Progressive Hyperactivity Research Articles

IL-2 Therapy Diminishes Renal Inflammation and the Activity of Kidney-Infiltrating CD4+ T Cells in Murine Lupus Nephritis.

An acquired deficiency of interleukin-2 (IL-2) and related disturbances in regulatory T cell (Treg) homeostasis play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Low-dose IL-2 therapy was shown to restore Treg homeostasis in patients with active SLE and its clinical efficacy is currently evaluated in clinical trials. Lupus nephritis (LN), a challenging organ manifestation in SLE, is characterized by the infiltration of pathogenic CD4+ T cells into the inflamed kidney. However, the role of the Treg-IL-2 axis in the pathogenesis of LN and the mode of action of IL-2 therapy in the inflamed kidneys are still poorly understood. Using the (NZB × NZW) F1 mouse model of SLE we studied whether intrarenal Treg are affected by a shortage of IL-2 in comparison with lymphatic organs and whether and how intrarenal T cells and renal inflammation can be influenced by IL-2 therapy. We found that intrarenal Treg show phenotypic signs that are reminiscent of IL-2 deprivation in parallel to a progressive hyperactivity of intrarenal conventional CD4+ T cells (Tcon). Short-term IL-2 treatment of mice with active LN induced an expansion the intrarenal Treg population whereas long-term IL-2 treatment reduced the activity and proliferation of intrarenal Tcon, which was accompanied by a clinical and histological amelioration of LN. The association of these immune pathologies with IL-2 deficiency and their reversibility by IL-2 therapy provides important rationales for an IL-2-based immunotherapy of LN.

A novel mutation R190H in the AT-hook 1 domain of MeCP2 identified in an atypical Rett syndrome.

BackgroundMutations in Methyl-CpG binding protein 2 (MECP2) have been identified as the disease-causing mutations in Rett Syndrome (RTT). However, no mutation in the AT-hook 1 domain of MECP2 has been reported in RTT yet. The function of AT-hook 1 domain of MECP2 has not been described either.MethodsThe clinical and radiological features of a girl with progressive hyperactivity and loss of acquired linguistic and motor functions were presented. Next generation sequencing was used to screen the causative gene. Effect of the mutant protein on histone 3 methylation was assessed in vitro experiment.ResultsThe patient was diagnosed with an atypical RTT at the age of nine. Magnetic resonance imaging revealed a loss of whole-brain volume and abnormal myelination. Genetic analysis identified a de novo novel missense mutation of MECP2 (NM_004992, c.570G->A, p.Arg190His). This mutation is located in the AT-hook 1 domain of MeCP2 protein. Overexpression of the mutant MeCP2 in cultured neuroblastoma cells SH-SY5Y revealed increased level of dimethylated histone 3 lysine 9, a transcriptional repressor marker.ConclusionA novel missense mutation in AT-hook 1 domain of MeCP2 was identified in a patient with atypical RTT. Clinical data and in vitro experiment result imply that R190H mutation in AT-hook1 may cause dysfunction of MeCP2 and be a pathogenic variant.

Dicer expression is essential for adult midbrain dopaminergic neuron maintenance and survival

The type III RNAse, Dicer, is responsible for the processing of microRNA (miRNA) precursors into functional miRNA molecules, non-coding RNAs that bind to and target messenger RNAs for repression. Dicer expression is essential for mouse midbrain development and dopaminergic (DAergic) neuron maintenance and survival during the early post-natal period. However, the role of Dicer in adult mouse DAergic neuron maintenance and survival is unknown. To bridge this gap in knowledge, we selectively knocked-down Dicer expression in individual DAergic midbrain areas, including the ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc) via viral-mediated expression of Cre in adult floxed Dicer knock-in mice (Dicer(flox/flox)). Bilateral Dicer loss in the VTA resulted in progressive hyperactivity that was significantly reduced by the dopamine agonist, amphetamine. In contrast, decreased Dicer expression in the SNpc did not affect locomotor activity but did induce motor-learning impairment on an accelerating rotarod. Knock-down of Dicer in both midbrain regions of adult Dicer(flox/flox) mice resulted in preferential, progressive loss of DAergic neurons likely explaining motor behavior phenotypes. In addition, knock-down of Dicer in midbrain areas triggered neuronal death via apoptosis. Together, these data indicate that Dicer expression and, as a consequence, miRNA function, are essential for DAergic neuronal maintenance and survival in adult midbrain DAergic neuron brain areas.

Neurofibromatosis type 1 (NF1) associated with tumor of the corpus callosum

Neurofibromatosis type 1 (NF1), one of the most common neurocutaneous disorders, is a multisystemic disease associated with tumors in any organ of the body, especially in the central nervous system and also the peripheral nervous system. Pilocytic astrocytomas have been described in almost all intracranial regions in patients with NF1. However, only a few patients with NF1 and tumor of the corpus callosum have been reported to date. An 11-year-old white Spanish boy was evaluated due to a family history of NF1 and low performance test scores in school. He was studied from the neurological and intellectual level points of view. Magnetic resonance (MR) study revealed a tumor in the anterior-middle portion of the corpus callosum and a Wechsler Intelligence Scale for Children-Revised showed verbal IQ of 92, a performance IQ of 108, and a total IQ of 100. In addition, he showed attention deficit and hyperactivity disorder. Tumors of corpus callosum in patients with NF1 are very uncommon. The patient presented in this paper consulted due to family history of NF1, progressive hyperactivity, and below average school performance. The MR study showed tumor in the corpus callosum. Tumor histology was not investigated.

β-Amyloid(Phe(SO 3H) 24)25–35 in rat nucleus basalis induces behavioral dysfunctions, impairs learning and memory and disrupts cortical cholinergic innervation

Long-term behavioral effects, changes in learning and memory functions and aberrations of cholinergic fibers projecting to the parietal cortex were investigated after bilateral injections of β-amyloid(Phe(SO 3H) 24)25–35 peptide in rat nucleus basalis magnocellularis ( nbm). The β-amyloid peptide used in these experiments contained the original β-amyloid 25–35 sequence which was coupled to a phenylalanine-sulphonate group at position 24. This additional residue serves as a protective cap on the molecule without influencing its neurotoxic properties and results in water-solubility, stability and low rates of peptide metabolism. In this paper, home cage, locomotor and open-field activities, passive shock-avoidance and `Morris' water maze learning abilities were assessed throughout a 35-day survival period. Subsequently, acetylcholinesterase (AChE) histochemistry was used to visualize alterations of parietal cortical cholinergic innervation. In response to the neurotoxic action of β-amyloid(Phe(SO 3H) 24)25–35, a progressive hyperactivity developed in the rats in their home cages which were maintained throughout the 5-week post-injection period. This was accompanied by a significant hypoactivity in the novel environment of a locomotor arena. β-Amyloid(Phe(SO 3H) 24)25–35-treated animals showed greatly impaired cortical memory functions in the step-through passive shock-avoidance paradigm, while spatial learning processes remained unaffected. Moreover, β-amyloid(Phe(SO 3H) 24)25–35 injections in the nucleus basalis suppressed explorative behavior in rats and inhibited conditioned stress responses 28 days after surgery. Reductions of cortical cholinergic (AChE-positive) projections provided anatomical substrate for the behavioral changes. This indicated extensive, long-lasting neurodegenerative processes as a result of β-amyloid(Phe(SO 3H) 24)25–35 infusion.

Prenatal and postnatal chronic lead intoxication and running wheel activity in the rat

Prenatal and postnatal chronic lead intoxicaton was induced in Wistar rats with 0.1 mg/ml PbCl 2 in the drinking water of pregnant and lactating females. Offspring were supplied lead water at weaning. Exposure totaled 14 months. Activity was measured in the Wahman LC-33 wheel. Running activity experimental and control rats was maximized with a 23-hr light cycle followed by a 5-hr dark period in the wheels. There was no significant difference in body weight gains or lead intake (as measured by water consumption) between any sex-matched group. Lead was found to produce overall hypoactivity in both males and females. Under auditory stress the hypoactivity in the males was normalized by combination of a hypoactivity component in the controls and a progressive hyperactivity in the lead animals. This study clearly shows a sex-dependent hypoactivity effect of chronic lead intoxication and suggests its mechanism as an interaction between lead and environmental stress.

Management of Alcohol Withdrawal Syndromes

Withdrawal from alcohol (ethanol, ethyl alcohol) or other general sedatives leads to progressive hyperactivity that progresses from tremulousness, sleep disturbance, and hallucinosis, to the more serious rum fits and delirium tremens (DTs). Withdrawal can be prevented and, in most cases, arrested by prompt replacement of alcohol with paraldehyde, benzodiazepines or other general sedatives. Diazepam is appropriate replacement therapy for most patients. When delirium is manifest, the chance is greater than 15% that the patient will die, and this reaction cannot be aborted. The patient with DTs must be calmed with a general sedative that has a rapid onset of maximal effect to prevent overdosage. Diazepam, 5 mg intravenously every five minutes, permits evaluation of the maximal effect of each dose before the next dose is administered. Although some patients have advance sedative or alcohol withdrawal, great care must be taken to elicit the proper history of alcohol abuse so that sedative replacement therapy will prevent or abort early withdrawal, thus sparing the patient a mortality equivalent to that of acute myocardial infarction or Russian roulette.