Differential contribution of Ih to the integration of excitatory synaptic inputs in substantia nigra pars compacta and ventral tegmental area dopaminergic neurons

The selective vulnerability of substantia nigra pars compacta (SNc) dopaminergic (DA) neurons is an enigmatic trait of Parkinson's disease (PD), especially if compared to the remarkable resistance of closely related DA neurons in the neighboring ventral tegmental area (VTA). Overall evidence indicates that specific electrophysiological, metabolic and molecular factors underlie SNc vulnerability, although many pieces of the puzzle are still missing. In this respect, we recently demonstrated that 1‐methyl‐4‐phenylpyridinium (MPP+), the active metabolite of the parkinsonizing toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP), alters the electrophysiological properties of SNc DA neurons in vitro by inhibiting the hyperpolarization‐activated current (Ih). Here, we present an electrophysiological investigation of the functional role of Ih in the integration of synaptic inputs in identified SNc and VTA DA neurons, comparatively, in acute midbrain slices from TH‐GFP mice. We show that pharmacological suppression of Ih increases the amplitude and decay time of excitatory postsynaptic potentials, leading to temporal summation of multiple excitatory potentials at somatic level. Importantly, these effects are quantitatively more evident in SNc DA neurons. We conclude that Ih regulates the responsiveness to excitatory synaptic transmission in SNc and VTA DA neurons differentially. Finally, we present the hypothesis that Ih loss of function may be linked to PD trigger mechanisms, such as mitochondrial failure and ATP depletion, and act in concert with SNc‐specific synaptic connectivity to promote selective vulnerability.     

Gabapentin treatment of neurogenic overactive bladder

OBJECTIVE: Detrusor overactivity is a well-recognized and distressing medical condition affecting both men and women, with a significant prevalence in the population and with a higher incidence rate in people older than 70 years. This pathological condition is characterized by irritative symptoms: urinary urgency, with or without incontinence, and urinary frequency, often seriously compromising the quality of life of the people who have it. The complaint of these symptoms is defined by the International Continence Society (www.continet.org) as "overactive bladder." Many neurological patients experience irritative symptoms of the lower urinary tract related to their disease, and this condition drastically limits their social life. Various drugs have been introduced in therapy protocols to treat neurogenic detrusor overactivity; however, in many cases, the outcomes of these treatments have proven to be unsatisfactory. This fact is probably related to the incomplete understanding of the pathophysiological aspects of detrusor overactivity. Recent studies suggest the possible role in the detrusor overactivity pathogenesis of bladder receptors, afferent pathways, and spinal cord interneurons; consequently, the modulation of bladder receptor and/or spinal cord centers activity has been proposed as a possible approach to control involuntary detrusor contractions, using drugs capable of acting on bladder afferent pathways.The aim of this study was to evaluate the efficacy of gabapentin, an anticonvulsive agent used by neurologists in the treatment of epilepsy and neurogenic pain, in the treatment of detrusor overactivity of neurogenic origin. METHODS: Sixteen patients affected by neurogenic overactive bladder were enrolled in the study. The clinical outcomes were assessed by symptomatic score evaluations, voiding diary, and urodynamic test before and after 31 days of gabapentin treatment. RESULTS: The preliminary results showed significant modifications of urodynamic indexes, particularly of the detrusor overactivity, whereas the symptomatic score evaluation and the voiding diary data demonstrated a significant lowering of the irritative symptoms. Furthermore, we did not record significant adverse effects and no patient interrupted the drug treatment. CONCLUSIONS: These data support the rationale that detrusor overactivity may be controlled by modulating the afferent input from the bladder and the excitability of the sacral reflex center and suggest a novel method to treat overactive bladder patients.     

Smoking cessation during alcohol treatment: a randomized trial of combination nicotine patch plus nicotine gum

Aims   The primary aim was to compare the efficacy of smoking cessation treatment using a combination of active nicotine patch plus active nicotine gum versus therapy consisting of active nicotine patch plus placebo gum in a sample of alcohol-dependent tobacco smokers in an early phase of out-patient alcohol treatment. A secondary aim was to determine whether or not there were any carry-over effects of combination nicotine replacement on drinking outcomes.
Design   Small-scale randomized double-blind placebo-controlled clinical trial with 1-year smoking and drinking outcome assessment.
Setting   Two out-patient substance abuse clinics provided a treatment platform of behavioral alcohol and smoking treatment delivered in 3 months of weekly sessions followed by three monthly booster sessions.
Participants   Participants were 96 men and women with a diagnosis of alcohol abuse or dependence and smoking 15 or more cigarettes per day.
Intervention   All participants received open-label transdermal nicotine patches and were randomized to receive either 2 mg nicotine gum or placebo gum under double-blind conditions.
Findings   Analysis of 1-year follow-up data revealed that patients receiving nicotine patch plus active gum had better smoking outcomes than those receiving patch plus placebo gum on measures of time to smoking relapse and prolonged abstinence at 12 months. Alcohol outcomes were not significantly different across medication conditions.
Conclusions   Results of this study were consistent with results of larger trials of smokers without alcohol problems, showing that combination therapy (nicotine patch plus gum) is more effective than monotherapy (nicotine patch) for smoking cessation.     

Allogeneic hematopoietic stem cell transplantation for neuromyelitis optica

Neuromyelitis optica is a rare neurological autoimmune disorder characterized by a poor prognosis. Immunosuppression can halt disease progression, but some patients are refractory to multiple treatments, experiencing frequent relapses with accumulating disability. Here we report on durable clinical remissions after allogeneic hematopoietic stem cell transplantation in 2 patients suffering from severe forms of the disease. Immunological data evidenced disappearance of the pathogenic antibodies and regeneration of a naive immune system of donor origin. These findings correlated with evident clinical and radiological improvement in both patients, warranting extended clinical trials to investigate this promising therapeutic option. ANN NEUROL 2014;75:447–453     

Presence of lysine at aa 335 of the hemagglutinin-neuraminidase protein of mumps virus vaccine strain Urabe AM9 is not a requirement for neurovirulence

The recent global resurgence of mumps has drawn attention to the continued need for robust mumps immunization programs. Unfortunately, some vaccines derived from inadequately attenuated vaccine strains of mumps virus have caused meningitis in vaccinees, leading to withdrawal of certain vaccine strains from the market, public resistance to vaccination, or in some cases, cessation of national mumps vaccination programs. The most widely implicated mumps vaccine in cases of postvaccination meningitis is derived from the Urabe AM9 strain, which remains in use in some countries. The Urabe AM9 vaccine virus has been shown to exhibit a considerable degree of nucleotide and amino acid heterogeneity. Some studies have specifically implicated variants containing a lysine residue at amino acid position 335 in the hemagglutinin-neuraminidase (HN) protein with neurotoxicity, whereas a glutamic acid residue at this position was associated with attenuation. To test this hypothesis we generated two modified Urabe AM9 cDNA clones coding either for a lysine or a glutamic acid at position 335 in the HN gene. The two viruses were rescued by reverse genetics and characterized in vitro and in vivo. Both viruses exhibited similar growth kinetics in neuronal and non-neuronal cell lines and were of similar neurotoxicity when tested in rats, suggesting that amino acid 335 is not a crucial determinant of Urabe AM9 growth or neurovirulence.     

Monosomy 7 syndrome in an infant with neurofibromatosis.

A 9-month-old boy with known familial neurofibromatosis type I (NF-1) presented with a clinical and laboratory picture suggestive of juvenile chronic myelomonocytic leukemia (JCMMoL). Chromosomal studies obtained from the bone marrow indicated, however, that he had monosomy 7 syndrome. We believe this is the first reported case of monosomy 7 syndrome in a child with NF in the United States, and that this case complements a recent report of two cases of NF, JCMMoL, and monosomy 7 in Japanese children. Since monosomy 7 syndrome is very difficult to differentiate from JCMMoL or acute nonlymphocytic leukemia (ANLL) unless appropriate chromosomal studies are obtained, we believe it is possible that monosomy 7 may occur with increased frequency in patients with NF-1. Monosomy 7 syndrome might therefore be a significant cause of the known association between NF-1 and nonlymphoid leukemia.