Pathway-specific dopaminergic deficits in a mouse model of Angelman syndrome

Angelman syndrome (AS) is a neurodevelopmental disorder caused by maternal deletions or mutations of the ubiquitin ligase E3A (UBE3A) allele and characterized by minimal verbal communication, seizures, and disorders of voluntary movement. Previous studies have suggested that abnormal dopamine neurotransmission may underlie some of these deficits, but no effective treatment currently exists for the core features of AS. A clinical trial of levodopa (l-DOPA) in AS is ongoing, although the underlying rationale for this treatment strategy has not yet been thoroughly examined in preclinical models. We found that AS model mice lacking maternal Ube3a (Ube3a^m–/p+ mice) exhibit behavioral deficits that correlated with abnormal dopamine signaling. These deficits were not due to loss of dopaminergic neurons or impaired dopamine synthesis. Unexpectedly, Ube3a^m–/p+ mice exhibited increased dopamine release in the mesolimbic pathway while also exhibiting a decrease in dopamine release in the nigrostriatal pathway, as measured with fast-scan cyclic voltammetry. These findings demonstrate the complex effects of UBE3A loss on dopamine signaling in subcortical motor pathways that may inform ongoing clinical trials of l-DOPA therapy in patients with AS.     

Communicative functioning in individuals with Angelman syndrome: a comparative study

PURPOSE: To assess expressive communication in individuals with Angelman syndrome. METHOD: Communicative functioning of individuals with Angelman syndrome (AS) (n = 109) was compared with individuals with mixed etiologies (n = 117) using the Verbal Behaviour Assessment Scale (VerBAS). RESULTS: Within-group analyses of those with AS revealed that the communicative function of manding was significantly more developed than tacting and echoing, and that tacting was significantly more developed than echoing. Low mean total VerBAS-scores were found with individuals who had epilepsy and used anticonvulsant medication, and with those who had profound developmental disabilities. In the comparison group, the function of manding was significantly more developed than both tacting and echoing, while tacting did not differ from echoing. Between-groups analyses revealed that individuals with AS had significantly lower scores on tacting and echoing, but not on manding. CONCLUSION: The overall pattern of VerBAS scores for individuals with AS suggests a possible communicative phenotype.     

Communicative functioning in individuals with Angelman syndrome: a comparative study

Purpose: To assess expressive communication in individuals with Angelman syndrome. Method: Communicative functioning of individuals with Angelman syndrome (AS) (n?=?109) was compared with individuals with mixed etiologies (n?=?117) using the Verbal Behaviour Assessment Scale (VerBAS). Results: Within-group analyses of those with AS revealed that the communicative function of manding was significantly more developed than tacting and echoing, and that tacting was significantly more developed than echoing. Low mean total VerBAS-scores were found with individuals who had epilepsy and used anticonvulsant medication, and with those who had profound developmental disabilities. In the comparison group, the function of manding was significantly more developed than both tacting and echoing, while tacting did not differ from echoing. Between-groups analyses revealed that individuals with AS had significantly lower scores on tacting and echoing, but not on manding. Conclusion: The overall pattern of VerBAS scores for individuals with AS suggests a possible communicative phenotype.     

Communicative functioning in individuals with Angelman syndrome: a comparative study

Purpose: To assess expressive communication in individuals with Angelman syndrome. Method: Communicative functioning of individuals with Angelman syndrome (AS) (n = 109) was compared with individuals with mixed etiologies (n = 117) using the Verbal Behaviour Assessment Scale (VerBAS). Results: Within-group analyses of those with AS revealed that the communicative function of manding was significantly more developed than tacting and echoing, and that tacting was significantly more developed than echoing. Low mean total VerBAS-scores were found with individuals who had epilepsy and used anticonvulsant medication, and with those who had profound developmental disabilities. In the comparison group, the function of manding was significantly more developed than both tacting and echoing, while tacting did not differ from echoing. Between-groups analyses revealed that individuals with AS had significantly lower scores on tacting and echoing, but not on manding. Conclusion: The overall pattern of VerBAS scores for individuals with AS suggests a possible communicative phenotype.     

Dissociation of locomotor and cerebellar deficits in a murine Angelman syndrome model

Angelman syndrome (AS) is a severe neurological disorder that is associated with prominent movement and balance impairments that are widely considered to be due to defects of cerebellar origin. Here, using the cerebellar-specific vestibulo-ocular reflex (VOR) paradigm, we determined that cerebellar function is only mildly impaired in the Ube3a^m–/p+ mouse model of AS. VOR phase-reversal learning was singularly impaired in these animals and correlated with reduced tonic inhibition between Golgi cells and granule cells. Purkinje cell physiology, in contrast, was normal in AS mice as shown by synaptic plasticity and spontaneous firing properties that resembled those of controls. Accordingly, neither VOR phase-reversal learning nor locomotion was impaired following selective deletion of Ube3a in Purkinje cells. However, genetic normalization of αCaMKII inhibitory phosphorylation fully rescued locomotor deficits despite failing to improve cerebellar learning in AS mice, suggesting extracerebellar circuit involvement in locomotor learning. We confirmed this hypothesis through cerebellum-specific reinstatement of Ube3a, which ameliorated cerebellar learning deficits but did not rescue locomotor deficits. This double dissociation of locomotion and cerebellar phenotypes strongly suggests that the locomotor deficits of AS mice do not arise from impaired cerebellar cortex function. Our results provide important insights into the etiology of the motor deficits associated with AS.     

慢性疲劳综合征患儿的全脑功能连接异常

目的 评估慢性疲劳综合征（CFS）患儿静息状态下全脑功能连接异常。方法 对31例CFS患儿（实验组）以及34名健康儿童（对照组）,进行静息态fMRI扫描,应用REST软件包进行后处理。两两计算脑区间自发BOLD变化相关系数的z值。应用双尾t检验比较各自的z值来确定实验组与对照组间功能连接的差异。结果 实验组中共发现15个显著的功能连接异常,其中7个脑区功能连接增强,分别为右侧丘脑-右侧内侧前额叶皮层、右侧岛叶-右侧前扣带回皮层、右侧丘脑-右侧岛叶、右侧丘脑-右侧第二躯体感觉皮层、右侧第一躯体感觉皮层-右侧第二躯体感觉皮层、左侧丘脑-左侧内侧前额叶皮层、左侧丘脑-左侧第二躯体感觉皮层,8个脑区功能连接减弱,分别为右侧丘脑-右侧前扣带回皮层、右侧丘脑-右侧壳核、右侧前扣带回皮层-右侧第一躯体感觉皮层、右侧前扣带回皮层-右侧第二躯体感觉皮层、右侧岛叶-右侧第二躯体感觉皮层、左侧丘脑-左侧壳核、左侧第一躯体感觉皮层-左侧岛叶、左侧第一躯体感觉皮层-左侧第二躯体感觉皮层）。结论 内侧前额叶皮层、岛叶、躯体感觉皮质、前扣带回皮层之间的脑区功能连接异常有可能与CFS的发病和进展有关。     

Multiple organ dysfunction syndrome

Multiple organ dysfunction syndrome (MODS) is a clinical situation that has been described as a result of the rapid progress and advances that have been made in recent decades in the physiology, diagnosis, and therapeutic support of critically ill patients. In 1991, in view of the confusing terminology used to characterize processes coursing with systemic inflammatory response syndrome (SIRS), a consensus conference was held. A series of basic definitions were established and the term "multiple organ failure" was replace by MODS. In response to outside aggression, the organism tries to defend itself with two mechanisms: a non-specific humoral and cellular response called inflammation, and a specific antigenic response that modifies the genetic codes of cells of the defense system and constitutes an immunological response. At present it is thought that the inflammatory response is activated (SIRS) in response to an uncontrolled aggression, but an antiinflammatory response syndrome (ARS) exists as well. An exaggerated SIRS can lead to MODS. MODS usually debuts with pulmonary dysfunction. If the aggression persists, cardiovascular, renal, hepatic, coagulation, central nervous system, gastrointestinal metabolism, neuroendocrine and musculoskeletal failure follow. A series of causes often trigger this syndrome and certain factors favor it. Prevention of these causes and factors in fundamental for controlling the occurrence of MODS. At present, there is no clear treatment for MODS, although numerous studies designed to block the release of certain proinflammatory mediators or to neutralize antiinflammatory responses are being carried out.     

Reactive airways dysfunction syndrome

A possible variant of occupational asthma is induced by acute exposure to high concentrations of nonsensitizing respiratory irritants. This entity is referred to as reactive airways dysfunction syndrome. A case is presented in which the patient developed this syndrome secondary to exposure to a floor sealant. A portable peak expiratory flow meter was used to assess and document work-related airway reactivity changes.     

Sensory dysfunction in burning mouth syndrome

The release of cytosol from damaged cells has been proposed to be a chemical trigger for nociception. K(+), H(+), adenosine triphosphate (ATP), and glutamate are algogenic agents within cytosol that might contribute to such an effect. To examine which, if any, compounds in cytosol activate ion channels on nociceptors, we recorded currents in dissociated nociceptors when nearby skin cells were damaged. Skin cell damage caused action potential firing and inward currents in nociceptors. Extracts of fibroblast cytosol did the same. Virtually all response to extract and cell killing was eliminated by enzymatic degradation of ATP or desensitization or blockade of P2X receptors, ion channels that are activated by extracellular ATP. Thus, if cytosol provides a rapid nociceptive signal from damaged tissue, then ATP is a critical messenger and P2X receptors are its sensor.     

Allelic dropout can cause false-positive results for Prader-Willi and Angelman syndrome testing

The diagnosis of many genetic disorders relies on a combination of clinical suspicion and confirmatory genetic testing. Our laboratory uses a standard methylation-sensitive PCR (MSP) to target the differentially methylated SNRPN gene to test for Prader-Willi syndrome (PWS) and Angelman syndrome. One patient, a 27-month-old female, who lacked the classical clinical features of PWS, but had a molecular diagnosis of PWS by MSP by another laboratory, had repeat testing in our laboratory. Testing by MSP in our laboratory also identified an apparent loss of the unmethylated paternal allele, consistent with a diagnosis of PWS. Confirmatory testing using Southern blot analysis with a methylation-sensitive restriction enzyme showed a normal pattern of methylation, detecting both the methylated maternal and unmethylated paternal alleles. To investigate these discrepant results, we amplified and sequenced the SNRPN locus in this patient and identified a single nucleotide change within the binding site for the unmethylated DNA-specific primer. These results indicate this nucleotide change led to allelic dropout in the MSP analysis, yielding the false-positive result. Subsequently, MSP analysis using an alternate primer set that was developed by our laboratory detected both methylated and unmethylated alleles. These findings illustrate that allelic dropout due to the presence of rare polymorphisms can cause false-positive results in commonly used MSP assays and lead to molecular misdiagnosis.     

Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model

Angelman syndrome (AS) is a severe neurodevelopmental disorder that results from loss of function of the maternal ubiquitin protein ligase E3A (UBE3A) allele. Due to neuron-specific imprinting, the paternal UBE3A copy is silenced. Previous studies in murine models have demonstrated that strategies to activate the paternal Ube3a allele are feasible; however, a recent study showed that pharmacological Ube3a gene reactivation in adulthood failed to rescue the majority of neurocognitive phenotypes in a murine AS model. Here, we performed a systematic study to investigate the possibility that neurocognitive rescue can be achieved by reinstating Ube3a during earlier neurodevelopmental windows. We developed an AS model that allows for temporally controlled Cre-dependent induction of the maternal Ube3a allele and determined that there are distinct neurodevelopmental windows during which Ube3a restoration can rescue AS-relevant phenotypes. Motor deficits were rescued by Ube3a reinstatement in adolescent mice, whereas anxiety, repetitive behavior, and epilepsy were only rescued when Ube3a was reinstated during early development. In contrast, hippocampal synaptic plasticity could be restored at any age. Together, these findings suggest that Ube3a reinstatement early in development may be necessary to prevent or rescue most AS-associated phenotypes and should be considered in future clinical trial design.     

Multiple organ dysfunction syndrome in newborn infants

The present paper outlines the basic idea on multiple organ dysfunctions in the newborn. The major clinical manifestations of multiple organ dysfunctions (MOD) have been studied and are described. The basic systems most susceptible to MOD are determined, and the critical stages of neonality when the development of MOD is extremely high are identified.     

Acute multiple organ dysfunction syndrome in peritonitis

The laws of logic and logical research methods were made use of to assess the already published definitions of "polyorgan insufficiency" and "systemic inflammatory response". Many of them were proven to be far from being perfect; hence, the authors' independent understanding of such notions was suggested.     

Metabolic syndrome and erectile dysfunction

AIM: To study aspects of erectile dysfunction (ED) pathogenesis in patients with metabolic syndrome (MS) and its diagnosis. MATERIAL AND METHODS: Epidemiology of ED in MS patients was studied by determination of MS prevalence among patients with organic ED (MS diagnosis according to NCEP/ATP III criteria), questionnaire assessment of erectile function in MS patients observed by the cardiologist or therapist. ED patients with MS (n = 385) entered the study group. Patients with organic ED free of MS (n = 210) entered the control group. A complex andrologic examination was made to analyse vascular, neurological and hormonal disorders. RESULTS: About 46.4% patients with organic ED had clinical symptoms of MS while 57.02% patients with MS had ED. In the study group ED arose earlier than in the controls (43.46 +/- 9.87 and 50.38 +/- 13.35 years, respectively; p < 0.05) and stood longer (6.36 +/- 4.13 and 3.55 +/- 3.27 years; p < 0.05). From the study group half of the patients had severe ED. Among the controls cases of severe ED were 2 times less frequent. ED in MS was primarily of arteriogenic nature. Blood androgens levels were subnormal in 36.36% patients, neurogenic disorders occurred in 42.2% cases. Endothelial dysfunction was a leading pathogenetic mechanism of ED development in MS. CONCLUSION: MS patients often have ED. The presence of MS entails a severe course and earlier onset of ED.     

肠功能障碍与多器官功能障碍综合征

多器官功能障碍综合征（MODS）是指在严重感染、创伤、大手术、休克、病理产科、心肺复苏后等状态下，机体同时或相继发生2个或2个以上器官功能损伤或衰竭的临床综合征。MODS是一种独立疾病，是机体遭受严重损害后的一种临床综合征，其发病机制非常复杂，至今尚未完全阐明。