Reconstruction of soft tissue injuries of the foot and ankle with microsurgical techniques

Microsurgical reconstruction for injuries of the foot and ankle includes, in addition to repair of small nerves, vessels, and tendons, coverage of soft tissue defects. Local transpositional and island pedicle flaps are ideal when available and adequate. The choice of free vascularized flaps is based on its potential durability, contour, bulk, and appearance. Thin cutaneous flaps, fascial flaps, and muscle flaps covered with split thickness skin grafts are appropriate in specific areas. Neurosensory flaps and methods of reinnervation may have a place in extensively denervated feet. Good postoperative pedorthic care aids in the final outcome.     

Development of a novel class of cyclic hexapeptide oxytocin antagonists based on a natural product.

A new structural class of cyclic hexapeptide oxytocin antagonists derived from Streptomyces silvensis and typified by L-365,209 (cyclo-[L-prolyl1-D-phenylalanyl2-L- isoleucyl3-D-dehydropiperazyl4-L-dehydroperazyl5-D-(N- methyl)phenylalanyl6]) was recently reported. In this paper we further delineate the structure-activity profile for this new class by systematic study of L-365,209 analogs obtained by total synthesis. The optimal combination of cyclic amino acid ring sizes at positions 1, 4, and 5 and the role of the N-alkyl substituent at position 6 was elucidated. The lipophilic amino acids at positions 2 and 3 and the unusual amino acid D-dehydropiperazic acid at position 4 were found to be the most critical residues for obtaining good oxytocin receptor affinity. Analogs containing a basic side chain at the less critical 5- and 6-positions maintained good receptor affinity and also had useful levels of water solubility for intravenous formulation. By combining potency- and solubility-enhancing substitutions, several analogs were identified that have the desired combination of properties in vitro (22, cyclo-[L-prolyl-D-tryptophanyl-L-isoleucyl-D-pipecolyl-L-pipeco lyl-D- histidyl]; 25, cyclo-[L-prolyl-D-2-naphthylalanyl-L-isoleucyl-D-pipecolyl-L -pipecolyl-D- histidyl]; 26, cyclo-[L-prolyl-D-tryptophanyl-L-isoleucyl-D-dehydropiperazyl-L-++ pipecolyl-D-histidyl]; 33, cyclo-[L-prolyl-D-tryptophanyl-L-isoleucyl-D-pipecolyl-L- piperazinylcarboxy-D-(N-methyl)phenylalanyl]; 34, cyclo-[L-prolyl-D-phenylalanyl-L-isoleucyl-D-dehydropiperazyl-L-or nithyl- D-(N-methyl)phenylalanyl]). In general, this class exhibited good selectivity for binding to the oxytocin receptor versus the arginine vasopressin V1a and V2 receptor subtypes, although increased V2 receptor affinity was observed in one case (32, cyclo[L-prolyl-D-2-naphthylalanyl-L-isoleucyl-D-pipecolyl-L- lysyl-D-(N- methyl)phenylalanyl]). Unexpectedly, compound 33 was found to stimulate contractions of the isolated rat uterus via activation of the uterine bradykinin receptor. Compounds 22, 25, 26, 33, and 34 were found to be potent antagonists of oxytocin-stimulated contraction of the rat uterus in vitro and in vivo. Compounds 22 and 25 were additionally characterized as potent antagonists of oxytocin-stimulated uterine contractions in the near-term pregnant rhesus monkey. These studies thus demonstrate the selectivity and efficacy of certain members of this novel class of antagonists and suggest their use as pharmacological tools in further defining the role of oxytocin in both term and preterm labor.     

MANAGEMENT OF SEMINOMA OF THE TESTIS: RECOMMENDATIONS BASED ON TREATMENT RESULTS

Background : The results of management of seminoma of the testis at the Department of Radiation Oncology St Vincent's Hospital, Sydney were evaluated retrospectively to: (i) establish that outcomes were in keeping with published results from centres in Australia and overseas; (ii) assess the impact of chemotherapy on management; and (iii) to determine ‘best practice’ management protocols based on our results and a review of the relevant literature. Methods : (i) Assessment of treatment results for stage I and II seminoma of the testis treated by post-orchidectomy radiotherapy and/or chemotherapy at St Vincent's Hospital between 1979 and 1993; (ii) literature review of published data from Australian and overseas centres on the management of seminoma of the testis, and in particular the use of surveillance or chemotherapy either alone, at time of relapse or combined with radiotherapy; and (iii) development of recommendations for use as management protocols in our department. Results : Our data and a review of the literature suggest that post-orchidectomy radiotherapy with chemotherapy for relapse in stage I and IIA disease results in long-term cure rates approaching 100%. Treatment with chemotherapy either routinely or selectively or using a surveillance policy is unlikely to show any improvement in outcome and may be less cost-effective and/or produce increased morbidity and the risk of secondary leukaemia. For stage IIB disease (5–10 cm) the use of initial combination chemotherapy with or without subsequent radiotherapy did not appear to give better outcomes than initial radical radiotherapy alone, reserving chemotherapy or further radiotherapy for relapse. For bulkier stage IIB disease (> 10cm). the use of initial chemotherapy plus consolidation radiotherapy appeared to be an appropriate treatment. Conclusions : Management protocols for seminoma of the testis at St Vincent's Hospital, Sydney Department of Radiation Oncology currently are (i) stage I, IA and IIB (5–10 cm): post-orchidectomy radiotherapy alone with chemotherapy or further radiotherapy for relapse; and (ii) stage IIB (> 10 cm) disease: initial chemotherapy post-orchidectomy followed by radiotherapy to sites of initial disease involvement.     

Human small intestine facilitative fructose/glucose transporter (GLUT5) is also present in insulin-responsive tissues and brain. Investigation of biochemical characteristics and translocation.

A recent study by C.F. Burant et al. (13) demonstrates that GLUT5 is a high-affinity fructose transporter with a much lower capacity to transport glucose. To characterize the potential role of GLUT5 in fructose and glucose transport in insulin-sensitive tissues, we investigated the distribution and insulin-stimulated translocation of the GLUT5 protein in human tissues by immunoblotting with an antibody to the COOH-terminus of the human GLUT5 sequence. GLUT5 was detected in postnuclear membranes from the small intestine, kidney, heart, four different skeletal muscle groups, and the brain, and in plasma membranes from adipocytes. Cytochalasin-B photolabeled a 53,000-M(r) protein in small intestine membranes that was immunoprecipitated by the GLUT5 antibody; labeling was inhibited by D- but not L-glucose. N-glycanase treatment resulted in a band of 45,000 M(r) in all tissues. Plasma membranes were prepared from isolated adipocytes from 5 nonobese and 4 obese subjects. Incubation of adipocytes from either group with 7 nM insulin did not recruit GLUT5 to the plasma membrane, in spite of a 54% insulin-stimulated increase in GLUT4 in nonobese subjects. Thus, GLUT5 appears to be a constitutive sugar transporter that is expressed in many tissues. Further studies are needed to define its overall contribution to fructose and glucose transport in insulin-responsive tissues and brain.     

Stereotaxic Interstitial Laser Therapy of Early-Stage Breast Cancer

Abstract: Coagulation leading to fibrosis of mammo-graphically detected breast cancers by interstitial laser therapy was tested as an alternative to surgical removal. Availability of computerized stereotaxic digital imaging allows the precise placement of laser and thermal needles into the target tumor and its controlled ablation by heat. The methodology of interstitial laser therapy (ILT), evolution of the subsequently removed tumors, and their histologic appearance are outlined.
Eight patients with mammographically well-defined tumors were selected. Definitive diagnosis and receptor evaluation were made on core biopsies. Under local anesthesia, stereotaxically guided diode laser energy at 5–10 w was delivered via a 400 xm fiber in a 19-gauge needle placed into the center of the tumor until the peripheral temperature exceeded 60°C. Patients experienced transient pain and pyrexia. Subsequent to ILT, seven invasive carcinomas were excised while one case of multiple papillomas was kept under surveillance. Histologic study revealed central necrosis but some peripheral residual tumor in the first five cases. In the last two, central necrosis surrounded by concentrically arranged, recognizable but severely injured, focally "windswept" and "ghostlike" tumor and granulation tissue were noted. The multiple papillomas showed radiologic shrinkage at 5 months and extensive fibrosis on needle biopsy.
ILT is an attractive new method of treating small, well-defined breast tumors and offers a potentially significant alternative to surgical removal; further exploration is warranted.     

Effect of training on postural control in figure skaters: a randomized controlled trial of neuromuscular versus basic off-ice training programs.

OBJECTIVES: To compare the effect of a neuromuscular training program and a basic exercise program on postural control in figure skaters. DESIGN: Two groups; parallel design; prospective, randomized controlled trial. SETTING: Postural control laboratory, arenas, September 2001 to December 2002. PARTICIPANTS: Forty-four young, healthy figure skaters (18 years +/- 3 years). INTERVENTIONS: Participants were randomly assigned to receive a neuromuscular training program (n = 22) or a basic exercise training program (n = 22). Both programs were completed 3 times per week for 4 weeks, and each session was supervised. MAIN OUTCOME MEASUREMENTS: Participants completed baseline and postintervention measures of postural control on a force plate. Postural control was quantified as the center of pressure (CoP) path length during tests of single-limb standing balance that mimicked figure skating skills and challenged the postural control system to varying degrees. The primary outcome measure was the CoP path length observed during a landing jump test completed with eyes closed. RESULTS: The post intervention CoP path lengths during the more challenging tests were significantly (P < 0.05) lower (indicating better postural control) for the neuromuscular trained group than for the basic exercise-trained group. For the landing jump test completed with eyes closed, the percent improvement in the neuromuscular trained group was significantly greater (mean = 21.0 +/- 22.0%) than the basic exercise trained group (mean = -4.9 +/- 24.9%; P < 0.05). The magnitude of improvement in the neuromuscular-trained group ranged from approximately 1% to 21%, depending on the specific postural control test used. CONCLUSIONS: The results suggest that off-ice neuromuscular training can significantly improve postural control in figure skaters, whereas basic exercise training does not.     

Nasal response of rhinitic and non-rhinitic subjects to histamine and methacholine: a comparative study.

The nasal responses to provocation with histamine and methacholine were compared in 20 subjects with and 20 without rhinitis. Two variables were measured: nasal airways resistance and the development of rhinorrhoea. Histamine had a greater effect than methacholine in increasing nasal airways resistance while the converse was true for rhinorrhoea. Rhinitic subjects had a significantly greater response to histamine induced changes in nasal airways resistance (p less than 0.05), rhinorrhoea (p less than 0.05) and methacholine induced rhinorrhoea (p less than 0.01) than those without rhinitis. No significant differences were found between the two groups in methacholine induced changes in nasal airways resistance. The findings show that, like the lower airways of patients with asthma, the nasal mucosa of rhinitic subjects shows a greater responsiveness to non-specific agonists than that of non-rhinitic subjects.     

Antibiograms of resistant Gram-negative bacteria from Scottish CF patients.

BACKGROUND: Over a 19-month pilot phase, 93 multiply resistant Gram-negative isolates from Scottish cystic fibrosis patients were sent to a referral laboratory for further investigation. METHODS: In common with the referring diagnostic laboratories, disc diffusion testing was carried out. Antibiotic susceptibility testing was also established by MIC methodology. NCCLS methods were used throughout. Twenty antibiotics were tested. RESULTS: Comparing disc diffusion results against MIC results, there were 167 (14%) major errors. By MIC, Pseudomonas aeruginosa (n = 59), Stenotrophomonas maltophilia (n = 16), Burkholderia cepacia (n = 10) and Alcaligenes xylosoxidans (n = 7) were susceptible to 18%, 11%, 4% and 35% of the antibiotics tested, respectively. Colistin and tobramycin were the most active agents against P. aeruginosa with 60% and 49%, respectively, testing susceptible. Minocycline and gentamicin were most active against S. maltophilia with 58% and 18%, respectively, testing susceptible. B. cepacia were most susceptible to co-trimoxazole (10%) and ciprofloxacin (10%). Five and six of the seven A. xylosoxidans isolates were susceptible to piperacillin and imipenem, respectively. CONCLUSIONS: Improved methods for susceptibility testing of such clinical isolates need to be employed in routine diagnostic laboratories. Levels of resistance in referred isolates were very high and similar to those described in the USA.     

Safety and Efficacy of ECT in Depressed Patients with Dementia: A Review of Clinical Experience

The authors review the results of electroconvulsive therpay (ECT) in 135 cases of depression occurring in conjunction with organic dementia, subcortical leukoencephalopathy without dementia, and depressive dementia (22 cases). Overall, 86% had a positive therapeutic response to ECT, whereas 21% experienced significant cognitive or memory side effects, virtually all of which were transient and reversible. Forty-nine percent of the patients with organic or depressive dementias experienced improvement in cognitive or memory function consequent to ECT.     

Comparative uptake and retention of adriamycin andN-benzyladriamycin-14-valerate in human CEM leukemic lymphocyte cell cultures

Summary N-Benzyladriamycin-14-valerate (AD 198) is a new lipophilic adriamycin (ADR) analogue that shows marked therapeutic superiority to ADR in murine tumor model systems yet differs mechanistically from ADR in a number of ways. Among its other properties, AD 198 produces a delayed but profound effect on cell-cycle progression and a pattern of continuing DNA damage in cultured cells briefly exposed to the drug. Using radiolabeled drug forms and radioassays combined with HPLC separation and fluorimetric detection techniques, aspects of drug accumulation, biotransformation, and retention in cultured human CEM leukemic lymphocytes were studied, in part to determine a possible pharmacologic basis for the latent effects seen with this drug. In addition, the cellular pharmacology of AD 198 and ADR were comparatively examined under identical experimental conditions. When CEM cells were incubated with drug at equi-growth inhibitory/minimally cytotoxic concentrations (AD 198, 1.0 M; ADR, 0.1 M), a number of differences were apparent. Under conditions of continuous 24-h drug exposure, a slow cellular accumulation and equilibration was observed with ADR (cell: medium equilibrium, 1:11 after 4–6 h), whereas the uptake of AD 198 was rapid and extensive (cell: medium equilibrium, 3:1 within 30 min). In drug-retention studies, when cells were pretreated at the same drug concentrations as before (AD 198 for 1 h; ADR for 4 h) and then transferred to drug-free media, both compounds re-equilibrated their intracellular drug content with the fresh media, losing about 50% of their respective anthracycline levels. Liquid chromatographic analysis of ADR-treated cultures under both sets of conditions showed the parent drug to be the only intracellular anthracycline species, whereas analysis of AD 198-treated cultures revealed two fluorescent signals corresponding to the parent drug and its 14-deesterified biotransformation product,N-benzyladriamycin (AD 288). Levels of AD 288 rose from 2% of the total intracellular anthracycline content immediately on drug admixture to 61% following 24 h continuous drug exposure and to 69% at 24 h in cells exposed to drug for 1 h and then continued in drug-free media for 24 h. At all times, the balance of the intracellular anthracycline fluorescence was attributable to the parent drug; no ADR was detectable in AD 198-treated cells by either fluorescence detection or radioassay. Thus, AD 198 is not a prodrug form of ADR, and the in vitro effects of this agent, including the latent effects on cell-cycle inhibition and DNA damage seen in cells following short-term drug exposure, can be explained on the basis of the high levels of active parent drug and biotransformation product that accumulate and persist in the cells.Abbreviations ADR adriamycin (doxorubicin) - AD 198 N-benzyladriamycin-14-valerate - AD 288 N-benzyladriamycin - AD 32 N-trifluoroacetyladriamycin-14-valerate - AD 143 N-trifluoroacetyladriamycin-14-0-hemiadipate - AD 41 N-trifluoroacetyladriamycin - [¹⁴C]-AD 198 [benzyl]--methylene-¹⁴C]-N-benzyladriamycin-14-valerate - [¹⁴C]-ADR [14-¹⁴C]-adriamycin - HPLC high-performance liquid chromatography - TLC thin-layer chromatography - DMSO dimethylsulfoxide - S-MEM Eagle's minimum essential medium for suspension culture - PBS phosphate-buffered saline (pH 7.0)