Effect of T(3) treatment and food ration on hepatic deiodination and conjugation of thyroid hormones in rainbow trout, Oncorhynchus mykiss.

We studied the 7-day effects of 3,5,3'-triiodothyronine (T(3)) hyperthyroidism (induced by 12 ppm T(3) in food) and food ration (0, 0.5, or 2% body weight/day) on in vitro hepatic glucuronidation, sulfation, and deiodination of thyroxine (T(4)), T(3), and 3,3', 5'-triiodothyronine (rT(3)). T(3) treatment doubled plasma T(3) with no change in plasma T(4), depressed hepatic low-K(m) (1 nM) outer-ring deiodination (ORD) of T(4), induced low-K(m) (1 nM) inner-ring deiodination (IRD) of both T(4) and T(3) but did not alter high-K(m) (1 microM) rT(3)ORD, glucuronidation, or sulfation of T(4), T(3), or rT(3). Plasma T(4) levels were greater for 0 and 2% rations than for a 0.5% ration. Fasting decreased low-K(m) T(4)ORD activity and increased high-K(m) rT(3)ORD activity but did not alter T(4)IRD or T(3)IRD activities. T(4), T(3), and rT(3) glucuronidation were greater for 0 and 0.5% rations than for a 2% ration. T(3) glucuronidation was greater for a 0.5% ration than for a 0% ration. T(3) and rT(3) sulfation were greater for a 2% ration than for a 0 or a 0.5% ration; ration did not change T(4) sulfation. We conclude that (i) modest experimental T(3) hyperthyroidism induces T(3) autoregulation by adjusting hepatic low-K(m) ORD and IRD activities but not high-K(m) rT(3)ORD or conjugation activities; (ii) in contrast, ration level changes both deiodination and conjugation pathways, suggesting that the response to ration does not solely reflect altered T(3) production; (iii) deiodination and conjugation appear complementary in regulating thyroidal status in response to ration; and (iv) high-K(m) rT(3)ORD in trout differs from rat type I deiodination in that it does not respond to T(3) hyperthyroidism and it increases, rather than decreases, its activity during fasting.     

Time of day for exercise on blood pressure reduction in dipping and nondipping hypertension

Time of day (TOD) for exercise may influence blood pressure (BP) reduction in hypertension because of the diurnal variation of BP and the duration of BP reduction following a single bout of exercise. The purpose of this study was to observe the effects of TOD for exercise on ambulatory blood pressure reduction in dipping (n=5) and nondipping (n=9) hypertension (<10% drop in nighttime BP (BP(night))). HYPOTHESES: (1) evening exercise (PM(ex)) would exhibit a greater BP(night) reduction in Non-Dippers than Dippers, (2) morning exercise (AM(ex)) would exhibit similar daytime BP (BP(day)) reduction in Dippers and Non-Dippers, (3) AM(ex) would exhibit greater 24 h BP (BP(24 h)) reduction than PM(ex) in Dippers, and (4) AM(ex) and PM(ex) would exhibit similar BP(24 h) reduction in Non-Dippers. BP responses to AM(ex) (0600-0800 h; 30 min at 50% VO(2peak)) and PM(ex) (1700-1900 h) were compared to each control day in a randomized design. Systolic (S) and diastolic (D) BP were averaged for BP(24 h), BP(day), and BP(night). A two-way ANOVA (dipping X time of exercise) using BP reduction with repeated measures were performed at P<0.05. FINDINGS: (1) Non-Dippers respond to exercise despite of TOD for exercise, (2) PM(ex) exhibited a greater SBP(night) reduction in Non-Dippers than Dippers, (3) AM(ex) exhibited similar SBP(day) reductions in Dippers and Non-Dippers, and (4) AM(ex) and PM(ex) exhibited similar SBP(24 h) reduction in Dippers and Non-Dippers. Dippers and Non-Dippers respond differently to TOD for exercise. The duration of the BP reduction persists up to 24 h after exercise.     

Performance of existing diagnosis/classification criteria for Behcet's disease in Iranian patients: analysis of 5666 patients and 2406 controls

Aim: To analyse the performance of existing diagnosis/classification criteria for Behcet's disease (BD) in Iranian patients. There are 13 sets: Curth (1946), Hewitt (1969), Mason and Barnes (1969), Hewitt revised (1971), Japan (1972), Hubault and Hamza (1974), O'Duffy (1974), Cheng and Zhang (1980), Dilsen (1986), Japan revised (1988), International (1990), Iran (1993), Classification Tree (1993), and Dilsen revised criteria (2000). Methods: All patients from the Behcet's Disease Registry (5666) and control patients (2406) entered the study. Sensitivity, specificity and accuracy were calculated. Results: The most sensitive was Curth criteria with (99.7%), followed by Classification Tree (97.3%), Zhang (93.5%), Iran (91.4%), Japan revised (86.4%), Japan (85.3%), Dilsen (83.7%), Hubault and Hamza (81.6%), Dilsen revised (81.2%), International criteria (79.8%), Hewitt (73.8%), O'Duffy (70.7%), and Masson and Barnes (65.7%). The most specific was Masson and Barnes (99.6%), followed by the International criteria (98.3%), Dilsen revised (98.2%), O'Duffy (97.6%), Japan (97.1%), Japan revised (97%), Classification Tree (96.7%), Hewitt (95.8%), Iran (95.8%), Zhang (92.4%), Dilsen (91.4%), Hubault (90.8%), and Curth (78.6%). The most accurate criteria was Classification Tree (97.1%), followed by Curth (93.4%), Zhang (93.1%), Iran (92.7%), Japan revised (89.6%), Japan (88.8%), Dilsen revised (86.2%), Dilsen (86%), International criteria (85.3%), Hubault (84.3%), Hewitt (80.4%), O'Duffy (78.8%), and Mason and Barnes (75.8%). Discussion: Among the existing criteria, the best to classify Iranian patients is the Classification Tree. The second most accurate is Curth criteria. The difference is statistically significant. Further, Curth criteria is not optimized, having very high sensitivity and low specificity.     

Effects of thyroxine therapy on right ventricular systolic and diastolic function in patients with subclinical hypothyroidism: a study by pulsed wave tissue Doppler imaging

INTRODUCTION: The effects of l-thyroxine (l-T(4)) replacement for subclinical hypothyroidism (SH) on right ventricle (RV) functions has not been previously studied by means of pulsed wave tissue Doppler imaging (PWTDI). We investigated the effects of l-T(4) therapy on RV function in patients with SH using PWTDI. PATIENTS AND METHODS: Fifty-three patients with newly diagnosed SH and 25 controls were evaluated by standard echocardiography and PWTDI. After euthyroidism was restored by l-T(4), measurements were repeated. Myocardial systolic wave (S(m)) velocity, isovolumic acceleration (IVA), myocardial precontraction time (PCT(m)), and PCT(m) to contraction time (CT(m)) ratio were calculated as systolic indices. Early (E(m)) velocity, late (A(m)) velocity, E(m) to A(m) ratio, and myocardial relaxation time (RT(m)) were determined as diastolic measurements. RESULTS: S(m) was similar in patients and controls, whereas IVA was significantly lower in patients with SH (P < 0.001). SH patients had significantly decreased E(m) velocity, whereas A(m) velocity and E(m) to A(m) ratio did not differ. PCT(m) and RT(m) were significantly longer, and PCT(m) to CT(m) ratio was significantly higher in patients (P = 0.002, P = 0.002, P < 0.001, respectively). S(m) velocities were similar before and after l-T(4) replacement, whereas IVA significantly increased after therapy (P < 0.001). E(m) tended to increase (P = 0.05), whereas A(m) and E(m) to A(m) ratio were not changed. PCT(m), PCT(m) to CT(m) ratio, and RT(m) decreased significantly (P < 0.001 for all). CONCLUSIONS: SH is associated with RV systolic and diastolic dysfunction, and l-T(4) treatment improves these abnormalities. PWTDI, especially IVA, may be a suitable tool for the early detection of RV systolic dysfunction.     

Silicon-Carbon bond cleavage reactions of Ansa tungstenocene compounds: the [Me2Si] bridge as a site for metallocene functionalization

[Me(2)Si(Cp(Me(2)))(2)]W(H)Cl is obtained via reaction of WCl(6) with a mixture of [Me(2)Si(Cp(Me(2)))(2)]Li(2) and NaBH(4), from which the dichloride [Me(2)Si(Cp(Me(2)))(2)]WCl(2) is obtained via treatment with CHCl(3). [Me(2)Si(Cp(Me(2)))(2)]WCl(2) provides a means to access other ansa tungstenocene compounds, such as [Me(2)Si(Cp(Me(2)))(2)]WH(2), [Me(2)Si(Cp(Me(2)))(2)]WMe(2), and [Me(2)Si(Cp(Me(2)))(2)]WCO. Of most interest, the reactions of [Me(2)Si(Cp(Me(2)))(2)]W(H)Cl with organolithium reagents do not yield simple ansa tungstenocene derivatives. Specifically, the reactions of [Me(2)Si(Cp(Me(2)))(2)]W(H)Cl with MeLi, Bu(n)Li, or PhLi result in the formation of mixed-ring tungstenocene compounds resulting from C-Si cleavage and functionalization of the ansa bridge, namely (Cp(Me(2)))(eta(5),kappa(1)-C(5)H(2)Me(2)SiMe(2)CH(2))WH, (Cp(Me(2)))[eta(5),kappa(1)-C(5)H(2)Me(2)Si(Me)(Bu(n))CH(2)]WH, and (Cp(Me(2)))[eta(5),kappa(1)-C(5)H(2)Me(2)SiMe(2)(C(6)H(4))]WH, respectively. In contrast to the C-Si cleavage achieved by MeLi, Bu(n)Li, and PhLi, the ansa bridge of [Me(2)Si(Cp(Me(2)))(2)]W(H)Cl is inert to Bu(t)Li and the product obtained is the fulvene ("tuck-in") complex [Me(2)Si(Cp(Me(2)))(eta(6)-C(5)MeH(2)CH(2))]WH derived from dehydrohalogenation.     

Colossal kinetic isotope effects in proton-coupled electron transfer

The kinetics of reduction of benzoquinone (Q) to hydroquinone (H(2)Q) by the Os(IV) hydrazido (trans-[Os(IV)(tpy)(Cl)(2)(N(H)N(CH(2))(4)O)]-PF(6) = [1]PF(6), tpy = 2,2':6',2"-terpyridine), sulfilimido (trans-[Os(IV)-(tpy)(Cl)(2)(NS(H)-4-C(6)H(4)Me)]PF(6) = [2]PF(6)), and phosphoraniminato (trans-[Os(IV)(Tp)(Cl)(2)(NP(H)(Et)(2))] = [3], Tp(-) = tris(pyrazolyl)-borate) complexes have been studied in 1:1 (vol/vol) CH(3)CN/H(2)O and CH(3)CN/D(2)O (1.0 M in NH(4)PF(6)/KNO(3) at 25.0 +/- 0.1 degrees C). The reactions are first order in both [Q] and Os(IV) complex and occur by parallel pH-independent (k(1)) and pH-dependent (k(2)) pathways that can be separated by pH-dependent measurements. Saturation kinetics are observed for the acid-independent pathway, consistent with formation of a H-bonded intermediate (K(A)) followed by a redox step (k(red)). For the pH-independent pathway, k(1)(H(2)O)/k(1)(D(2)O) kinetic isotope effects are 455 +/- 8 for [1(+)], 198 +/- 6 for [2(+)], and 178 +/- 5 for [3]. These results provide an example of colossal kinetic isotope effects for proton-coupled electron transfer reactions involving nitrogen, sulfur, and phosphorus as proton-donor atoms.     

Dopamine D1 and adenosine A1 receptors form functionally interacting heteromeric complexes

The possible molecular basis for the previously described antagonistic interactions between adenosine A(1) receptors (A(1)R) and dopamine D(1) receptors (D(1)R) in the brain have been studied in mouse fibroblast Ltk(-) cells cotransfected with human A(1)R and D(1)R cDNAs or with human A(1)R and dopamine D(2) receptor (long-form) (D(2)R) cDNAs and in cortical neurons in culture. A(1)R and D(1)R, but not A(1)R and D(2)R, were found to coimmunoprecipitate in cotransfected fibroblasts. This selective A(1)R/D(1)R heteromerization disappeared after pretreatment with the D(1)R agonist, but not after combined pretreatment with D(1)R and A(1)R agonists. A high degree of A(1)R and D(1)R colocalization, demonstrated in double immunofluorescence experiments with confocal laser microscopy, was found in both cotransfected fibroblast cells and cortical neurons in culture. On the other hand, a low degree of A(1)R and D(2)R colocalization was observed in cotransfected fibroblasts. Pretreatment with the A(1)R agonist caused coclustering (coaggregation) of A(1)R and D(1)R, which was blocked by combined pretreatment with the D(1)R and A(1)R agonists in both fibroblast cells and in cortical neurons in culture. Combined pretreatment with D(1)R and A(1)R agonists, but not with either one alone, substantially reduced the D(1)R agonist-induced accumulation of cAMP. The A(1)R/D(1)R heteromerization may be one molecular basis for the demonstrated antagonistic modulation of A(1)R of D(1)R receptor signaling in the brain. The persistence of A(1)R/D(1)R heteromerization seems to be essential for the blockade of A(1)R agonist-induced A(1)R/D(1)R coclustering and for the desensitization of the D(1)R agonist-induced cAMP accumulation seen on combined pretreatment with D(1)R and A(1)R agonists, which indicates a potential role of A(1)R/D(1)R heteromers also in desensitization mechanisms and receptor trafficking.     

T-Type and tetrodotoxin-sensitive Ca(2+) currents coexist in guinea pig ventricular myocytes and are both blocked by mibefradil

Under Na(+)-free conditions, low-voltage-activated Ca(2+) currents in cardiomyocytes from various species have been described either as Ni(2+)-sensitive T-type Ca(2+) current (I(Ca(T))) or as tetrodotoxin (TTX)-sensitive Ca(2+) current (I(Ca(TTX))). So far, coexistence of the 2 currents within the same type of myocyte has never been reported. We describe experimental conditions under which I(Ca(T)) and I(Ca(TTX)) can be separated and studied in the same cell. Rat and guinea pig ventricular myocytes were investigated with the whole-cell voltage-clamp technique in Na(+)-free solutions. Whereas rat myocytes lack I(Ca(T)) and exhibit I(Ca(TTX)) only, guinea pig myocytes possess both of these low-voltage-activated Ca(2+) currents, which are separated pharmacologically by superfusion with TTX or Ni(2+). I(Ca(T)) and I(Ca(TTX)) were of similar amplitude but significantly differed in their electrophysiological properties: I(Ca(TTX)) activated at more negative potentials than did I(Ca(T)), the potential for half-maximum steady-state inactivation was more negative, and current deactivation and recovery from inactivation were faster. I(Ca(TTX)) but not I(Ca(T)) increased after membrane rupture ("run-up"). Isolation of I(Ca(TTX)) by application of the bivalent cation Ni(2+) is critical because of possible shifts in voltage dependence. Therefore, we investigated whether the T-type Ca(2+) channel blocker mibefradil (10 micromol/L) is a suitable tool for the study of I(Ca(TTX)). However, mibefradil not only blocked I(Ca(T)) by 85+/-2% but also decreased I(Ca(TTX)) by 48+/-8%. We conclude that under Na(+)-free conditions I(Ca(T)) and I(Ca(TTX)) coexist in guinea pig ventricular myocytes and that both currents are sensitive to mibefradil. Future investigations of I(Ca(T)) will have to consider the TTX-sensitive current component to avoid possible interference.     

Agostic interaction and intramolecular proton transfer from the protonation of dihydrogen ortho metalated ruthenium complexes

Protonation of the ortho-metalated ruthenium complexes RuH(H(2))(X)(P(i)Pr(3))(2) [X = 2-phenylpyridine (ph-py) (1), benzoquinoline (bq) (2)] and RuH(CO)(ph-py)(P(i)Pr(3))(2) (3) with [H(OEt(2))(2)](+)[BAr'(4)](-) (BAr'(4) = [(3,5-(CF(3))(2)C(6)H(3))(4)B]) under H(2) atmosphere yields the corresponding cationic hydrido dihydrogen ruthenium complexes [RuH(H(2))(H-X)(P(i)Pr(3))(2)][BAr'(4)] [X = phenylpyridine (ph-py) (1-H); benzoquinoline (bq) (2-H)] and the carbonyl complex [RuH(CO)(H-ph-py)(P(i)Pr(3))(2)][BAr'(4)] (3-H). The complexes accommodate an agostic C H interaction characterized by NMR and in the case of 1-H by x-ray diffraction. Fluxional processes involve the hydride and dihydrogen ligands in 1-H and 2-H and the rotation of the phenyl ring displaying the agostic interaction in 1-H and 3-H. NMR studies (lineshape analysis of the temperature-dependent NMR spectra) and density functional theory calculations are used to understand these processes. Under vacuum, one equivalent of dihydrogen can be removed from 1-H and 2-H leading to the formation of the corresponding cationic ortho-metalated complexes [Ru(H(2))(THF)(X)(P(i)Pr(3))(2)](+) [X = ph-py (1-THF), bq (2-THF)]. The reaction is fully reversible. Density functional theory calculations and NMR data give information about the reversible mechanism of C H activation in these ortho-metalated ruthenium complexes. Our study highlights the subtle interplay between key ligands such as hydrides, sigma-dihydrogen, and agostic bonds, in C H activation processes.     

Metal ion-binding properties of (N3)-deprotonated uridine, thymidine, and related pyrimidine nucleosides in aqueous solution

The acidity constants for (N3)H of the uridine-type ligands (U) 5-fluorouridine, 5-chloro-2'-deoxyuridine, uridine, and thymidine (2'-deoxy-5-methyluridine) and the stability constants of the M(U-H)(+) complexes for M(2+) = Mg(2+), Ca(2+), Sr(2+), Ba(2+), Mn(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), and Pb(2+) were measured (potentiometric pH titrations; aqueous solution; 25 degrees C; I = 0.1 M, NaNO(3)). Plots of logK(M(U-H))(M) vs. pK(U)(H) result in straight lines that are compared with previous plots for simple pyridine-type and o-amino(methyl)pyridine-type ligands as well as with the stabilities of the corresponding M(cytidine)(2+) complexes. The results indicate monodentate coordination to (N3)(-) in M(U-H)(+) for Co(2+) and Ni(2+). For the M(U-H)(+) species of Cd(2+), Zn(2+), or Cu(2+), increased stabilities imply that semichelates form, i.e., M(2+) is (N3)(-)-bound and coordinated water molecules form hydrogen bonds to (C2)O and (C4)O; these "double" semichelates are in equilibrium with "single" semichelates involving either (C2)O or (C4)O and possibly also with four-membered chelates for which M(2+) is innersphere-coordinated to (N3)(-) and a carbonyl oxygen. For the alkaline earth ions, semichelates dominate with the M(2+) outersphere bound to (N3)(-) and innersphere to one of the carbonyl oxygens. Mn(U-H)(+) is with its properties between those of Cd(2+) (which probably also hold for Pb(2+)) and the alkaline earth ions. In nucleic acids, M(2+)-C(O) interactions are expected, if support is provided by other primary binding sites. (N3)H may possibly be acidified via carbonyl-coordinated M(2+) to become a proton donor in the physiological pH range, at which direct (N3)(-) binding of M(2+) also seems possible.     

Electrophysiologic characteristics of atrial myocytes in levo-thyroxine-treated rats.

To investigate whether thyroid hormone modulates electrical properties of atrial myocytes, electrocardiogram (ECG), action potentials (APs), and ionic currents were measured. Male Sprague-Dawley rats were randomly divided into control and levo-thyroxine (T4)-treated groups at 6 weeks of age. Levo-thyroxine (500 microg/kg of body weight) was injected daily into the peritoneal cavity for 14 days (T4-treated rats) and the same volume of saline was injected in control rats daily. ECG signals were recorded using apex-base leads. APs, voltage-dependent Na+ and L-type Ca2+ channel current (I(Na) and I(Ca(L))), inwardly rectifying K+ channel current (I(K1)), transient outward K+ channel current (I(to)), and delayed rectifier K+ channel current (I(K(delay))) were measured using patch-clamp techniques. T4 treatment significantly changed electrical properties in rat atrial myocytes, including (1) the increase in heart rate, (2) the increase in cell size, (3) the shortening of action potential duration (APD), (4) the increase in cell membrane capacitance (C(m)), and (5) the decrease in input resistance (R(in)). Although the current densities of I(Na) and I(K1) in T4-treated atrial myocytes did not differ from those in control cells, I(Ca(L)) was significantly decreased and I(K(delay)) was significantly increased in T4-treated rats. Thus, thyrotoxicosis could induce the shortening of APD by alterations in current density of both I(Ca(L)) and I(K(delay)) in rat atrial myocytes.     

Evidence for P(2)-purinoceptors contribution in H(2)O(2)-induced contraction of rat aorta in the absence of endothelium

OBJECTIVE: H(2)O(2) can contract many arteries, however the underlying mechanisms are not fully understood. This study aims to test whether H(2)O(2)-induced vasoconstriction could be functionally attributed to the activation of P(2)-purinoceptors in rat aorta and to explore its possible signaling mechanisms. METHODS: Isometric tension recording of H(2)O(2) and ATP-induced contractions of rat aortic rings were compared in the absence or presence of various pharmacological tools to identify their possible common signaling pathways. RESULTS: Both H(2)O(2) and ATP induced transient phasic contractions in a concentration-dependent manner (1-1000 microM). Removal of endothelium potentiated the contractile responses to H(2)O(2) and to ATP. H(2)O(2) (30 microM)-induced phasic contraction could be abolished by catalase (800 U/ml), but not affected by SOD (150 U/ml), DMSO (5 mM) and apyrase (5 U/ml), suggesting no involvement of O(2)(-), hydroxyl free radicals and ATP release. Also, several receptor antagonists including phentolamine, atropine, methysergide and chlorpheniramine (each 3 microM) were without effect on H(2)O(2) (30 microM)-induced phasic contraction, suggesting no involvement of typical neurotransmitter release. However, both H(2)O(2) (30 microM) and ATP (1 mM)-induced phasic contractions not only presented homologous desensitization, but also showed heterogeneous desensitization. Furthermore, the phasic contractions in response to H(2)O(2) (30 microM) or ATP (100 microM) could be inhibited or abolished in a concentration dependent manner by RB-2 and suramin (10-100 microM), two widely used P(2)-purinoceptor antagonists, with only partial inhibition by Evans blue (300 microM), a moderately selective P(2x) receptor blocker, or by alpha-beta-methylene-ATP (100 microM), a selective P(2x) receptor desensitizer. On the other hand, both H(2)O(2) (30 microM) and ATP (100 microM)-induced phasic contractions were also attenuated, to different degree, by inhibitors of several enzymes including PLC, PKC, PLA(2) and cyclooxygenase. Lastly, removal of extracellular Ca(2+) or pretreatment with procaine (10 mM) and dantrolene (30 microM), two putative intracellular Ca(2+) release blockers, or with Ni(2+) (100 microM) and tetrandrine (5 microM), two Ca(2+) channel blockers, all significantly inhibited H(2)O(2) and ATP-induced contractions. However, nifedipine (1 microM), a voltage-dependent L-type Ca(2+) channel blocker, was without effect. CONCLUSIONS: Our results demonstrate that H(2)O(2)-induced phasic contraction of rat aorta involves, at least in part, the activation of P(2)-purinoceptors in the aortic smooth muscle cells     

Nitroxyl and its anion in aqueous solutions: spin states,protic equilibria,and reactivities toward oxygen and nitric oxide

The thermodynamic properties of aqueous nitroxyl (HNO) and its anion (NO(-)) have been revised to show that the ground state of NO(-) is triplet and that HNO in its singlet ground state has much lower acidity, pKa((1)HNO/(3)NO(-)) approximately 11.4, than previously believed. These conclusions are in accord with the observed large differences between (1)HNO and (3)NO(-) in their reactivities toward O(2) and NO. Laser flash photolysis was used to generate (1)HNO and (3)NO(-) by photochemical cleavage of trioxodinitrate (Angeli's anion). The spin-allowed addition of (3)O(2) to (3)NO(-) produced peroxynitrite with nearly diffusion-controlled rate (k = 2.7 x 10(9) M(-1) x s(-1)). In contrast, the spin-forbidden addition of (3)O(2) to (1)HNO was not detected (k < 3 x 10(5) M(-1) x s(-1)). Both (1)HNO and (3)NO(-) reacted sequentially with two NO to generate N(3)O as a long-lived intermediate; the rate laws of N(3)O formation were linear in concentrations of NO and (1)HNO (k = 5.8 x 10(6) M(-1) x s(-1)) or NO and (3)NO(-) (k = 2.3 x 10(9) M(-1) x s(-1)). Catalysis by the hydroxide ion was observed for the reactions of (1)HNO with both O(2) and NO. This effect is explicable by a spin-forbidden deprotonation by OH(-) (k = 4.9 x 10(4) M(-1) x s(-1)) of the relatively unreactive (1)HNO into the extremely reactive (3)NO(-). Dimerization of (1)HNO to produce N(2)O occurred much more slowly (k = 8 x 10(6) M(-1) x s(-1)) than previously suggested. The implications of these results for evaluating the biological roles of nitroxyl are discussed.     

艾司洛尔对瑞芬太尼诱导气管插管时血流动力学的影响

目的研究艾司洛尔在抑制瑞芬太尼联合丙泊酚诱导气管插管时心血管反应的临床效果与安全性。方法美国麻醉医师协会(ASA)分级Ⅰ级的100例患者按随机数法均分为对照组和艾司洛尔组。两组患者均采用瑞芬太尼、丙泊酚及罗库溴铵诱导,插管前1 min给予药物,对照组给予生理盐水10 ml静脉注射,艾司洛尔组给予0.5 mg/kg艾司洛尔稀释于生理盐水10 ml中静脉注射。监测并比较麻醉诱导前(T0)、气管插管前(T1)、插管后1 min(T2)、2 min(T3)和3 min(T4)时的平均动脉压(MAP)和心率(HR)。结果 T1时,艾司洛尔组和对照组的MAP[(76±13)mm Hg,(75±12)mm Hg]及HR[(65±9)次/min,(64±8)次/min]较T0时的MAP[(87±12)mm Hg,(86±12)mm Hg]及HR[(75±12)次/min,(74±12)次/min]明显下降(P<0.01),下降程度组间比较差异无统计学意义(P>0.05)。T2、T3和T4时,对照组的MAP[(103±23)mm Hg,(106±21)mm Hg,(89±19)mm Hg]和HR[(85±7)次/min,(83±8)次/min,(79±9)次/min]较T1时MAP[(75±12)mmHg]和HR[(64±8)次/min]明显升高(P<0.05),而艾司洛尔组的MAP和HR在插管后升高不明显[插管后MAP:(89±15)mm Hg,(86±14)mm Hg,(74±12)mm Hg,HR:(66±13)次/min,(74±12)次/min,(72±5)次/min;插管前MAP:(76±13)mm Hg,HR(65±9)次/min,P<0.01]。艾司洛尔组有8例患者在插管后HR下降到60次/min以下,最低为53次/min。结论艾司洛尔能有效抑制气管插管时的心血管反应,0.5 mg/kg艾司洛尔与瑞芬太尼合用是安全的。     

Quantification of wave reflection in the human aorta from pressure alone: a proof of principle

Wave reflections affect the proximal aortic pressure and flow waves and play a role in systolic hypertension. A measure of wave reflection, receiving much attention, is the augmentation index (AI), the ratio of the secondary rise in pressure and pulse pressure. AI can be limiting, because it depends not only on the magnitude of wave reflection but also on wave shapes and timing of incident and reflected waves. More accurate measures are obtainable after separation of pressure in its forward (P(f)) and reflected (P(b)) components. However, this calculation requires measurement of aortic flow. We explore the possibility of replacing the unknown flow by a triangular wave, with duration equal to ejection time, and peak flow at the inflection point of pressure (F(tIP)) and, for a second analysis, at 30% of ejection time (F(t30)). Wave form analysis gave forward and backward pressure waves. Reflection magnitude (RM) and reflection index (RI) were defined as RM=P(b)/P(f) and RI=P(b)/(P(f)+P(b)), respectively. Healthy subjects, including interventions such as exercise and Valsalva maneuvers, and patients with ischemic heart disease and failure were analyzed. RMs and RIs using F(tIP) and F(t30) were compared with those using measured flow (F(m)). Pressure and flow were recorded with high fidelity pressure and velocity sensors. Relations are: RM(tIP)=0.82RM(mf)+0.06 (R(2)=0.79; n=24), RM(t30)=0.79RM(mf)+0.08 (R(2)=0.85; n=29) and RI(tIP)=0.89RI(mf)+0.02 (R(2)=0.81; n=24), RI(t30)=0.83RI(mf)+0.05 (R(2)=0.88; n=29). We suggest that wave reflection can be derived from uncalibrated aortic pressure alone, even when no clear inflection point is distinguishable and AI cannot be obtained. Epidemiological studies should establish its clinical value.     

缺氧肺动脉高压大鼠肺组织中白细胞介素6和Janus激酶表达的变化

目的　研究缺氧肺动脉高压 (HPH)肺组织中白细胞介素 6(IL 6)及Janus激酶 (JAKs)表达的变化。方法　雄性Wistar大鼠 60只 ,随机分为缺氧 1周 (H1)、缺氧 2周 (H2 )、缺氧 3周 (H3)、缺氧4周 (H4)和常氧 (N)组 ,每组 12只。常压缺氧舱复制HPH大鼠模型。应用逆转录 聚合酶链反应 (RT PCR)检测肺组织IL 6和JAKsmRNA的表达水平 ;免疫组化法检测肺组织JAKs蛋白的含量和细胞形态学变化。结果　 (1)H1、H2 和H3 组大鼠肺组织IL 6mRNA水平 (分别为 1 67± 0 0 9、2 2 6± 0 12、1 55± 0 11)显著高于N组 (1 2 0± 0 11,P均 <0 0 1) ;H1、H2 和H3 组大鼠肺组织JAK1mRNA水平 (分别为 2 11± 0 0 9、2 85± 0 12、2 3 6± 0 13 )显著高于N组 (1 62± 0 10 ,P均 <0 0 1) ;H1、H2 和H3 组大鼠JAK2mRNA水平 (分别为 1 41± 0 0 7、2 0 2± 0 13、1 3 6± 0 0 9)显著高于N组 (1 0 1± 0 0 9,P均 <0 0 1) ;H1、H2 和H3 组大鼠肺组织JAK3mRNA水平 (分别为 0 86± 0 11、1 45± 0 10、0 91± 0 13 )显著高于N组 (0 55± 0 0 8,P均 <0 0 1) ;H1、H2 组大鼠肺组织TYK2mRNA水平 (分别为 1.3 6± 0 .10 ,1.76± 0 .11)显著高于N组 (0 .57± 0 .0 7,P均 <0 .0 1) ;其中H2 组大鼠肺组织表达IL 6和J     

Suppression of circulating interleukin-6 concentrations is associated with decreased endothelial activation in rheumatoid arthritis

BACKGROUND: Circulating interleukin (IL)-6 concentrations are associated with endothelial activation in rheumatoid arthritis (RA). OBJECTIVE: To assess endothelial activation before and after suppression of cytokine production in RA. METHODS: Twenty-one patients (mean (SD) age 59 (9) years; disease duration 6 (4) years) were treated with intraarticular methylprednisolone acetate (417 (152) mg) together with disease modifying agent (DMARD) initiation (n = 10) or intensification (n = 11) employing methotrexate (n = 11), leflunomide (n = 8), minocyclin (n = 6) and sulphasalazine (n = 1). Disease activity, circulating cytokines (IL-1, tumor necrosis factor alpha (TNF-alpha) and IL-6) and biomarkers of endothelial activation (circulating vascular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and endothelial leukocyte adhesion molecule-1 (ELAM-1)) were evaluated before and 2 weeks after treatment. RESULTS: The intervention resulted in reductions in 8 disease activity markers (p < or = 0.002). Serum IL-6 concentrations decreased from 17 (2.9) to 4.9 (4.6) pg/ml (p = 0.0008). Serum IL-1 and TNF-alpha levels did not change (p > or = 0.4). Serum VCAM-1 concentrations decreased from 912 (402) to 752 (252) (p = 0.003), ICAM-1 from 398 (205) to 323 (179) (p = 0.04) and ELAM-1 from 68 (28) to 53 (25) (p = 0.02) pg/ml, respectively. Baseline rheumatoid factor titers were associated with reductions in VCAM-1 (r(s) = 0.481, p = 0.03). In multivariable regression models, decreases in circulating interleukin-6 concentrations were associated with reductions in VCAM-1 (p < 0.0001), ICAM-1 (p = 0.005) and ELAM-1 (p = 0.02) independent of changes in disease activity, weight and blood pressure. CONCLUSION: Our results suggest that suppression of circulating IL-6 concentrations attenuates atherogenesis in active RA.     

Mathematical analysis of urea rebound in long-term hemodialysis patients

Quantifying hemodialysis (HD) treatment requires knowledge of the equilibrated concentrations of the post-HD small molecule rebounds. However, measurement of the equilibrated concentrations is only possible after resting in bed after HD for at least 30 min, and this is often impractical. Therefore, we have analyzed mathematically the time course of post-HD urea rebound, and from this, have derived a new formula for predicting its equilibrated concentration. The blood urea nitrogen (BUN) was measured at 10 time points (immediately following HD, and 0.5, 2.5, 5, 7.5, 10, 15, 20, 25, and 30 min post-HD) in 12 anuric HD patients. The absolute change in the urea rebound (DeltaeqBUN) was approximated (DeltaestBUN) using the equation: DeltaestBUN = b -[1-exp x (-c x time (min))] + a x time (min). After the good correlation between DeltaeqBUN and DeltaestBUN, we compared the value of DeltaeqBUN measured at 30 min (DeltaeqBUN(30)) with that calculated (DeltaestBUN(30)) using only four sample points (immediately following HD, and 2.5, 5 and 10 min post-HD). Based on this result, we tried to predict post-HD BUN at 30 min (estBUN(30)). This study was undertaken to determine whether estBUN(30) may be representative of the equilibrated BUN (eqBUN(30)), and to compare with Kt/V using estBUN(30) and eqBUN(30). There was a significant correlation between DeltaeqBUN and DeltaestBUN (0.97 < r < 0.99, P < 0.001). Thus, there was a significant positive linear correlation between eqBUN(30) and estBUN(30) (eqBUN(30): 25.7 +/- 2.25 mg/dL, estBUN(30): 26.3 +/- 2.31 mg/dL; r(2) = 0.99, P < 0.001). A Kt/V measurement was obtained with single pool model using BUN just after HD (Kt/V(sp)), eqBUN(30) (Kt/V(eq)), and estBUN(30) (Kt/V(est)), and with double pool model using Kt/V(sp) (Kt/V(dp)) and was compared with them. Though Kt/V(sp) was significantly higher than Kt/V(eq) (1.26 +/- 0.08 vs. 1.09 +/- 0.07, P < 0.001), there were no differences among Kt/V(eq), Kt/V(est) and Kt/V(dp) (Kt/V(est): 1.06 +/- 0.07, Kt/V(dp): 1.10 +/- 0.07) and all values were clinically acceptable. Furthermore, there was a significant positive linear correlation between Kt/V(eq) and Kt/V(est) (r(2) = 0.98, P < 0.001). In conclusion, we have devised the method to predict equilibrated BUN and calculate double pool Kt/V, which requires samples up to 10 min post-HD.     

Can diaphragmatic contractility be assessed by twitch airway pressures in patients with chronic obstructive pulmonary disease?

In healthy subjects and in patients without lung diseases, twitch airway pressure (Paw(tw)) responses to phrenic nerve stimulation can be used to predict twitch esophageal pressure (Pes(tw)) and twitch transdiaphragmatic pressure (Pdi(tw)), thus overcoming the need for placement of esophageal and gastric balloons. The aim of this study was to determine whether measurements of Paw(tw) combined with simple maneuvers could be used to predict Pes(tw), and possibly Pdi(tw), in patients with severe chronic obstructive pulmonary disease (COPD) (n = 12). Stimulations delivered at relaxed FRC produced a correlation coefficient (r) between Paw(tw) and Pes(tw) of 0.44 (p < 0.001) and of 0.62 (p < 0.001) during stimulations while patients performed a gentle exhalation from FRC. Stimulations performed during a gentle inhalation produced a good correlation between Paw(tw) and Pes(tw) (r = 0.92, p < 0.001); however, the limits of agreement between Paw(tw) and Pes(tw) were wide. Correlations between Paw(tw) and Pdi(tw) during the three experimental conditions were weak. In conclusion, during a gentle inspiratory effort in patients with severe COPD the correlation between Paw(tw) and Pdi(tw) was weak, whereas the correlation between Paw(tw) and Pes(tw) was good, but it was not sufficient to allow the prediction of Pes(tw) from Paw(tw) in all patients.     

Immunohistochemical localization of type IV collagen alpha chains in the basement membrane of the pancreatic duct in human normal pancreas and pancreatic diseases

The type IV collagen (Col-IV) consists of 3 alpha chains. Six different alpha chains [alpha1(IV), alpha2(IV), alpha3(IV), alpha4(IV), alpha5(IV), and alpha6(IV)] have been identified, and their combination is considered to be organ specific. We investigated the immunohistochemical localization of alpha (IV) chains in the basement membrane (BM) of the pancreatic duct in human normal pancreas (NP) and pancreatic diseases. Fifty specimens [10 NP, 10 chronic pancreatitis (CP), 10 intraductal papillary mucinous tumor (IPMT), and 20 pancreatic adenocarcinoma (PAC)] were examined. Alpha 1(IV), alpha2(IV), alpha5(IV), and alpha6(IV) were linearly immunostained in NP, CP, and IPMT. In PAC, alpha(IV) and alpha2(IV) were immunostained, but alpha5(IV) and alpha6(IV) were not stained in 30% and 40% of the cases, respectively. In conclusion, immunohistochemically, the Col-IV of human normal pancreatic duct consisted of alpha1(IV), alpha2(IV), alpha5(IV), and alpha6(IV). alpha5(IV) and alpha6(IV) were frequently absent in PAC, and their absence might be related to the invasion of cancer cells.