IMMUNOHISTOCHEMICAL IDENTIFICATION OF PENICILLIUM MARNEFFEI BY MONOCLONAL ANTIBODY

We present an experimental study on the immunohistochemical identification of Penicillium marneffei in paraffin-embedded, formalin-fixed tissue. The monoclonal antibody EB-A1 detects a specific galactomannan that appears to have at least one epitope identical in P. marneffei and Aspergillus sp. This immunohistochemical approach could be useful in the diagnosis of a rare diseae, penicilliosis marneffei, which proves to be difficult to identify by conventional microscopy.     

A Prospective Randomized Cross-Over Comparison of Mono- and Biphasic Defibrillation Using Nonthoracotomy Lead Configurations in Humans

Biphasic Defibrillation with Nonthoracotomy Leads. Introduction: For current implantable defibrillators, the nonthoracotomy approach to implantation fails in a substantial number of patients. In a prospective randomized cross-over study the defibrillation efficacy of a standard monophasic and a new biphasic waveform was compared for different lead configurations.
Methods and Results: Intraoperatively, in 79 patients receiving nonthoracotomy defibrillation leads, the defibrillation threshold was determined in the initial lead configuration for the mono-and biphasic waveform. In each patient, both waveforms were used alternately with declining energies (20, 15,10, 5 J) until failure of defibrillation occurred. Three different initial lead configurations were tested in different, consecutive, nonrandomized patients using a bipolar endocardial defibrillation lead alone (A; n = 36) or in combination with a subcutaneous defibrillation patch (B; n = 24) or array (C; n = 19) lead. The lowest successful defibrillation energy with the biphasic waveform was less than, equal to, or higher than with the monophasic waveform in 64%, 28%, and 8% of patients, respectively, and on average significantly lower with the biphasic waveform for all three lead configurations (A: 11.3 ± 4.4 J vs 14.5 ± 4.5.); B: 9.7 ± 4.7 J vs 15.1 ± 4.5 J; C: 7.9 ± 4.5 J vs 12.4 ± 4.9 J). Defibrillation efficacy at 20 J was significantly improved by the biphasic waveform (91% vs 76%).
Conclusion: In combination with nonthoracotomy defibrillation leads, the biphasic waveform of a new implantable cardioverter defibrillator showed superior defibrillation efficacy in comparison to the standard monophasic waveform. Defibrillation thresholds were improved for lead systems with and without a subcutaneous patch or array lead.     

ICD Leads:

GRADAUS, R., et al .: ICD Leads: Design and Chronic Dysfunctions. The treatment of ventricular tachyarrhythmias has changed over the last 10 years. Implantable cardioverter defibrillators (ICDs), once used only as a last resort therapy, have now become the treatment of choice. This change occurred before the first results of randomized studies on ICD therapy in patients with life-threatening ventricular tachyarrhythmias were published by the end of 1997. Technological advances of ICD therapy, in particular the development of transvenous leads, were to a large extent responsible for this change. Modern leads are characterized by their multilumen design that incorporates straight wires and coiled conductors into a single electrode body. Conductors and insulation are sheathed with additional insulation layers. The most frequently used insulating materials are silicone, polyurethane, and fluoropolymers. Lead failures are an important complication of ICD therapy. Fractured conductors, compression, creeping, or insulation defects from abrasion can cause such lead dysfunctions. Chronically implanted leads will inevitably have an increased risk of failure due to defects despite all technological advances. In the light of improving survival figures in patients with ventricular tachyarrhythmias and increasing numbers of ICD implantations, lead failures are becoming a clinical problem of ever increasing importance. Therefore, the question of which lead types necessitate extraction when a certain failure occurs and which leads can be left in place. Despite continuous improvements in lead extraction systems and growing experience in their use, the extraction of any pacemaker or ICD lead is associated with some risk of complications. (PACE 2003; 26[Pt. I]:649–657)     

Annual direct medical cost and contributing factors to total cost of epilepsy in Oman

OBJECTIVES: To describe the pharmaceutical use, health care resource utilisation patterns, and annual direct medical cost of epilepsy as well as determining the impact of various demographic and clinical characteristics on total costs of epilepsy in Oman. METHODS: Medical and pharmacy data were collected for 6 months on all patients aged > or =13 years attending the Sultan Qaboos University Hospital. Unit pharmacy and medical costs were retrieved for each patient, and multiple linear regression was utilised to analyse the impact of various demographic and clinical characteristics on total cost. RESULTS: A total of 486 patients were seen over the study period. Annual direct medical costs of epilepsy amounted to 1,426 US dollars. In-patient care, the antiepileptic drug (AED) lamotrigine and specialist visits, respectively, were the first, second and third most significant predictors of total cost. Age was associated positively, and was the most significant predictor of total costs among demographic and clinical parameters. CONCLUSIONS: This analysis, the first economic study of epilepsy in Oman, could assist in health care allocation of scarce resources and in pharmacoeconomic analysis of AEDs. Besides in-patient admission, our findings demonstrate that the newer drugs are significant predictors of total cost, and hence any incremental benefits derived from them must be rigorously assessed for their cost-effectiveness.     

Synthesis and biological activities of ψ(CH2NH) pseudopeptide analogues of the C-terminal hexapeptide of neurotensin

Each peptide CO-NH function in the biologically important C-terminal 8-13 sequence of neurotensin was replaced by the reduced CH₂-NH isostere using the rapid in situ solid phase procedure developed by Sasaki & Coy. In general this modification resulted in a drop in receptor affinity except for the [Argψ(CH₂NH)Arg]-NT_8–13 analogue (PIC₅₀ 9.23 vs. NT_8–13 PIC₅₀ 8.03). This analogue also showed enhanced enzymatic stability, but acted as a full agonist as shown by the observation of relaxations of guinea-pig colon ascendens.     

Synthetic linear and cyclic glucagon antagonists

The synthesis and biological activities of seven new glucagon analogues are reported. The design of com- pounds 2-5 is based on potent antagonists recently reported from this laboratory, where we have focused on modifications in the N-terminal region. In this report we have concentrated specifically on modifications to histidine-1. In addition we have prepared two cyclic compounds 7 and 8 , related to a linear in vivo antagonist [Glu⁹]glucagon, reported by Medeld (Unson et al. (1987) Proc. Natl. Acad. Sci. USA 84 , 4083-4087). The N-terminal modifications involved substitution of His¹ by the unnatural conformationally constrained residue (S)-5,6,7,8-tetrahydro-5-oxoimidazo(1,5-c)pyrimidine-7-carboxylic acid (Toc), desaminohistidine (dHis) and 3-(4-nitrobenzyl)histidine. The structures of the new compounds are as follows. [Toc¹,d -Phe⁴,Tyr⁵,Arg¹²,Lys^17,18,Glu²¹]glucagon ( 2 ); [Toc¹,d Phe⁴,Tyr⁵,Arg¹²,Lys^17,18,Glu²¹]glucagon amide ( 3 ); [3-(4-nitrobenzyl)His¹,d Phe⁴,Tyr⁵,Arg¹²,Lys^17,18,Glu²¹]glucagon ( 4 ); [dHis¹,d -Phe⁴,Tyr⁵,Arg¹²,Lys^17,18,Glu²¹]glucagon ( 5 ); [dHis¹,Glu⁹]glucagon ( 6 ); (desHis¹)glucagon amide ( 7 ); (desHis¹)-glucagon amide ( 8 ). The binding potencies of the linear analogues, as expressed a percentage of glucagon binding, are 2.6 ( 2 ), 0.13 ( 3 ), 0.8 ( 4 ), 0.8 ( 5 ), 2.2 ( 6 ). Both cyclic analogues 7 and 8 show biphasic binding curves. The IC₅₀ values for 7 at the high and low finity sites are 1.5 and 167 nm , respectively (IC₅₀ of glucagon = 1.3 nm ). The IC₅₀ values for ₅₀ at the high and low affinity sites are 4.7 and 3451 nm , respectively. The cyclic analogues are characterized by fast atom bombardment mass spectrometry of endoproteinase ASP-N digests. The specificity of the enzyme used in these studies enables differentiation of isomers of the cyclic glucagon analogues which differ only in the position of cyclic amide bond. Analogues 2,3 and 5–8 are glucagon receptor antagonists with respect to the glucagon receptor coupled to the adenylate cyclase (AC) system. Analogue 4 is a partial agonist (5.7% compared to glucagon) of AC. Introduction of unusual amino acids which do not contain a primary α-amino group such as Toc at the N-terminus is expected to increase in vivo metabolic stability by protecting against degradation by aminopeptidases.