Acute aortic dissection in a patient with extremely low body mass index due to anorexia nervosa.

We report a case of successful surgical repair of an acute aortic dissection (Stanford Type A) in a severely malnourished 39-year old patient with anorexia nervosa (body mass index [BMI] 11.3 kg/m2) and essential hypertension. The case is of interest since 1) acute aortic dissection in patients with anorexia nervosa has not previously been described; 2) hypertension is extremely rare in patients with eating disorders; and 3) successful aortic repair in a patient with so low BMI has not been reported before. We conclude that extremely low BMI due to anorexia nervosa is not an absolute contraindication for major aortic surgery.

Targeting transcriptional control of soluble guanylyl cyclase via NOTCH for prevention of cardiovascular disease.

Soluble guanylyl cyclase (sGC) is an effector enzyme of nitric oxide (NO). Recent work has unravelled how levels of this enzyme are controlled, and highlighted a role in vascular disease. We provide a timely summary of available knowledge on transcriptional regulation of sGC, including influences from the NOTCH signalling pathway and genetic variants. It is speculated that hypertension-induced repression of sGC starts a vicious circle that can be initiated by periods of stress, diet or genetic factors, and a key tenet is that reduction in sGC further raises blood pressure. The idea that dysregulation of sGC contributes to syndromes caused by defective NOTCH signalling is advanced, and we discuss drug repositioning for vascular disease prevention. The advantage of targeting sGC expression rather than activity is also considered. It is argued that transcriptional inputs on sGC arise from interactions with other cells, the extracellular matrix and microRNAs (miRNAs), and concluded that the promise of sGC as a target for prevention of cardiovascular disease has increased in recent time.

Reasons for declining computerized insulin protocol recommendations: application of a framework.

Clinical decision support systems (CDS) can interpret detailed treatment protocols for ICU care providers. In open-loop systems, clinicians can decline protocol recommendations. We capture their reasons for declining as part of ongoing, iterative protocol validation and refinement processes. Even though our protocol was well-accepted by clinicians overall, noncompliance patterns revealed potential protocol improvement targets, and suggested ways to reduce barriers impeding software use. We applied Rita Kukafka and colleagues' (2003) IT implementation framework to identify and categorize reasons documented by ICU nurses when declining recommendations from an insulin-titration protocol. Two methods were used to operationalize the framework: reasons for declining recommendations from actual software use, and a nurse questionnaire. Applying the framework exposed limitations of our data sources, and suggested ways to address those limitations; and facilitated our analyses and interpretations.

A frame-based representation for a bedside ventilator weaning protocol.

We describe the use of a frame-based knowledge representation to construct an adequately-explicit bedside clinical decision support application for ventilator weaning. The application consists of a data entry form, a knowledge base, an inference engine, and a patient database. The knowledge base contains database queries, a data dictionary, and decision frames. A frame consists of a title, a list of findings necessary to make a decision or carry out an action, and a logic or mathematical statement to determine its output. Frames for knowledge representation are advantageous because they can be created, visualized, and conceptualized as self-contained entities that correspond to accepted medical constructs. They facilitate knowledge engineering and provide understandable explanations of protocol outputs for clinicians. Our frames are elements of a hierarchical decision process. In addition to running diagnostic and therapeutic logic, frames can run database queries, make changes to the user interface, and modify computer variables.

Spontaneous activity and stretch-induced contractile differentiation are reduced in vascular smooth muscle of miR-143/145 knockout mice.

AIM: Stretch is essential for maintaining the contractile phenotype of vascular smooth muscle cells, and small non-coding microRNAs are known to be important in this process. Using a Dicer knockout model, we have previously reported that microRNAs are essential for stretch-induced differentiation and regulation of L-type calcium channel expression. The aim of this study was to investigate the importance of the smooth muscle-enriched miR-143/145 microRNA cluster for stretch-induced differentiation of the portal vein. METHODS: Contractile force and depolarization-induced calcium influx were determined in portal veins from wild-type and miR-143/145 knockout mice. Stretch-induced contractile differentiation was investigated by determination of mRNA expression following organ culture for 24 h under longitudinal load by a hanging weight. RESULTS: In the absence of miR-143/145, stretch-induced mRNA expression of contractile markers in the portal vein was reduced. This was associated with decreased amplitude of spontaneous activity and depolarization-induced contractile and intracellular calcium responses, while contractile responses to 5-HT were largely maintained. We found that these effects correlated with a reduced basal expression of the pore-forming subunit of L-type calcium channels and an increased expression of CaMKIIδ and the transcriptional repressor DREAM. CONCLUSION: Our results suggest that the microRNA-143/145 cluster plays a role in maintaining stretch-induced contractile differentiation and calcium signalling in the portal vein. This may have important implications for the use of these microRNAs as therapeutic targets in vascular disease.

Gender comparison of RPE at absolute and relative physiological criteria.

PURPOSE: The effect of gender on ratings of perceived exertion for the overall body (RPE-O), chest (RPE-C), legs (RPE-L), and arms (RPE-A (ski)) was determined. METHODS: Comparisons were made at, a) absolute oxygen uptake (VO2, L x min(-1); mL x kg(-1) x min(-1)) and heart rate (HR, b x min(-1)) and b) relative VO2 (%VO2max/peak) and HR (% HRmax/peak) reference criteria. Nine male and 10 female subjects were compared using a perceptual estimation paradigm for treadmill (weight bearing), simulated ski (partial weight bearing), and cycle (nonweight bearing) exercise. RPE was determined by the Borg 15-category scale. RESULTS: For each exercise mode, RPE-O, RPE-L, RPE-A (ski), and RPE-C were higher (P < 0.05) in the female than male cohort when compared at submaximal absolute VO2 criteria. RPE did not differ between female and male cohorts when compared at mode specific relative VO2 criteria. Differences in RPE-O, RPE-L, RPE-A (ski), and RPE-C were not found between female and male subjects when comparisons were made at both absolute and relative HR. Responses were consistent for the three exercise modes. CONCLUSION: RPE did not differ between gender when comparisons were made at relativized VO2 and HR reference criteria at exercise intensities between 70 and 90% of mode specific maximal/peak values.

Birth center outcomes reported through automated technology.

UNLABELLED: BirthCare HealthCare is a multidisciplinary health care clinic and freestanding birth center in Salt Lake City, Utah. Highlights of a woman's labor assessment and birth outcomes are summarized in a paper birth log. The authors developed a relational database that facilitates efficient outcomes reporting. Examples of outcomes from this database are reported. OBJECTIVES: This study describes clinical outcomes from a freestanding birth center and the automated birth log database used to manage outcomes reporting. DESIGN: Retrospective data obtained primarily from a paper birth log and secondarily from the paper chart were entered into and extracted from an electronic database. PARTICIPANTS: 231 women who were evaluated in 269 encounters for delivery at the birth center between July 1, 1997, and June 30, 1999. MAIN CLINICAL OUTCOME MEASURES: The number of deliveries at the birth center; the percentage of intrapartum, postpartum, and newborn transfers to the inpatient hospital setting; cause-specific transfer rates; method of transfer; medication in labor; low and high birth weights; percentage of low Apgar scores; and average times from admission to birth and birth to discharge. CONCLUSION: Birth center clinical outcomes can be efficiently reported using an automated birth log. Clinical outcomes reported in this study are consistent with finding of previous research that demonstrates that birth centers are a safe alternative site for delivery.

The role of caveolin-1 in cardiovascular regulation.

Caveolae are omega-shaped membrane invaginations present in essentially all cell types in the cardiovascular system, and numerous functions have been ascribed to these structures. Caveolae formation depends on caveolins, cholesterol and polymerase I and transcript release factor-Cavin (PTRF-Cavin). The current review summarizes and critically discusses the cardiovascular phenotypes reported in caveolin-1-deficient mice. Major changes in the structure and function of heart, lung and blood vessels have been documented, suggesting that caveolae play a critical role at the interface between blood and surrounding tissue. According to an emerging paradigm, many of these changes are secondary to uncoupling of endothelial nitric oxide synthase. Thus, nitric oxide synthase not only synthesizes more nitric oxide in the absence of caveolin-1, but also more superoxide with potential pathogenic consequences. It is further argued that the vasodilating drive from increased nitric oxide production in caveolin-1-deficient mice is balanced by changes in the vascular media that favour increased dynamic resistance regulation. Harnessing the therapeutic opportunities buried in caveolae, while challenging, could expand the arsenal of treatment options in cancer, lung disease and atherosclerosis.

Computer protocols: how to implement.

Variation in clinical practice impedes control, is associated with unwanted and widespread error, and may preclude replicability. Methodologic replicability enhances our ability to detect signals of interest by both increasing the signal through consistent application of the intervention, and by reducing the obscuring effects of noise. Decision-support tools are intended to standardize some aspect of clinical care and thereby help lead to uniform implementation of clinical interventions. This is realized by explicit replicable computer protocols that can produce appropriate patient-specific decisions and introduce control of process into clinical care. Development of such protocols has required around-the-clock implementation for patient management because of the influence of patient history and previous patient states on the output of the computer protocol. Three successful computer protocols for management of blood glucose provide compelling examples. This clinician driven "bottom-up" approach complements the common information technology service driven "top-down" approach to clinical problems.

Long-term regulation of contractility and calcium current in smooth muscle.

Longitudinal smooth muscle strips from guinea pig ileum were cultured in vitro for 5 days, and the relationship between extracellular Ca2+ and force in high-K+ medium was evaluated. In strips cultured with 10% fetal calf serum (FCS), this relationship was shifted to the right (50% effective concentration changed by 2-3 mM) compared with strips cultured without FCS. The shift was prevented by inclusion of verapamil (1 microM) during culture and mimicked by ionomycin in the absence of FCS. The intracellular Ca2+ concentration ([Ca2+]i) during stimulation with high-K+ solution or carbachol was reduced after culture with FCS, whereas the [Ca2+]i-force relationship was unaffected. Cells were isolated from cultured strips, and whole cell voltage-clamp experiments were performed. Maximum inward Ca2+ current (10 mM Ba2+), normalized to cell capacitance, was almost three times smaller in cells isolated from strips cultured with FCS. Culture with 1 microM verapamil prevented this reduction. These results suggest that increased [Ca2+]i during culture downregulates Ca2+ current density, with associated effects on contractility.

Contractile effects of polycations in permeabilized smooth muscle.

The polycations spermine, neomycin and polylysine potentiated Ca(2+)-activated force in beta-escin permeabilized guinea-pig ileum strips. The effect was inhibited by the calmodulin antagonists trifluoperazine, mastoparan and W13. Potentiation was slow or absent in chi-toxin permeabilized strips, indicating dependence on penetration of the polycations into cells. The effects of spermine and neomycin were maintained after extensive permeabilization by beta-escin, which eliminated the contractile effect of GTPgammaS. Replacement of ATP by CTP, which is not a substrate for myosin light chain kinase, inhibited contractile potentiation. Potentiation of Ca(2+)-activated contractions was associated with increased phosphorylation of the myosin regulatory light chains (LC20). A contractile effect of polylysine and neomycin was also seen in Ca(2+)-free medium and after partial LC20 thiophosphorylation, indicating that phosphorylation-independent processes may contribute to the response. Although spermine does not cause contraction in Ca(2+)-free medium at physiological [MgATP], it did so when [MgATP] was lowered to 40 micron. Similar to high-[Mg2+], the rate of contraction on addition of ATP to strips incubated with microcystin-LR in inhibit phosphatase activity was increased by the polycations, but only at [Ca2+] < 0.3 micron. The results suggest that polycations increase Ca(2+)-activated force by inhibiting myosin phosphatase activity, thereby increasing myosin LC20 phosphorylation. However, additional activation mechanisms, evident at low [Ca2+] and at low [ATP] and possibly involving direct activation of myosin, contribute to their effect.

Effects of metabolic inhibition on cytoplasmic calcium and contraction in smooth muscle of rat portal vein.

Contractions in the rat portal vein, evoked by spontaneous action potentials or depolarizing high-K+ solution, are rapidly and reversibly inhibited by hypoxia or respiratory blockade. Intracellular free calcium ([Ca2+]i) was measured using Fura-2 to evaluate the effects of metabolic blockade on excitation-contraction coupling. Spontaneous contractions were associated with transient increases in [Ca2+]i. During exposure to cyanide (0.2-0.4 mM) or 2,4-dinitrophenol (30 microM) the duration and amplitude of the Ca2+ transients were decreased, leading to a decreased mean time integral of the individual [Ca2+]i transient, and corresponding decrease in the duration and amplitude of the contraction. Basal [Ca2+]i was increased in the presence of the metabolic inhibitors. High-K+ (40 mM) contractions caused a sustained increase in [Ca2+]i, which was not inhibited by exposure to cyanide, although the amplitude of the associated contraction was greatly reduced. Together with the earlier demonstration of decreased 20 kD myosin light chain phosphorylation under these conditions, this indicates that the activation of contraction is influenced by metabolism via the energy dependence of the light chain phosphorylation reaction. Thus at least three steps in the excitation-contraction sequence are influenced by inhibition of oxidative metabolism: membrane excitation, light chain phosphorylation, and the cross-bridge cycle. This provides mechanisms for a high degree of metabolic sensitivity of vascular tone, of importance for the adaptation of blood flow to tissue metabolic demands.

Inhibition of polyamine synthesis influences contractility of intestinal smooth muscle in culture.

Smooth muscle strips from guinea pig ileum were cultured for 5 days and then tested for contractile properties to investigate whether endogenous polyamines influence excitation-contraction coupling. Inhibition of spermidine and spermine synthesis by culture in the presence of the adenosylmethionine decarboxylase (EC4.1.1.50) inhibitor CGP-48664 (1-10 microM) decreased spermidine and spermine levels by 50% and increased putrescine by 20-fold. After culture with 10 microM, but not 1 microM, CGP-48664, the relationship between extracellular Ca2+ concentration and force in high K(+)-depolarized strips was shifted to the right, and phasic contractile activity as well as sensitivity to muscarinic stimulation was enhanced. When spermidine and spermine (each 50 microM) were available for cellular uptake during culture in the presence of 10 microM CGP-48664, spermidine and spermine concentrations were increased, and the effect on Ca2+ sensitivity was reversed. In strips cultured with 0 or 1 microM CGP-48664 in the presence of 50 microM spermidine and 50 microM spermine, no effect on Ca2+ sensitivity was observed. Force development relative to intracellular Ca2+ concentration was decreased in CGP-48664 (10 microM)-treated strips. The results suggest that endogenous polyamines influence excitation-contraction coupling in smooth muscle, although overall tissue concentrations may not reflect the polyamine pools responsible for this effect.

Polyamines increase Ca2+ sensitivity in permeabilized smooth muscle of guinea pig ileum.

The effects of polyamines were investigated in strips of smooth muscle from guinea pig ileum permeabilized with beta-escin (0.005%). Spermine (1 mM) inhibited transient contractions induced in Ca(2+)-free medium by carbachol (0.1 mM) and GTP gamma S (0.1 mM) but potentiated responses to caffeine (20 mM) and D-myo-inositol 1,4,5-trisphosphate (40 microM). At high ethylene glycol-bis(beta-amino-ethyl ether)-N,N,N',N'-tetraacetic acid concentration (10 mM) and in the presence of A-23187 (10 microM), force at optimal and suboptimal Ca2+ concentrations was increased both by spermine and by carbachol. Spermine did not potentiate contraction in Ca(2+)-free medium or after full thiophosphorylation of the regulatory 20-kDa myosin light chains but slightly potentiated contractions produced by partial thiophosphorylation. Also, spermidine and putrescine, as well as the aminoglycoside antibiotic neomycin, increased sensitivity to Ca2+, with potency correlating with number of positive charges. After permeabilization by a high concentration (0.1%) of beta-escin, the sensitivity to Ca2+ was increased by spermine but not by GTP gamma S. In preparations permeabilized by Triton X-100, spermine slightly increased Ca2+ sensitivity but not maximal force. Tissue contents of putrescine, spermidine, and spermine in intact ileum muscle were 8, 98, and 184 nmol/g, respectively. Permeabilization by 0.005 and 0.1% beta-escin reduced spermine contents by 40 and 53%, respectively. Effects of added polyamines in permeabilized preparations may thus reflect physiological effects of endogenous polyamines modulating contraction in the intact tissue.

Effect of glibenclamide on membrane response to metabolic inhibition in smooth muscle of rat portal vein.

Vascular smooth muscle tone is dependent on oxidative metabolism, a phenomenon of potential importance for the metabolic regulation of blood flow to tissues. The response of the rat portal vein to inhibition of cell respiration by cyanide (0.1-1 mM) is a reduction of its spontaneous myogenic activity. The trains of action potentials triggering phasic contractions are reduced in duration, while the frequency of trains is often somewhat increased as the resting membrane potential in the intervals between spike trains is less negative by 6.5 mV. Glibenclamide (10(-7) M) did not affect the resting membrane potential or spontaneous mechanical activity of oxygenated portal veins, but partly restored the depressed myogenic activity in the presence of cyanide (0.5 mM). The spike trains were longer, while the membrane was depolarized by 3 mV compared with the effects of cyanide alone. Inhibition of both oxidative and glycolytic metabolism by 2 mM NaCN in a medium where glucose was replaced by beta-hydroxybutyrate caused a hyperpolarization which was abolished by 10(-7) M glibenclamide. The relaxing effect of the K+ channel opener cromakalim (5 x 10(-9) to 6.25 x 10(-7) M) was partly antagonized by glibenclamide. Basal cytosolic [Ca2+] was increased by cyanide, while the Ca2+ transients associated with phasic contractions were reduced in duration. This latter effect was partially reversed by glibenclamide. The effect of cyanide on high-K+ contractures, which are associated with sustained membrane depolarization and not dependent on repetitive spike activity, was not influenced by 10(-7) M glibenclamide. The effects of inhibited cell respiration on spontaneous electrical activity seem to reflect a depolarizing drive caused by inhibited active ion exchange mechanisms, modified by a repolarizing drive, possibly from ATP-regulated K+ channels, causing reduced duration of the spike trains. While glibenclamide affects spontaneous activity at all levels of oxidative blockade, glibenclamide-sensitive hyperpolarization is seen only when both oxidative and glycolytic metabolism is inhibited.

Long-term infusion of atrial natriuretic peptide (ANP) improves renal blood flow and glomerular filtration rate in clinical acute renal failure.

BACKGROUND: Short-term infusion of atrial natriuretic peptide (ANP) increases renal blood flow (RBF) and glomerular filtration rate (GFR) in patients with acute renal dysfunction. In the present study we evaluated the effects of long-term infusion (>48 h) of ANP on (RBF) and (GFR) in 11 postcardiac surgical patients requiring pharmacological circulatory support and with acute renal impairment. METHODS: Urinary clearance of Cr-EDTA and PAH as well as central hemodynamic measurements were performed for 2-3 consecutive 30-min periods during ANP infusion (50 ng. kg-1. min-1), one hour after abrupt discontinuation of ANP and again immediately after reinstitution of ANP infusion. RESULTS: During ANP infusion, urine flow (UF), GFR, RBF and renal vascular resistance (RVR) were 6.4+/-1.1 ml. min-1, 19.9+/-3.1 ml. min-1, 408+/-108 ml. min-1 and 0.286+/-0.054 mmHg. min. ml-1, respectively. UF, GFR and RBF decreased significantly by 28% (P<0.001), 32% (P<0.01) and 31% (P<0.05), respectively when ANP infusion was discontinued. RVR increased by 93% (P<0.05) while there was no change in filtration fraction. After reinstitution of ANP infusion, all measured renal variables returned to baseline. There was no significant correlation between the number of ANP treatment days and the percentage decrease in GFR (r=0.18) or RBF (r=0.22) during ANP withdrawal. Central hemodynamic variables were not affected by ANP withdrawal. CONCLUSIONS: ANP infusion improves RBF and GFR in patients with acute renal impairment after cardiac surgery. This renal vasodilatory effect is maintained during a long-term infusion and seems to be hemodynamically safe.

Effects of polyamine synthesis inhibition on polyamines, growth and mechanical properties in hypertrophic rat urinary bladder.

The polyamines putrescine, spermidine and spermine, are ubiquitous intracellular metabolites associated with growth and protein synthesis. In this study effects of polyamine synthesis inhibition on bladder growth, polyamine levels and mechanical properties were investigated in rat urinary bladder subjected to partial outflow obstruction that causes bladder hypertrophy. The S-adenosyl methionine decarboxylase inhibitor CGP-48664 (5 and 20 mg kg-1) was administered alone or in combination with the ornithine decarboxylase inhibitor DFMO (500 mg kg-1), starting one day before creation of partial outflow obstruction and then daily for 7 days. The bladder muscle level of putrescine was increased 38 times and that of spermine reduced by 4 times while spermidine was unchanged after treatment with CGP-48664 (20 mg kg-1). The increase in putrescine was abolished in animals receiving CGP-48664 in combination with DFMO. Treatment with polyamine synthesis inhibitors could not prevent or reduce the hypertrophy of the bladder as judged by bladder wet weight and protein contents. The effects on polyamine quantities were not associated with changes in Ca(2+)-force relationship or in agonist and electrically stimulated force. In summary, treatment of rats with polyamine synthesis inhibitors resulted in changes in polyamine levels in the growing urinary bladder but did not affect growth or mechanical properties.

Polyamines inhibit myosin phosphatase and increase LC20 phosphorylation and force in smooth muscle.

The increase in Ca(2+)-activated force caused by polyamines in beta-escin-permeabilized guinda pig ileum is shown to be associated with increased myosin 20-kDa light chain (LC20) phosphorylation and shortening velocity. Myosin LC20 dephosphorylation with arrested kinase activity was slower in the presence of 1 mM spermine. Smooth muscle phosphatases (SMP-I, -II, -III, and -IV) isolated from turkey gizzard are all active against phosphorylated LC20, but only SMP-III and -IV dephosphorylate heavy meromyosin (HMM). Spermine inhibited SMP-III activity toward LC20 but stimulated HMM dephosphorylation, whereas SMP-IV was inhibited with both substrates. In contrast, SMP-I and -II were stimulated by spermine. The relative effects of different polyamines correlated with an increasing number of positive charges. Spermine did not affect binding of SMP-IV to myosin and did not dissociate any of the subunits of the enzyme. Incubation of permeabilized strips with SMP-IV resulted in attenuated responses to Ca2+, an effect that was opposed by spermine and abolished by microcystin-LR. We conclude that spermine selectively inhibits myosin phosphatase activity and suggest that polyamines function as endogenous myosin phosphatase inhibitors.