Identification of potent P2Y-purinoceptor agonists that are derivatives of adenosine 5'-monophosphate

1. A series of chain-extended 2-thioether derivatives of adenosine monophosphate were synthesized and tested as agonists for activation of the phospholipase C-linked P2Y-purinoceptor of turkey erythrocyte membranes, the adenylyl cyclase-linked P2Y-purinoceptor of C6 rat glioma cells, and the cloned human P2U-receptor stably expressed in 1321N1 human astrocytoma cells. 2. Although adenosine monophosphate itself was not an agonist in the two P2Y-purinoceptor test systems, eleven different 2-thioether-substituted adenosine monophosphate analogues were full agonists. The most potent of these agonists, 2-hexylthio AMP, exhibited an EC50 value of 0.2 nM for activation of the C6 cell receptor. This potency was 16,000 fold greater than that of ATP and was only 10 fold less than the potency of 2-hexylthio ATP in the same system. 2-hexylthio adenosine was inactive. 3. Monophosphate analogues that were the most potent activators of the C6 cell P2Y-purinoceptor were also the most potent activators of the turkey erythrocyte P2Y-purinoceptor. However, agonists were in general more potent at the C6 cell receptor, and potency differences varied between 10 fold and 300 fold between the two receptors. 4. Although 2-thioether derivatives of adenosine monophosphate were potent P2Y-purinoceptor agonists no effect of these analogues on the human P2U-purinoceptor were observed. 5. These results support the view that a single monophosphate is sufficient and necessary for full agonist activity at P2Y-purinoceptors, and provide insight for strategies for development of novel P2Y-purinoceptor agonists of high potency and selectivity.     

A PET study of the neural systems of stuttering

The cause of stuttering is unknown. Failure to develop left-hemispheric dominance for speech is a long-standing theory although others implicated the motor system more broadly, often postulating hyperactivity of the right (language nondominant) cerebral hemisphere. As knowledge of motor circuitry has advanced, theories of stuttering have become more anatomically specific, postulating hyperactivity of premotor cortex, either directly or through connectivity with the thalamus and basal ganglia. Alternative theories target the auditory and speech production systems. By contrasting stuttering with fluent speech using positron emission tomography combined with chorus reading to induce fluency, we found support for each of these hypotheses. Stuttering induced widespread overactivations of the motor system in both cerebrum and cerebellum, with right cerebral dominance. Stuttered reading lacked left-lateralized activations of the auditory system, which are thought to support the self-monitoring of speech, and selectively deactivated a frontal-temporal system implicated in speech production. Induced fluency decreased or eliminated the overactivity in most motor areas, and largely reversed the auditory-system underactivations and the deactivation of the speech production system. Thus stuttering is a disorder affecting the multiple neural systems used for speaking.     

Orbital volume measurement in the management of pure blowout fractures of the orbital floor

With the recent advent of accurate orbital volume assessment by computed tomography, a retrospective analysis was made of 31 patients with 'pure' blowout fracture of the orbital floor, managed either surgically or conservatively, to determine whether orbital volume measurement could provide an additional parameter of use in the management of such fractures. There was a significant difference in orbital volume discrepancy between patients managed surgically or conservatively suggesting that this investigation may be of use in decision making on surgical intervention in patients with orbital blowout fractures.     

Professionally-led support groups for cancer patients: an intervention in search of a model

OBJECTIVE: The objective of this review was to evaluate the clinical and research literature on professionally-led support groups for cancer patients and to propose an approach that would address patients' needs from diagnosis through survivorship. METHOD: Computerized and manual searches, including Medline and Psychlit searches, were completed for reviews of the literature. Twelve research studies were identified that met our criteria for in-depth review. A clinical model emerged from discussions of an oncology study group based on theoretical formulations and clinical experience with oncology patients. RESULTS: We found that recent research suggests that professionally-led support groups are increasing in number and that participation in such groups seems to enhance patients' quality, and possibly even quantity, of survival. Despite this, little effort has been made to determine what type of group may be appropriate for which patients and when in their course of care. CONCLUSIONS: If psychosocial intervention, in the form of professionally-led support groups for cancer patients, is to be more effective, it should be guided by a model which takes into consideration the changing needs and concerns of patients over the course of illness and, in many cases, recovery. The authors present an outline delineating what such a model might entail.     

Enterocolitis associated with Clostridium perfringens infection in neonatal foals: 54 cases (1988-1997)

OBJECTIVE: To identify clinical signs, physical examination findings, results of diagnostic tests, treatments administered, and clinical outcome of neonatal foals with enterocolitis associated with Clostridium perfringens infection. DESIGN: Retrospective study. ANIMALS: 54 neonatal foals. RESULTS: Most foals had acute onset of obtunded mentation, colic, or diarrhea and developed leukopenia, neutropenia, an abnormally high number of band neutrophils, toxic WBC, and hypoproteinemia within 24 hours after admission, despite high serum IgG concentrations (> 800 mg/dl). Abdominocentesis and abdominal radiography of some foals revealed exudative peritonitis and gaseous distention of the small and large intestine, respectively. Cytologic examination of feces revealed spores or gram-positive rods in 8 of 10 foals. The most common genotypes of C perfringens isolates were type A and C, alone or in combination. Treatment did not alter mortality rate for most foals that had a positive culture for C perfringens type C. Of 54 foals, 29 (54%) that had C perfringens-associated enterocolitis died. Foals that had a culture that yielded C perfringens had higher sepsis scores, IgG concentrations, and mortality rates, compared with the overall hospital population of neonatal foals. CLINICAL IMPLICATIONS: Foals less than 7 days old that have enterocolitis associated with C perfringens infections, especially type C, have a guarded prognosis. Cytologic examination of feces to determine spore counts and detect rods may be a means for early identification of C perfringens infections. Polymerase chain reaction assays to determine genotype are important for designing preventive treatment regimens.     

Sequence diversity in the NIb coding region of eight sugarcane mosaic potyvirus isolates infecting sugarcane in Australia

We have sequenced the NIb coding region of sugarcane mosaic potyvirus strain SC (SCMV-SC) and eight field isolates of SCMV from Australia. This region comprised 1563 nucleotides and encoded a putative protein of 521 amino acids containing the consensus motif GDD. The protease cleavage sites between the NIa/NIb and the NIb/coat protein were found to be Q/C and Q/A, respectively. The SCMV sequences were most similar to sorghum mosaic potyvirus with identities of 70% and 78% at the nucleotide and amino acid levels, respectively. When the sequences were compared to each other, there was a maximum of 3.3% variation between isolates at the nucleotide level and a maximum of 0.8% at the amino acid level. Phylogenetic analysis of the sequences indicated the field isolates were grouped according to their geographical location. The SCMV sequence with most homology to all other isolates has been selected to generate constructs for replicase-mediated resistance.