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Biomedical subjects

N Bakry

Publications and source records attributed to N Bakry.

14 recordsLinked to original sources
PubMed1999

[Why patients do not comply with reference decision made by general practitioners?].

SUBJECT: A health system's efficacy depends on the efficacy of its different components (first-level health services and hospitals). It also depends on the system's ability to ensure the continuity of care among the various levels of the system. Health care officials in Settat Province, Morocco, found continuity in this province to be unsatisfactory. Depending on the health centre involved, only 31 to 52% of patients referred from the first to the second level of care reached the hospital. METHODS: The study was conducted in two rural and two urban health centres (HCs) covering a total population of around 94,000. The methodology consisted of two steps. First we analysed retrospectively various determinants (age, gender, distance, time until appointment) that might influence the compliance of patients referred by the four health centres in 1994. Then we observed curative medical consultations conducted in each of these health centres over a three-day period; the 38 patients referred to the hospital over this period were interviewed and the organisation of the hospital used on was analysed. RESULTS: The results revealed low compliance: only 43% (782/1807) of the patients referred actually consulted the hospital's departments. The compliance rates varied from one HC to the other and were lower in rural than urban areas taken as a whole (34% (207/607) versus 48% (575/1200), respectively). The interviews revealed that patients did not trust the last-year medical students who staffed the emergency rooms. Another organisational problem in the hospital was identified: patients referred to the hospital to consult a specialist were not seen immediately but given appointments at later dates, and these waiting times influenced the final success of the referral process. Thus, if the patients were seen immediately, compliance increased from 48 to 77% in the case of the urban HCs and from 34 to 67% in the case of the rural HCs. CONCLUSION: The most important determinants of compliance were above all associated with the way health services were organized and the quality of communication between health professionals and patients.

Adolescent↗
PubMed1997

In vitro characterization of botulinum toxin types A, C and D action on human tissues: combined electrophysiologic, pharmacologic and molecular biologic approaches.

Human exposure to botulinum toxin typically occurs in two settings: 1) as an etiologic agent in the disease botulism and 2) as a therapeutic agent for the treatment of dystonia. Epidemiologic studies on botulism suggest that the human nervous system is susceptible to five toxin serotypes (A, B, E, F and G) and resistant to two (C and D). In the past, these epidemiologic findings have been used as the basis for selecting serotypes that should be tested as therapeutic agents for dystonia. Epidemiologic data have been utilized because there are no studies of botulinum neurotoxin action on isolated human nerves. In the present study, electrophysiologic techniques were used to monitor toxin effects on neuromuscular transmission in surgically excised human pyramidalis muscles, ligand binding studies were done to detect and characterize toxin receptors in human nerve membrane preparations, and molecular biologic techniques were used to isolate and sequence a human gene that encodes a substrate for botulinum neurotoxin. The results demonstrated that stable resting membrane potentials (-61.5 mV; S.E.M. +/- 0.7) were maintained in individual fibers of pyramidalis muscle for up to 6 hr at 33 degrees C. The rate of spontaneous miniature endplate potentials was low in physiologic solution (0.14 sec(-1)) but increased in response to elevations in extracellular potassium concentration. In keeping with epidemiologic findings, botulinum toxin type A (10(-8) M) paralyzed transmission in human preparations (ca. 90 min). In contrast to epidemiologic findings, serotype C (10(-8) M) also paralyzed human tissues (ca. 65 min). Iodinated botulinum toxin displayed high-affinity binding to receptors in human nerve membrane preparations (serotype A high-affinity site: K(d) = 0.3 nM, B(max) = 0.78 pmol/mg protein; serotype C high-affinity site: K(d) = 1.96 nM, B(max) = 8.9 pmol/mg protein). In addition, the human nervous system was found to encode polypeptides that are substrates for botulinum neurotoxin types A (synaptosomal-associated protein of M(r) 25,000) and C (syntaxin 1A). These data have important implications bearing on: 1) the development and administration of vaccines against botulism and 2) the testing of toxin serotypes for the treatment of dystonia.

Botulinum Toxins↗
PubMed1994

Inhibition of vacuolar adenosine triphosphatase antagonizes the effects of clostridial neurotoxins but not phospholipase A2 neurotoxins.

Bafilomycin A1, an inhibitor of vacuolar adenosine triphosphatase, was tested for its ability to antagonize botulinum neurotoxins (serotypes A-G), tetanus toxin and phospholipase A2 neurotoxins (notexin, beta-bungarotoxin, taipoxin and textilotoxin) on the mouse phrenic nerve-hemidiaphragm preparation. Bafilomycin itself produced concentration-dependent blockade of neuromuscular transmission without blocking nerve action potentials or muscle action potentials. This effect may have been due to inhibition of the proton pump that regulates acetylcholine transport into vesicles. At submaximal concentrations, bafilomycin was very effective in delaying the onset of paralysis due to all clostridial neurotoxins, but it had no protective effect against phospholipase A2 neurotoxins. Experiments were done to determine which of the three steps in clostridial neurotoxin action was antagonized by bafilomycin (e.g., binding, internalization and intracellular poisoning). Both pharmacological experiments and ligand-binding experiments showed that the drug did not block toxin binding to the plasma membrane. Similarly, pharmacological experiments on the time-dependent effects of bafilomycin showed that the drug did not antagonize the intracellular actions of toxins. The data indicated that bafilomycin acted at the intermediate step of internalization. This is in keeping with the facts that: 1) bafilomycin inhibits vacuolar adenosine triphosphatase, which in turn leads to inhibition of acidification in endosomes and 2) clostridial neurotoxins depend upon acidification of endosomes for translocation to the cytosol. The finding that bafilomycin antagonizes tetanus toxin may provide important clues for understanding how this toxin can act locally to produce flaccid paralysis. The finding that bafilomycin is a universal antagonist that protects against all clostridial neurotoxins may have important implications for developing therapeutic drugs.

Adenosine Triphosphatases↗
PubMed1993

Low molecular weight poly(A)+ mRNA species encode factors that modulate gating of a non-Shaker A-type K+ channel.

Voltage-dependent K+ channels control repolarization of action potentials and help establish firing patterns in nerve cells. To determine the nature and role of molecular components that modulate K+ channel function in vivo, we coinjected Xenopus oocytes with cRNA encoding a cloned subthreshold A-type K+ channel (mShal1, also referred to as mKv4.1) and a low molecular weight (LMW) fraction (2-4 kb) of poly(A)+ mRNA (both from rodent brain). Coinjected oocytes exhibited a significant (fourfold) increase in the surface expression of mShal1 K+ channels with no change in the open-channel conductance. Coexpression also modified the gating kinetics of mShal1 current in several respects. Macroscopic inactivation of whole oocyte currents was fitted with the sum of two exponential components. Both fast and slow time constants of inactivation were accelerated at all membrane potentials in coinjected oocytes (tau f = 47.2 ms vs 56.5 ms at 0 mV and tau s = 157 ms vs 225 ms at 0 mV), and the corresponding ratios of amplitude terms were shifted toward domination by the fast component (Af/As = 2.71 vs 1.17 at 0 mV). Macroscopic activation was characterized in terms of the time-to-peak current, and it was found to be more rapid at all membrane potentials in coinjected oocytes (9.9 ms vs 13.5 ms at 0 mV). Coexpression also leads to more rapid recovery from inactivation (approximately 2.4-fold faster at -100 mV). The coexpressed K+ currents in oocytes resemble currents expressed in mouse fibroblasts (NIH3T3) transfected only with mShal1 cDNA. These results indicate that mammalian regulatory subunits or enzymes encoded by LMW mRNA species, which are apparently missing or expressed at low levels in Xenopus oocytes, may modulate gating in some native subthreshold A-type K+ channels.

3T3 Cells↗
PubMed1993

Chelation of zinc antagonizes the neuromuscular blocking properties of the seven serotypes of botulinum neurotoxin as well as tetanus toxin.

Botulinum neurotoxin types A, B (unactivated and activated), C, D, E, F and G, as well as tetanus toxin, paralyzed transmission in mouse phrenic nerve-hemidiaphragm preparations. Toxin-induced blockade of transmission was antagonized by chelators [e.g., ethylenediamine tetraacetic acid, tetrakis(2-pyridylmethyl)ethylenediamine or diethylene-triaminepentaacetic anhydride], but this effect was dependent on incubation conditions. Pretreatment of toxin with chelators failed to produce antagonism, but pretreatment of tissues did produce antagonism. Of the various chelators tested, tetrakis(2-pyridylmethyl)ethylenediamine produced the greatest effect. Antagonism of toxin-induced neuromuscular blockade could be partially reversed by washing chelators from tissues and could be fully reversed by adding an excess of zinc. The ability of chelators to antagonize clostridial neurotoxins was specific and did not extend to phospholipase A2 neurotoxins. Ligand-binding studies with radioiodinated toxin and brain membrane preparations showed that chelators did not antagonize toxicity by inhibiting toxin association with receptors. Similarly, pharmacological experiments with unlabeled toxin- and type-specific antibodies demonstrated that chelators did not act by blocking receptor-mediated internalization of toxin. The chelators appeared to exert their effects by antagonizing the intracellular actions of clostridial neurotoxins. Electrophysiological studies showed that chelators, at concentrations relevant to antagonism of botulinum neurotoxin and tetanus toxin, did not enhance transmitter release.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Lectins from Triticum vulgaris and Limax flavus are universal antagonists of botulinum neurotoxin and tetanus toxin.

Lectins from Anguilla anguilla, Artocarpus integrifolia, Canavalia ensiformis, Datora stramonium, Glycine max, Limax flavus, Ricinus communis and Triticum vulgaris were tested for their abilities to antagonize the binding of botulinum neurotoxin and tetanus toxin to rat brain membranes and to antagonize the ability of these toxins to block neuromuscular transmission in mouse phrenic nerve-hemidiaphragm preparations. Lectins from Limax flavus and Triticum vulgaris, both of which have affinity for sialic acid, were antagonists of the various serotypes of botulinum neurotoxin and tetanus toxin. When tested against the high affinity binding site for botulinum neurotoxin type B, the lectin from Limax flavus had a Ki of 3.1 x 10(-7) M and the lectin from Triticum vulgaris had a Ki of 3.75 x 10(-7) M. When tested against the high affinity binding site for tetanus toxin, the lectins from Limax flavus and Triticum vulgaris had Ki values of 1.5 x 10(-7) and 1 x 10(-6) M, respectively. In all cases the lectins behaved as competitive antagonists. In reverse experiments, neither botulinum toxin nor tetanus toxin was a very effective antagonist of lectin binding to brain membranes. Studies on isolated neuromuscular preparations showed that the lectin from Triticum vulgaris did not affect transmission at concentrations of 10(-6) to 10(-3) M, but at a concentration of 3 x 10(-5) M the lectin produced highly statistically significant antagonism of the neuromuscular blocking properties of botulinum neurotoxin types A, B, C, D, E and F as well as tetanus toxin. The lectin did not antagonize beta-bungarotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Tetanus toxin and neuronal membranes: the relationship between binding and toxicity.

Tetanus toxin labeled by the Bolton-Hunter technique possesses high specific activity and retains substantial biological activity. This material can be used to characterize tetanus toxin binding to receptors in brain membrane preparations. In experiments aimed at measuring the absorption of labeled toxin, the displacement of labeled toxin by unlabeled toxin and the on-rate and off-rate constants, the data revealed two binding sites. The high affinity site had a Kd of 0.033 to 0.070 nM and a Bmax of 0.26 to 0.4 pmol/mg of protein; the low affinity site had a Kd of 0.89 to 6.9 nM and a Bmax of 1.55 to 3.0 pmol/mg of protein. The binding of tetanus toxin to brain membranes was enhanced greatly by low pH and ionic strength. Similarly to tetanus toxin, botulinum neurotoxin could be labeled by the Bolton-Hunter technique, and its binding to brain membranes was also enhanced by low pH and ionic strength. In studies with a neutralizing monoclonal antibody against tetanus toxin, the antigen-antibody interaction was not significantly altered by media with low ionic strength and pH. On the other hand, the ability of the antibody to block toxin binding to brain membranes was reduced substantially in nonphysiologic media. In a bioassay aimed at determining the effect of pH and tonicity on tissue association by toxin, low pH and ionic strength did not enhance toxicity. The biological activity of tetanus toxin was unaffected and that of botulinum neurotoxin was greatly diminished. The present findings confirm the widely reported observation that low pH and ionic strength promote tissue association by tetanus toxin, but they challenge the premise that this binding is relevant to the normal process of cell poisoning.

Animals↗
PubMed1982

Structure-activity relationships of amantadine. I. Interaction of the N-alkyl analogues with the ionic channels of the nicotinic acetylcholine receptor and electrically excitable membrane.

In this study the effects of amantadine (1-adamantanamine) and its N-alkyl-substituted analogues [N-methyl- (NMA), N-ethyl- (NEA), N-propyl- (NPA), N-butyl- (NBA), and N,N-diethyl-amantidine (NNDEA)] were investigated on ionic channels of the electrically excitable membrane and of the nicotinic acetylcholine (ACh) receptors in frog sartorius muscles and on the binding of perhydrohistrionicotoxin (H12-HTX) to isolated membranes of the electric organ of the electric ray Torpedo. Amantadine and each analogue blocked the indirectly elicited twitch, but NPA, NBA, and NNDEA also potentiated the directly elicited twitch. The order of potency in inhibiting the indirect twitch was: NEA = NPA = NNDEA (10 microM) greater than NMA (15 microM) greater than NBA (40 microM) much greater than amantadine (130 microM). Neither amantadine nor its N-alkyl analogues affected miniature end-plate potential frequency or resting membrane potential but decreased miniature end-plate potential amplitude. Each compound prolonged the directly elicited action potential but did not alter delayed rectification. All of the compounds induced a concentration-dependent depression of the peak end-plate current (EPC) amplitude at negative membrane potentials and induced nonlinearity in the response at membrane potentials more negative than -40 mV. The order of potency in inhibiting the EPC (at -90 mV) was NNDEA (less than 0.5 microM) greater than NPA (less than 1.0 microM) greater than NBA (less than 2.0 microM) greater than NEA (19 microM) greater than NMA (42 microM) greater than amantadine (64 microM). Only NPA, NBA, and NNDEA depressed the peak EPC amplitude at positive membrane potentials as well. The shortening of the time constant of EPC decay by all compounds was concentration-dependent. At the higher concentrations examined, the slope of the relationship between the time constant of decay and membrane potential was reversed for all compounds. Only NPA induced a double-exponential decay of the EPC at positive membrane potentials. Neither amantadine nor its N-alkyl analogues inhibited the binding of [3H]ACh to its receptor in Torpedo electroplax but they inhibited the binding of [3H]H12-HTX binding to the ionic channel sites of the ACh receptor. The Ki for inhibition of [3H]H12-HTX binding was NEA = NNDEA (15 microM) greater than NMA (30 microM) greater than NPA = NBA (40 microM) greater than amantadine (60 microM). A gross correlation exists between their ability to block the indirect muscle twitch, miniature end-plate potential amplitude, peak EPC amplitude and the binding of [3H]H12-HTX. But, no correlation was found between these potencies and their antiviral activity. It is suggested that these compounds may interact with the ionic channel of the ACh receptor in its open and closed conformation.

Action Potentials↗
PubMed1972

The nature of the adrenoceptors in the post-partum rat uterus.

1. Uteri were removed from rats 0.5 h to 8 days after parturition and were suspended in Locke solution at 37 degrees C.2. The agonists isoprenaline, adrenaline, noradrenaline and phenylephrine produced an inhibition of the post-partum rat uterus.3. In the presence of propranolol, the agonists noradrenaline, adrenaline, and phenylephrine had an excitatory effect on the post-partum rat uterus. This excitatory effect was blocked by phenoxybenzamine indicating that it is mediated through alpha-adrenoceptors.4. These excitatory alpha-adrenoceptors could be demonstrated for 5-6 days after parturition. By the 7th-8th days their existence was no longer apparent.5. Excitatory alpha-adrenoceptors were also demonstrated in the late pregnant rat uterus.

Action Potentials↗