Dose escalation study of rhenium-186 hydroxyethylidene diphosphonate in patients with metastatic prostate cancer

Rhenium-186 hydroxyethylidene diphosphonate (¹⁸⁶Re-HEDP) has been used for the palliative treatment of metastatic bone pain. A phase 1 dose escalation study was performed using ¹⁸⁶Re-HEDP Twenty-four patients with hormone-resistant prostate cancer entered the study. Each patient had at least four bone metastases and adequate haematological function. Groups of at least three consecutive patients were treated with doses starting at 1295 MBq and increasing to 3515 MBq (escalated in increments of 555 MBq). Thrombocytopenia proved to be the dose-limiting toxicity, while leucopenia played a minor role. Early death occurred in one patient (10 days after administration) without clear relationship to the ¹⁸⁶Re-HEDP therapy. Transient neurological dysfunction was seen in two cases. Two patients who received 3515 MBq ¹⁸⁶Re-HEDP showed grade 3 toxicity (thrombocytes 25–50 × 10⁹/1), defined as unacceptable toxicity. After treatment alkaline phosphatase levels showed a transient decrease in all patients (mean: 26% ± 10% IUA; range: 11%–44%). Prostate-specific antigen values showed a decline in eight patients, preceded by a temporary increase in three patients. From this study we conclude that the maximally tolerated dose of ¹⁸⁶Re-HEDP is 2960 MBq. A placebo-controlled comparative study on the efficacy of ¹⁸⁶Re-HEDP has been initiated.     

INGUINAL SURGERY IN ATHLETES WITH CHRONIC GROIN PAIN: THE ‘SPORTSMAN'S’ HERNIA

Book reviews in this article: Fifty athletes with chronic undiagnosed groin pain underwent surgical exploration and inguinal hernia repair. Six months later, all athletes were sent questionnaires to assess their return to sport, level of pain (using analogue pain scores) and the overall result of their surgery. Operative findings revealed a significant bulge in the posterior inguinal wall in 40 athletes. Forty-four athletes (88%) replied to the questionnaire. Forty-one athletes (93% of respondents) had returned to normal activities. Pain scores indicated a marked improvement in their level of pain (P < 0.001). Thirty-three athletes (75%) rated the result as good and 10 (23%) as improved. It is concluded that athletes with chronic groin pain who are unable to compete in active sport should be considered for routine inguinal hernia repair if no other pathology is evident after clinical examination and investigation.     

SPROUT,HIPPO and CAESA: Tools for de novo structure generation and estimation of synthetic accessibility

Summary Several components of a system for structure generation are now well developed. HIPPO is a program that characterises a receptor binding site for potential target sites within the cavity that can be used in de novo design. The target sites include simple and complex hydrogen bonds, covalent bonds and bonds to metal ions. The SPROUT program for structure generation consists of two main components: the first is skeleton generation, followed by atom substitution to convert the solution skeletons to molecules. A new method of skeleton generation is presented here, where part skeletons are grown outwards from each target site. The part skeletons are then connected together to form solution skeletons. Finally the CAESA program is described, that ranks the output from SPROUT according to ease of synthesis.     

MR imaging of primary epidermoid tumors

The magnetic resonance (MR) imaging characteristics of five primary intradural epidermoid tumors are described. At 0.35 T, the most consistent finding on spin echo imaging was a tumor signal intensity that differed from brain and CSF. On T1-weighted images [repetition time (TR) 0.5 s, echo time (TE) 30-40 ms] all tumors exhibited a signal intensity intermediate between brain and CSF. On moderately T2-weighted images (TR 2.0 ms, TE 60-80 ms) the tumor signal intensity was greater than brain and CSF in all cases. The tumor signal consistency was mixed in four of five lesions and homogeneous in one. The tumor margins were well defined in all cases; in three cases the tumor margins were irregular, in one case smooth, and in the last case, one margin was irregular and the remaining margins were smooth. These findings are contrasted with the MR appearance of arachnoid cysts. Using identical imaging factors, four arachnoid cysts were studied and exhibited a homogeneous signal intensity that was identical to CSF on all pulse sequences; their margins were smooth and well defined in each case. These MR findings contribute to the characterization of extraaxial lesions.     

Manipulating prefabricated flaps: An experimental study examining flap viability

As flap prefabrication becomes a more commonly used clinical tool, it is necessary to investigate the limitations of this technique. Reconstructive procedures of the face often require “custom fitted” flaps to satisfy esthetic demands. This study examines and compares the safety of manipulating thin prefabricated skin flaps versus established axial pattern skin flaps. Twenty-seven New Zealand white rabbits were used to determine if prefabricated flaps can be folded 180° around the edge of the rabbits' ears. The survival of these folded prefabricated flaps was compared with the survival of axial pattern flaps sutured into an identically recipient site. In addition, flaps prefabricated in the same manner were sutured onto a straight recipient bed to evaluate the viability of the newly vascularized tissue. The folded prefabricated flaps had reduced survival (56%) compared to equivalent folded axial pattern flaps (85%), P<0.005. The nonmanipulated prefabricated flaps and axial pattern flaps survived completely. © 1994 Wiley-Liss, Inc.     

Segmental distribution and peptide content of primary afferent neurons innervating the urogenital organs and colon of male rats.

Many visceral afferent neurons contain peptides, which have been proposed as histochemical markers for nerve pathways of particular targets or as transmitter candidates. The former possibility was investigated in the present study. Primary afferent neurons which project to the urinary bladder, distal colon or penis of rats, and the colon of cats were labelled with retrogradely transported fluorescent dyes (Fast Blue, True Blue, or Fluoro Gold). One to six weeks after dye injection into the organs, lumbosacral dorsal root ganglia were removed, treated with colchicine, and processed for immunohistochemical identification of five peptides. Dye-labelled neurons were distributed in an organ-specific manner in the lower lumbosacral ganglia, where colon afferent neurons were almost exclusively found in S1 ganglia, penis neurons primarily in L6, and bladder neurons at both levels. Substance P- (SP), calcitonin gene-related peptide-(CGRP), vasoactive intestinal peptide- (VIP), enkephalin- (ENK), and somatostatin- (SOM) immunoreactivity (IR) were detected in neurons in all lumbosacral ganglia but only some of these peptides were present in a large percentage of labelled neurons. The numbers of peptide-containing neurons innervating each organ were CGRP greater than SP greater than VIP greater than ENK greater than SOM; however some differences were observed in the relative proportions of these neuronal populations between upper lumbar and lower lumbosacral ganglia and between different organs. The major difference seen at the upper lumbar level was amongst the SP-IR neurons, which were common (25-30%) amongst bladder and colon afferent neurons but absent in penis neurons.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serotonin-binding proteins in the bovine cerebral cortex: interaction with serotonin and catecholamines.

The soluble serotonin-binding proteins (SBP) present in bovine frontal cortex are very similar to those reported in rat brain. Binding of [3H]serotonin to SBP, present in ammonium sulphate-precipitated proteins from bovine cortex, requires Fe2+ but not Fe3+. In the presence of an optimal concentration of Fe2+ (0.1 mM), bovine SBP behave as a single class of non-cooperative sites for [3H]serotonin binding (Bmax = 120 +/- 12 pmol/mg protein, KD = 0.12 +/- 0.04 microM, n = 3). Binding of [3H]serotonin is decreased by nucleotides and by reagents which modify sulfhydryl groups and reduce disulfide bonds and by metal ion chelators. Serotonin analogs possessing an hydroxyl group on the indole ring and catecholamine analogs possessing an intact catechol moiety are effective competitors (Ki from 0.1 to 0.3 microM). In both cases, the aliphatic amino group does not contribute to the binding, but the affinity is strongly decreased if aromatic hydroxyl groups are methoxylated. Catecholamine-SBP interactions can also be demonstrated directly by binding experiments. Binding of [3H]dopamine is greatly enhanced by Fe2+, Cu2+ and Mn2+, but not by Fe3+. The Fe(2+)-dependent binding component of [3H]dopamine is saturable (Bmax = 279 +/- 64 pmol/mg protein, KD = 0.19 +/- 0.02 microM, n = 3), and possesses the same physicochemical properties as SBP: it elutes immediately after the void volume on a Sephacryl S100 HR (1.6 x 140 cm) gel filtration column (reflecting aggregation) and it migrates with an apparent molecular weight of 57-58 kDa on native polyacrylamide gel electrophoresis. Whereas the serotonin-storing role of SBP in serotonergic neurons has already been well documented, the present data advocate that these proteins may also possess catecholamine-storing properties.