Discovery of a pituitary adenoma following treatment with a gonadotropin-releasing hormone agonist in a patient with prostate cancer

We report the case of a T3 prostate cancer in a 70-year-old white man. Hormone therapy represents a prominent branch in the treatment of locally advanced and metastatic prostate cancer. Gonadotropin-releasing hormone agonists have been proven to have a double effect on androgen metabolism: an initially stimulating, followed by an inhibitory, effect on the pituitary gland. This phenomenon may be noxious in the case of gonadotroph adenoma, with subsequent symptoms of intracranial hypertension. Gonadotropin-releasing hormone antagonists (abarelix), by avoiding the flare-up reaction, might be used in such instances.     

Applications of BOP reagent in solid phase synthesis Advantages of BOP reagent for difficult couplings exemplified by a synthesis of [Ala 15]-GRF(1–29)-NH2

The BOP reagent [benzotriazol-l-yl-oxy-tris-(dimethylamino)phosphonium hexafluorophosphate] introduced by Castro et al. [Tetrahedron Lett. (1975) 14, 1219–1222] is ideally suited for solid phase peptide synthesis. The rate of coupling using BOP compared favorably to DCC and other methods of activation including the symmetrical anhydride and DCC/HOBt procedures. BOP couplings using the solid phase procedure proceeded more rapidly and to a greater degree of completion for peptide bond formations that were previously determined to be very slow using the conventional DCC method. Stepwise solid phase peptide synthesis using BOP was successfully utilized for the preparation of the (22–29) and (13–29) fragments of [Ala¹⁵]-GRF(1–29)-NH₂. Single couplings with 3 equiv. BOP and Boc-amino acids and 5.3 equiv. of diisopropylethylamine in DMF were used for each cycle. The yields of the fragments were superior and the purities comparable using the BOP procedure (single couplings) to those observed using multiple couplings via the DCC coupling method. A total synthesis of [Ala¹⁵]-GRF(1–29)-NH₂ was also carried out using the BOP procedure (single couplings and 3 equiv. BOP and Boc-amino acids and 5.3 equiv. diisopropylethylamine in DMF for each cycle). Multiple couplings were only required for Boc-Asn-OH due to the proposed formation of Boc-aminosuccinimide during activation. The resultant GRF(1–29) analog was comparable to a control prepared with multiple DCC couplings under optimized conditions. In a parallel study, unprotected Boc-(hydroxy)-amino acids were successfully coupled with the BOP reagent. However, the number of coupling cycles after the introduction of unprotected hydroxy-amino acid must be minimal (<10). The use of the BOP reagent with unprotected Tyr in solid phase peptide synthesis was also clearly established.     

Effect of Fat Substitutes,Sucrose Polyester and Tricarballylate Triester,on Digitoxin Absorption in the Rat

Abstract— The effect of non-absorbable fat substitutes (sucrose polyester (SPE) and tricarballylate triester (TCTE)) on [³H]digitoxin intestinal absorption was studied in the rat using a small intestine in-situ perfusion technique. The effect of SPE and TCTE was compared with that of sunflower oil, oleic acid, and saline. After 120 min perfusion, 5% SPE emulsion significantly reduced (P < 0·001) digitoxin absorption compared with all other treated groups. Five per cent TCTE emulsion had a less marked effect than SPE (P = 0·0002) and did not differ from sunflower oil. No difference was found between saline and 5% oleate emulsion, which did not reduce digitoxin absorption compared with other treated groups (P < 0·02). When taurocholic acid and lipase were added, results for the saline-, TCTE-, and SPE-treated groups were similar to those above, but the sunflower oil-treated group showed significantly enhanced (P < 0·01) digitoxin absorption. Thin-layer chromatography of the lipid phases showed hydrolysis of sunflower oil in the presence of taurocholic acid and lipase, but not of TCTE or SPE. The inhibitory effect of the nonabsorbable fat substitutes on digitoxin absorption could be related to drug sequestration by the persistent oil phase constituted by the undigested and then unabsorbed fat substitutes. That part of digitoxin dissolved in the undigested oil phase is consequently unavailable for intestinal absorption.     

Resin immobilized synthetic peptides used to characterize phosphorylation and antigenic properties of insulin receptor autophosphorylation domains

To develop a common strategy in peptide design for kinase assay, antibody production and affinity purification, we investigated phosphorylation and antigenic properties of peptides immobilized on an aminated polyacrylic resin (Expansin ?) corresponding to autophosphorylation domains of the insulin receptor tyrosine kinase. Immobilized peptides (1143–1155) and peptide (1314–1330), designated pl 151 and p1322, respectively, were good substrates for the insulin receptor with K_m, of 0.74 and 0.78 mM. By contrast, peptide (952–963), designated p960, was poorly phosphorylated. p1151 showed distinctive behaviour as a substrate, displaying a higher basal phosphorylation, a leftward shift of the insulin dose-response curve (ED₅₀= 0.7 ng mL- ¹ insulin compared to 20 ng mL ¹ for other substrates) and an inhibition by 90% of receptor autophosphorylation (ID₅₀So = 0.5 mM). Similar substrate behaviour was observed with another tyrosine kinase, the pp60^c-src. Antibodies against P1151 and p1322 have comparable reactivity in ELISA, but the antibody against p960 was poor. While purified immunoglobulins (IgG) against both p1151 and p1322 were inhibitors of receptor autophosphorylation and kinase, in immunoprecipitation the IgG against p1151 mainly interacted with the phosphorylated receptor and that against p1322 with non-phosphorylated forms. Functional mapping of the receptor with oligoclonal 1322-antibody revealed inhibition of phosphate transfer to exogenous substrate poly(Glu,Tyr) (4:l) but not towards immobilized p1151. These data provide further support for the distinctive features of endogenous phosphorylation domain 1151. We conclude that immobilized peptides on polyacrylic resin offer a major new potential for use in kinase assays, immunization, immunoabsorbent techniques and purification of well defined oligoclonal antibodies.     

Idiopathic hypersomnia

Abstract Identification of idiopathic hypersomnia dates back 20 years only. It typically consists of prolonged nocturnal sleep, great difficulty waking up in the morning or at the end of a nap, and constant or recurrent excessive daytime sleepiness. Complete and incomplete forms are encountered. Twenty-three subjects fulfilling ICSD criteria are reported with clinical, polysomnographic and immunogenetic data. Considering differential diagnosis is an important step in the diagnosis of idiopathic hypersomnia. Idiopathic hypersomnia is much less frequent than narcolepsy. A strong genetic component is suggested by the high proportion of familial cases. No association with HLA has been evidenced to date.     

BOP reagent for the coupling of pGlu and Boc-His(Tos) in solid phase peptide synthesis

The model peptide TRH was successfully synthesized using benzotriazol-l-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent). The coupling reactions were carried out in N,N-dimethylformamide or N-methylpyrrolidone. These solvents allowed the incorporation of the N-terminal pyroglutamic acid residue into the peptide chain, without using the derivative bearing the N-benzyloxycarbonyl group, which acts as a solubility promoter. A comparative racemization study showed that Boc-His(Tos) can be coupled by means of BOP reagent with less racemization than with DCC when the amount of diisopropylethylamine (DIEA) is kept minimal (same ratio of equivalents as for Boc-His(Tos), i.e. 3 equiv.). However, with the use of a larger amount of DIEA in the coupling mixture (9 equiv.), approximately 3% of epimer was found in the crude product. Our study showed that even under low DIEA conditions, the rate of coupling of the residues with BOP remained comparable to that observed with DCC.     

Intermodal selective attention: Evidence for processing in tonotopic auditory fields

Auditory event-related brain potentials (ERPs) were recorded for 250- and 4,000-Hz tone bursts in an intermodal selective attention task. Tonotopic changes were evident in the scalp distribution of the rising phase of the auditory N1 (mean peak latency 116 ms); the N1 was more frontally distributed following the 4,000-Hz than following the 250-Hz tone bursts, and it included a contralateral P90 component that was absent following 250-Hz tones. ERPs related to intermodal selective attention were isolated as negative and positive auditory difference waves (Nd_a and Pd_as). Neither the Nd_a nor the Pd_a showed changes in distribution with tone frequency, but both showed Ear × Frequency changes in distribution. ERPs for deviant tones included mismatch negativities (MMNs) and, in attend auditory conditions, N2b and P3 components. These components did not change in scalp distribution with tone frequency. One possible explanation is that tonotopic displacements of ERP distributions on the scalp surface depend on angular displacements in generator fields on gyral convexities. The results are consistent with the possibility that auditory processing radiates outward with increasing latency from tonotopic fields on Heschl's gyri to more gyrus-free regions of the planun temporale and anterior superior temporal plane.     

BCL6 gene rearrangements also occur in marginal zone B-cell lymphoma

Marginal zone B-cell lymphoma (MZBCL) represents a distinct subtype of B-cell non-Hodgkin's lymphoma (NHL) which has been recently recognized and defined as a disease entity. Cytogenetically, these lymphomas reveal a high prevalence of trisomy 3, and recent data obtained by comparative genomic hybridization indicate that the chromosomal regions 3q21-23 and 3q25-29 might be of particular pathogenetic significance. We identified structural chromosomal abnormalities involving the region 3q27 and rearrangements of the BCL6 proto-oncogene in three out of 34 (9%) well-defined cases of extranodal, nodal and splenic MZBCL using cytogenetic analysis, Southern blot, and fluorescence in situ hybridization (FISH). All three cases were characterized by a t(3;14)(q27;q32). Two of them showed additional chromosomal abnormalities including trisomy 3, which was found in one case. The patients displayed extranodal disease and did not demonstrate any striking clinical and histological differences when compared with MZBCL lacking BCL6 rearrangement. The present study for the first time demonstrates the occurrence of t(3;14)/ BCL6 gene rearrangement in MZBCL, thus suggesting a role of the BCL6 proto-oncogene in the pathogenesis of MZBCL.