Dietary potassium deficiency, common in modern diets, raises blood pressure and enhances salt sensitivity. Potassium homeostasis requires a molecular switch in the distal convoluted tubule (DCT), ...which fails in familial hyperkalemic hypertension (pseudohypoaldosteronism type 2), activating the thiazide-sensitive NaCl cotransporter, NCC. Here, we show that dietary potassium deficiency activates NCC, even in the setting of high salt intake, thereby causing sodium retention and a rise in blood pressure. The effect is dependent on plasma potassium, which modulates DCT cell membrane voltage and, in turn, intracellular chloride. Low intracellular chloride stimulates WNK kinases to activate NCC, limiting potassium losses, even at the expense of increased blood pressure. These data show that DCT cells, like adrenal cells, sense potassium via membrane voltage. In the DCT, hyperpolarization activates NCC via WNK kinases, whereas in the adrenal gland, it inhibits aldosterone secretion. These effects work in concert to maintain potassium homeostasis.
Display omitted
•Dietary potassium deficiency activates thiazide-sensitive NaCl cotransport•Plasma potassium’s effects on NCC are mediated by membrane voltage•Membrane voltage alters cell chloride, affecting WNK kinase activity•Defects in distal potassium sensing cause human disease
Terker et al. show that dietary potassium deficiency stimulates renal NaCl reabsorption, even in the setting of high salt intake, by hyperpolarizing distal convoluted tubule cells and reducing cell chloride. Low chloride activates WNK kinases, which stimulate the NaCl cotransporter, limiting potassium loss but raising arterial pressure.
The contribution of innate immunity to inflammatory bowel disease (IBD) remains an area of intense interest. Macrophages (MØ) and dendritic cells (DC) are considered important factors in regulating ...the onset of IBD. The goal of this study was to determine if intestinal mononuclear phagocytes (iMNP) serve a pathological or protective role in dextran sulfate sodium (DSS)‐induced colitis in mice. Using a conditional MØ/DC depletion transgenic mouse line—MØ Fas‐induced apoptosis—to systemically deplete iMNP, DSS colitis histopathology was shown to be more severe in MØ/DC‐depleted compared with MØ/DC‐intact mice. Similarly, localized iMNP depletion by clodronate‐encapsulated liposomes into C57BL/6, BALB/c, and CB.17/SCID mice also increased DSS colitis severity, as indicated by increased histopathology, weight loss, rectal bleeding, decreased stool consistency, and colon length compared with MØ/DC‐intact, DSS‐treated mice. Histology revealed that iMNP depletion during DSS treatment led to increased neutrophilic inflammation, increased epithelial injury, and enhanced mucin depletion from Goblet cells. iMNP depletion did not further elevate DSS‐induced expression of TNF‐α and IFN‐γ mRNA but significantly increased expression of CXCL1 chemokine mRNA. Myeloperoxidase activity was increased in colons of MØ/DC‐depleted, DSS‐treated mice, compared with DSS alone, coincident with increased neutrophil infiltration in diseased colons. Neutrophil depletion combined with MØ/DC depletion prevented the increase in DSS colitis severity compared with MØ/DC depletion alone. This study demonstrates that iMNP can serve a protective role during development of acute colitis and that protection is associated with MØ/DC‐mediated down‐regulation of neutrophil infiltration.
Guidelines for patient radiation dose management Stecker, Michael S; Balter, Stephen; Towbin, Richard B ...
Journal of vascular and interventional radiology,
07/2009, Volume:
20, Issue:
7 Suppl
Journal Article
We hypothesized that patients with pelvic fractures and hemorrhage admitted during daytime hours were undergoing interventional radiology (IR) earlier than those admitted at night and on weekends, ...thereby establishing two standards of time to hemorrhage control.
The trauma registry (January 2008 to December 2011) was reviewed for patients admitted with pelvic fractures, hemorrhagic shock, and transfusion of at least 1 U of blood. The control group (DAY) was admitted from 7:30 AM to 5:30 PM Monday to Friday, while the study group (after hours AHR) was admitted from 5:30 PM to 7:30 AM, on weekends or holidays.
A total of 191 patients met the criteria (45 DAY, 146 AHR); 103 died less than 24 hours and without undergoing IR (29% DAY group vs. 62% AHR, p < 0.001). Sixteen patients (all in AHR group) died while awaiting IR (p = 0.032). Eighty-eight patients (32 DAY, 56 AHR) survived to receive IR. Among these, the AHR group were younger (median, 30 years vs. 54 years; p = 0.007), more tachycardic (median pulse, 119 beats/min vs. 90 beats/min; p = 0.001), and had more profound shock (median base, -10 vs. -6; p = 0.006) on arrival. Time from admission to IR (median, 301 minutes vs. 193 minutes; p < 0.001) and computed tomographic scan to IR (176 minutes vs. 87 minutes, p = 0.011) were longer in the AHR group. There was no difference in the 30-day mortality by univariate analysis. However, after controlling for age, arrival physiology, injury severity, and degree of shock, the AHR group had a 94% increased risk of mortality.
The current study demonstrated that patients admitted at night and on weekends have a significant increase in time to angioembolization compared with those arriving during the daytime and during the week. Multivariate regression noted that AHR management was associated with an almost 100% increase in mortality. While this is a single-center study and retrospective in nature, it suggests that we are currently delivering two standards of care for pelvic trauma, depending on the day and time of admission.
Therapeutic study, level II.
The risk of patient-prosthesis mismatch drives most surgeons to select the largest bioprosthesis possible during aortic valve replacement, but interactions between the native aortic annulus and valve ...prosthesis remain poorly defined. We examined the hemodynamic and functional consequences of oversizing contemporary bioprostheses in an in vitro model.
Three sizes each (21, 23, and 25 mm) of 5 aortic bioprostheses (Magna, Edwards Lifesciences, Irvine, CA; Trifecta and Epic, St. Jude, St. Paul, MN; and Mosaic and Hancock II, Medtronic, Minneapolis, MN) were tested on a mock annulus in a pulsatile aortic simulator. After the annulus was sized to match each valve, the annulus was decreased by 3 mm and then by 6 mm to simulate oversizing. We measured the effective orifice area and the mean pressure gradient. Changes in prosthetic leaflet behavior and geometric orifice area were assessed with slow-motion video. Statistical analysis used mixed-effects models for repeated-measures data, allowing comparison within and between groups.
For each valve model and size, oversizing resulted in decreased effective orifice areas and geometric orifice areas and increased pressure gradients. This was more pronounced with smaller valve sizes and higher flow rates but varied between valve types. Slow-motion imaging revealed this change in geometric orifice area was a result of an inward shift of the valve leaflet hinge point.
Bioprosthetic oversizing impairs hemodynamic performance of aortic valve bioprostheses. The magnitude of this effect varies by valve model and size. Clinically, these data suggest that during aortic valve replacement, placing a valve whose internal orifice closely matches the aortic annulus will provide the optimal hemodynamic performance.
The concept of acting intentionally is an important nexus where theory of mind and moral judgment meet. Preschool children's judgments of intentional action show a valence-driven asymmetry. Children ...say that a foreseen but disavowed side effect is brought about "on purpose" when the side effect itself is morally bad, but not when it is morally good. This is the first demonstration in preschoolers that moral judgment influences judgments of whether something was done on purpose (as opposed to judgments of purpose influencing moral judgment). Judgments of intentionality are usually assumed to be purely factual. That these judgments are sometimes partly normative--even in preschoolers--challenges current understanding. Young children's judgments regarding foreseen side effects depend on whether the children process the idea that the character does not care about the side effect. As soon as preschoolers effectively process the theory-of-mind concept "not care that P," children show the side-effect effect.
Transgenic mice expressing an inducible suicide gene, which allows systemic and reversible elimination of macrophages, were developed. A macrophage‐specific c‐fms promoter was used to express ...enhanced green fluorescent protein and a drug‐inducible suicide gene that leads to Fas‐mediated apoptosis in resting and cycling cells of the macrophage lineage. Transgenic mice were fertile, of normal weight, and showed no abnormal phenotype before drug exposure. The transgene was expressed constitutively in macrophages and dendritic cells (DC) but not significantly in T cells or B cells. Induction of the suicide gene led to depletion of 70–95% of macrophages and DC in nearly all tissues examined. Depletion reduced the ability to clear bacteria from the blood and led to increased bacterial growth in the liver. Depleted mice displayed several abnormalities, including splenomegaly, lymphadenopathy, thymic atrophy, extramedullary hematopoiesis, and development of peritoneal adhesions. This new, transgenic line will be useful in investigating the role of macrophages and DC.
Objective: To assess differential item functioning and observed mean differences across two modes of administration for PROMIS® measure scores in a sample of adults with traumatic injury. Method: ...Items from 7 PROMIS® adult measures (v1.0 Physical Function, Fatigue, Pain Interference, Anger, Anxiety, and Depression and v2.0 Social Health-Emotional Support) were administered as fixed-length short forms in random order to a cross-sectional sample. Participants were randomly assigned to interviewer-administered (phone or in-person) or self-administered (via the Assessment Center website) conditions. The research was conducted at 5 medical rehabilitation institutions across the U.S. Participants included 277 adults with spinal cord injury (n = 148) or traumatic brain injury (n = 129). Results: DIF analyses indicated that all items were invariant to mode of administration. There was no significant effect of mode of administration for the majority of PROMIS® measures tested. Regarding observed scores, there were small but significant effects of mode of administration on the Emotional Support and Depression measures, with participants in the interview condition reporting better support/fewer symptoms. Conclusions: PROMIS® instruments demonstrated measurement equivalence across interviewer-administered and self-administered conditions. These findings are particularly important for research or clinical applications where administration of PROMIS® measures by independent web- or tablet-based administration is not ideal, for example with individuals with physical or cognitive disabilities or with individuals who lack computer and/or Internet access. PROMIS® v1.0 Depression and PROMIS® v2.0 Emotional Support scores displayed a tendency toward social desirability that should be considered when these measures are interviewer-administered.
PDF
