Pharmacological properties of a novel class of 5-HT3 receptor antagonists.

The pharmacological profile of six representative members of a novel class of 5-HT3 receptor antagonists is described. The compounds are esters and amides of benzimidazolone-1-carboxylic acid with a basic azabicycloalkyl moiety (compounds 1-3) and their respective ethyl derivatives (compounds 4-6). In isolated preparations (rabbit heart and guinea pig ileum) all compounds antagonized the 5-HT3 receptor-mediated effects of serotonin, with potencies comparable with those of the reference compounds, ICS 205.930 and GR 38032F (-log IC50 9.30-11.9 and 6.8-8.20, in heart and ileum, respectively). In the anaesthetised rat, all agents potently inhibited the Bezold-Jarisch reflex whether given i.v. or i.d. I.v. administration of compounds prevented cisplatin-induced emesis in dogs (ID50 ranging from 3.7 to 147 micrograms/kg). All agents accelerated gastric emptying of solids in rats (ED50 about 10-160 micrograms/kg i.p.). In addition, compounds 4 and 5 were able to stimulate 5-HT4 receptors in the isolated guinea pig ileum, as well as enhance contractile activity in the Heidenhain gastric pouch of dogs, showing clearcut prokinetic properties.     

Anhidrosis in multiple system atrophy: A preganglionic sudomotor dysfunction?

Anhidrosis occurs in the majority of multiple system atrophy (MSA) patients but the underlying site of lesion is not well established. We describe three patients with long‐standing MSA and anhidrosis diagnosed on the basis of a thermoregulatory sweating test. In biopsies of anhidrotic skin, immunofluorescence analysis disclosed a well preserved postganglionic sudomotor innervation in all three patients supporting the hypothesis of a preganglionic nerve fiber lesion underlying their anhidrosis. Postganglionic sudomotor fiber integrity was also confirmed by normal electrodermal responses in one patient, whereas such responses and microneurographically detectable skin sympathetic nerve activity were absent in the other two MSA patients, suggesting a functional inactivity of structurally intact postganglionic sympathetic skin fibers. © 2008 Movement Disorder Society.     

The genetics of migraine

Migraine is currently considered to be a multifactorial disease in that it is modified by environmental and genetic factors and has a polygenic determination. Familial hemiplegic migraine (FHM), a subtype of migraine with aura conforming to simple mendelian transmission, has been shown to result from mutations in the CACNA1A gene, a neural calcium channel gene. FHM is allelic with episodic ataxia type 2 and spinocerebellar ataxia type 6. FHM is genetically heterogeneous, with at least another linkage locus on chromosome 1. Association and linkage studies have also been performed in migraine with and without aura, the so–called typical migraines, without however definite results up to now.     

Antioxidant treatment of hindlimb-unloaded mouse counteracts fiber type transition but not atrophy of disused muscles

Oxidative stress was proposed as a trigger of muscle impairment in various muscle diseases. The hindlimb-unloaded (HU) rodent is a model of disuse inducing atrophy and slow-to-fast transition of postural muscles. Here, mice unloaded for 14 days were chronically treated with the selective antioxidant trolox. After HU, atrophy was more pronounced in the slow-twitch soleus muscle (Sol) than in the fast-twitch gastrocnemius and tibialis anterior muscles, and was absent in extensor digitorum longus muscle. In accord with the phenotype transition, HU Sol showed a reduced expression of myosin heavy chain type 2A (MHC-2A) and increase in MHC-2X and MHC-2B isoforms. In parallel, HU Sol displayed an increased sarcolemma chloride conductance related to an increased expression of ClC-1 channels, changes in excitability parameters, a positive shift of the mechanical threshold, and a decrease of the resting cytosolic calcium concentration. Moreover, the level of lipoperoxidation increased proportionally to the degree of atrophy of each muscle type. As expected, trolox treatment fully prevented oxidative stress in HU mice. Atrophy was not prevented but the drug significantly attenuated Sol phenotypic transition and excitability changes. Trolox treatment had no effect on control mice. These results suggest possible benefits of antioxidants in protecting muscle against disuse.     

Paroxysmal arousals during sleep

Six patients complained of distressing sudden awakenings with abnormal motor activity during sleep causing insomnia. Polysomnography showed paroxysmal short-lasting arousals during NREM, especially slow-wave sleep, associated with complex movements and autonomic activation. Ictal and interictal EEG never showed epileptic discharges except in 1 patient who also had a tonic-clonic seizure during sleep. Carbamazepine was the only effective medication in 2 patients. Paroxysmal arousals represent a sleep disturbance that may be related to deep epileptic foci.     

p46, a Novel Natural Killer Cell–specific Surface Molecule That Mediates Cell Activation

Limited information is available on the surface molecules that are involved in natural killer (NK) cell triggering. In this study, we selected the BAB281 monoclonal antibody (mAb) on the basis of its ability to trigger NK-mediated target cell lysis. BAB281 identified a novel NK cell–specific surface molecule of 46 kD (p46) that is expressed by all resting or activated NK cells. Importantly, unlike the NK cell antigens identified so far, the expression of p46 was strictly confined to NK cells. Upon mAb-mediated cross-linking, p46 molecules induced strong cell triggering leading to [Ca²⁺]i increases, lymphokine production, and cytolytic activity both in resting NK cells and NK cell clones. The p46-mediated induction of Ca²⁺ increases or triggering of cytolytic activity was downregulated by the simultaneous engagement of inhibitory receptors including p58, p70, and CD94/NKG2A. Both the unique cellular distribution and functional capability of p46 molecules suggest a possible role in the mechanisms of non-major histocompatibility complex–restricted cytolysis mediated by human NK cells.     

Identification of a human endogenous LTR-like sequence using HIV-1 LTR specific primers

Using «consensus» primers derived from the LTR region of 15 HIV-1 isolates, a fragment of 583 bp was amplified from human DNA. Even though specificity was confirmed by Southern blot analysis with a conserved LTR oligonucleotide probe, no significant homologies were detected to either retroviral regions or human or non-human published sequences. Nevertheless, when used as a probe, the 583-bp fragment identified a unique DNA sequence in the human genome on chromosome 1, and cross-reactive sequences in monkey, but not mouse, DNA. This novel, unique and conserved sequence of 583 bp was used to isolate a human HS-1 clone in which the structural property of a viral LTR could be identified.     

Pp65 antigenemia,plasma real-time PCR and DBS test in symptomatic and asymptomatic cytomegalovirus congenitally infected newborns

Background  

Many congenitally cytomegalovirus-infected (cCMV) neonates are at risk for severe consequences, even if they are asymptomatic at birth. The assessment of the viral load in neonatal blood could help in identifying the babies at risk of sequelae.     

An In Vivo Autotransplant Model of Renal Preservation: Cold Storage Versus Machine Perfusion in the Prevention of Ischemia/Reperfusion Injury

There is increasing proof that organ preservation by machine perfusion is able to limit ischemia/reperfusion injury in kidney transplantation. This study was designed to compare the efficiency in hypothermic organ preservation by machine perfusion or cold storage in an animal model of kidney autotransplantation.
Twelve pigs underwent left nephrectomy after warm ischemic time; the organs were preserved in machine perfusion ( n  = 6) or cold storage ( n  = 6) and then autotransplanted with immediate contralateral nephrectomy. The following parameters were compared between the two groups of animals: hematological and urine indexes of renal function, blood/gas analysis values, histological features, tissue adenosine-5'-triphosphate (ATP) content, perforin gene expression in kidney biopsies, and organ weight changes were compared before and after preservation.
The amount of cellular ATP was significantly higher in organs preserved by machine perfusion; moreover, the study of apoptosis induction revealed an enhanced perforin expression in the kidneys, which underwent simple hypothermic preservation compared to the machine-preserved ones. Organ weight was significantly decreased after cold storage, but it remained quite stable for machine-perfused kidneys.
The present model seems to suggest that organ preservation by hypothermic machine perfusion is able to better control cellular impairment in comparison with cold storage.