Linkage analysis of SLE susceptibility: confirmation of SLER1 at 5p15.3

We detected a novel susceptibility gene, SLER1, for systemic lupus erythematosus (SLE) at 5p15.3.(1) This finding was based on a selected subgroup of SLE families, where two or more family members have had alleged rheumatoid arthritis (SLE-RA). The main objective of this study was to replicate the linkage at 5p15.3 based on an independent data set of 88 SLE-RA families. Heterogeneity in the genetic model led us to use a nonparametric allele-sharing method. Since our a priori hypothesis of linkage at 5p15.3 was fixed, we genotyped six markers at the linked region. Our new results replicate the initial linkage at 5p15.3 (Zlr=2.58, P<0.005, LOD=1.45). Moreover, evidence of linkage was sustained when analysis was restricted to the subset of SLE families who had 3 or more individuals with alleged RA (Zlr=3.32, P=0.008, LOD=2.40) The results of our previous findings, together with these new results, confirm the SLER1 linkage at 5p15.3. Our results also demonstrate the utility of clinically defined subgroup analysis for detecting susceptibility loci for complex genetic diseases, such as SLE.     

Dose distributions produced by shielded applicators using 241Am for intracavitary irradiation of tumors in the vagina.

Dosimetric characteristics of shielded vaginal applicators containing encapsulated 241Am sources are investigated in this work. Encapsulated 241Am sources emit primarily 60-keV photons which are more effectively shielded by thin layers of high atomic number materials than the 662-keV photons from 137Cs sources. With 241Am, it is possible to achieve almost unidirectional irradiation of localized vaginal tumors. The drastic decrease in irradiation volume on the contralateral side (uninvolved with tumor) is observed to decrease dose by up to 20%, even in the forward direction (unshielded side toward the tumor) of the applicator. A possible explanation for the observed effects of shields in both the forward and backward directions is the reduction of scattered photon fluence due to absorption of photons in the lead shield via photoelectric effect. Current theoretical models do not include this perturbation effect caused by shields on brachytherapy applicators.     

Experimental determination of the anisotropy function for the model 200 103Pd "light seed" and derivation of the anisotropy constant based upon the linear quadratic model

Since the publication of the AAPM Task Group 43 report in 1995, Model 200 103Pd seed, which has been widely used in prostate seed implants and other brachytherapy procedures, has undergone some changes in its internal geometry resulting from the manufacturer's transition from lower specific activity reactor-produced 103Pd ("heavy seeds") to higher specific activity accelerator-produced radioactive material ("light seeds"). Based on previously reported theoretical calculations and measurements, the dose rate constants and the radial dose functions of the two types of seeds are nearly the same and have already been reported. In this work, the anisotropy function of the "light seed" was experimentally measured and an averaging method for the determination of the anisotropy constant from distance-dependent values of anisotropy factors is presented based upon the continuous low dose rate irradiation linear quadratic model for cell killing. The anisotropy function of Model 200 103Pd "light seeds" was measured in a Solid Water phantom using 1 X 1 x 1 mm micro LiF TLD chips at radial distances of 1, 2, 3, 4, 5, and 6 cm and at angles from 0 to 90 degrees with respect to the longitudinal axis of the seeds. At a radial distance of 1 cm, the measured anisotropy function of the 103Pd "light seed" is considerably lower than that of the 103Pd "heavy seed" reported in the TG 43 report. Our measured values at all radial distances are in excellent agreement with the results of a Monte Carlo simulation reported by Weaver, except for points along and near the seed longitudinal axis. The anisotropy constant of the 103Pd "light seed" was calculated using the linear quadratic biological model for cell killing in 30 clinical implants. For the model 200 "light seed," it has a value of 0.865. However, our biological model calculations lead us to conclude that if the anisotropy factors of an interstitial brachytherapy seed vary significantly over radial distances anisotropy constant should not be used as an approximation for anisotropy characteristics of a brachytherapy seed.     

Clinical implementation of AAPM Task Group 32 recommendations on brachytherapy source strength specification

Historically the strength of sealed brachytherapy sources has been described by many physical quantities, including true activity, apparent activity, and equivalent mass of radium. Recently, the AAPM Task Group 32 recommended that these quantities be replaced by a single quantity, air-kerma strength, with units of muGy m2h-1. A set of equations has been developed for unambiguously converting source strength estimates and renormalizing published dose-rate tables, which assume traditional quantities and units, into forms consistent with air-kerma strength. For commonly used brachytherapy sources, multiplicative conversion factors for each source-strength formalism and set of units are given. To convert equivalent mass of radium to air-kerma strength requires a single multiplicative factor, 7.23 muGy m2h-1/mgRaEq, applicable to all sources. Based upon a review of vendor source specification practices, the factors for converting source strength of 198Au, 103Pd, and 125I seeds from apparent mCi to air-kerma strength are 2.06, 1.29, and 1.27 muGy m2h-1/mCi(apparent), respectively. These factors are independent of source geometry but depend on the nominal exposure rate constant value selected by the vendor. Conversion factors applicable to mass of radium or true activity depend upon both source geometry and radionuclide identity. Because many of these conversion factors depend upon vendor choices of physical constants and exposure rate constants, readers are cautioned to carefully review vendor source strength specification practices before adopting these values clinically. Finally, the relationships between the various source strength quantities and absorbed dose rate in the medium surrounding the source are elucidated.     

The characterization of Gardnerella vaginalis DNA using non-radioactive DNA probes

DNA restriction profiles of various Gardnerella vaginalis isolates, generated by BamHI, EcoRI, PstI and other restriction enzymes, varied considerably. Only a few DNA fragments were identified as common in ethidium bromide fluorescence profile and Southern-blot hybridization patterns (employing a digoxigenin-labelled G. vaginalis DNA probe and an enzyme-linked immunoassay detection method). While the efficiencies of Southern-blot hybridization appeared inconsistent, in dot-blot assays, DNA from each isolate hybridized readily, enabling the detection of at least 10 ng DNA. A 5.7-kb DNA fragment from G. vaginalis ATCC 14018 genomic library, cloned in the BamHI site of pBR322, could replace the total genomic DNA probe. This specific DNA fragment was present in different sizes in 12 analysed G. vaginalis strains, describing a restriction fragment length polymorphism. In control studies, none of the DNA from bacteria other than G. vaginalis (including some genitourinary tract residents) hybridized with the G. vaginalis total or specific DNA probes. Non-radioactive G. vaginalis DNA probes can thus form the basis of a useful detection method for further studies of this organism.     

Modification of electron-beam dose distributions by transverse magnetic fields

By applying a transverse magnetic field to a dosimetry phantom, an incident high-energy electron beam is made to follow a spiral path in the course of slowing down. Certain levels, determined by the electron energy and the magnetic field strength, will be traversed several times by the same electrons. The net result of this process is an enhancement of the depth dose in relation to the entrance dose, and a more sharply defined depth of penetration. Experiments with 50- and 55-MeV electrons traversing a 20.5-kG field are shown to support the predictions of a detailed Monte Carlo calculation.     

Evaluation of inhibitory effect of diphenhydramine on benzodiazepine dependence in rats

Effect of diphenhydramine was investigated on withdrawal signs in lorazepam dependent rats. Physical dependence was produced by giving lorazepam admixed with the food in the following dose schedule: 10 x 4, 20 x 4, 40 x 4, 80 x 4 and 120 x 7 (mg/kg, daily x days). The parameters observed during the periods of administration of lorazepam and after its withdrawal were spontaneous locomotor activity (SLA), body temperature, reaction time to pain, foot shock aggression (FSA) and audiogenic seizures. Diphenhydramine was administered orally in the dose schedules of once daily (10, 20 and 40 mg/kg) and twice daily (5, 10 and 20 mg/kg) in separate groups during the withdrawal period. The withdrawal signs observed in control group (without diphenhydramine) were hyperkinesia, hyperthermia, hyperaggression and audiogenic seizures. Hyperkinesia and hyperthermia were blocked in all the groups of diphenhydramine-treated rats. FSA was inhibited only by diphenhydramine (10 and 20 mg/kg) given twice daily. Audiogenic seizures were completely blocked by once daily (20 and 40 mg/kg) as well as twice daily (20 mg/kg) doses of diphenhydramine. It may be concluded that diphenhydramine exerts a protective effects on benzodiazepine withdrawal syndrome.     

Synthesis and antimicrobial activity of Schiff and Mannich bases of isatin and its derivatives with pyrimidine.

Isatin and its derivatives have been reacted with 4-(4'-chlorophenyl)-6-(4"-methyl phenyl)-2-aminopyrimidine to form Schiff bases and the N-Mannich bases of these compounds were synthesized by reacting them with formaldehyde and several secondary amines. Investigation of antimicrobial activity of the compounds was made by the agar dilution method against 28 pathogenic bacteria, eight pathogenic fungi and anti-HIV activity against replication of HIV-1 (III B) in MT-4 cells. The compounds are significantly active against bacteria and fungi.     

Buprenorphine pharmacokinetics: relative bioavailability of sublingual tablet and liquid formulations.

Buprenorphine is an effective new treatment for opiate dependence. This study compared the bioavailability of buprenorphine from a tablet to that from a reference solution. Six men experienced with, but not dependent on, opiates (DSM-III-R) were each administered 7.7 mg of buprenorphine in liquid form and 8 mg in tablet form 1 week apart in a balanced crossover design. Plasma levels were measured by electron capture capillary gas chromatography (GC), and concentration-time curves were constructed. Pharmacokinetic data were analyzed by analysis of variance. The bioavailability from the tablet was approximately 50% that from the liquid and was not affected by saliva pH. Lower bioavailability from the tablet may be due to slow dissolution.