Biomedical subjects

A Najib

Publications and source records attributed to A Najib.

13 recordsLinked to original sources

PubMed2006

Moderate therapeutic efficacy of positron emission tomography-navigated repetitive transcranial magnetic stimulation for chronic tinnitus: a randomised, controlled pilot study.

BACKGROUND: Tinnitus has been shown to respond to modulations of cortical activity by high-frequency and low-frequency repetitive transcranial magnetic stimulation (rTMS). OBJECTIVE: To determine the tinnitus-attenuating effects of a 2-week daily regimen of rTMS, navigated to the maximum of tinnitus-related increase in regional cerebral blood flow. METHODS: Six patients with chronic tinnitus were enrolled in this sham-controlled crossover study and treated with 2x2 weeks of suprathreshold 1 Hz rTMS (30 min) applied to the region with maximal tinnitus-related increase in regional cerebral blood flow delineated by functional imaging with [15O]H2O positron emission tomography and a control area. Tinnitus-related distress was assessed before and after each treatment and 2 weeks after the end of the 4-week course of stimulation using a validated tinnitus questionnaire. Additional self-assessment scores of tinnitus change, loudness and annoyance were obtained. RESULTS: In five of six patients, rTMS induced greater reduction of the tinnitus questionnaire score than sham stimulation. In two patients, all parameters measured (tinnitus change score, tinnitus loudness, tinnitus annoyance) showed unequivocal improvement. At the group level, the degree of response in the tinnitus questionnaire score was correlated with tinnitus-associated activation of the anterior cingulate cortex. Two weeks after the final stimulation, tinnitus had returned to baseline in all patients but one. CONCLUSION: Tinnitus can be attenuated by low-frequency rTMS navigated to each person's maximum tinnitus-related cortical hyperactivity. The effects are only moderate; interindividual responsiveness varies and the attenuation seems to wear off within 2 weeks after the last stimulation session. Notably, tinnitus-related anterior cingulate cortex activation seems to predict the response to rTMS treatment.

Aged↗

PubMed2004

Doping strategies to optimise the oxide ion conductivity in apatite-type ionic conductors.

The apatite-type phases, La(9.33+x)(Si/Ge)(6)O(26+3x/2), have recently been attracting considerable interest as potential electrolytes for solid oxide fuel cells. In this paper we report results from a range of doping studies in the Si based systems, aimed at determining the key features required for the optimisation of the conductivities. Systems examined have included alkaline earth doping on the rare earth site, and P, B, Ga, V doping on the Si site. By suitable doping strategies, factors such as the level of cation vacancies and oxygen excess have been investigated. The results show that the oxide ion conductivities of these apatite systems are maximised by the incorporation of either oxygen excess or cation vacancies, with the former producing the best oxide ion conductors. In terms of samples containing cation vacancies, conductivities are enhanced by doping lower valent ions, Ga, B, on the Si site. The presence of higher valent ions on these sites, e.g. P, appears to inhibit the incorporation of excess oxygen within the channels, and so limits the maximum conductivity that can be obtained. Overall the results suggest that the tetrahedral sites play a key role in the conduction properties of these materials, supporting recent modelling studies, which have suggested that these tetrahedra aid in the motion of the oxide ions down the conduction channels by co-operative displacements.

Journal Article↗

PubMed2001

Tetanus toxin modulates serotonin transport in rat-brain neuronal cultures.

As has been previously described, tetanus toxin (TeTx) and its H(C) fragment inhibit the sodium-dependent 5-hydroxytryptamine (5-HT) uptake in rat-brain synaptosomes, probably through a kinase mechanism affecting the 5-HT transporter. Now, the inhibition of 5-HT uptake in neurons in primary culture by TeTx in a dose-dependent manner is described in this work. This effect is also produced by the nontoxic C-terminal fragment of the TeTx heavy chain (H(C)-fragment), indicating that 5-HT uptake inhibition is a consequence of the toxin binding to the plasmatic membrane and not to its catalytic activity. This conclusion is supported by the fact that the 5-HT accumulation was not inhibited by the light chain of TeTx or the toxoid, and was even potentiated by botulinum neurotoxin A. These results correlate with the activation of phosphoinositide-phospholipase C activity in the cultures used in this study, this activity only being enhanced by TeTx and by its Hc-fragment. On the other hand, the use of tyrosine phosphorylation modulators indicates that both Na3VO4 and basic fibroblast growth factor (bFGF) produce an enhancement of 5-HT uptake in this system, which is also sensitive to TeTx inhibition. On the other hand, genistein alone is able to reduce the 5-HT transport in cultured neurons, and this effect did not appear to be additive to that elicited by TeTx. This result suggests that TeTx and genistein may share some events in their respective mechanisms of action. Furthermore, the incubation at different concentrations of 12-O-tetradecanoylphorbol 13-acetate (TPA) confirms the involvement of protein kinase C (PKC) in 5-HT transport modulation in rat-brain neuronal primary cultures. In summary, we shall demonstrate in this work that TeTx induces, through its Hc fragment, an inhibition of both basal and stimulated serotonin uptakes in primary neuronal cultures, in parallel to the activation of phosphoinositide-phospholipase C activity and PKC activation.

Animals↗

PubMed2000

Serotonin transporter phosphorylation modulated by tetanus toxin.

Tetanus toxin (TeTx) modifies Na(+)-dependent, high-affinity 5-hydroxytryptamine (5-HT, serotonin) uptake in a synaptosomal-enriched P(2) fraction from rat brain. The effect corresponds to a rapid and non-competitive uptake inhibition, and it is preceded by induction of phospholipase C (PLC) activity and translocation and down-regulation of the classical protein kinase C (PKC-alpha, -beta and -gamma) isoforms. The effects on serotonin transport and on cPKC activation were similar to the effects exhibited by phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA). Moreover, after treatment with TeTx, an increase in Ser- and Tyr-specific phosphorylation was found. Activation of PKC by both TeTx and TPA results in a loss of transport capacity and serotonin transporter (SERT) phosphorylation, which are abolished by coapplication of the specific PKC inhibitor bisindolylmaleimide-1. Since a specific PLCgamma1 phosphorylation prior to TeTx's inducing SERT phosphorylation was found, the studies suggest that part of the action of TeTx consists of modifying the signal cascade initiated in tyrosine kinase receptors on nerve tissue previous to its cellular internalization, resulting in transporter phosphorylation.

Animals↗

PubMed1999

Inhibition by tetanus toxin of sodium-dependent, high-affinity [3H]5-hydroxytryptamine uptake in rat synaptosomes.

Tetanus toxin (TeTx) is a powerful clostridial neurotoxin that inhibits Ca2+-dependent neurotransmitter secretion as do the botulinum neurotoxins (BoNTs). We found that TeTx (but not BoNT/A) produced a specific time- and dose-dependent inhibition of Na+-dependent [3H]5-hydroxytryptamine (serotonin, 5-HT) uptake in rat CNS synaptosomes. This effect was found in all CNS tryptaminergic areas, being maximal in the hippocampus and occipital cortex. TeTx produced the maximum reduction in [3H]5-HT uptake after 30 min of preincubation, being significant also at lower doses (10(-12) M) or shorter incubation times (10 min). Serotonin transport inhibitors such as fenfluramine (IC50, 11.0 +/- 0.9 microM), paroxetine (IC50, 33.5 +/- 0.1 microM), and imipramine (IC50, 89.9 +/- 5.7 microM) were 3 or 4 orders of magnitude less potent than TeTx (IC50, 8.7 +/- 1.0 nM). Of the two fragments of TeTx, (the C-terminal portion of the neurotoxin heavy chain, which is responsible for the binding to the nerve tissue) was consistently more effective than the L-H(N) fragment (the light neurotoxin chain disulfide linked to the N-terminal portion of the heavy chain, which is responsible for the toxic metalloprotease action) as inhibitor of [3H]5-HT uptake in synaptosomal preparations (56 +/- 5% and 95 +/- 3% with respect to control, respectively). Antagonism of the toxin-induced [3H]5-HT uptake blockade could not be reversed by zinc chelators but did have the ability to antagonize the TeTx inhibition of basal and K+-evoked [3H]5-HT release in rat synaptosomes. The reduction in serotonin accumulation induced by TeTx could be responsible for some tetanic symptoms that have been related to the serotonergic system.

Animals↗

PubMed1999

Clostridium neurotoxins influence serotonin uptake and release differently in rat brain synaptosomes.

Clostridium neurotoxins produce inhibition of both basal and K(+)-evoked serotonin release in rat brain synaptosomes. To produce these effects, tetanus toxin (TeTx), as well as botulinum neurotoxin type A (BoNT/A), added to brain synaptosomes, must be incubated at 37 degrees C over a long interval (hours). This serotonin exocytosis inhibition was abolished with previous treatment with specific Zn2(+)-metalloprotease inhibitors. Nevertheless, a short incubation time produces different behavior of the indicated neurotoxins: TeTx significantly blocks the sodium-dependent, high-affinity serotonin uptake, whereas a small increase of this uptake was found with BoNT/A. Both Zn2(+)-metalloprotease active fragments, light chains of TeTx and BoNT/A, are unable to reproduce the block of the serotonin uptake, whereas the C-terminal portion of the TeTx heavy chain (Hc-TeTx), which binds specifically to the target tissue, inhibited the serotonin uptake in a dose-dependent manner. The IC50 of Hc-TeTx ranges from 0.62 to 2.08 nM. Binding of [3H]imipramine and [3H]serotonin did not change after toxin treatments, which indicates that these clostridium neurotoxins do not act on the serotonin high-affinity site at the serotonin transporter or at other serotonin high-affinity sites. These results could indicate that TeTx and Hc-TeTx bind to different targets than BoNT/A in the plasma membrane.

Animals↗

PubMed1992

Thoracic esophageal perforations at a Virginia hospital 1979-1990.

A study was made of all patients who underwent management for distal esophageal perforation at the Fairfax Hospital from September 1979 to September 1990. The study group consisted of 13 patients. Nine were male, four female. Mean age was 60.8 yrs, ranging from 36 to 83 yrs. In the group of nine patients diagnosed early (less than 24 hrs), hospital mortality was 22.2% versus 75% in the group of four diagnosed late (greater than 24 hrs). Of the six patients treated conservatively, either medically or surgically, only one survived, but all seven patients diagnosed early and aggressively operated upon survived. Thus the authors agree with others in espousing aggressive, definitive surgery for patients diagnosed early.

Adult↗

PubMed1988