AT-1 receptor antagonism modifies the mediation of endothelin-1, thromboxane A2, and catecholamines in the renal constrictor response to angiotensin II

OBJECTIVE: The present study investigated the consequences of partial AT(1) receptor blockade on the participation of catecholamines, thromboxane A(2) (TXA(2)), and endothelin-1 (ET-1) in the renal vasoconstriction induced by angiotensin II (Ang II). METHODS: For this purpose, the increase in renal perfusion pressure (RPP) produced by Ang II was studied in isolated kidneys from untreated or irbesartan-treated Wistar Kyoto and spontaneously hypertensive rats (SHR), in absence or presence of the alfa-1 receptor antagonist, prazosin, the TXA(2) receptor antagonist, ifetroban, or the ET(A)/ET(B) receptor antagonist, PD145065. RESULTS: Systolic arterial pressure (SAP) was higher (P < 0.05) in SHR than in WKY. Increases in RPP produced by Ang II were comparable in kidneys from both untreated groups. Treatment with irbesartan reduced SAP and RPP in both strains in a comparable extent. Presence of prazosin, ifetroban, or PD145065 in perfusion media reduced (P < 0.05) Ang II maximal response in all groups. Maximal inhibition of Ang II-induced vasoconstriction produced by the 3 antagonists was comparable in untreated WKY, but that of ifetroban and PD145065 was lower (P < 0.05) than that of prazosin in untreated SHR. Maximal inhibition of Ang II-induced vasoconstriction produced by the 3 antagonists was comparable in WKY treated with irbesartan, and not different to that observed in untreated WKY. Maximal inhibitory effect of the 3 antagonists was higher (P < 0.05) in treated than in untreated SHR. CONCLUSION: The study further supports the importance of catecholamines, TXA(2), and ET-1 as mediators of the renal vasoconstriction induced by Ang II in both normotensive and hypertensive rats. Hypertensive conditions appeared to reduce the participation of TXA(2) and ET-1 in Ang II-induced vasoconstriction when compared with normotensive conditions. Chronic partial blockade of AT(1) receptors did not affect the participation of catecholamines, TXA(2), and ET-1 in normotensive rats, but increased the participation of the 3 mediators in SHR. This suggests that when AT(1) receptors are partially blocked, other vasoconstrictor factors could exert part of the renal vasoconstrictor effects of Ang II.     

Conceptualizing a resilience research framework at The National Institutes of Health

The National Institutes of Health (NIH) have recently gathered internal and external input towards a shared understanding of resilience in the wide context of human health and the biomedical sciences that would help accelerate advances in human health and its maintenance. This shared view is that resilience refers in general to a system's capacity to recover, grow, adapt, or resist perturbation from a challenge or stressor. Over time, a system's response to a challenge might show varied degrees of reactions that likely fluctuate in response to the type of challenge (internal and/or external), severity of the challenge, the length of time exposed to the challenge, other external factors and/or biological factors (innate and/or external). We have embarked on this special issue as an opportunity to explore commonalities amongst viewpoints on the science of resilience covered by the various NIH Institutes, Centers, and Offices (ICOs) with respect to the characterization of various systems, stressors, outcomes measures and metrics, and interventions and/or protective factors that are shared within each domain and across multiple domains. Here, resilience is characterized broadly by four areas of scientific study: molecular/cellular, physiologic, psychosocial and spiritual, and environmental/community resilience. Each area or domain provides general frameworks for designing studies that may help advance the science of resilience within the context of health maintenance. This special issue will also acknowledge the remaining gaps that impede advancement of the science of resilience and offer considerations for potential next steps towards addressing the research gaps.     

Chimerism and tolerance in rat recipients of intestinal allografts from ALS-treated donors with and without adjunct naïve-donor-strain bone-marrow cells

BACKGROUND: BN --> LEW small-intestine transplantation (SITx) given a 28-day course of tacrolimus results in partial tolerance and prolonged alloengraftment despite the development of indolent chronic rejection (CR). We determined whether the CR was associated with the quantity or quality of passenger leukocytes contained in the unmodified or antilymphocyte serum (ALS)-depleted BN intestine at the time of transplantation, and with the subsequent migration and persistence of these donor leukocytes in the LEW recipients (chimerism). METHODS: Four experimental cohorts were defined by differences of the BN allografts and by the infusion (or not) of na?ve donor (bone marrow cells [BMC]) on the day of the BN --> LEW SITx. All LEW recipients were treated with the same 28-day course of tacrolimus. The LEW animals received: (1) unaltered intestine; (2) intestine from ALS-treated donor; (3) intestine from ALS-treated donor plus BMC from naive BN donor on day 0; and (4) unaltered intestine and BMC from unmodified (na?ve) BN donor. RESULTS: Blood chimerism during the first 2 weeks after transplantation was lowest in the recipients of intestine from ALS-treated donors (groups 2 and 3), apparently because of the nearly complete elimination from the bowel of alphabetaTCR+ passenger leukocytes. After 2 weeks posttransplant to 5 months, greater than 2% of circulating donor cells were seen in animals given adjunct BMC from na?ve BN donors (groups 3 and 4); this was associated with the absence of CR in the intestinal allografts. With lower levels of chimerism, moderate CR including arteritis and fibrosis in the Peyer's patches and mesenteric lymph nodes was found in the intestinal grafts of all group 1 and group 2 animals. Nevertheless, the CR-prone recipients in groups 1 and 2 had equivalent weight gain for greater than or equal to 150 days as in the CR-free groups 3 and 4. Detailed tissue chimerism studies in groups 1 to 3 showed that most of the donor cells in the gut-associated lymphoid tissues were rapidly replaced, but that the residual donor constituency of up to 6% in the allografts of group 3 was nearly 10-fold greater at 150 days than in groups 1 and 2 and closely reflected the findings in blood. CONCLUSION: The development of CR in intestinal allografts to which the recipients are partially tolerant is associated with a decline with time of donor-leukocyte chimerism. Multilineage chimerism in the recipient, and a similar profile of donor cells in the allografts, is better achieved with infused donor BMC than with the normal intestinal passenger leukocytes of the intestine. The difference may be because of a higher number of precursor and pluripotent stem cells in BMC.     

Acute vision impairment: does it affect an anesthesiologist's ability to intubate the trachea?

The result of impaired vision on an anesthesiologist's ability to intubate the trachea is unknown. We studied 12 attending staff anesthesiologists as they intubated 2 anesthesia mannequins (A and B) under 6 conditions. The conditions were: 1) usual vision, 2) central-vision loss with 20/500 bilaterally and a 24 degrees central scotoma, 3) peripheral-field loss with 20/20 bilaterally and a 7 degrees visual field, 4) peripheral-field loss with 20/20 bilaterally and a 3.5 degrees visual field, 5) central-vision loss with 20/200 bilaterally and a 12 degrees central scotoma, and 6) right eye ocular media opacity and 20/70 left eye usual acuity. The time to intubation was recorded by stopwatch from gripping the laryngoscope until the anesthesiologist signaled that the endotracheal tube was properly placed in the trachea. The mean +/- SD times to intubation for Mannequins A and B were 16.0 +/- 3.3, 31.9 +/- 10.4, 26.4 +/- 9.0, 26.4 +/- 7.7, 22.4 +/- 5.1, 25.5 +/- 16.9 and 16.6 +/- 6.6, 26.9 +/- 10.0, 21.4 +/- 9.2, 21.4 +/- 5.8, 21.5 +/- 7.7, 17.7 +/- 5.1 s for the 6 conditions, respectively. Multiple analysis of variance revealed a highly significant difference for the time to successful intubation between the anesthesiologists' usual vision and the vision-impaired conditions. There was a significant improvement in time to successful intubation from the first to subsequent intubation attempts. There were also more esophageal intubations in the vision-impaired conditions. This implies that anesthesiologists who develop acute severe vision impairment might have more difficulty intubating the trachea, which could initiate more critical incidents. The results of this study cannot be applied to anesthesiologists with chronic vision impairment. IMPLICATIONS: We found that acute severe vision impairment adversely affects the anesthesiologist's ability to intubate the trachea. This implies that anesthesiologists with acute onset of severe visual handicaps might have more difficulty intubating the trachea, which could initiate more critical incidents.     

Bilateral plasmacytoma of the breast: a case report

Plasmacytoma of the breast is a rare condition that may occur as a solitary finding or in association with multiple myeloma. Of the cases of plasmacytoma of the breast that have been described, nearly half have been bilateral. We report a case of bilateral plasmacytoma of the breast detected on a routine screening mammogram in a patient with a recent diagnosis of multiple myeloma.     

Natural and Prosthetic Heart Valve Calcification: Morphology and Chemical Composition Characterization

Calcification is the most common cause of damage and subsequent failure of heart valves. Although it is a common phenomenon, little is known about it, and less about the inorganic phase obtained from this type of calcification. This article describes the scanning electron microscopy (SEM)/energy dispersive X‐ray spectroscopy and Ca K‐edge X‐ray absorption near edge structure (XANES) characterization performed in natural and bioprosthetic heart valves calcified in vivo (in comparison to in vitro‐calcified valves). SEM micrographs indicated the presence of deposits of similar morphology, and XANES results indicate, at a molecular level, that the calcification mechanism of both types of valves are probably similar, resulting in formation of poorly crystalline hydroxyapatite deposits, with Ca/P ratios that increase with time, depending on the maturation state. These findings may contribute to the search for long‐term efficient anticalcification treatments.     

Interaction of Propofol and Sevoflurane on Loss of Consciousness and Movement to Skin Incision during General Anesthesia

Background: Loss of consciousness (LOC) and immobility to surgical incision seem to be mediated at different levels of the central nervous system. Pharmacologic studies of hypnotic agents have previously focused on combinations of either volatile or intravenous anesthetics. This study examined the combination of inhaled sevoflurane and intravenous propofol at these two clinically relevant anesthetic end points.

Methods: Thirty-six elective surgical patients were initially enrolled. Conditions approximating steady state were obtained for sevoflurane and target-controlled propofol infusions. Patients were sequentially evaluated for LOC (loud voice plus mild prodding) and immobility to surgical incision. The study was designed using the Dixon up-down method.

Results: The observed propofol effect target with 50% response plus sevoflurane (0.46% end-tidal concentration) was 1.2 [mu]g/ml (95% confidence interval, 1.1-1.3 [mu]g/ml). It was not significantly different from that predicted (1.5 [mu]g/ml; 95% confidence interval, 1.2-1.7 [mu]g/ml) by simple additivity. The effective plasma concentration of propofol that suppressed movement to skin incision in 50% of patients was 5.4 [mu]g/ml (95% confidence interval, 4.8-6.0 [mu]g/ml) plus sevoflurane (0.86%) and was not significantly different from that predicted by additivity (5.4 [mu]g/ml; 95% confidence interval, 4.8-5.9 [mu]g/ml). Both analyses had adequate power (90%) to detect a significant change (+/-19 to 25%) from predicted value. Repeated-measures analysis of variance identified a Bispectral Index value of 70 as the break point between those who responded at LOC or did not.     

Acute Myeloid Leukemia With Myelodysplasia-Related Changes: A New Definition

Acute myeloid leukemia (AML) with multilineage dysplasia was introduced in the 2001 World Health Organization (WHO) classification to encompass cases of AML characterized by myelodysplastic syndrome–like features. The 2008 WHO classification revised this group into a new category, AML with myelodysplasia-related changes (AML-MRC). The category now includes patients with at least 20% blasts in peripheral blood or bone marrow and any of the following: (1) AML arising from a previous MDS or mixed MDS/myeloproliferative neoplasm, (2) AML with a specific MDS-associated cytogenetic abnormality and/or (3) AML with multilineage dysplasia. Up to 48% of all patients with AML are encompassed within the AML-MRC subgroup. AML-MRC patients have worse prognosis compared with patients with AML, not otherwise specified.