Association of gallbladder hyperkinesia with acalculous chronic cholecystitis: A case-control study.

BACKGROUND: This is the first case-control study investigating an association between gallbladder hyperkinesia and symptomatic acalculous chronic cholecystitis. METHODS: This retrospective study in a single academic center compared resolution of biliary pain in adults with gallbladder hyperkinesia, defined as a hepatobiliary iminodiacetic acid scan ejection fraction ≥80%, undergoing cholecystectomy (study group) with those treated medically without cholecystectomy (control group). Of 1,477 hepatobiliary iminodiacetic acid scans done between 2013 and 2018, a total of 296 adults without gallstones had an ejection fraction ≥80%, of whom 46 patients met predetermined eligibility criteria. Demographic data, hepatobiliary iminodiacetic acid scan ejection fraction, chronicity of pain, and resolution of pain were compared between groups. RESULTS: Demographics (mean ± standard deviation) in the control group (n = 25) and in the study group (n = 21) were, respectively, age 40 y ± 16 y and 39 y ± 14 y, body mass index 28.9 ± 5.2 and 29.1 ± 7.1 kg/m2, with 15 (60%) and 18 (86%) females in each. Resolution of pain after cholecystectomy occurred in 18 of 21 patients (86%); however, pain persisted in 20 of 25 patients (80%) treated medically after mean follow-up of 36 ± 28 months (range 10-120 months) (P < .01). Pain resolution with cholecystectomy was independent of demographic variables, hepatobiliary iminodiacetic acid scan ejection fraction, and chronicity of pain. The odds of pain resolution was 19.7 times greater with cholecystectomy than without (odds ratio, 19.7; 95% confidence interval, 4.34, 89.43; P < .01), and remained robust even with the odds adjusted for each covariate. Gallbladder histopathology confirmed chronic cholecystitis in all 21 cholecystectomy specimens. CONCLUSION: Symptomatic gallbladder hyperkinesia could be a new indication for cholecystectomy in adults.

Adult Brain Serotonin Deficiency Causes Hyperactivity, Circadian Disruption, and Elimination of Siestas.

UNLABELLED: Serotonin (5-HT) is a crucial neuromodulator linked to many psychiatric disorders. However, after more than 60 years of study, its role in behavior remains poorly understood, in part because of a lack of methods to target 5-HT synthesis specifically in the adult brain. Here, we have developed a genetic approach that reproducibly achieves near-complete elimination of 5-HT synthesis from the adult ascending 5-HT system by stereotaxic injection of an adeno-associated virus expressing Cre recombinase (AAV-Cre) into the midbrain/pons of mice carrying a loxP-conditional tryptophan hydroxylase 2 (Tph2) allele. We investigated the behavioral effects of deficient brain 5-HT synthesis and discovered a unique composite phenotype. Surprisingly, adult 5-HT deficiency did not affect anxiety-like behavior, but resulted in a robust hyperactivity phenotype in novel and home cage environments. Moreover, loss of 5-HT led to an altered pattern of circadian behavior characterized by an advance in the onset and a delay in the offset of daily activity, thus revealing a requirement for adult 5-HT in the control of daily activity patterns. Notably, after normalizing for hyperactivity, we found that the normal prolonged break in nocturnal activity (siesta), a period of rapid eye movement (REM) and non-REM sleep, was absent in all animals in which 5-HT deficiency was verified. Our findings identify adult 5-HT as a requirement for siestas, implicate adult 5-HT in sleep-wake homeostasis, and highlight the importance of our adult-specific 5-HT-synthesis-targeting approach in understanding 5-HT's role in controlling behavior. SIGNIFICANCE STATEMENT: Serotonin (5-HT) is a crucial neuromodulator, yet its role in behavior remains poorly understood, in part because of a lack of methods to target specifically adult brain 5-HT synthesis. We developed an approach that reproducibly achieves near-complete elimination of 5-HT synthesis from the adult ascending 5-HT system. Using this technique, we discovered that adult 5-HT deficiency led to a novel compound phenotype consisting of hyperactivity, disrupted circadian behavior patterns, and elimination of siestas, a period of increased sleep during the active phase. These findings highlight the importance of our approach in understanding 5-HT's role in behavior, especially in controlling activity levels, circadian behavior, and sleep-wake homeostasis, behaviors that are disrupted in many psychiatric disorders such as attention deficit hyperactivity disorder.

Biallelic Mutations in PDE10A Lead to Loss of Striatal PDE10A and a Hyperkinetic Movement Disorder with Onset in Infancy.

Deficits in the basal ganglia pathways modulating cortical motor activity underlie both Parkinson disease (PD) and Huntington disease (HD). Phosphodiesterase 10A (PDE10A) is enriched in the striatum, and animal data suggest that it is a key regulator of this circuitry. Here, we report on germline PDE10A mutations in eight individuals from two families affected by a hyperkinetic movement disorder due to homozygous mutations c.320A>G (p.Tyr107Cys) and c.346G>C (p.Ala116Pro). Both mutations lead to a reduction in PDE10A levels in recombinant cellular systems, and critically, positron-emission-tomography (PET) studies with a specific PDE10A ligand confirmed that the p.Tyr107Cys variant also reduced striatal PDE10A levels in one of the affected individuals. A knock-in mouse model carrying the homologous p.Tyr97Cys variant had decreased striatal PDE10A and also displayed motor abnormalities. Striatal preparations from this animal had an impaired capacity to degrade cyclic adenosine monophosphate (cAMP) and a blunted pharmacological response to PDE10A inhibitors. These observations highlight the critical role of PDE10A in motor control across species.

Rodent model of activity-based anorexia.

Activity-based anorexia (ABA) consists of a procedure that involves the simultaneous exposure of animals to a restricted feeding schedule, while free access is allowed to an activity wheel. Under these conditions, animals show a progressive increase in wheel running, a reduced efficiency in food intake to compensate for their increased activity, and a severe progression of weight loss. Due to the parallelism with the clinical manifestations of anorexia nervosa including increased activity, reduced food intake and severe weight loss, the ABA procedure has been proposed as the best analog of human anorexia nervosa (AN). Thus, ABA research could both allow a better understanding of the mechanisms underlying AN and generate useful leads for treatment development in AN.

Clinical case of anti-N-methyl-D-aspartate receptor encephalitis in an 8-month-old patient with hyperkinetic movement disorder.

This article describes an 8-month-old boy with the full clinical spectrum anti-N-methyl-d-aspartate receptor encephalitis. He was admitted to the hospital with involuntary orofacial head movements, behavioral changes, and fluctuation in consciousness. His examination showed tongue thrusting, decreased responsiveness, and hypotonia without fever. Analysis of the cerebrospinal fluid revealed increased protein levels (62 mg/dL). The next day he developed oral dyskinesia and choreoathetosis. Video-electroencephalogram polygraphy showed coreo-dystonic movements without electrographic correlation. A putative diagnosis of autoimmune encephalopathy was made, and treatment with intravenous immunoglobulin and methylprednisolone was started, with improvement in the abnormal movements. Antibodies to the N-methyl-d-aspartate receptor were identified in the cerebrospinal fluid and blood. He began receiving immunoglobulin once a month for a year. Two months after the treatment had started, the involuntary movement disappeared and his development has been normal. N-methyl-d-aspartate receptor encephalitis is a recently identified disorder. This is the youngest case reported. Prompt diagnosis and treatment are important to obtain full recovery.

Rapid development of semistarvation-induced hyperactivity in Dark Agouti rats. Excessive wheel running and effect of 3,4-methylenedioxymethamphetamine (MDMA).

Clinical studies have found that patients with anorexia develop high activity levels. These data suggest a possible implication of activity in the aetiology of anorexia and are in line with findings obtained in animals during experimental procedures to model interactions between activity and weight loss. Activity-based anorexia (ABA) and semistarvation-induced hyperactivity (SIH) develop when laboratory rats have food access restricted to a single period in the day and are given free access to an activity wheel. This experiment sought to show the effect on weight loss of the excessive activity normally seen in Dark Agouti rats and of hyperactivity induced by 3,4-methylenedioxymethamphetamine (MDMA). To this end, 32 female rats of the Dark Agouti strain were selected and divided into four groups in accordance with a 2 × 2 factorial design, in which one factor was treatment (saline or MDMA) and the other was access or lack of access to an activity wheel. Animals with wheel running access displayed a marked increase in running combined with accelerated weight loss. Although pharmacological treatment resulted in no observable effect on weight loss, rats treated with 12.5mg/kg MDMA generally registered more wheel running than did those treated with saline. Analysis of data on the temporal distribution of wheel running revealed an alteration in circadian activity patterns as a consequence of MDMA. These results, by showing a general high level of wheel running in Dark Agouti rats, once again emphasise the close relationship between activity and weight loss in the development of SIH and related phenomena such as ABA.

The synaptic adhesion molecule SynCAM 1 contributes to cocaine effects on synapse structure and psychostimulant behavior.

Drugs of abuse have acute and persistent effects on synapse structure and addiction-related behaviors. Trans-synaptic interactions can control synapse development, and synaptic cell adhesion molecule (SynCAM) proteins (also named nectin-like molecules) are immunoglobulin adhesion proteins that span the synaptic cleft and induce excitatory synapses. Our studies now reveal that the loss of SynCAM 1 in knockout (KO) mice reduces excitatory synapse number in nucleus accumbens (NAc). SynCAM 1 additionally contributes to the structural remodeling of NAc synapses in response to the psychostimulant cocaine. Specifically, we find that cocaine administration increases the density of stubby spines on medium spiny neurons in NAc, and that maintaining this increase requires SynCAM 1. Furthermore, mushroom-type spines on these neurons are structurally more plastic when SynCAM 1 is absent, and challenging drug-withdrawn mice with cocaine shortens these spines in SynCAM 1 KO mice. These effects are correlated with changes on the behavioral level, where SynCAM 1 contributes to the psychostimulant effects of cocaine as measured after acute and repeated administration, and in drug-withdrawn mice. Together, our results provide evidence that the loss of a synapse-organizing adhesion molecule can modulate cocaine effects on spine structures in NAc and increases vulnerability to the behavioral actions of cocaine. SynCAM-dependent pathways may therefore represent novel points of therapeutic intervention after exposure to drugs of abuse.

Double disruption of α2A- and α2C-adrenoceptors results in sympathetic hyperactivity and high-bone-mass phenotype.

Evidence demonstrates that sympathetic nervous system (SNS) activation causes osteopenia via ß(2)-adrenoceptor (ß2-AR) signaling. Here we show that female mice with chronic sympathetic hyperactivity owing to double knockout of adrenoceptors that negatively regulate norepinephrine release, α(2A)-AR and α(2C)-AR (α(2A) /α(2C)-ARKO), present an unexpected and generalized phenotype of high bone mass with decreased bone resorption and increased formation. In α(2A) /α(2C)-ARKO versus wild-type (WT) mice, micro-computed tomographic (µCT) analysis showed increased, better connected, and more plate-shaped trabeculae in the femur and vertebra and increased cortical thickness in the vertebra, whereas biomechanical analysis showed increased tibial and femoral strength. Tibial mRNA expression of tartrate-resistant acid phosphatase (TRACP) and receptor activator of NF-κB (RANK), which are osteoclast-related factors, was lower in knockout (KO) mice. Plasma leptin and brain mRNA levels of cocaine amphetamine-regulated transcript (CART), which are factors that centrally affect bone turnover, and serum levels of estradiol were similar between mice strains. Tibial ß(2)-AR mRNA expression also was similar in KO and WT littermates, whereas α(2A)-, α(2B)- and α(2C)-AR mRNAs were detected in the tibia of WT mice and in osteoblast-like MC3T3-E1 cells. By immunohistochemistry, we detected α(2A)-, α(2B)-, α(2C)- and ß(2)-ARs in osteoblasts, osteoclasts, and chondrocytes of 18.5-day-old mouse fetuses and 35-day-old mice. Finally, we showed that isolated osteoclasts in culture are responsive to the selective α(2)-AR agonist clonidine and to the nonspecific α-AR antagonist phentolamine. These findings suggest that ß(2)-AR is not the single adrenoceptor involved in bone turnover regulation and show that α(2)-AR signaling also may mediate the SNS actions in the skeleton.

Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2.

GluR2 is a subunit of the AMPA receptor, and the adenosine for the Q/R site of its pre-mRNA is converted to inosine (A-to-I conversion) by the enzyme called adenosine deaminase acting on RNA 2 (ADAR2). Failure of A-to-I conversion at this site affects multiple AMPA receptor properties, including the Ca(2+) permeability of the receptor-coupled ion channel, thereby inducing fatal epilepsy in mice (Brusa et al., 1995; Feldmeyer et al., 1999). In addition, inefficient GluR2 Q/R site editing is a disease-specific molecular dysfunction found in the motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients (Kawahara et al., 2004). Here, we generated genetically modified mice (designated as AR2) in which the ADAR2 gene was conditionally targeted in motor neurons using the Cre/loxP system. These AR2 mice showed a decline in motor function commensurate with the slow death of ADAR2-deficient motor neurons in the spinal cord and cranial motor nerve nuclei. Notably, neurons in nuclei of oculomotor nerves, which often escape degeneration in ALS, were not decreased in number despite a significant decrease in GluR2 Q/R site editing. All cellular and phenotypic changes in AR2 mice were prevented when the mice carried endogenous GluR2 alleles engineered to express edited GluR2 without ADAR2 activity (Higuchi et al., 2000). Thus, loss of ADAR2 activity causes AMPA receptor-mediated death of motor neurons.

Receptor fingerprinting the circling ci2 rat mutant: insights into brain asymmetry and motor control.

Circling behaviour of the ci2 rat mutant, a model for hyperkinetic movement disorders, is associated with an abnormal asymmetry in striatal dopaminergic activity. Since it is more likely that imbalances in several neurotransmitter systems result in the cascade of neurochemical disturbances underlying disorders involving motor dysfunctions, we measured the densities of 12 neurotransmitter receptors in the basal ganglia and vestibular nuclei of adult circling mutants (ci2/ci2), non-circling littermates (ci2/+) and controls from the background strain (LEW/Ztm). In controls, the left caudate putamen (CPu) contains lower kainate and the left globus pallidus higher AMPA densities than their right counterparts. The medial vestibular nucleus of mutants ipsilateral to the preferred direction of rotation contained higher M2 densities than the contralateral one. ci2/+ animals presented no interhemispheric differences, did not differ behaviourally from controls, but contained lower GABAA densities in the CPu, nucleus accumbens (Acb) and reticular (Rt), ventromedial (VM) and ventral posterolateral (VPL) thalamic nuclei. Mutants contained lower GABAA (CPu, Acb, Rt, VPL) but higher nicotinic (Rt, VM) densities than controls and higher GABAA (CPu, VM) densities than ci2/+ rats. Hyperactivity level of mutants was positively correlated with the adenosine A2A receptor densities in the ipsilateral Acb, but negatively correlated with those of the ipsilateral thalamus. Concluding, ci2/ci2 mutants show alterations in GABAA, cholinergic and A2A receptor densities. Our data add to the hypothesis that motor disorders such as hyperkinesias cannot be explained solely by absolute functional increases or decreases in the dopaminergic system, but are due to imbalances in several neurotransmitter systems.

Nicotine produces selective degeneration in the medial habenula and fasciculus retroflexus.

Nicotine's neurotoxic properties in rats were investigated by administering (-)-nicotine tartrate for 5 days either continuously in doses of 5.01, 5.72, 6.44, 7.13, 20.41 and 43.1 mg/kg/day via osmotic minipump or intermittently at 11.32 mg/kg/day via one daily subcutaneous injection. As assessed by silver staining, neurotoxicity was seen almost exclusively in the axons of the medial habenula and its output tract, the fasciculus retroflexus, in all treatment groups except the lowest dose. Within the habenula, the damage was noted in the ventral-medial-most portion of the nucleus which is thought to be dense with the alpha 4 beta 2 and/or alpha 3 beta 4 receptor subtypes. Past research has shown the medial habenula to be highly sensitive to the effects of nicotine, and these findings, in conjunction with related research using dopaminergic stimulants, indicate that the habenula may be a weak link in the neurotoxicity seen following stimulant drugs of abuse.

[The biopsy of brain structures in patients with extrapyramidal hyperkinesia]. / Biopsiia mozgovykh struktur u bol'nykh s ékstrapiramidnymi giperkinezami.

A new device for brain biopsy is presented, the techniques and method of biopsy of brain structures are described which allow full value biopsy material to be obtained from any area of the brain with minimal risk for the patient and high accuracy of hitting the aim. Biopsy of the cerebral and cerebellar cortex, and thalamic and cerebellar nuclei was conducted in 82 patients during stereotaxic operations (34 patients with infantile cerebral paralysis, 8 with torsion dystonia, 8 with spasmodic torticollis). Stereotaxic biopsy of brain tumors of various localization was also performed in 20 patients.

[Chronic toluene intoxication and hyperkinésie volitionnelle].

Hyperkinésie volitionnelle is one of the involuntary movements discriminated from intention tremor. It occurs idiopathically and with cerebral infarction, head trauma, brain tumors, multiple sclerosis, hepatolenticular degeneration and polyneuropathy. Here, we report a case of toluene intoxication presenting hyperkinésie volitionnelle. A 28-year-old painter noticed a tremor of the upper extremities on December 1979. The tremor occurred both in posture and in voluntary movements. The tremor gradually developed and appeared in the legs in May 1980. Slight titubation of the trunk and head was marked in sitting posture. He showed staggering of gait. On August 1980, he exhibited slurred speech. He was admitted to the Department of Neurology of Chiba University Hospital on January 19th, 1981. Neurological examination revealed slight mental deterioration, pendular nystagmus, bradylalia, 4-5 c/s violent postural tremor of the upper extremities, action myoclonus, head and truncal titubation, mild leg tremor in sitting posture. The tremor increased terminally on finger to nose testing, and showed fast, coarse, convulsive movement (movement oppositionniste). But there was no dysmetria. The involuntary movements, above mentioned, were summarized as hyperkinésie volitionnelle. Muscle tone was hypotonic. Muscle weakness and atrophy were not seen. Deep tendon reflexes were all exaggerated, but there was no pathological reflex. He showed wide-based ataxic gait. Sensory and autonomic functions were normal. Blood, urine and cerebrospinal fluid analysis appeared normal. Electroencephalography showed 40-50 microV, 9-10 c/s alpha waves with a few fast waves.(ABSTRACT TRUNCATED AT 250 WORDS)

[Ultrastructural changes in the red bone marrow in hyper- and hypokinesia]. / Ultrastrukturni promeni v cherveniia kosten mozuk pri khiper- i khipokineziia.

Changes were looked for in the bone marrow of rats, put for a long period of ontogenesis under different degrees of muscular activity. The experiment was carried out on three groups of animals of the same age--those for the purpose of control, those loaded with movements, and those immobilized. The ultrastructural picture of the bone marrow with the rats loaded with movements showed an active hematopoiesis which was especially pronounced in the erythrocyte row. We found also an increased activity all over the cellular surface, pinocyte invaginations and vesicles, which were a sign of an intense exchange between the cells and the environment. A lower erythropoietic activity was found in the marrow of the immobilized animals. In this group no erythroblastic isles were found, which is typical of normal erythropoesis. Some young cells showed reduced small organs, whereas others were characterized by a more pronounced vacuolation of the cytoplasm.

Hemiballismus complicating stereotactic thalamotomy.

The pathology of poststereotactic hyperkinesis has been rarely documented and the pathophysiology is still poorly understood. In a case of hemiballismus following thalamotomy for parkinsonism, detailed anatomical studies showed bilateral cortical pseudolaminar necrosis and no involvement of the subthalamic nuclei by the thalamic lesions. The structural and functional effects of surgical lesions upon the preexisting pharmacological abnormalities present in parkinsonism probably constitute the substrate necessary for occurrence of hemiballismus following stereotactic surgery.