Role of the kdr and super-kdr sodium channel mutations in pyrethroid resistance: correlation of allelic frequency to resistance level in wild and laboratory populations of horn flies (Haematobia irritans)

The kdr and super-kdr point mutations found in the insect sodium channel gene are postulated to confer knockdown resistance (kdr) to pyrethroids. Using an allele-specific PCR assay to detect these mutations in individual horn flies, Haematobia irritans (L.), we determined the allelic frequency of the kdr and super-kdr mutations in several wild and laboratory populations. Wild populations with very similar allelic frequencies had resistance levels that ranged widely from 3- to 18-fold relative to a susceptible population. Conversely, the kdr allele frequency in a lab population with 17-fold resistance was nearly double that found in a heavily pressured wild population with 18-fold resistance. We conclude that, although the kdr mutation confers significant levels of pyrethroid resistance, a substantial component of resistance in insecticidally pressured populations is conferred by mechanisms that are PBO-suppressible. High super-kdr allele frequencies were detected in two resistant lab populations, but in wild populations with equivalent resistance the super-kdr allele frequency was very low. Interestingly, in over 1200 individuals assayed, the super-kdr mutation was never detected in the absence of the kdr mutation.     

Inhibition of experimental autoimmune encephalomyelitis in Lewis rats by nasal administration of encephalitogenic MBP peptides: synergistic effects of MBP 68-86 and 87-99

Induction of mucosal tolerance by inhalation of soluble peptides with defined T cell epitopes is receiving much attention as a means of specifically down-regulating pathogenic T cell reactivities in autoimmune and allergic disorders. Experimental autoimmune encephalomyelitis (EAE) induced in the Lewis rat by immunization with myelin basic protein (MBP) and Freund's adjuvant (CFA) is mediated by CD4+ T cells specific for the MBP amino acid sequences 68-86 and 87-99. To further define the principles of nasal tolerance induction, we generated three different MBP peptides (MBP 68-86, 87-99 and the non-encephalitogenic peptide 110-128), and evaluated whether their nasal administration on day -11, -10, -9, -8 and -7 prior to immunization with guinea pig MBP (gp-MBP) + CFA confers protection to Lewis rat EAE. Protection was achieved with the encephalitogenic peptides MBP 68-86 and 87-99, MBP 68-86 being more potent, but not with MBP 110-128. Neither MBP 68-86 nor 87-99 at doses used conferred complete protection to gp-MBP-induced EAE. In contrast, nasal administration of a mixture of MBP 68-86 and 87-99 completely blocked gp-MBP-induced EAE even at lower dosage compared to that being used for individual peptides. Rats tolerized with MBP 68-86 + 87-99 nasally showed decreased T cell responses to MBP reflected by lymphocyte proliferation and IFN-gamma ELISPOT assays. Rats tolerized with MBP 68-86 + 87-99 also had abrogated MBP-reactive IFN-gamma and tumor necrosis factor-alpha mRNA expression in lymph node cells compared to rats receiving MBP 110-128 nasally, while similar low levels of MBP-reactive transforming growth factor-beta and IL-4 mRNA expressing cells were observed in the two groups. Nasal administration of MBP 68-86 + 87-99 only slightly inhibited guinea pig spinal cord homogenate-induced EAE, and passive transfer of spleen mononuclear cells from MBP 68-86 + 87-99-tolerized rats did not protect na?ve rats from EAE. Finally, we show that nasal administration of MBP 68-86 + 87-99 can reverse ongoing EAE induced with gp-MBP, although higher doses are required compared to the dosage needed for prevention. In conclusion, nasal administration of encephalitogenic MBP peptides can induce antigen-specific T cell tolerance and confer incomplete protection to gp-MBP-induced EAE, and MBP 68-86 and 87-99 have synergistic effects. Non-regulatory mechanisms are proposed to be responsible for tolerance development after nasal peptide administration.     

The discovery and structure-activity relationships of nonpeptide, low molecular weight antagonists selective for the endothelin ET(B) receptor

The systematic modification of the ETA selective N-(5-isoxazolyl)benzene-sulfonamide endothelin antagonists to give ETB selective antagonists is reported. The reversal in selectivity was brought about by substitution of the 4-position with aryl and substituted aryl groups. Of all the aromatic substituents studied, the para-tolyl group gave rise to the most active and selective ETB antagonist. Larger substituents caused a decrease in both ETB activity and selectivity. A similar trend was observed by substitution at the 5-position of the N-(5-isoxazolyl)-2-thiophenesulfonamide ETA receptor antagonists. The para-tolyl group was again found to be optimal for the ETB activity and selectivity. The structural features that were found to be favorable for binding to the ETB receptor, that is, the presence of a linear, conjugated pi-system of definite shape and size, have been successfully incorporated into the design of ETB selective polycyclic aromatic sulfonamides antagonists.     

Long-term test-retest reliability of personality disorder diagnoses in opiate dependent patients

Continuous wave Doppler methods have been widely used clinically for evaluating the severity of aortic regurgitation; however, there have been no studies comparing these continuous wave Doppler methods with a strictly quantifiable reference for regurgitant severity. The purpose of this study was to test the applicability of continuous wave Doppler methods (deceleration slope and pressure half-time) for evaluation of chronic aortic regurgitation in an animal model. Eight sheep were studied 8 to 20 weeks after surgery to create chronic aortic regurgitation. Twenty-nine hemodynamically different states were obtained pharmacologically. A Vingmed 775 system was used for recording continuous wave Doppler traces with a 5 MHz annular array transducer directly placed on the heart near the apex. The aortic regurgitation was quantified as peak and mean regurgitant flow rates, regurgitant stroke volumes and regurgitant fractions determined with pulmonary and aortic electromagnetic flow probes and meters balanced against each other. Peak regurgitant flow rates varied from 1.8 to 13.6 L/min (6.3 +/- 3.2 L/min) (mean +/- SD), mean regurgitant flow rates varied from 0.7 to 4.9 L/min (2.7 +/- 1.3 L/min), regurgitant stroke volume varied from 7.0 to 48.0 ml/beat (26.9 +/- 12.2 ml/beat), and regurgitant fraction varied from 23% to 78% (53% +/- 16%). Only marginal correlations were obtained between reference indexes and continuous wave Doppler deceleration slope and pressure half-time (r = 0.55 to 0.74). A deceleration slope greater than 3 m/sec2 and pressure half-time less than 400 msec did, however, provide 100% specificity for detecting severe AR (regurgitant fraction > 50%). Our study shows that the continuous wave Doppler deceleration slope and pressure half-time methods have limited use for quantifying aortic regurgitation.     

The lives of female physicians

Survey data from 113 female physicians, 634 male physicians, and 41 female dentists were compared. Instruments designed to assess work satisfaction, work stress, marital satisfaction, family competence, and psychiatric symptoms and treatment were used, thereby exploring important life domains concurrently. The results suggest that female physicians are much more like both male physicians and female dentists than anticipated. Generally, female physicians describe high levels of work satisfaction, moderate levels of work stress, average-to-high levels of marital satisfaction, and relatively low levels of psychiatric distress. Their lower levels of practice income remain something of an enigma as gender remains the most powerful predictor of income and is not replaced in statistical analyses by specialty, hours worked, or other significant variables. Finally, female physicians who find higher levels of satisfaction in work also report higher levels of marital satisfaction and fewer psychiatric symptoms. For these women, a highly satisfying medical career does not apparently need to be experienced at the cost of marital or personal distress.     

Fluoridation in Anglesey 1993: a clinical study of dental caries in 5-year-old children who had experienced sub-optimal fluoridation

Several studies since the commencement of fluoridation in 1955 have demonstrated over 50% reduction in mean dmft for 5-year-old Anglesey children in comparison with local control groups. From 1987 fluoridation became intermittent and in 1991 it was terminated. In the present study, carried out in 1993, the total number of children examined was 725 (88.4% of the entire population of 5-year-old school children), of whom 498 had continually resided in specific water distribution zones. The mean dmft for the entire number examined was 2.01 (SD = 3.27). For those who had experienced fluoridation during approximately 35% of their lives (n = 230) it was 1.81 (SD = 2.86) and for those who had experienced fluoridation for less than 10% of their lives (n = 268) it was 2.28 (SD = 3.48). In 1987/88, the last year of optimal fluoridation, the mean dmft of Anglesey 5-year-old children was 0.80 (SD = 1.43) and for those resident on the non-fluoridated Gwynedd mainland it was 2.26 (SD = 3.17). The study demonstrates the serious consequences for dental health when fluoridation is withdrawn and how difficult it will be to reach dental health targets in North Wales without fluoridation.     

Intraoperative echocardiography is indicated in high-risk coronary artery bypass grafting

BACKGROUND: Intraoperative echocardiography is a valuable monitoring and diagnostic technology used in cardiac surgery. This reports our clinical study of the usefulness of intraoperative echocardiography to both surgeons and anesthesiologists for high-risk coronary artery bypass grafting. METHODS: From March to November 1995, 82 consecutive high-risk patients undergoing coronary artery bypass grafting were studied in a four-stage protocol to determine the efficacy of intraoperative echocardiography in management planning. Alterations in surgical and anesthetic/hemodynamic management initiated by intraoperative echocardiography findings were documented in addition to perioperative morbidity and mortality. RESULTS: Intraoperative echocardiography initiated at least one major surgical management alteration in 27 patients (33%) and at least one major anesthetic/hemodynamic change in 42 (51%). Mortality and the rate of myocardial infarction in this consecutive high-risk study population using intraoperative echocardiography and in a similar group of patients without the use of intraoperative echocardiography was 1.2% versus 3.8% (not significant) and 1.2% versus 3.5% (not significant), respectively. CONCLUSIONS: We conclude that when all of the isolated diagnostic and monitoring applications of perioperative echocardiography are routinely and systematically performed together, it is a safe and viable tool that significantly affects the decision-making process in the intraoperative care of high-risk patients undergoing primary isolated coronary artery bypass grafting and may contribute to the optimal care of these patients.