Disorder-to-order transition of long fibers contained in evaporating sessile drops.

A liquid drop containing a long fiber is a complex system whose configuration is determined by an interplay of elastic stresses in the fiber and capillary forces due to the liquid. We study the morphological evolution of fibers that are much longer than the drop diameter in evaporating sessile drops. After insertion, the fibers are either found in an ordered or disordered state, with increasing disorder for increasing fiber length. Upon evaporation, the order increases, in such a way that the final configuration deposited on the solid surface is either a circle, an ellipse, or 8-shaped. The morphology of the deposit depends on the fiber length and the elastocapillary length, both non-dimensionalized with the characteristic drop size, which we classify in a morphology regime map. The disorder-to-order transition allows depositing ordered fiber structures on solid surfaces even in cases of a strongly disordered state after fiber insertion. Combined with technologies such as inkjet printing, this process could open new avenues to decorate surfaces with filamental structures whose morphology can be controlled by varying the fiber length.

Using personal monitoring data to derive organ doses for medical radiation workers in the Million Person Study-considerations regarding NCRP Commentary no. 30.

The study of low dose and low-dose rate exposure is of central importance in understanding the possible range of health effects from prolonged exposures to radiation. The One Million Person Study of Radiation Workers and Veterans (MPS) of low-dose health effects was designed to evaluate radiation risks among healthy American workers and veterans. The MPS is evaluating low-dose and dose-rate effects, intakes of radioactive elements, cancer and non-cancer outcomes, as well as differences in risks between women and men. Medical radiation workers make up a large group of individuals occupationally exposed to low doses of radiation from external x-ray/gamma exposures. For the MPS, about 100 000 United States medical radiation workers have been selected for study. The approach to the complex dosimetry circumstances for such workers over three to four decades of occupation were initially and broadly described in National Council on Radiation Protection and Measurements (NCRP) Report No. 178. NCRP Commentary No. 30 provides more detail and describes an optimum approach for using personal monitoring data to estimate lung and other organ doses applicable to the cohort and provides specific precautions/considerations applicable to the dosimetry of medical radiation worker organ doses for use in epidemiologic studies. The use of protective aprons creates dosimetric complexity. It is recommended that dose values from dosimeters worn over a protective apron be reduced by a factor of 20 for estimating mean organ doses to tissues located in the torso and that 15% of the marrow should be assumed to remain unshielded for exposure scenarios when aprons are worn. Conversion coefficients relating personal dose equivalent,Hp(10) in mSv, to mean absorbed doses to organs and tissues,DTin mGy, for females and males for six exposure scenarios have been determined and presented for use in the MPS. This Memorandum summarises several key points in NCRP Commentary No. 30.

Susceptibility of cat fleas (Siphonaptera: Pulicidae) to fipronil and imidacloprid using adult and larval bioassays.

The monitoring of the susceptibility offleas to insecticides has typically been conducted by exposing adults on treated surfaces. Other methods such as topical applications of insecticides to adults and larval bioassays on treated rearing media have been developed. Unfortunately, baseline responses of susceptible strains of cat flea, Ctenocephalides felis (Bouchè), except for imidacloprid, have not been determined for all on-animal therapies and new classes of chemistry now being used. However, the relationship between adult and larval bioassays of fleas has not been previously investigated. The adult and larval bioassays of fipronil and imidacloprid were compared for both field-collected isolates and laboratory strains. Adult topical bioassays of fipronil and imidacloprid to laboratory strains and field-collected isolates demonstrated that LD50s of fipronil and imidacloprid ranged from 0.11 to 0.40 nanograms per flea and 0.02 to 0.18 nanograms per flea, respectively. Resistance ratios for fipronil and imidacloprid ranged from 0.11 to 2.21. Based on the larval bioassay published for imidacloprid, a larval bioassay was established for fipronil and reported in this article. The ranges of the LC50s of fipronil and imidacloprid in the larval rearing media were 0.07-0.16 and 0.11-0.21 ppm, respectively. Resistance ratios for adult and larval bioassays ranged from 0.11 to 2.2 and 0.58 to 1.75, respectively. Both adult and larval bioassays provided similar patterns for fipronil and imidacloprid. Although the adult bioassays permitted a more precise dosage applied, the larval bioassays allowed for testing isolates without the need to maintain on synthetic or natural hosts.

[Diagnostics and exclusion of hereditary angioedema : a standarized approach for the practice]. / Diagnostik und Ausschluss des hereditären Angioödems : Ein standardisierter Ansatz für die Praxis.

The differentiation between mast cell mediator-mediated and bradykinin-mediated forms of angioedema can be difficult. Bradykinin-mediated hereditary angioedema is a rare autosomal dominant hereditary disease which is characterized by recurrent edema attacks of varying magnitude. The edema occurs in the skin and mucous membranes and can be temporarily disfiguring, very painful and life-threatening by attacks in the laryngeal region. Because of the multitude of differential diagnoses, a final diagnosis is only achieved after an average duration of more than 10 years. The anamnestic and laboratory diagnostic algorithm presented here is designed to assist a simpler differentiation of the various forms of angioedema and to reach the correct diagnosis more quickly.

microRNA122-regulated transgene expression increases specificity of cardiac gene transfer upon intravenous delivery of AAV9 vectors.

Adeno-associated virus (AAV) vectors with capsids of AAV serotype 9 enable an efficient transduction of the heart upon intravenous injection of adult mice but also transduce the liver. The aim of this study was to improve specificity of AAV9 vector-mediated cardiac gene transfer by microRNA (miR)-dependent control of transgene expression. We constructed plasmids and AAV vectors containing target sites (TSs) of liver-specific miR122, miR192 and miR148a in the 3' untranslated region (3'UTR) of a luciferase expression cassette. Luciferase expression was efficiently suppressed in liver cell lines expressing high levels of the corresponding miRs, whereas luciferase expression was unaffected in cardiac myocytes. Intravenous injections of AAV9 vectors bearing three repeats of miR122 TS in the 3'UTR of an enhanced green fluorescent expression (EGFP) expression cassette resulted in the absence of EGFP expression in the liver of adult mice, whereas the control vectors without miR TS displayed significant hepatic EGFP expression. EGFP expression levels in the heart, however, were comparable between miR122-regulated and control vectors. The liver-specific de-targeting in vivo using miR122 was even more efficient than transcriptional targeting with a cardiac cytomegalovirus (CMV)-enhanced myosin light chain (MLC) promoter. These data indicate that miR-regulated targeting is a powerful new tool to further improve cardiospecificity of AAV9 vectors.

Deep-sea hydrocarbon seep communities: evidence for energy and nutritional carbon sources.

Mussels, clams, and tube worms collected in the vicinity of hydrocarbon seeps on the Louisiana slope contain mostly "dead" carbon, indicating that dietary carbon is largely derived from seeping oil and gas. Enzyme assays, elemental sulfur analysis, and carbon dioxide fixation studies demonstrate that vestimentiferan tube worms and three clam species contain intracellular, autotrophic sulfur bacterial symbionts. Carbon isotopic ratios of 246 individual animal tissues were used to differentiate heterotrophic (8(13)C = -14 to -20 per mil), sulfur-based (8(13)C = -30 to -42 per mil), and methane-based (8(13)C = <-40 per mil) energy sources. Mussels with symbiotic methanotrophic bacteria reflect the carbon isotopic composition of the methane source. Isotopically light nitrogen and sulfur confirm the chemoautotrophic nature of the seep animals. Sulfur-based chemosynthetic animals contain isotopically light sulfur, whereas methane-based symbiotic mussels more closely reflect the heavier oceanic sulfate pool. The nitrogen requirement of some seep animals may be supported by nitrogen-fixing bacteria. Some grazing neogastropods have isotopic values characteristic of chemosynthetic animals, suggesting the transfer of carbon into the background deep-sea fauna.

Cryptic speciation in the vermilion rockfish (Sebastes miniatus) and the role of bathymetry in the speciation process.

A recent phylogenetic review of the genus Sebastes suggested the existence of a cryptic species of vermilion rockfish (Sebastes miniatus). To evaluate the geographical and bathymetric range of the Type 1 and Type 2 forms reported in that study, cytochrome b sequences were examined from 548 fish. Type 1 fish were found primarily south of Point Conception on reefs deeper than 100 m. Type 2 fish were common range-wide at sites shallower than 100 m. Reproductive isolation between the two types was tested using nine microsatellite loci. Estimates of genetic divergence were made using the fixation index (F(ST)) and correspondence between haplotype and genotype was tested by Bayesian population assignment and multivariate plotting of individual genotypes. Microsatellite analyses gave strong support for the presence of two distinct groups of genotypes. All fish with Type 1 haplotypes and fish with Type 2 haplotypes from < 100 m depth had genotypes unique to their haplotype group. However, most (68%) fish with Type 2 haplotypes from > 100 m depth assigned strongly to the Type 1 genotype group. Morphometric comparisons between the two genotypic groups revealed significant differences at three of the six examined measurements. Differences in both genetics, depth of occurrence, and morphology suggest these are separate species. This observation along with evidence of depth segregation in many recent species pairs led us to hypothesize a speciation model for Sebastes spp. by which the loss or truncation of a depth-related ontogenetic migration can lead to the creation of reproductively isolated populations.

Abnormal response of tumor vasculature to vasoactive drugs.

The effects of the vasoconstrictor phenylephrine and the vasodilator hydralazine on blood flow to tumor were studied and compared to those on blood flow to normal tissues in vivo. Regional blood flow and cardiac output were measured with the use of radioactive microspheres in 150- to 250-g inbred Harlan F344 rats bearing subcutaneous nodules of two types of transplantable carcinoma ("hard" and "soft") with microscopically different vascular patterns. Three groups of rats were treated with hydralazine, saline, or phenylephrine, and regional blood flow was determined at the time of maximum blood pressure response. Results were correlated with quantitative morphometric analysis of arteriolar and capillary wall thickness in tumor and normal tissue. Phenylephrine decreased and hydralazine increased normal tissue perfusion as indicated by cardiac output. Tumor blood flow remained low and was not significantly influenced by drug treatment, except for the phenylephrine effect on hard tumors. Histologic study of tumor vessel walls revealed an absence of smooth muscle capable of responding to the vasoactive drugs by constriction or dilation. Evidently, by their selective action on normal vessels, vasoactive drugs can change the ratio of tumor:normal tissue perfusion. In particular, the increase of normal tissue: tumor blood flow by vasodilator drugs may enhance the selectivity of local heat therapy.

Cardiac endothelin system impairs left ventricular function in renin-dependent hypertension via decreased sarcoplasmic reticulum Ca(2+) uptake.

BACKGROUND: We evaluated the role of the cardiac endothelin (ET) system in compensated hypertensive left ventricular (LV) hypertrophy (LVH) and after the transition toward LV dysfunction. METHODS AND RESULTS: Hypertensive transgenic rats overexpressing the Ren2 gene (Ren2 rats) were investigated between the ages of 10 and 30 weeks (Ren2-10 and Ren2-30 groups, respectively) and compared with age-matched normotensive Sprague-Dawley (SD) rats (SD-10 and SD-30 groups, respectively). Systolic blood pressure and LV weight were elevated in both Ren2 groups compared with their age-matched SD control groups (P:<0.0001). In Ren2-30 rats, LV end-diastolic pressure increased and -dP/dt(max) decreased compared with the values in SD-30 and Ren2-10 rats (P:<0.05). This was paralleled by an activation of LV mRNA expression of preproET-1 and ET-converting enzyme-1 and ET subtype A (ETA) receptor binding in Ren2-30 compared with Ren2-10 rats (P:<0.001). Cardiac fibrosis was increased and sarcoplasmic reticulum (SR) Ca(2+) reuptake was reduced in Ren2-30 compared with SD-30 and Ren2-10 rats (P:<0.05). Treatment of Ren2 rats with the selective ETA receptor antagonist Lu135252 between 10 and 30 weeks of age did not lower systolic blood pressure, heart weight, or cardiac fibrosis but completely prevented the deterioration of LV end-diastolic pressure and abolished alterations in -dP/dt(max) and SR Ca(2+) reuptake compared with no treatment in Ren2-30 and SD-30 rats (P:<0.05). CONCLUSIONS: Activation of the cardiac ET system accounts at least in part for the LV dysfunction that gradually develops in LVH. The protective effect of ETA antagonism can be attributed to the improvement of diastolic LV function that is due to normalization of impaired SR Ca(2+) uptake.

Effect of pulsed progressive fluoroscopy on reduction of radiation dose in the cardiac catheterization laboratory.

The increased application of therapeutic interventional cardiology procedures is associated with increased radiation exposure to physicians, patients and technical personnel. New advances in imaging techniques have the potential for reducing radiation exposure. A progressive scanning video system with a standard vascular phantom has been shown to decrease entrance radiation exposure. The effect of this system on reducing actual radiation exposure to physicians and technicians was assessed from 1984 through 1987. During this time, progressive fluoroscopy was added sequentially to all four adult catheterization laboratories; no changes in shielding procedures were made. During this time, the case load per physician increased by 63% and the number of percutaneous transluminal coronary angioplasty procedures (a high radiation procedure) increased by 244%. Despite these increases in both case load and higher radiation procedures, the average radiation exposure per physician declined by 37%. During the same time, the radiation exposure for technicians decreased by 35%. Pulsed progressive fluoroscopy is effective for reducing radiation exposure to catheterization laboratory physicians and technical staff.

Effects of alpha-adrenergic stimulation on the sarcolemmal Na+/Ca(2+)-exchanger in adult rat ventricular cardiocytes.

OBJECTIVE: The cardiac sarcolemmal Na+/Ca(2+)-exchanger (NCX) plays an important role in the maintenance of the myocardial Ca2+ homeostasis which is altered in cardiac hypertrophy and failure. The aim of the present study was to investigate whether alpha-adrenergic stimulation known to induce cardiac hypertrophy might be involved in the regulation of the sarcolemmal NCX. METHODS: Adult rat ventricular cardiocytes (ARC) were isolated from male Sprague-Dawley rats. Phenylephrine, an alpha-adrenergic agonist, was used as hypertrophic agent. NCX expression was measured by competitive RT-PCR and Western blot analysis. RESULTS: alpha-Adrenergic stimulation of ARC with 10 microM phenylephrine for 24 h resulted in a significant increase of the NCX mRNA (2.5-fold) and the NCX protein level (1.8-fold). The changes on the expression level were blocked by the alpha 1-adrenoceptor antagonist prazosin. CONCLUSIONS: The data demonstrate that the NCX expression level is up-regulated by the activation of the alpha-adrenergic signal transduction pathway. The increased NCX mRNA level induced by alpha-adrenergic stimulation appeared to be translated into increased NCX protein level.

Thyroid hormones increase the contractility but suppress the effects of beta-adrenergic agonist by decreasing phospholamban expression in rat atria.

OBJECTIVE: The aim of the present study was to characterize the relationships between the thyroid-hormone-dependent changes in sarcoplasmic reticulum (SR) Ca2+ handling and contractile performance in atria. METHODS: Hypothyroidism in rats was induced by adding 0.05% 6-n-propyl-2-thiouracil to their drinking water for 6 weeks. Hyperthyroidism was induced by daily subcutaneous injections of L-thyroxine (1 microgram/g body weight) to euthyroid rats for 1 week. Left atria from the hearts with different thyroid states were examined by means of contractile measurements, SR oxalate-supported Ca(2+)-uptake, and Western blot of SR proteins. RESULTS: The tissue level of SR Ca(2+)-pump protein decreased in hypothyroid (46 +/- 6%) atria, but remained unchanged in hyperthyroid (110 +/- 8%) atria as compared with euthyroid atria. Hypothyroidism was associated with increased phospholamban expression (141 +/- 25%), whereas it was drastically downregulated under hyperthyroidism (21 +/- 4%). The rate of SR Ca(2+)-uptake, measured in the presence of the protein kinase A inhibitor, H-89, was higher in hyperthyroid atria and lower in hypothyroid atria than in euthyroid atria (397 +/- 40, 55 +/- 6 and 194 +/- 17 nmol Ca2+/g protein/min, respectively). However, the stimulation of SR Ca(2+)-uptake by the catalytic subunit of protein kinase A was relatively weaker in hyperthyroid (130 +/- 20% over control level without catalytic subunit) and stronger in hypothyroid (640 +/- 60%) than in euthyroid atria (280 +/- 40%). The rates of inotropic contraction (+dT/dt) were higher in the hyperthyroid atria (133 +/- 10 mN/s), but lower in hypothyroid atria (15 +/- 3 mN/s) than in their euthyroid counterparts (95 +/- 13 mN/s). Inversely, hypothyroid atria responded to isoproterenol with much larger increases in contractility (883 +/- 164% over the control values for the same muscle before addition of isoproterenol) and hyperthyroid with smaller increases (25 +/- 9%) than euthyroid preparations (207 +/- 17%) CONCLUSIONS: Thyroid hormones increase the contractility, but decrease the inotropic response to isoproterenol through decreasing the phospholamban/SR Ca(2+)-pump ratio in rat atria.

Cardiac Na+/Ca2+ exchange activity in patients with end-stage heart failure.

OBJECTIVE: The aim of the present study was to investigate the functional activity and expression of the sarcolemmal Na+/Ca2+-exchanger in the failing human heart. METHODS: Left ventricular samples were taken from eleven patients with end-stage heart failure and six organ donors (normal controls). The Na+/Ca2+-exchanger activity was assessed by measuring Na+ gradient-induced 45Ca2+ transport into sarcolemmal vesicles of quantitatively collected crude membrane preparations. The abundance of the Na+/Ca2+-exchanger protein was determined by Western blot analysis using a specific antiserum and the results were normalized to myocyte specific beta-myosin heavy chain protein content. RESULTS: In membrane preparations of failing human hearts, both the Na+ gradient-induced 45Ca2+ transport activity and the level of immunoreactive Na+/Ca2+-exchanger protein were increased (P < 0.01) by 87% and 160% compared to controls, respectively. CONCLUSIONS: In human end-stage heart failure the increased sarcolemmal Na+/Ca2+-exchanger activity appears to be due to an elevated expression of this protein. An increase in the expression and activity of the Na+/Ca2+-exchanger in the failing human heart may be of important functional significance: while a resulting increase in Ca2+ extrusion across the sarcolemma may limit diastolic Ca2+ overload, a corresponding influx of Na+ may be associated with membrane depolarization and enhanced arrhythmogenesis if the Na+/Ca2+-exchanger operates primarily in the forward mode.

Potentiating effect of calmodulin and catalytic subunit of cyclic AMP-dependent protein kinase on ATP-dependent Ca2+-transport by cardiac sarcolemma.

Highly purified sarcolemmal membranes were prepared from pig heart homogenates by differential and density gradient centrifugations. The membrane fragments exhibit ATP-dependent Ca2+-transport and Na+/Ca2+-exchange activities. ATP-dependent Ca2+-transport (K0.5Ca2+ = 0.3 microM; Vmax = 4.6 nmol Ca2+.mg protein-1.min-1) is not stimulated by oxalate. Ca2+-uptake is also not supported by p-nitro-phenylphosphate. Preincubation of sarcolemma with MgATP, calmodulin and catalytic subunit of cyclic AMP-dependent protein kinase stimulates active Ca2+-transport 1.8-fold. The effects of calmodulin and catalytic subunit are potentiating rather than additive. A large portion of the Ca2+ additionally accumulated after prephosphorylation of membranes is exchangeable for Na+ via the Na+/Ca2+-exchange system.

Early presence of phospholamban in developing a chick heart.

Phosphorylation of phospholamban and development of reticular Ca2+ transport were studied in crude membrane preparations of embryonic, newborn and adult chick heart. Maximal phosphorylation of phospholamban by added catalytic subunit of cyclic AMP-dependent protein kinase increases from embryonic day 4-15. It decreases with further development. In the same membrane preparations active Ca2+-uptake into vesicles of sarcoplasmic reticulum rises from day 4-7 and decreases then slightly until day 20. A several-fold increase in Ca2+-transport activity occurs at the time of hatching. The data indicate separate genetic control for synthesis of phospholamban and sarcoplasmic reticulum Ca2+-ATPase.

Dipeptidyl peptidase IV (DP IV, CD26) is involved in regulation of DNA synthesis in human keratinocytes.

Various studies have shown that the membrane ectoenzyme dipeptidyl peptidase IV (DP IV, CD26), expressed on T, NK, and B cells in the human immune system, is involved in the regulation of DNA synthesis and cytokine production. Here, we clearly demonstrate that this enzyme is highly expressed also on human epidermal foreskin and split-skin keratinocytes and that the specific DP IV inhibitors Lys[Z(NO2)]-thiazolidide, Lys[Z(NO2)]-pyrrolidide inhibit the enzymatic activity as well as the DNA synthesis of these cells. These data demonstrate that CD26 plays a role also in regulation of DNA synthesis of epidermal keratinocytes and that the enzymatic activity is required for mediating these effects.

Alterations of cardiac contractile function are related to changes in membrane calcium transport in spontaneously hypertensive rats.

OBJECTIVE: Transport activities of cardiac sodium-calcium exchange and sarcoplasmic reticulum calcium ATPase were measured biochemically in spontaneously hypertensive rats (SHR) with hypertrophied myocardium and in normotensive Wistar-Kyoto (WKY) rats and it was tested whether possible differences have consequences for the contractile properties of papillary muscle. METHODS: Sarcolemmal sodium-dependent calcium transport via sodium-calcium exchange and oxalate-supported sarcoplasmic reticulum calcium uptake were measured in left ventricular membranes of 22-week-old rats. Postextrastimulatory potentiated contractions, postrest potentiated contractions, the twitch-to-twitch decay of those potentiations and the response to increasing stimulation frequency of left ventricular papillary muscles were analysed. RESULTS: Compared with WKY rats we found in SHR: a significant increase in sodium-calcium exchange (65%) and in sarcoplasmic reticulum calcium uptake (24%); a steeper twitch-to-twitch decay in postextrastimulatory potentiated contractions and postrest potentiated contractions, suggesting a lower calcium fraction recirculating between myofilaments and sarcoplasmic reticulum and, consequently, a relatively higher calcium efflux via sodium-calcium exchange; a stronger rest-dependent decrease in recirculating calcium fraction in postrest potentiated contractions accompanied by accelerated relaxation, suggesting an increasing driving force for calcium extrusion via sodium-calcium exchange, probably caused by decreasing intracellular sodium during rest; a greater transient decrease in peak force of subsequent twitches after postrest potentiated contractions below pre-interventional level, indicating higher cellular calcium loss; and a smaller negative inotropic effect in response to doubling of stimulation rate as a manoeuvre to increase the intracellular sodium level. CONCLUSION: In SHR, the contractile properties suggest an increased contribution of sodium-calcium exchange to cellular calcium removal, which is strongly supported by the enhanced sodium-calcium exchange activity in cardiac membrane vesicles.

Effects of angiotensin II subtype 1 receptor blockade on cardiac fibrosis and sarcoplasmic reticulum Ca2+ handling in hypertensive transgenic rats overexpressing the Ren2 gene.

OBJECTIVE: We evaluated the effects of angiotensin II subtype 1 (AT1) receptor antagonism on cardiac fibrosis and sarcoplasmic (SR) Ca2+ handling in a transgenic rat model of renin-dependent left ventricular (LV) hypertrophy (LVH). METHODS: Hypertensive transgenic rats overexpressing the Ren2 gene (TGR(mRen2)27) were treated between 10 and 30 weeks of age with the angiotensin II subtype 1 (AT1) receptor antagonist, eprosartan, in an antihypertensive (Ren2-E60, 60 mg/kg per day) and a non-antihypertensive (Ren2-E6, 6 mg/kg per day) dose applied intraperitoneally via osmotic-mini-pumps. They were compared to age-matched Ren2 and Sprague-Dawley (SD) control rats receiving 0.9% NaCl as vehicle via osmotic mini-pumps (Ren2-Vehicle, SD-Vehicle, respectively). RESULTS: Systolic blood pressure (SBP), LV weight, LV end-diastolic pressure (LVEDP), and cardiac fibrosis were elevated in Ren2-Vehicle, while diastolic function (-dP/dt(max)) and sarcoplasmic reticulum (SR) Ca2+ uptake were decreased in Ren2-Vehicle compared to SD-Vehicle (P < 0.05, respectively). SBP was not altered in Ren2-E6, but reduced to normotensive levels in Ren2-E60 compared to Ren2-Vehicle and SD-Vehicle (P < 0.0001). In both Ren2-E6 and Ren2-E60, LV weights were reduced and LVEDP and -dP/dt(max)normalized compared to Ren2-Vehicle (P < 0.05). SR Ca2+ uptake was normalized in both Ren2-E6 and Ren2-E60. Cardiac fibrosis did not change in Ren2-E6, but perivascular LV fibrosis and hydroxyprolin content were reduced in Ren2-E60 compared to Ren2-Vehicle (P < 0.05, respectively). CONCLUSIONS: Normalization of LV SR Ca2+ uptake is an important mechanism by which AT1 receptor antagonism improves LV diastolic dysfunction independent from a reduction of SBP and cardiac fibrosis in the TGR (mRen2)27 model.

Dosimetry and biodistribution of an iodine-123-labeled somatostatin analog in patients with neuroendocrine tumors.

A modified method for the preparation of a radiolabeled analog of somatostatin (123I-octreotide) is described. The pharmacokinetics and dosimetry of this analog were evaluated in patients with neuroendocrine tumors. Thirty patients had multiple blood and urine samples and sequential anterior and posterior whole-body scintigraphy up to 40 hr postinjection of 123I-octreotide. Region of interest analysis of the whole-body images was used to determine organ and tumor doses. The 123I-octreotide was rapidly cleared from the blood with a T 1/2 of 10 min by the hepatobiliary system. By 40 hr, approximately 55% was eliminated in the feces. The gallbladder wall received the highest dose (0.48 rad/mCi), with other organs receiving doses of 0.12 rad/mCi or less. Tumors were identified in 25 of 28 satisfactory studies. Tumor doses ranged from 0.1 to 0.6 rad/mCi. Calculations with 131I instead of 123I indicated that the gallbladder wall would receive 2 rad/mCi, while average tumor doses would range from 0.9 to 5.0 rad/mCi. Iodine-123-octreotide is a useful agent for the visualization of neuroendocrine tumors. The rapid washout of this agent from tumors precludes the possibility of radiotherapy with 131I-octreotide in these patients.

Sarcoplasmic reticulum function and carnitine palmitoyltransferase-1 inhibition during progression of heart failure.

Failing cardiac hypertrophy is associated with an inadequate sarcoplasmic reticulum (SR) function. The hypothesis was examined that pressure overloaded hearts fail to increase SR Ca(2+) uptake rate proportionally to the hypertrophy and that carnitine palmitoyltransferase-1 inhibition by etomoxir ((+/-)-ethyl 2[6(4-chlorophenoxy)hexyl] oxirane-2-carboxylate) can counteract this process. Severe left ventricular pressure overload was induced in rats by constricting the ascending aorta for 8, 10, 14 and 28 weeks leading to cardiac hypertrophy (+62 - +103% of sham-operated rats) and pulmonary congestion. Homogenate oxalate-facilitated SR Ca(2+) uptake rate g wet wt(-1) was reduced (P<0.05) by 29.9+/-1.8% irrespective of phospholamban phosphorylation (in the presence of catalytic subunit of protein kinase A) and inhibition of SR Ca(2+) release channel by ruthenium red. SERCA2 protein level was reduced (P<0.05) by 30.4+/-0.8%. SR Ca(2+) uptake rate was inversely correlated (P<0.05) with left ventricular weight but was not affected by the occurrence of pulmonary congestion. Because SR Ca(2+) uptake rate of whole ventricles was not reduced, a hypertrophy proportional dilution of SR Ca(2+) uptake has to be inferred which precedes pulmonary congestion. Treatment with etomoxir (15 mg kg body wt(-1) day(-1) for 10 weeks) did not affect left ventricular weight but decreased (P:<0.05) the right ventricular hypertrophy related to pulmonary congestion. In parallel, SR Ca(2+) uptake rate of left ventricle and myosin isozyme V(1) were increased (P<0.05). Etomoxir represents a candidate approach for prevention of heart failure by inducing a hypertrophy proportional increase in SR Ca(2+) uptake rate.