Separate Sex-Influenced and Genetic Components in Spontaneously Hypertensive Rat Hypertension

Previous results from our laboratory indicated two major genetic components of spontaneously hypertensive rat (SHR) hypertension, an autosomal component and a Y chromosome component. Two new substrains, SHR/a and SHR/y, were developed using a series of backcrosses to isolate each of these components. The SHR/a substrain has the autosomal loci and X chromosome from the SHR strain and the Y chromosome from the Wistar-Kyoto (WKY) rat strain. The SHR/y substrain has only the Y chromosome from the SHR and autosomal loci and X chromosome from the WKY strain. Throughout these breeding programs parents were chosen at random without selection for blood pressure. Males of both substrains maintained blood pressures over 180 mm Hg. Comparisons of blood pressure in these new substrains with the original parental strains can be used to determine the relative proportions of each genetic component in hypertension. The Y chromosome component contributes 34 mm Hg, which is the difference between SHR/y male and WKY male blood pressure. The total autosomal component contributes 46 mm Hg, which is the difference between SHR/a male and WKY male blood pressure. The autosomal component is a sex-influenced trait; males in the SHR/a strain have significantly higher pressures than SHR/a females. Of the 46 mm Hg estimated for the autosomal component, 41 mm Hg is the result of these loci interacting with male phenotypic sex. This sex-influenced component is separate and distinct from the Y chromosome component

Genetic-Divergence Between the Wistar-Kyoto Rat and the Spontaneously Hypertensive Rat

A method of restriction fragment length polymorphism (RFLP) analysis was used to estimate the amount of genetic divergence between the spontaneously hypertensive rat (SHR) strain and the Wistar-Kyoto (WKY) strain. DNA from each strain was digested with eight restriction endonucleases and hybridized with six single copy gene sequences. The number of hybridization bands in each digestion was used to estimate the total number of bases analyzed and RFLPs were scored as single mutations. Divergence was then estimated by dividing the number of mutations by the number of bases analyzed. In a total of 808 bases analyzed in WKY rats, a minimum of 13 mutations were scored in SHR, which yields a nucleotide divergence of 1 change per 62 bp. This is an extremely high amount of divergence given the known origin of these two strains and is comparable to the maximum divergence possible between unrelated humans

Inconsistent Divergence of Mitochondrial-DNA in the Spontaneously Hypertensive Rat

We have recently shown that the spontaneously hypertensive rat (SHR) and the Wistar-Kyoto (WKY) rat differ at a frequency of 1 per 62 bases in their nuclear DNA (Hypertension 1992;19:425-427). Given the origin of these strains this level of divergence was unexpected. To investigate the origin of this nuclear divergence we have examined mitochondrial DNA. Mitochondrial DNA was isolated from SHR and WKY rats, digested with several restriction enzymes, electrophoresed in 1.0% agarose gels, and the fragments visualized with ethidium bromide staining. This approach allowed us to analyze 220 base pairs of mitochondrial DNA. No differences were detected between SHR and WKY rats. Comparison with the King-Holtzman rat strain produced differences at an average of 1 per 52 base pairs. We also examined several SHR and WKY rats from within our colonies and found no differences suggesting intrastrain homogeneity for mitochondrial DNA phenotypes. These data indicate that the SHR and WKY rat share a recent, common maternal ancestor. This result is consistent with the published origins of the SHR and WKY rat strains. Together with the nuclear divergence results, the data suggest that the original Wistar colony from which SHR and WKY rats were derived was probably highly polymorphic for nuclear genes

Androgen Receptor and the Testes Influence Hypertension in a Hybrid Rat Model

The objective of this study was to determine if males with a deficient androgen receptor would develop hypertension when crossed with a hypertensive parent. Female King-Holtzman rats (n = 15), heterozygous for the testicular feminization (Tfm) gene, were crossed with male spontaneously hypertensive rats (SHR), and blood pressure was measured weekly from 5-14 weeks in the F1 hybrid males. Approximately 50% of the F1 hybrid males were Tfm males and androgen receptor-deficient, and 50% were normal. Blood pressure in the parent King-Holtzman males, Tfms, and female rats was also followed for the same time period. The F1 normal male hybrids had a significantly higher (p \u3c 0.05) systolic blood pressure than the Tfm hybrid males after 12 weeks (195 +/- 8 versus 170 +/- 8 mm Hg, respectively). Blood pressure in the male and Tfm Holtzman rats was 120 +/- 5 mm Hg and 110 +/- 6 mm Hg, respectively. Castration lowered blood pressure by 38 mm Hg in the hybrid males and 27 mm Hg in the Tfm hybrids. Female F1 hybrids also showed a pressure rise above that of female Holtzman controls (155 +/- 6 mm Hg versus 110 +/- 6 mm Hg, p \u3c 0.01) but lower than the F1 males and Tfm hybrids. Ovariectomized females with testosterone implants did not show an elevation in blood pressure. Plasma electrolytes, norepinephrine, and cholesterol were not significantly different between normal and Tfm hybrid males. The results suggest that the presence of an androgen receptor and a testis-derived factor mediate the blood pressure rise in the hybrid males. A Y chromosome effect or sex-influenced locus may be involved since both the normal and Tfm males had significantly higher blood pressures than their female siblings

Alterations in vasomotor systems and mechanics of resistance-sized mesenteric arteries from SHR and WKY male rats following in vivo testosterone manipulation

<p>Abstract</p> <p>Background</p> <p>Testosterone (T) and the sympathetic nervous system each contribute to the pathology of hypertension. Altered blood vessel reactivity is also associated with the pathology of high blood pressure. The purpose of this study was to examine the effects of T manipulation in the regulation of resistance-sized blood vessel reactivity.</p> <p>Methods</p> <p>Adult spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) male rats at 8 weeks of age were used. The rats were divided into groups consisting of gonadally intact controls (CONT), castrate with sham implant (CAST) and castrate with T implant (CAST + T) (<it>n </it>= 6 to 12 per group). Following a short-term period of T treatment (approximately 4 weeks), plasma norepinephrine (NE) and plasma T were assessed by performing high-performance liquid chromatography and RIA, respectively. Resistance-sized mesenteric artery reactivity was assessed on a pressurized arteriograph for myogenic reactivity (MYO), phenylephrine (PE) responsiveness and passive structural mechanics.</p> <p>Results</p> <p>SHR and WKY males exhibited similar physiological trends in T manipulation, with castration significantly lowering plasma T and NE and T replacement significantly increasing plasma T and NE. T manipulation in general resulted in significant alterations in MYO of second-order mesenteric arteries, with T replacement decreasing MYO in SHR (<it>P </it>< 0.05) compared to CONT, T replacement increasing MYO, and CAST decreasing MYO in WKY rats (<it>P </it>< 0.001) compared to CONT rats. Additionally, PE-induced constriction was significantly altered in both strains following T treatment, with the effective concentration of PE to constrict the vessel to 50% of the total diameter significantly increased in the CAST + T SHR compared to CONT (<it>P </it>< 0.05). Comparisons of passive structural mechanics between SHR and WKY treatment groups indicated in SHR a significantly increased wall-to-lumen ratio and decreased circumferential wall stress compared to WKY treatment groups.</p> <p>Conclusions</p> <p>These data suggest that T and NE are involved in a complex interaction with both myogenic reactivity and structural alterations of resistance-sized blood vessels and that these factors likely contribute to the development and maintenance of hypertension.</p

Anomalous atmospheric circulation and large winter floods in six subregions of the southwestern United States

EXTRACT (SEE PDF FOR FULL ABSTRACT): We examined atmospheric circulation conditions conducive to occurrence of winter floods that exceed the 10-year peak discharge on rivers in six hydroclimatic subregions in Arizona, southern Utah, Nevada, and California. ... This relationship between flooding and broad-scale atmospheric patterns in the modern record will aid in paleoclimatic interpretations of paleoflood records over the last few thousand years

Neutron Detector Gamma Insensitivity Criteria

The shortage of 3He has triggered the search for an effective alternative neutron detection technology for radiation portal monitor applications. Any new detection technology must satisfy two basic criteria: 1) it must meet the neutron detection efficiency requirement, and 2) it must be insensitive to gamma ray interference at a prescribed level, while still meeting the neutron detection requirement. It is the purpose of this document to define this latter criterion

Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: an a priori-designed analysis of the MENDS randomized controlled trial

Abstract Introduction Benzodiazepines and α2 adrenoceptor agonists exert opposing effects on innate immunity and mortality in animal models of infection. We hypothesized that sedation with dexmedetomidine (an α2 adrenoceptor agonist), as compared with lorazepam (a benzodiazepine), would provide greater improvements in clinical outcomes among septic patients than among non-septic patients. Methods In this a priori-determined subgroup analysis of septic vs non-septic patients from the MENDS double-blind randomized controlled trial, adult medical/surgical mechanically ventilated patients were randomized to receive dexmedetomidine-based or lorazepam-based sedation for up to 5 days. Delirium and other clinical outcomes were analyzed comparing sedation groups, adjusting for clinically relevant covariates as well as assessing interactions between sedation group and sepsis. Results Of the 103 patients randomized, 63 (31 dexmedetomidine; 32 lorazepam) were admitted with sepsis and 40 (21 dexmedetomidine; 19 lorazepam) without sepsis. Baseline characteristics were similar between treatment groups for both septic and non-septic patients. Compared with septic patients who received lorazepam, the dexmedetomidine septic patients had 3.2 more delirium/coma-free days (DCFD) on average (95% CI for difference, 1.1 to 4.9), 1.5 (-0.1, 2.8) more delirium-free days (DFD) and 6 (0.3, 11.1) more ventilator-free days (VFD). The beneficial effects of dexmedetomidine were more pronounced in septic patients than in non-septic patients for both DCFDs and VFDs (P-value for interaction = 0.09 and 0.02 respectively). Additionally, sedation with dexmedetomidine, compared with lorazepam, reduced the daily risk of delirium [OR, CI 0.3 (0.1, 0.7)] in both septic and non-septic patients (P-value for interaction = 0.94). Risk of dying at 28 days was reduced by 70% [hazard ratio 0.3 (0.1, 0.9)] in dexmedetomidine patients with sepsis as compared to the lorazepam patients; this reduction in death was not seen in non-septic patients (P-value for interaction = 0.11). Conclusions In this subgroup analysis, septic patients receiving dexmedetomidine had more days free of brain dysfunction and mechanical ventilation and were less likely to die than those that received a lorazepam-based sedation regimen. These results were more pronounced in septic patients than in non-septic patients. Prospective clinical studies and further preclinical mechanistic studies are needed to confirm these results. Trial Registration NCT00095251

Physician-assisted suicide and euthanasia: Emerging issues from a global perspective

Medical professional societies have traditionally opposed physician-assisted suicide and euthanasia (PAS-E), but this opposition may be shifting. We present 5 reasons why physicians shouldn’t be involved in PAS-E. 1. Slippery slopes: There is evidence that safeguards in the Netherlands and Belgium are ineffective and violated, including administering lethal drugs without patient consent, absence of terminal illness, untreated psychiatric diagnoses, and nonreporting; 2. Lack of self-determination: Psychological and social motives characterize requests for PAS-E more than physical symptoms or rational choices; many requests disappear with improved symptom control and psychological support; 3. Inadequate palliative care: Better palliative care makes most patients physically comfortable. Many individuals requesting PAS-E don’t want to die but to escape their suffering. Adequate treatment for depression and pain decreases the desire for death; 4. Medical professionalism: PAS-E transgresses the inviolable rule that physicians heal and palliate suffering but never intentionally inflict death; 5. Differences between means and ends: Proeuthanasia advocates look to the ends (the patient’s death) and say the ends justify the means; opponents disagree and believe that killing patients to relieve suffering is different from allowing natural death and is not acceptable. Conclusions: Physicians have a duty to eliminate pain and suffering, not the person with the pain and suffering. Solutions for suffering lie in improving palliative care and social conditions and addressing the reasons for PAS-E requests. They should not include changing medical practice to allow PAS-E

Master crossover behavior of parachor correlations for one-component fluids

The master asymptotic behavior of the usual parachor correlations, expressing surface tension $\sigma$ as a power law of the density difference $\rho_{L}-\rho_{V}$ between coexisting liquid and vapor, is analyzed for a series of pure compounds close to their liquid-vapor critical point, using only four critical parameters $(\beta_{c})^{-1}$, $\alpha_{c}$, $Z_{c}$ and $Y_{c}$, for each fluid. ... The main consequences of these theoretical estimations are discussed in the light of engineering applications and process simulations where parachor correlations constitute one of the most practical method for estimating surface tension from density and capillary rise measurements