Adrenocorticotropin and cortisol hyperresponsiveness to hexarelin in patients with Cushing's disease bearing a pituitary microadenoma, but not in those with macroadenoma

We previously reported that in Cushing's disease (CD) the ACTH- and cortisol (F)-releasing activity of Hexarelin (HEX), a GH secretagogue, is exaggerated with respect to that in normal subjects and is higher than that of human CRH (hCRH), but it is absent in Cushing's syndrome. Our aim was to extend the study about the effects of HEX (2.0 microg/kg, iv) on ACTH and F secretion in 21 patients with CD (3 men and 18 women, 16-68 yr old). Based on magnetic resonance imaging, 15 CD patients had pituitary microadenoma, and 6 had macroadenoma. The results in CD patients were compared with those in 27 normal age-matched controls (NS; 10 men and 17 women, 24-69 yr old). Basal ACTH and F levels in CD were similar in patients with microadenom (mean+/-SEM, 78.3+/-7.2 pg/mL and 237.1+/-23.6 microg/L, respectively) and macroadenoma (57.4+/-9.0 pg/mL and 196.9+/-20.1 microg/L, respectively) and were higher (P < 0.001) than those in NS (17.7+/-2.0 pg/mL and 115.3+/-6.7 microg/L, respectively). In microadenoma CD patients, HEX induced marked ACTH and F increases (delta peak, mean+/-SEM: 261.2+/-77.6 pg/mL and 226.1+/-87.2 microg/L, respectively), which were higher (P < 0.04) than those induced by hCRH (45.6+/-16.9 pg/mL and 84.6+/-25.7 microg/L, respectively). Moreover, in microadenoma CD patients, the ACTH and F responses to HEX were higher (P < 0.001) than those in NS (18.5+/-4.0 pg/mL and 36.1+/-6.8 microg/L, respectively). In macroadenoma CD patients, HEX induced a slight, but significant increase (P < 0.02) in ACTH and F levels (33.9+/-18.0 pg/mL and 89.6+/-34.3 microg/L, respectively), which was not significantly different from that elicited by hCRH (20.0+/-7.0 pg/mL and 54.8+/-21.3 microg/L, respectively). In macroadenoma CD patients, the ACTH and F responses to HEX and hCRH were, in turn, similar to those in NS. In conclusion, our findings demonstrate that the ACTH and F hyperresponsiveness to HEX is present in Cushing's disease with micro-, but not macro- ACTH-secreting pituitary adenoma. This finding agrees with other evidence pointing toward differences in the hormonal behavior between micro- and ACTH-secreting pituitary macroadenomas.     

Cochlear implants in children: an analysis of use over a three-year period

OBJECTIVE: This study aimed to determine whether children continue to wear their cochlear implant systems 1 and 3 years after implantation. STUDY DESIGN: The design was a prospective study based on the analysis of forced-choice questionnaires on implant use completed independently by parents and teachers. SETTING: The study was performed at a dedicated pediatric cochlear implant program in a tertiary referral center in the United Kingdom. PATIENTS: All 85 consecutively implanted children who had reached the 1-year interval after implantation and 37 children who had reached the 3-year assessment interval after implantation participated. The patients represented all socioeconomic status groups, the entire range of educational settings, and often lived at a considerable distance from the implant center. MAIN OUTCOME MEASURES: Parents and local teachers were asked to describe implant use in the following categories: 1) all of the time; 2) most of the time; 3) some of the time; and 4) none of the time. RESULTS: One year after implantation, parents and teachers, respectively, rated 79 (93%) and 82 (96%) children as full-time users (category 1). Parents rated six children (7%) as users most of the time (category 2), and teachers rated three children (4%) as users most of the time. No child was rated as an occasional or nonuser (category 3 or 4). At 3 years after implantation, 33 (89%) and 34 (95%) children were rated as full-time users (category 1) by parents and teachers, respectively. Parents judged four children (11%) and teachers rated two children (5%) to be users most of the time (category 2). Again, no child was rated in category 3 or 4 as an occasional or nonuser. CONCLUSIONS: The majority of implanted children use their implant systems all of the time over a 3-year period after implantation when selected appropriately and given appropriate follow-up.     

Caspase 1-independent IL-1beta release and inflammation induced by the apoptosis inducer Fas ligand

Anchietia salutaris tea is traditionally used in Brazil to treat allergies, suggesting it contains compounds with antagonistic activity on the allergic mediators. We have evaluated extracts and semi-purified fractions of Anchietia salutaris as a source of compounds having this type of antagonism on the contraction induced in guinea-pig lung parenchymal strips and on platelet aggregation and shape change. After 10 min pre-incubation dichloromethane extracts containing 30 or 100 microg mL(-1) inhibited the contraction induced by prostaglandin D2 (PGD2) in guinea-pig lung parenchymal strips with dose ratios (DR) of 0.76+/-0.14 and 0.93+/-0.19, respectively; the amount of inhibition depended both on the concentration and on the time of pre-incubation (DR after 30 min pre-incubation was 1.21+/-0.51). The dichloromethane extract and its semi-purified fractions also inhibited the contractions induced by U46619, a more potent, stable, synthetic agonist of thromboxane A2 (TxA2) prostanoid (TP) receptors, the receptors acted upon by PGD2 to produce lung contractions. The dichloromethane extract did not inhibit the lung parenchymal contractions induced by histamine, leukotriene D4 (LTD4) or platelet-activating factor (PAF). Platelet aggregation induced by U46619, adenosine 5'-diphosphate (ADP) or PAF was not inhibited by the dichloromethane extract. Indeed, the extract potentiated platelet aggregation induced by low concentrations of these agonists and also potentiated the shape change induced by U46619. These results imply that the dichloromethane extract of Anchietia salutaris and its semi-purified fractions contain an active principle that competitively inhibits TxA2 TP receptors, the stimulation of which causes lung parenchymal contraction. The inhibition seems to be selective for this receptor subtype, because the extract fails to inhibit platelet aggregation or shape change. This provides additional support of earlier reports suggesting the occurrence of TP receptor subtypes.     

Acetylcholinesterase enhances neurite growth and synapse development through alternative contributions of its hydrolytic capacity, core protein, and variable C termini

Accumulated indirect evidence suggests nerve growth-promoting activities for acetylcholinesterase (AChE). To determine unequivocally whether such activities exist, whether they are related to the capacities of this enzyme to hydrolyze acetylcholine and enhance synapse development, and whether they are associated with alternative splicing variants of AChEmRNA, we used four recombinant human AChEDNA vectors. When Xenopus laevis embryos were injected with a vector expressing the synapse-characteristic human AChE-E6, which contains the exon 6-encoded C terminus, cultured spinal neurons expressing this enzyme grew threefold faster than co-cultured control neurons. Similar enhancement occurred in neurons expressing an insertion-inactivated human AChE-E6-IN protein, containing the same C terminus, and displaying indistinguishable immunochemical and electrophoretic migration properties from AChE-E6, but incapable of hydrolyzing acetylcholine. In contrast, the nonsynaptic secretory human AChE-I4, which contains the pseudointron 4-derived C terminus, did not affect neurite growth. Moreover, no growth promotion occurred in neurons expressing the catalytically active C-terminally truncated human AChE-E4, demonstrating a dominant role for the E6-derived C terminus in neurite extension. Also, AChE-E6 was the only active enzyme variant to be associated with Xenopus membranes. However, postsynaptic length measurements demonstrated that both AChE-E6 and AChE-E4 enhanced the development of neuromuscular junctions in vivo, unlike the catalytically inert AChE-E6-IN and the nonsynaptic AChE-I4. These findings demonstrate an evolutionarily conserved synaptogenic activity for AChE that depends on its hydrolytic capacity but not on its membrane association. Moreover, this synaptogenic effect differs from the growth-promoting activity of AChE, which is unrelated to its hydrolytic capacity yet depends on its exon 6-mediated membrane association.     

Insertional re-activation of a chloramphenicol acetyltransferase misfolding mutant protein

The deletion of nine residues from the C-terminus of the bacterialchloramphenicol acetyltransferase (CAT) results in depositionof the mutant protein in cytoplasmic inclusion bodies and lossof chloramphenicol resistance in Escherichia coli. This foldingdefect is relieved by C-terminal fusion of the polypeptide withas few as two residues. Based on these observations, efficientpositive selection for the cloning of DNA fragments has beendemonstrated. The cloning vector encodes a C-terminally truncatedCAT protein. Restriction sites in front of the stop codon allowthe insertion of target DNA, resulting in the production ofproperly folded CAT fusion proteins and regained chloramphenicolresistance. The positive selection of recombinants is accomplishedby growth of transformants on chloramphenicol-containing agarplates. The method appears particularly convenient for the cloningof DNA fragments amplified by the PCR because minimal informationto restore CAT folding can be included in the primers. The cloningof random sequences shows that the folding defect can be relievedby fusion to a wide variety of peptides, providing great flexibilityto the positive selection system. This vector may also contributeto the determination of the role of the C-terminus in CAT folding.     

Static-state feedback control of discrete-event systems underpartial observation

Studies static-state feedback control of discrete-event systems under partial observation. The authors present a necessary and sufficient condition for the existence of a static-state feedback controller. A static controller is a special case of a dynamic controller studied by Kumar et al. The authors' condition, however, has computational advantage in contrast to those obtained by Kumar et al. The authors also present a necessary and sufficient condition under which the modular feedback synthesis is possible     

Familial bilateral blepharoptosis and subvalvular aortic stenosis

PURPOSE: To select ideal radiologic projections for mapping and ablation of tachycardias of right ventricular outflow tract (RVOT). METHODS: Ten hearts from human corpses were studied utilizing radiopaque material to identify the pulmonary valve and three distinct sites on this valve: septal anterior (A), septal posterior (P) and free-wall (L). Next, the hearts were filmed in the frontal plane and in oblique projections with 15 degrees increments to the right and to the left. The projections in which the sites were lateralized on the valve, eased radiologic interpretation and were considered ideal for mapping and ablation. Depending on the proximity of the sites to the lateral extremes of the pulmonary valve, the projections were considered ideal ( ), intermediary (++) and inadequate (+). RESULTS: Projections [table: see text] CONCLUSION: The A site of RVOT was best indicated in the 60 and 45 degrees left anterior oblique projections; the 0 degree postero anterior projection was best for mapping the P site; the L region was best explored in the 60 degrees right anterior oblique projection.