels. K V7.4 and 7.5 channels were visualized by confocal immunofluorescence in both circular and longitudinal muscle layers. In conclusion, in the rat proximal stomach, K V7 channels appear to contribute to the resting muscle tone and to VIP- and high-frequency EFS-induced relaxation. K V7 channel activators could be useful relaxant agents of the gastric smooth muscle.

Interaction between sleep mechanisms and orexin neurons

Orexin is a neuropeptide that plays a highly important role in mechanisms that regulate sleep/wake states. Lack of the orexin gene or orexin-producing neurons (orexin neurons) results in narcolepsy in several mammalian species, suggesting that orexin is an important factor for the maintenance of wakefulness. Constitutive, ectopic expression of orexin in transgenic mice resulted in severe fragmentation of non–rapid eye movement sleep, along with abnormal muscle tone regulation during REM sleep, suggesting that activity of orexin neurons should be appropriately decreased during sleep to maintain consolidated sleep states. This review will discuss the mechanisms by which the orexin system is regulated during sleep.

Minor neurological dysfunction in children with dyslexia

to improve understanding of brain function in children with severe dyslexia in terms of minor neurological dysfunctions (MNDs). one hundred and four children (81 males, 23 females; age range 7-12y; mean age 9y 7mo, SD 1y 2mo;) with severe dyslexia (the presence of a Full-scale IQ score of ≥ 85, retardation in single-word or text reading of ≥2y), assessed in a department of dyslexia of a third-level regional psychiatric centre, underwent a neurological examination according to Touwen and a multidisciplinary child psychiatric assessment. Special attention was paid to severity and type of MND. Data were compared with neurological morbidity data of children in the general population. most children had MND (87%): 43% had simple MND, 44% complex MND. The incidence of MND was significantly higher (p<0.001) in the children with dyslexia than in the general population (simple MND 15%, complex MND 6%). Children with dyslexia showed especially fine manipulative disability and - to a lesser extent - mild dysfunction in muscle tone regulation and excessive presence of associated movements. A comorbid psychiatric syndrome was diagnosed in 66 children (63%): emotional disturbances (27%), adjustment disorder (42%), hyperkinetic disorder (15%), autism spectrum disorder (3%), specific disturbances of childhood not otherwise specified (13%). The neurological findings of children with dyslexia with and without psychiatric comorbidity were similar. our results demonstrate the importance of neurological and child psychiatric assessment in children with severe dyslexia. Our findings suggest that dysfunction of cortical structures plays a dominant role in dyslexia.

Handwriting, visuomotor integration, and neurological condition at school age

the study investigated the relationships between handwriting, visuomotor integration, and neurological condition. We paid particular attention to the presence of minor neurological dysfunction (MND). participants were 200 children (131 males, 69 females; age range 8-13y) of whom 118 received mainstream education (mean age 10y 5mo, SD 1y 4mo) and 82 special education (mean age 10y 8mo, SD 1y 2mo). Each child had four assessments: a neurological examination, which paid attention to the type and severity of MND, a test to measure motor performance, a handwriting test, and the Developmental Test of Visual Motor Integration. dysgraphic handwriting and slow writing speed were closely related to the severity of neurological dysfunction (both p<0.001); impaired visuomotor integration was related to the presence of MND (p<0.001) but somewhat less to its severity. Impaired handwriting and visuomotor integration were strongly related to two specific dysfunctions: fine manipulative disability and coordination problems (both p<0.001). Impaired visuomotor integration was weakly related to dysfunctional muscle tone regulation (p=0.009) and sensory dysfunction (p=0.042). poor handwriting and impaired visuomotor integration are related to MND, but in a differential way. Poor handwriting is related to the severity of neurological dysfunction and to dysfunctions of complex supraspinal circuitries. Impaired visuomotor integration is associated with the presence of any of the most common types of MND.

Ectopic Overexpression of Orexin Alters Sleep/Wakefulness States and Muscle Tone Regulation during REM Sleep in Mice

Orexins (also called hypocretins), which are neuropeptides exclusively expressed by a population of neurons specifically localized in the lateral hypothalamic area, are critically implicated in the regulation of sleep/wake states. Orexin deficiency results in narcoleptic phenotype in rodents, dogs, and humans, suggesting that orexins are important for maintaining consolidated wakefulness states. However, the physiological effect of constitutive increased orexinergic transmission tone, which might be important for understanding the effects of orexin agonists that are promising candidates for therapeutic agents of narcolepsy, has not been fully characterized. We report here the sleep/wakefulness abnormalities in transgenic mice that exhibit widespread overexpression of a rat prepro-orexin transgene driven by a β-actin/cytomegalovirus hybrid promoter (CAG/orexin transgenic mice). CAG/orexin mice exhibit sleep abnormalities with fragmentation of non-rapid eye movement (REM) sleep episode and a reduction in REM sleep. Non-REM sleep was frequently disturbed by short episodes of wakefulness. EEG/EMG studies also reveal incomplete REM sleep atonia with abnormal myoclonic activity during this sleep stage. These results suggest that endogenous orexinergic activity should be appropriately regulated for normal maintenance of sleep states. Orexinergic transmission should be activated during wakefulness, while it should be inactivated or decreased during sleep state to maintain appropriate vigilance states.

Cochrane review: Inhaled nitric oxide for respiratory failure in preterm infants

AbstractBackgroundInhaled nitric oxide (iNO) has been proven to be effective in term infants with hypoxic respiratory failure. The pathophysiology of respiratory failure, and the potential risks, differ substantially in preterm infants. Therefore, analysis of the efficacy and toxicities of iNO in infants born before 35 weeks is necessary.ObjectivesTo determine the effect of treatment with iNO on the rates of death, bronchopulmonary dysplasia (BPD), intraventricular haemorrhage (IVH), or neurodevelopmental disability in preterm newborn infants (&lt; 35 weeks gestation) with respiratory disease.Search strategyStandard methods of the Cochrane Neonatal Review Group were used. MEDLINE, EMBASE, Healthstar and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) were searched, using the following keywords: nitric oxide, clinical trial, and newborn covering the years from 1985 to 2006. In addition, the abstracts of the Pediatric Academic Societies were also searched.Selection criteriaRandomised and quasi‐randomised studies in preterm infants with respiratory disease that compared the effects of administration of iNO gas compared to control, with or without placebo are included in this review.Data collection and analysisData regarding clinical outcomes including death, BPD (defined as oxygen dependence at 36 weeks postmenstrual age), IVH, periventricular leukomalacia (PVL), long term neurodevelopmental outcome and short term effects on oxygenation were excerpted from the trial reports by the investigators. Standard methods of the Cochrane Neonatal Review Group were used. Two investigators extracted, assessed and coded separately all data for each study. Any disagreement was resolved by discussion.Main resultsEleven randomised controlled trials of inhaled nitric oxide therapy in preterm infants were found. The trials have been grouped post hoc into three categories depending on the entry criteria; entry in the first three days of life based on oxygenation criteria (Kinsella 1999; Hascoet 2004; INNOVO 2005; Van Meurs 2004; Mercier 1999; Dani 2006), routine use in intubated preterm babies (Schreiber 2003; Kinsella 2006) and later enrolment based on an increased risk of BPD (Subhedar 1997; Ballard 2006). The usefulness of the overall analyses was considered limited by the differing characteristics of the studies, and only subgroup analyses were performed.Trials of early rescue treatment of infants based on oxygenation criteria demonstrated no significant effect of iNO on mortality or BPD. The subgroup of studies with routine use of iNO in intubated preterm infants demonstrated a marginally significant reduction in the combined outcome of death or BPD [typical RR 0.91 (95% CI 0.84, 0.99); typical RD ‐0.06 (95% CI ‐0.12, ‐0.01)]. Later treatment with iNO based on the risk of BPD demonstrated no significant benefit for this outcome in our analysis.Studies of early rescue treatment with iNO demonstrated a trend toward increased risk of severe IVH, whereas the subgroup of studies with routine use in intubated preterm infants seems to show a reduction in the risk of having either a severe IVH or PVL [typical RR 0.70 (95% CI 0.53, 0.91); typical RD ‐0.07 (95% CI ‐0.12, ‐0.02)].Later iNO treatment of infants at risk of BPD is given after the major risk period for IVH, and does not appear to lead to progression of old lesions.Two studies (Schreiber 2003; INNOVO 2005) presented data on long term neurodevelopmental outcome. The early routine treatment study (Schreiber 2003) showed an improved outcome at two years corrected age, while the rescue treatment study (INNOVO 2005) showed no effect of iNO.Authors' conclusionsiNO as rescue therapy for the very ill ventilated preterm infant does not appear to be effective and may increase the risk of severe IVH. Later use of iNO to prevent BPD also does not appear to be effective. Early routine use of iNO in mildly sick preterm infants may decrease serious brain injury and may improve survival without BPD. Further studies are needed to confirm these findings, to define groups most likely to benefit, and to describe long term outcomes.Plain Language SummaryInhaled nitric oxide for respiratory failure in preterm infantsThe use of inhaled nitric oxide (iNO) may help reduce breathing failure in preterm babies.Breathing failure in premature newborn babies may be complicated by raised pressure within the vessels that carry blood to the lung (pulmonary hypertension). Medications that cause sedation or muscle relaxation and mechanically assisted breathing (mechanical or assisted ventilation) are used to treat pulmonary hypertension. Nitric oxide is believed to help regulate muscle tone in the arteries of the lungs and, thereby lessen pulmonary hypertension; however, iNO may also cause excessive bleeding (haemorrhage). This review of studies found that nitric oxide therapy may improve the chances of the baby having an improved outcome, but only when used in babies who were mildly ill. These studies indicated that there may be a decrease in serious bleeding in the brain (intracranial hemorrhage). When given to babies who were very ill, iNO did not seem to help, and may have contributed to an increase in intracranial hemorrhage.

IRAG determines nitric oxide- and atrial natriuretic peptide-mediated smooth muscle relaxation

Nitric oxide (NO) and atrial natriuretic peptide (ANP) signalling via cGMP controls smooth muscle tone. One important signalling pathway of cGMP-dependent protein kinase type I (cGKI) is mediated by IRAG (IP(3) receptor associated cGKI substrate) which is highly expressed in smooth muscle tissues. To elucidate the role of IRAG for NO- and ANP-mediated smooth muscle tone regulation, cGKI localization, and for its possible function in blood pressure adjustment, we generated IRAG-knockout mice by targeted deletion of exon 3. IRAG deletion prevented stable interaction of IP(3) receptor type I (IP(3)RI) with cGKIbeta determined by cGMP affinity chromatography. Confocal microscopy in vascular smooth muscle cells (VSMCs) showed that localization of cGKIbeta and cGKIalpha did not change in absence of IRAG. NO-, ANP-, and cGMP-dependent relaxation of hormone-contracted aortic vessels and colon was significantly affected in IRAG-knockout mice. The suppression of cGMP-induced relaxation was not rescued by selective expression of cGKIbeta in smooth muscle from cGKIbeta-transgenic mice. NO-, ANP-, and cGMP-mediated inhibition of the hormone-induced increase in intracellular calcium concentration measured by Fura2 was suppressed in IRAG-deficient VSMC. Telemetric measurements revealed that IRAG-deficient animals exhibited normal basal tone, but were resistant to blood pressure reduction induced by lipopolysaccharide-treatment. These findings indicate that signalling of cGKIbeta via IRAG is an essential functional part for regulation of smooth muscle tone and of intracellular calcium by NO (exogenously applicated or endogenously synthesized) and by ANP. IRAG signalling does not modulate basal tone but might be important for blood pressure regulation under pathophysiological conditions.

Botulinum toxin type A and a rehabilitation program in the treatment of Pisa syndrome in Parkinson’s disease

Lateral flexion in idiopathic Parkinson’s disease (PD) represents one of atypical postural disturbances [1]. Several authors differentiated this particular clinical picture from Pisa syndrome (pleurothotonus) [1, 2], a rare type of trunk dystonia characterized by abnormal and severe axial lateral flexion of the trunk accompanied by contraction of the trunk musculature with marked flexion of the thoracolumbar spine and backward axial rotation. In 1972, Ekbom and colleagues described Pisa syndrome (PS) for the first time [3], which initially was considered as a subtype of dystonia in patients taking typical or atypical antipsychotic agents. Later, this syndrome was described in idiopathic cases, in patients with neurodegenerative diseases or in those receiving other drugs (cholinesterase inhibitors, selective serotonin reuptake inhibitors or antiparkinsonian agents) [4–8]. A cholinegic-dopaminergic imbalance, which is strategic in the regulation of axial muscle tone, or the interactions among noradrenaline, serotonin and dopamine could be involved in the development of PS [5, 7]. In recent years, the term PS has been used to describe this feature in PD, although no universal agreement has been reached with regard to the appropriate nomenclature [1, 2, 4]. Actually, there are not common defined criteria to classify features of PS and other lateral trunk flexions in PD [1]. In the present article, we describe the case of a 68year-old man with a diagnosis of PD (stage III Hoehn & Yahr) who came to us for observation of a severe axial lateral flexion of the trunk. He was a pensioner, with about 5 years of education, and without a family history of PD. In 2000, he was first seen by a neurologist who made a diagnosis of probable idiopathic PD according to published criteria [9] and prescribed up to 400 mg/day controlled-release levodopa plus 100 mg/day decarboxylase inhibitor. The patient showed a slowly progressing clinical picture, with a gradual increase of dopaminergic drugs (600 mg/day controlled-release levodopa plus 150 mg/day decarboxylase inhibitor). A selective serotonin reuptake inhibitors drug was added to reduce a progressive depressive disorder (sertraline 50 mg/day). The patient did not effectuate a clinical checkup for 1 year, assuming drugs without any medical control. A CT scan of the brain and the cervical-thoraco-lumbar spinal cord excluded ankylosis or vertebral column deformity. He did not remember when he had developed the postural disorder. Initial symptoms involved the neck area, with subsequent spread to the back. He reported movement difficulty and severe pain in the lower back region. Physiatric examination revealed a marked trunkal deviation to the right side with increased tone of the dorsal and lumbar muscles, particularly evident on walking and sitting, suggesting a diagnosis of PS. He had severe gait disturbance and postural instability, too, caused by continuous dystonic movement of trunk. In standing position, the patient presented an angle of about 35 with trunk A. Santamato (&) M. T. Amoruso L. Amoruso P. Fiore Department of Physical Medicine and Rehabilitation, University of Foggia, ‘‘OORR’’, Viale Pinto, 71100 Foggia, Italy e-mail: a.santamato@unifg.it

大脳基底核による運動の制御

The cerebral cortex controls cognitive and voluntary process of movements. The brainstem and spinal cord are involved in the execution of innately acquired motor patterns such as postural reflexes, muscle tone regulation and locomotion. Cortico-reticular projections arising from the motor cortical areas contribute to the postural control that precedes the voluntary movement process. The basal ganglia cooperatively regulates the activities of the cerebral cortex and the brainstem-spinal cord by its strong inhibitory and dis-inhibitory effects upon these target structures so that goal-directed movements could be appropriately performed. We propose that basal ganglia disfunction, including the abnormality in the dopaminergic projection system, may disturb the cooperative regulation, resulting in motor deficiencies expressed in basal diseases.

Rehabilitation of children with cerebral palsy from a physiotherapist’s perspective

Pediatric rehabilitation requires a multidisciplinary team approach to disabilities or handicaps caused by physical, mental, sensory-perceptional, or cognitive disorders due to prenatal, natal, or postnatal causes. Cerebral palsy (CP) is defined as persistent but not progressive disorder of posture and movement system, associated with functional activity limitations and sensorial, cognitive, communication problems, epilepsy, and musculoskeletal system problems. Physiotherapy approaches in rehabilitation applications aim to normalize sensorial and motor functions, provide normal posture and independent functional activity, regulate muscle tone, improve visual and auditory reactions, support normal motor development and motor control, improve ambulation and endurance, increase the quality of the existing movements, prevent soft tissue, joint and postural disorders, support orthopedic and surgical procedures, and finally to prepare the child for the adolescent and adult periods. Setting realistic goals, determination of the priorities, informing the family and enhancing family participation in physiotherapy programs will increase the success of physiotherapy. This article reviews current rehabilitation approaches and physiotherapy applications for children with CP.