Management of chronic medical conditions in children and adolescents

The care of children and adolescents with chronic medical conditions is an area of great interest for primary care physicians. With longer lives and more "mainstreaming" of care, the primary care physician often finds an increased role in the management of children and adolescents with chronic conditions such as mental retardation, Down syndrome, and diabetes mellitus. This article discusses familiarity with the most common chronic conditions and common pitfalls of management.     

Neurodevelopmental consequences of early exposure to phencyclidine and related drugs

In the early development of the central nervous system, stimulation of N-methyl-D-aspartate (NMDA) receptors may be critical for neuronal cell survival and differentiation, as well as the establishment of neural networks resulting from "experience-dependent plasticity." The trophic influence of NMDA receptor stimulation may be present only during a certain critical period of development. There are, therefore, major concerns associated with the administration of noncompetitive NMDA receptor antagonists (such as MK-801 [dizocilpine]) as neuroprotective and anticonvulsant agents to pregnant women, neonates, infants, and young children. Several studies showing disruptive effects of noncompetitive NMDA receptor antagonists on normal neurobehavioral development are reviewed in this article. This research has important public health implications because phencyclidine (PCP), a noncompetitive NMDA receptor antagonist, is a frequently-abused drug that may disrupt brain development in utero when abused by pregnant women. The article also reviews studies of neonatal blockade of the NMDA receptor complex in animals; studies that may lead to useful models of human neurodevelopmental disorders. These models may even mimic the relevant neurodevelopmental aspects of at least some forms of schizophrenia, especially the early developmental disconnection of circuits between the hippocampus and frontal cortex.     

Detection of a conserved alpha-helix in the kinase-docking region of the aspartate receptor by cysteine and disulfide scanning

The transmembrane aspartate receptor of Escherichia coli and Salmonella typhimurium propagates extracellular signals to the cytoplasm, where its cytoplasmic domain regulates the histidine kinase, CheA. Different signaling states of the cytoplasmic domain modulate the kinase autophosphorylation rate over at least a 100-fold range. Biochemical and genetic studies have implicated a specific region of the cytoplasmic domain, termed the signaling subdomain, as the region that transmits regulation from the receptor to the kinase. Here cysteine and disulfide scanning are applied to the N-terminal half of the signaling subdomain to probe its secondary structure, solvent exposure, and protein-protein interactions. The chemical reactivities of the scanned cysteines exhibit the characteristic periodicity of an alpha-helix with distinct solvent-exposed and buried faces. This helix, termed alpha7, ranges approximately from residue 355 through 386. Activity measurements probing the effects of cysteine substitutions in vivo and in vitro reveal that both faces of helix alpha7 are critical for kinase activation, while the buried face is especially critical for kinase down-regulation. Disulfide scanning of the region suggests that helix alpha7 is not in direct contact with its symmetric partner (alpha7') from the other subunit; presently, the structural element that packs against the buried face of the helix remains unidentified. Finally, a novel approach termed "protein interactions by cysteine modification" indicates that the exposed C-terminal face of helix alpha7 provides an essential docking site for the kinase CheA or for the coupling protein CheW.     

Cooperative Answering of Fuzzy Queries

The majority of existing information systems deals with crisp data through crisp database systems.Traditional Database Management Systems(DBMS) have not taken into account imprecision so one can say there is some sort of lack of flexibility.The reason is that queries retrieve only elements which precisely match to the given Boolean query.That is,an element belongs to the result if the query is true for this element;otherwise,no answers are returned to the user.The aim of this paper is to present a cooper...     

Human, mouse, and rat calnexin cDNA cloning: identification of potential calcium binding motifs and gene localization to human chromosome 5

Calnexin is a 90-kDa integral membrane protein of the endoplasmic reticulum (ER). Calnexin binds Ca2+ and may function as a chaperone in the transition of proteins from the ER to the outer cellular membrane. We have purified human calnexin in association with the human interferon-gamma receptor and cloned calnexin cDNA from placenta. Fragments of calnexin have been prepared as glutathione S-transferase fusion proteins and analyzed for their abilities to bind 45Ca2+ and ruthenium red. A subdomain containing four internal repeats binds Ca2+ with the highest affinity. This sequence is highly conserved when compared to calreticulin (a luminal ER protein), an Onchocerca surface antigen, and yeast and plant calnexin homologues. Consequently, this sequence represents a conserved motif for the high-affinity binding of Ca2+, which is clearly distinct from the "E-F hand" motif. An adjacent subdomain, also highly conserved and containing four internal repeats, fails to bind Ca2+. The carboxyl-terminal, cytosolic domain is highly charged and binds Ca2+ with moderate affinity, presumably by electrostatic interactions. The calnexin amino-terminal domain (residues 1-253) also binds Ca2+, in contrast to the amino-terminal domain of calreticulin, which is relatively less acidic. We have also determined the cDNA sequences of mouse and rat calnexins. Comparison of the known mammalian calnexin sequences reveals very high conservation of sequence identity (93-98%), suggesting that calnexin performs important cellular functions. The gene for human calnexin is located on the distal end of the long arm of human chromosome 5, at 5q35.     

Phenomenologic comparison of the idiopathic psychosis of schizophrenia and drug-induced cocaine and phencyclidine psychoses: a retrospective study

Both stimulant-induced and phencyclidine (PCP)-induced psychoses have been proposed as models of the idiopathic psychosis of schizopherenia. In this two-part study, the phenomenology of the psychosis associated with a period of cocaine intoxication was evaluated retrospectively in 34 male crack cocaine-dependent patients without concomitant psychiatric disorder and then was compared with the psychosis of 16 actively psychotic schizophrenic men (without a history of drug or alcohol abuse in the past year). Certain First Rank Schneiderian Symptoms (FRSS) were more commonly observed in the schizophrenic patients (e.g., thought broadcasting, thought withdrawal) than in the cocaine addicts. In the second part of this study, we retrospectively examined the cocaine and PCP experiences of an additional 22 cocaine addicts who had a past history of separate periods of cocaine and PCP use. Overall, the frequency of FRSS recalled during periods of cocaine and PCP intoxication was similar. However, the psychosis related to cocaine intoxication was more associated with an intense suspiciousness and paranoia related to a fear of being discovered or harmed while using cocaine. PCP-induced psychosis was less associated with suspiciousness and more associated with delusions of physical power, altered sensations, and unusual experiences [e.g., out of body experiences, experiencing religious figures or events directly (e.g., being with Noah at the time of the Arc)]. As elements of both cocaine and PCP psychosis can be found in schizophrenia, a model integrating the mechanisms of several psychotogenic drugs may be more informative. Such an integrative model might better capture the heterogeneity of psychotic symptoms that can be seen in schizophrenia. Furthermore, different pharmacologic interventions (e.g., "anti-stimulant" versus "anti-PCP") might address different aspects of the positive symptom picture in schizophrenia.     

Conformational and aggregational properties of the gene 9 minor coat protein of bacteriophage M13 in membrane-mimicking systems

The membrane-bound state of the gene 9 minor coat protein of bacteriophage M13 was studied in various membrane-mimicking systems, including organic solvents, detergent micelles, and phospholipid bilayers. For this purpose we determined the conformational and aggregational properties of the chemically synthesized protein by CD, FTIR, and HPSEC. The protein appears to be in a monomeric or small oligomeric alpha-helical state in TFE but adopts a mixture of alpha-helical and random structure after subsequent incorporation into SDS or DOPG. When solubilized by sodium cholate, however, the protein undergoes a transition in time into large aggregates, which contain mainly beta-sheet conformation. The rate of this beta-polymerization process was decreased at lower temperature and higher concentrations of sodium cholate. This aggregation was reversed only upon addition of high concentrations of the strong detergent SDS. By reconstitution of the cholate-solubilized protein into DOPG, it was found that the state of the protein, whether initially alpha-helical monomeric/oligomeric or beta-sheet aggregate, did not change. On the basis of our results, we propose that the principal conformational state of membrane-bound gene 9 protein in vivo is alpha-helical.     

Engineered assembly of intertwined oligomers of an immunoglobulin chain

Domain 1 of CD2 (CD2.D1) forms a conventional Ig fold stabilised by non-covalent antiparallel contacts between beta-strands. Removing two residues from the middle of the protein sequence, where the polypeptide chain normally folds back upon itself, stabilises an open conformation. In this modified molecule, the optimum evolved contacts between side-chains can only be satisfied through the antiparallel association of two chains to create a symmetrical pair of pseudo-domains. Here, we describe the dynamics of the switch between monomeric and dimeric states and demonstrate the extension of this novel underlying principle to trimer and tetramer formation. The ability of a protein molecule to form higher-order antiparallel structures is reminiscent of the behaviour of hairpins, duplexes, three-way and Holliday junctions in DNA.     

Rasmussen's encephalitis with concomitant cortical dysplasia: the role of GluR3

The role of the glutamate receptor GluR3 in Rasmussen's encephalitis is actively under investigation. Autoimmune processes with this receptor as the target are currently theorized. We provide an additional case of pathologically proved Rasmussen's encephalitis (with concomitant cortical dysplasia) in the presence of antibodies against the GluR3 receptor.     

Respiratory sinus dysrhythmia persists in transplanted human hearts following autonomic blockade

1. The present study was performed to test whether beat-to-beat cardiovascular control in cardiac allograft recipients resides in cholinergic and/or adrenergic nerves that are intrinsic to the heart. 2. Heart rate (HR) fluctuations synchronous with respiration during spontaneous, double tidal volume and metronome-synchronized breathing were quantified in 13 human heart transplant recipients. We also examined the effects of sequential cholinergic and beta-adrenoceptor (combined) autonomic blockade on respiratory sinus arrhythmia (RSA). We computed RSA amplitude and the correlation between respiration and changes in HR (cardiopulmonary synchronization; CPS). Group means were compared using repeated-measures analysis of variance. Transplant recipients served as their own controls. 3. In the basal state, moderate RSA amplitude and CPS were observed. During cholinergic and combined blockade, we observed no significant change in RSA amplitude, whereas CPS increased significantly during combined blockade (P < 0.05). The amplitude of RSA increased during respiration at double baseline tidal volume, but not at any of the other breathing manoeuvres (P < 0.01). In contrast, CPS increased significantly during both patterned breathing manoeuvres. No significant correlation was seen between mean right atrial pressure and RSA amplitude. In 23% of subjects with low CPS, HR oscillated with arterial pressure. These oscillations were independent of respiration. During all three patterns of respiration, a significant inverse correlation was observed between CPS and pulse pressure (r = -0.53 to -0.73). Thus, as the amplitude of pulse pressure increased, respiration accounted for a smaller percentage of HR variation. 4. In conclusion, RSA persists and the magnitude of CPS increases following combined autonomic blockade. These studies suggest that while RSA after cardiac transplantation is not cholinergically or adrenergically mediated, it may be related to mechanical stretch of the sinus node caused by changes in intrathoracic pressure and perfusion pressure.