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Alzheimer's disease (AD) involves selective loss of muscarinic m2, but not m1, subtype neuroreceptors in the posterior parietal cortex of the human brain. Emission tomographic study of the loss of m2 receptors in AD is limited by the fact that there is currently no available m2-selective radioligand which can penetrate the blood-brain barrier. In our efforts to prepare such a radioligand, we have used competition studies against currently existing muscarinic receptor radioligands to infer the in vitro and in vivo properties of a novel muscarinic receptor ligand, 5-[[4-[4-(diisobutylamino)butyl]-1-phenyl]acetyl]-10,11-dihydro-5H - -dibenzo [b,e][1,4]diazepin-11-one (DIBD). In vitro competition studies against [3H](R)-3-quinuclidinylbenzilate ([3H]QNB) and [3H]N-methylscopolamine ([3H]NMS), using membranes derived from transfected cells expressing only m1, m2, m3, or m4 receptor subtypes, indicate that DIBD is selective for m2/m4 over m1/m3. In vivo competition studies against (R,R)-[125I]IQNB indicate that DIBD crosses the blood brain barrier (BBB). The relationship of the regional percentage decrease in (R,R)-[125I]IQNB versus the percentage of each of the receptor subtypes indicates that DIBD competes more effectively in those brain regions which are known to be enriched in the m2, relative to the m1, m3, and m4, receptor subtype; however, analysis of the data using a mathematical model shows that caution is required when interpreting the in vivo results. We conclude that a suitably radiolabeled derivative of DIBD may be of potential use in emission tomographic study of changes in m2 receptors in the central nervous system.

The GABAergic innervation of the extraocular motor nuclei in the cat was evaluated using postembedding immunocytochemical techniques. The characterization of GABA-immunoreactive terminals in the oculomotor nucleus was carried out at the light and electron microscopic levels. GABA-immunopositive puncta suggestive of boutons were abundant in semithin sections throughout the oculomotor nucleus, and were found in close apposition to somata and dendrites. Ultrathin sections revealed an extensive and dense distribution of GABA-immunoreactive synaptic endings that established contacts with the perikarya and proximal dendrites of motoneurons and were also abundant in the surrounding neuropil. GABAergic boutons were characterized by the presence of numerous mitochondria, pleiomorphic vesicles and multiple small symmetrical synaptic contacts. The trochlear nucleus exhibited the highest density of GABAergic terminations. In contrast, scarce GABA immunostaining was associated with the motoneurons and internuclear neurons of the abducens nucleus. In order to further elucidate the role of this neurotransmitter in the oculomotor system, retrograde tracing of horseradish peroxidase was used in combination with the GABA immunostaining. First, medial rectus motoneurons were identified following horseradish peroxidase injection into the corresponding muscle. This was carried out because of the peculiar afferent organization of medial rectus motoneurons that contrasts with the remaining extraocular motoneurons, especially their lack of direct vestibular inhibition. Semithin sections of the oculomotor nucleus containing retrogradely labeled medial rectus motoneurons and immunostained for GABA revealed numerous immunoreactive puncta in close apposition to horseradish peroxidase-labeled somata and in the surrounding neuropil. At the ultrastructural level, GABAergic terminals established synaptic contacts with the somata and proximal dendrites of medial rectus motoneurons. Their features and density were similar to those found in the remaining motoneuronal subgroups of the oculomotor nucleus. Second, oculomotor internuclear neurons were identified following the injection of horseradish peroxidase into the abducens nucleus to determine whether they could give rise to GABAergic terminations in the abducens nucleus. About 20% of the oculomotor internuclear neurons were doubly labeled by retrograde horseradish peroxidase and GABA immunostaining. A high percentage (80%) of the oculomotor internuclear neurons projecting to the abducens nucleus showed immunonegative perikarya. It was concluded that the oculomotor internuclear pathway to the abducens nucleus comprises both GABAergic and non-GABAergic neurons and, at least in part, the GABA input to the abducens nucleus originates from this source. It is suggested that this pathway might carry excitatory and inhibitory influences on abducens neurons arising bilaterally.

Five analogues of 3-quinuclidinyl benzilate were prepared in which one phenyl ring was substituted by a heterocycle; a bromine was included on either the remaining phenyl or the heterocycle to provide information relating to the affinity of potential radiohalogenated derivatives. Their affinities for the muscarinic cholinergic receptor were determined. Replacing a phenyl ring with either the 2- or 3-furyl moiety or the 2- or 3-thienyl moiety did not significantly alter the affinity to the muscarinic receptor compared with 3-quinuclidinyl 4-bromobenzilate.

Seven analogues of 3-quinuclidinyl benzilate (QNB) in which one phenyl ring was replaced by an alkoxyalkyl moiety were synthesized and their affinities for the muscarinic cholinergic receptor determined. An oxygen in the beta-position of the moiety was not well-tolerated. By contrast, an oxygen in the gamma-position did not change the affinity for the muscarinic receptor. However, when a bromine was placed on the remaining phenyl ring, the affinity was significantly reduced in striking contrast to results obtained on halogenation of QNB.

The equilibrium dissociation constant and the kinetic rate constants were determined for the binding of (R)-[3H]3-quinuclidinyl benzilate ([3H]QNB) and [125I]3-quinuclidinyl-4-iodobenzilate ((R,R)- and (R,S)-[125I]IQNB) to transfected cell membranes expressing one single muscarinic acetylcholine receptor (mAChR) subtype. The association and dissociation kinetics for the m2 subtype were more rapid than for the m1 and m3 subtypes. The differential kinetic properties may be useful for the single photon emission computed tomographic (SPECT) evaluation of regional mAChR subtype alterations in disease states.

The aim of this investigation was to study the behavior of identified abducens motoneurons in the chronic cat following a single injection of toxic ricin into the lateral rectus muscle. Lateral rectus electromyographic potentials induced by VIth nerve stimulation disappeared, and abducens antidromic field potentials decreased by 90% 3 days following ricin injection. Several abnormalities and a significant decrease in eye position and velocity sensitivities were observed in motoneuron activity up to 8-10 days following ricin injection. Contrary to a previous report for axotomized abducens motoneurons, no functional sign of recovery was observed. Histological analysis showed a survival of 10-15% of the abducens motoneuron population 10 days following ricin injection. From this time on, recorded motoneurons behaved like controls, but showed a specific retraction signal suggesting an exclusive projection onto the retractor bulbi muscle. Although intermingled in the nucleus with motoneurons, no recorded abducens internuclear interneuron was affected by the ricin during one month following the injection.

The morphological and physiological integrity of abducens internuclear interneurons was evaluated following chemical removal of their almost exclusive target, i.e. the contralateral medial rectus motoneuron population. Motoneuron death was induced by toxic ricin injection into the ipsilateral medial rectus muscle. The main advantage of this method is that target removal is not associated with presynaptic axon damage. The activity of identified abducens internuclear interneurons was recorded before and after target removal during spontaneous eye movements in the chronic cat preparation. Several abnormalities and a remarkable decrease in eye position and velocity sensitivities were observed in the discharge pattern of these neurons for a period of 15-20 days following target removal. After that time all recorded interneurons behaved normally. A parallel morphological study showed the absence of any abducens internuclear interneuron death. These results indicate that, after a critical period, the abducens internuclear interneuron population recovers its normal behavior following target removal with no evidence of neuronal loss.

We have reviewed in a retrospective study 38 children treated in our Hospital, during the last seven years, because of non congenital gall-bladder disease. The diagnosis established were cholelithiasis 58 for 100, hydrops 26 for 100, acalculous cholecystitis 13 for 100 and hemobilia in one child. Cholelithiasis was more frequent in females at a rate of 2/1. Just the opposite incidence was found for acalculous gall-bladder pathology. Mean age at time of first hospitalization was 7.6 years for the cholelithiasis group and 6.6 years for the rest. Symptoms in order of frequency were abdominal pain, vomiting and fever. Abdominal sonography has been basic in establishing to correct diagnosis in practically all cases. Our most interesting finding has been the clinical manifestations of patients with "Hydrops", consisting of abdominal pain which disappears spontaneously after 24 to 48 hours. The diagnosis has been established only after performing abdominal sonographic studies in children with abdominal pain of unclear etiology.

The Ministry of Education of Guatemala requested from the Institute of Nutrition of Central America and Panama (INCAP), the development of a solid food for delivery to school children who attend the official schools throughout the country. INCAP developed and transferred the processing technology to produce a nutritionally improved cookie to artisan bakers from the different regions of the country. The present paper describes the technological process, focusing on the training, supervision and quality control actions executed with approximately 100 micro baking enterprises, in 1988 and 1989. These actions have had a positive impact on the bakeries, a fact evidenced by the significant improvement of the conditions and processes of the nutritionally improved cookie production. The performance of the above-mentioned activities has allowed us to detect necessities, for the solution of which research and development of technologies are most important for their immediate transference to artisan bakers. Nevertheless, it is necessary to monitor and control the transferred technology, and efforts must continue to increase the effectiveness of the whole system which involves technology transference model, created for this project.

Two classes of 8-substituted analogs of theophylline (1,3-dialkylxanthines), having 8-cycloalkyl, 8-cycloalkenyl or 8-(para-substituted aryl) groups, were shown to be potent and, in some cases, receptor subtype selective antagonists at A1- and A2-adenosine receptors. New analogs based on a functionalized cogener approach and on classical medicinal chemical approaches were prepared. Affinity at A1-adenosine receptors was evaluated by inhibition of binding of [3H]N6-phenylisopropyladenosine to rat brain membranes. Activity at A2-adenosine receptors was measured by the reversal of 5'-N-ethylcarboxamidoadenosine (NECA)-stimulated production of cyclic AMP in membranes from rat pheochromocytoma PC12 cells. Cycloalkenyl analogs containing rigid olefinic bonds differed greatly in potency from the saturated analogs. The selectivity of phenylsulfonamide analogs depended on distal structural features. Novel xanthine analogs include diamino-, thiol-, aldehyde, and halogen-substituted derivatives, peptide conjugates of 8-[4-[2-aminoethylaminocarbonylmethyloxy]phenyl]1,3-dipropylxan thi ne (XAC), and a hydroxyethylamide analog of XAC.

Since being recognized in 1976 and 1983, respectively, penicillinase-producing strains of Neisseria gonorrhoeae (PPNG) and chromosomally mediated resistance (CMRNG) have attained a worldwide distribution. The high endemicity of both types of resistance in some regions precludes the continued routine use of procaine penicillin (APPG) as treatment for gonorrhea. In this study, we have evaluated 72/216 men with uncomplicated gonococcal urethritis at the venereal clinic in Mexico City. These men were part of a blinded randomized comparative study for treatment with group (P) penicillin having 33 patients and group (S) spectinomycin having 39. Efficacy with (P) was 24/33 (72.7%); nine failures retreated and were cured with spectinomycin. Efficacy with (S) was 35/39 (89.7%); four failures retreated and were cured with cefotaxime. We found correlation between MICs and resistance; all the strains with MICs of greater than or equal to 1.0 mcg/ml of penicillin failed to be cured, the MICs of greater than or equal to 32 mcg/ml of spectinomycin failed to be cured. The overall resistance to both regimens was 23/72 to penicillin (31.9%) (22 PPNG and one CMRNG) and 4/72 (5.5%) to spectinomycin.

The activity of medial vestibular nucleus neurons projecting to the contralateral abducens nucleus (premotor vestibular neurons) has been recorded during spontaneous and vestibular induced eye movements in the alert cat. Recorded neurons were identified by their antidromic activation from the abducens nucleus and by the post-synaptic field potential induced in this nucleus. The activity of identified medial vestibular neurons increased significantly with horizontal eye position and velocity toward the contralateral side, and decreased abruptly during ipsilateral saccades. The activity of these neurons was also related to head velocity toward the ipsilateral side. The functional role and origin of eye position and velocity signals present in these vestibular neurons are discussed.

Recently a method for theophylline assay on the Ames Seralyzer was introduced. We compared the interday variability of this method to the established interday variability of an enzyme multiplied immunoassay (Emit) technique used in the service laboratory of a hospital. Control sera and calibrator prepared to known concentrations (10, 15, and 25 micrograms/mL) were assayed singly daily for ten days with the Seralyzer machine. Assays were done singly to simulate the in-office use of the machine. Their respective coefficients of variations (CVs) were 6.96%, 5.50%, and 5.23%, which compared favorably with the established CVs for the Emit of 6.7%, 5.8%, and 6.1% respectively at comparable test concentrations. Two hundred and fifty-one sera were assayed in parallel on both machines in eight batches. Linear regression analysis of these data showed a slope of 0.995, intercept of 0.468, and a correlation coefficient of 0.945. These data suggest that the Seralyzer values compared favorably with the Emit values.

Activation of alpha 1-adrenergic receptors by norepinephrine in guinea pig cortical synaptoneurosomes augments accumulations of cyclic AMP elicited by 2-chloroadenosine and concomitantly increases formation of inositol phosphates. Various agents that affect calcium channels or sites of action of calcium have little or no effect on cyclic AMP accumulation elicited either with 2-chloroadenosine, or with a 2-chloroadenosine/norepinephrine combination, nor did they markedly affect formation of inositol phosphates elicited by norepinephrine. However, EGTA reduces both cyclic AMP accumulation and inositol phosphate formation. Agents such as batrachotoxin, scorpion (Leiurus) venom and pumiliotoxin B that are active at voltage-dependent sodium channels enhance accumulations of cyclic AMP and inositol phosphates. These effects are blocked by tetrodotoxin. It is proposed that enhanced influx of sodium ions increases phosphatidylinositol metabolism, resulting in formation of diacylglycerols and inositol phosphates, and that the former, through activation of protein kinase, causes an enhancement of cyclic AMP accumulations in brain tissue.

2-Chloroadenosine, 5'-N-ethylcarboxamidoadenosine, N6-cyclohexyladenosine and other adenosine analogs enhance histamine-elicited, but not norepinephrine- or carbamylcholine-elicited accumulations of inositol phosphates in [3H]inositol-labeled guinea-pig cerebral cortical slices. The adenosine analogs alone have no effect on accumulations of inositol phosphates. The effect of 2-chloroadenosine is blocked by the adenosine receptor antagonists theophylline and 1,3-dialkyl-8-p-sulfophenylxanthines. The rank order of activity of the six adenosine analogs with respect to augmentation of histamine-elicited accumulation of inositol phosphates in guinea-pig cerebral cortical slices is different from the rank order at an A2-adenosine receptor that mediates synergistic accumulations of cyclic AMP by adenosine analogs and histamine in guinea-pig cerebral cortical slices.

Over a period of 5 years, 25 children between 1 day and 26 months of age were prospectively evaluated because of the presence of meningomyeloceles. Cranial sonography was used to ascertain the types of associated cranial alterations. Twenty-three children (92%) presented signs of Chiari II malformation. In only two (8%) were the ultra-sonographic results normal. The abnormalities detected were classified as alterations of the ventricular system, extraventricular alterations, and associated findings. The most frequent alteration of the ventricular system was the "bat-wing" configuration of the frontal horns, which appeared in 22 children (88%). Among the extraventricular alterations, 23 children (92%) had a downward displaced cerebellum, obliterated basal cisterns and low positioning of the tentorium cerebelli. Associated findings were a polymicrogyria in 1 case and intracranial hemorrhage in 2. The 23 children with Chiari II malformation were followed up clinically and sonographically. Our findings were similar to those of other published series. In spite of the introduction of magnetic resonance imaging, we consider cranial sonography to be an inexpensive and convenient method of evaluating the existence of Chiari II malformation in the child with meningomyelocele and of following up its evolution after shunt procedures.

A six year old boy is described who suffured from recurrent and protracted infections of multiple organs by various catalase positive bacteria. A severe episode of osteomyelitis involving several bones was caused by Aspergillus fumigatus. Studies of his PMNs revealed impaired metabolic as well as microbicidal functions characteristic of CGD. Chemiluminescence in response to both opsonized zymosan and sodium fluoride was markedly depressed, while control PMNs showed significant responses. Control leukocytes suspended in patient's serum likewise evoked normal chemiluminescence. Microbicidal activity against staphylococcus aureus 502A was also decreased using patient's PMNs, whereas control PMNs were able to reduce the number of colony forming bacteria by 2 logs in 120 minutes. Viable intracellular bacteria after lysis of extracellular bacteria formed 3 X 10(7) colonies from patient's PMNs and less than 2 X 10(5) colonies from the control. NBT dye reduction studies of the family members suggested an x-linked recessive mode of inheritance. The extraordinary nature of this case lies in the discovery of an associated intrinsic cellular defect of chemotaxis involving his polymorphonuclear leukocytes. Specifically, the Rebuck skin window showed predominantly mononuclear cells from 4 up to 24 hours. In addition, the patient's PMNs failed to migrate in response to cultured filtrates of E. coli as the chemoattractant. This abnormality persisted in the presence of autologous plasma or serum as well as in control plasma or serum. Control PMNs showed normal chemotaxis in the presence of the patient's plasma or serum. The extent to which the rare coexistence of these two phenomena influence the clinical disease is not known and remains to be elucidated.

Kasai's procedure has changed significantly the prognosis of biliary atresia. However, ascending cholangitis is a relatively frequent postoperative complication with high morbidity and mortality rates. We have developed a modification of that technic consisting in the isolation of a segment of jejunum-with its blood supply carefully preserved, after fashioning an antireflux valve in its distal end. This segment of bowel, less than 10 cm. in length, is anastomosed to the porta hepatis proximally and to the duodenum distally. Using this technic, we have operated upon three infants with biliary atresia and a child with extended rabdosarcoma of the biliary tree. After a follow up of 10 to 17 months with an average of 12.5 months, all children remain free of cholangitis and two of them are anicteric.

The activity of identified medial rectus motoneurons was recorded in alert cats during spontaneous and vestibular induced eye movements. Medial rectus motoneurons fired a burst of spikes slightly preceding adducting saccades and increased their discharge rate linearly with successive eye positions in the adducting direction. Conduction velocity (21.3 - 98.2 m/s), eye position sensitivity (ks, 7.1 +/- 1.5 spikes/s/deg), and eye velocity sensitivity (rs, 1 +/- 0.2 spikes/s/deg/s) during spontaneous eye movements, and time constants calculated from phase lead analysis (To, 135 +/- 36 ms) showed values similar to those described previously for cat abducens motoneurons. The firing rate during repeated fixation of the same eye position was affected significantly by the direction of the preceding saccade and by the animal's level of alertness. Eye velocity sensitivity was not significantly affected by changes in the animal's level of alertness. A weak negative relationship (coefficient of correlation=-0.56) was observed between eye velocity sensitivity (rv) and sinusoidal rotational frequency, with no change in eye position sensitivity (kv) with stimulus frequency. The subsequent changes in the time constant (Tv) calculated as Tv=rv/kv in relation to stimulus frequency suggests that the oculomotor system deviates from a (linear) first-order model.