An interpretation of fluctuations in enzyme catalysis rate, spectral diffusion, and radiative component of lifetimes in terms of electric field fluctuations

Time-dependent fluctuations in the catalysis rate (deltak(t)) observed in single-enzyme experiments were found in a particular study to have an autocorrelation function decaying on the same time scale as that of spectral diffusion deltaomega(0)(t). To interpret this similarity, the present analysis focuses on a factor in enzyme catalysis, the local electrostatic interaction energy (E) at the active site and its effect on the activation free energy barrier. We consider the slow fluctuations of the electrostatic interaction energy (deltaE(t)) as a contributor to deltak(t) and relate the latter to deltaomega(0)(t). The resulting relation between deltak(t) and deltaomega(0)(t) is a dynamic analog of the solvatochromism used in interpreting solvent effects on organic reaction rates. The effect of the postulated deltaE(t) on fluctuations in the radiative component (deltagamma(r)(-1)(t)) of the fluorescence decay of chromophores in proteins also is examined, and a relation between deltagamma(r)(-1)(t) and deltaomega(0)(t) is obtained. Experimental tests will determine whether the correlation functions for deltak(t), deltaomega(0)(t), and deltagamma(r)(-1) are indeed similar for any enzyme. Measurements of dielectric dispersion, epsilon(omega), for the enzyme discussed elsewhere will provide further insight into the correlation function for deltaE(t). They also will determine whether fluctuations in the nonradiative component gamma(nr)(-1) of the lifetime decay has a different origin, fluctuations in distance for example.     

Electron tunneling in protein crystals

The current understanding of electron tunneling through proteins has come from work on systems where donors and acceptors are held at fixed distances and orientations. The factors that control electron flow between proteins are less well understood, owing to uncertainties in the relative orientations and structures of the reactants during the very short time that tunneling occurs. As we report here, the way around such structural ambiguity is to examine oxidation-reduction reactions in protein crystals. Accordingly, we have measured and analyzed the kinetics of electron transfer between native and Zn-substituted tuna cytochrome c (cyt c) molecules in crystals of known structure. Electron transfer rates [(320 s(-1) for *Zn-cyt c --> Fe(III)-cyt c; 2000 s(-1) for Fe(II)-cyt c --> Zn-cyt c(+))] over a Zn-Fe distance of 24.1 A closely match those for intraprotein electron tunneling over similar donor-acceptor separations. Our results indicate that van der Waals interactions and water-mediated hydrogen bonds are effective coupling elements for tunneling across a protein-protein interface.     

Evaluation of the distribution of distances between energy donors and acceptors by fluorescence decay

When transfer of electronic excitation energy occurs between a donor-acceptor pair by the Förster mechanism, the decay of fluorescence of the donor follows first-order kinetics, with a rate constant that depends on the distance from donor to acceptor. In a system that contains donor-acceptor pairs of different separations, the fluorescence decay of the donors will not be exponential, but will depend on the distribution function of donor-acceptor distances, f(r). Various approaches are outlined for the extraction of information about f(r) from the decay curve of donor fluorescence. Specifically, if a plausible expression with adjustable parameters is assumed for f(r), numerical methods can be used to evaluate the parameters that yield the closest fit between the observed decay curve and that calculated from the assumed f(r). The technique of fluorescence decay may prove to be useful for determination of distribution functions of end-to-end distances of polymers to the edges of which suitable donor-acceptor chromophore pairs have been attached.     

Theory of the dependence of population levels on environmental history for semelparous species with short reproductive seasons

A population that is strongly self-regulating through density-dependent effects is expected to be such that, if many generations have elapsed since its establishment, its present size should not be sensitive to its initial size but should instead be determined by the history of the variables that describe the influence of the environment on fecundity, mortality, and dispersal. Here we discuss the dependence of abundance on environmental history for a semelparous population in which reproduction is synchronous. It is assumed that at each instant t: (i) the rate of loss of members of age a by mortality and dispersal is given by a function rho of t, a, and the present number x = x(a,t) of such members; and (ii) the number x(0,t) of members born in the population is given by a function F of t and the number of x(a(f),t) at a specified age a(f) of fecundity. It is further assumed that the functions rho and F have the forms rho(x,a,t) = pi(1)(a,t)x + pi(2)(a,t)x(2) and F(x(a(f),t),t) = nu(t)x(a(f),t). For such a population, a change in the environment is significant only if it results in a change in nu(t) pi(1)(a,t), or pi(2)(a,t), and, hence, the history of the environment up to time t is described by giving nu(tau), pi(1)(a,tau), and pi(2)(a,tau) for each tau 相似文献   

Probing conformational dynamics in single donor-acceptor synthetic molecules by means of photoinduced reversible electron transfer

We use single-molecule fluorescence lifetimes to probe dynamics of photoinduced reversible electron transfer occurring between triphenylamine (donor) and perylenediimide (acceptor) in single molecules of a polyphenylenic rigid dendrimer embedded in polystyrene. Here, reversible electron transfer in individual donor-acceptor molecules results in delayed fluorescence that is emitted with a high photon count rate. By monitoring fluorescence decay times on a photon-by-photon basis, we find fluctuations in both forward and reverse electron transfer spanning a broad time range, from milliseconds to seconds. Fluctuations are induced by conformational changes in the dendrimer structure as well by polystyrene chain reorientation. The conformational changes are related to changes in the dihedral angle of adjacent phenyl rings located in the dendritic branch near the donor transferring the charge, a torsional motion that results in millisecond fluctuations in the "through-bond" donor-acceptor electronic coupling. Polymer chain reorientation leads to changes in the local polarity experienced by the donors and to changes in the solvation of the charge-separated state. As a result, switching between different donor moieties within the same single molecule becomes possible and induces fluctuations in decay time on a time scale of seconds.     

Atorvastatin improves metabolic control and endothelial function in type 2 diabetic patients: a placebo-controlled study

Several pieces of evidence support a role of inflammatory processes in the pathogenesis of atherosclerosis; it is also known that endothelial dysfunction is the initial lesion of the atherosclerotic process. Among other markers of endothelial dysfunction, some adhesion molecules seem to play an interesting role. The aim of the present study was to evaluate the effect of atorvastatin vs placebo on some indexes of leukocytes adhesion in a group of Type 2 diabetic patients. Twenty-five Type 2 diabetic patients free from microangiopathic complications and with LDL-cholesterol lower than 180 mg/dl were randomized to receive either atorvastatin (T2DA) or placebo (T2Dp) for twelve months. BMI, fasting plasma glucose, glycated hemoglobin (HbA1c), albumin excretion rate (AER), lipid profile, and serum concentrations of vascular cell adhesion molecule-1 (VCAM1), E-selectin and cadherin-5 were measured at baseline and at the end of the follow-up. At T0 E-selectin was 16 +/- 6 ng/ml in T2DA and 17 +/- 13 in T2Dp; VCAM1 was 413 +/- 112 ng/ml in T2DA and 411 +/- 112 in T2Dp. At T12 VCAM1 and E-selectin did not vary in T2Dp, while a significant reduction was observed in T2DA (VCAM1 275 +/- 104 ng/ml and E-selectin 8 +/- 3 ng/ml; p < 0.001 and p < 0.01, respectively). T2DA also showed a reduction of total and LDL cholesterol and an improved glycemic control respect to T2Dp. Hypolipidemic therapy was the strongest independent predictor of the cytokines variations along the time. These results confirm the role of statins in modulating endothelial function also in Type 2 diabetes, outlining a therapeutic role of these molecules probably independent from the hypolipidemic effect.     

Variable effects of testosterone on dopamine activity in several microdissected regions in the preoptic area and medial basal hypothalamus

We have observed previously that systemic treatments or local implants of testosterone (T) suppress dopamine (DA) turnover in the preoptic area-anterior hypothalamus of male rats. In the present study, we sought to identify discrete regions innervated by the incertohypothalamic DA system and the tuberoinfundibular DA system which respond to T replacement. Adult male rats were orchidectomized and immediately treated with either empty (controls) or T-containing Silastic implants. After 14 days, animals from each group were treated with alpha-methylparatyrosine and killed 0, 45, and 90 min later for analysis of DA turnover in eight microdissected brain regions. The T implants produced an increase in serum T and 5 alpha-dihydrotestosterone and reduced serum LH to concentrations observed in intact male rats without affecting serum PRL levels. Serum levels of T within the physiological range caused a profound decrease in the DA turnover rate in the medical preoptic nuclei and anterior hypothalamic nuclei without influencing DA activity in the periventricular nuclei, the site of perikarya for these DA projections. In contrast, DA turnover in the median eminence was increased 3-fold by T treatment, while DA activity in the arcuate nuclei, the locus of cell bodies of the tuberoinfundibular DA system, was not affected. These studies reveal disparate effects of T on the terminal fields of the two DA systems. While augmentation in the median eminence DA activity may participate in the negative feedback effects of T on gonadotropin secretion, the T-induced suppression of DA turnover in the medial preoptic nuclei and anterior hypothalamic nuclei may well be involved in androgen-dependent aggression and copulatory behavior.     

Moderate-level prenatal alcohol exposure alters striatal dopamine system function in rhesus monkeys

BACKGROUND: Moderate prenatal alcohol exposure can cause impairments even in the absence of gross morphological defects associated with fetal alcohol syndrome. The basal ganglia, which include the dopamine-rich striatum, are sensitive to fetal alcohol-induced injury. In this study, we manipulated the timing of moderate-level alcohol exposure and compared the risk of adverse effects on striatal dopamine (DA) system function in rhesus monkeys. METHODS: Thirty-five young adult rhesus monkeys (Macaca mulatta) from four groups of females were assessed: (1) an early alcohol-exposed group (n=9), in which mothers voluntarily consumed 0.6 g/kg alcohol solution on gestational days 0 through 50; (2) a middle-to-late gestation alcohol-exposed group (n=7), in which mothers voluntarily consumed 0.6 g/kg alcohol solution on gestational days 50 through 135; (3) a continuous-exposure group (n=9), in which mothers voluntarily consumed 0.6 g/kg alcohol solution on days 0 through 135; and (4) controls (n=10), in which mothers voluntarily consumed an isocaloric control solution on gestational days 0 through 50, 50 through 135, or 0 through 135. We studied striatal DA system function by positron emission tomography in separate scans for trapping of [(18)F]fallypride and 6-[(18)F]fluoro-m-tyrosine to assess striatal DA D2 receptor (D2R) binding and DA synthesis, respectively, via dopadecarboxylase activity. RESULTS: Moderate-level alcohol exposure during early gestation and continuous exposure throughout gestation (early + middle-to-late exposure) reduced the striatal D2R binding to DA synthesis ratio, whereas middle-to-late alcohol gestation exposure increased the striatal D2R binding to DA synthesis ratio. The continuous-exposure group showed the largest effect. Moreover, the D2R binding/DA synthesis ratio was related to neonatal neurobehavior measures in control monkeys, but these relationships were disrupted in the fetal alcohol-exposed monkeys. CONCLUSION: These results suggest that the vulnerability of the DA system to the effects of moderate doses of alcohol during gestation depend on the timing of the alcohol exposure. Early-gestation moderate alcohol exposure resulted in a reduction or blunting of dopaminergic function in adulthood, whereas middle to late exposure (without early exposure) either induced the opposite pattern or heightened dopaminergic function. Continuously exposed monkeys showed the largest effect, suggesting that the sooner women stop drinking, the better it is for the fetus.     

Clinical validity of measuring time difference between onset of mitral inflow and onset of early diastolic mitral annulus velocity in the evaluation of left ventricular diastolic function

OBJECTIVES: This study was performed to validate the clinical usefulness of measuring the time difference between onset of mitral inflow and onset of early diastolic mitral annulus velocity (T(E'-E)) for the evaluation of left ventricular (LV) diastolic function. BACKGROUND: In recent studies, T(E'-E) correlated well with the time constant of LV pressure decay (tau), and the ratio of IVRT/T(E'-E), where IVRT is isovolumic relaxation time, was useful in the prediction of elevated LV filling pressure. METHODS: Simultaneous left heart catheterization and Doppler echocardiography were performed in 40 patients. RESULTS: The T(E'-E) was evaluated in the same cardiac cycle and in the same hemodynamic status in 31 patients. Despite the wide range of tau (31 to 70 ms), there was no delay in the onset of mitral annulus velocity compared with the onset of mitral inflow (T(E'-E) = 0) in 27 patients and, therefore, T(E'-E) did not correlate with tau. Only three patients showed prolongation in T(E'-E), and all three showed tau >or=50 ms and pre-A-wave pressure >or=18 mm Hg. In one patient, mitral annulus velocity began earlier than the onset of mitral inflow. Because T(E'-E) was 0 in the majority of patients, the LV filling pressure could not be predicted by the previously suggested index of IVRT/T(E'-E.) CONCLUSIONS: In contrast to previous studies, T(E'-E) did not correlate with tau, and IVRT/ T(E'-E) could not be applied in the prediction of filling pressure, because of the limitation of a zero denominator. However, prolongation of T(E'-E) might suggest an elevated filling pressure in the setting of prolonged tau.     

Dopamine and L-dopa: inhibition of thyrotropin-stimulated thyroidal thyroxine release

Previous studies had suggested that norepinephrine (NE) and its precursors dopamine (DA) and L-DOPA acted similarly on iodine metabolism of isolated thyroid cells. Present studies indicate that this similarity extends to the inhibition by catecholamines of TSH-stimulated T4 release by mouse thyroids incubated in vitro. DA (5 X 10(-4) M), like NE, shown previously, inhibits TSH-stimulated T4 release. This inhibition was reversed by the alpha-blockers phentolamine, prazosin, and yohimbine, but not by the beta-blocker L-propranolol. DU-18288 and diethyldithiocarbamate, inhibitors of DA beta-hydroxylase, did not reduce DA inhibition, suggesting that prior conversion to NE was not a condition for DA activity. Apomorphine, a dopaminergic agonist but not a NE precursor, acted like DA, and its inhibition was also reversed by alpha-blockers. Furthermore, sulpiride, a dopaminergic blocker, reversed DA and apomorphine inhibition of TSH stimulation. These results suggest that DA inhibits TSH-stimulated T4 release through both adrenergic and dopaminergic receptors. On the other hand, L-DOPA, exerting an inhibition like that of DA, was also reversed by alpha-blockers, but its activity was greatly diminished by carbidopa, an inhibitor of aromatic L-amino acid decarboxylase, the enzyme converting L-DOPA to DA. This indicated that L-DOPA had to be converted to DA for activity. Both DA and L-DOPA inhibited stimulation of T4 release induced by (Bu)2cAMP, suggesting that their effect was exerted at a locus distal to cAMP generation. Indirect confirmation of a cAMP-independent pathway was obtained when DA inhibited TSH-stimulated cAMP formation, but, contrary to T4 release, this inhibition was not reversed by dopaminergic or adrenergic blockers. Presumably, therefore, DA inhibition of TSH-stimulated cAMP production was not related to T4 release. We conclude that 1) DA inhibits TSH-stimulated T4 release in mouse thyroids via alpha-adrenergic and dopaminergic receptors; 2) L-DOPA has to be converted to DA to produce inhibition; and 3) cAMP is unlikely to be an intermediary in DA inhibition.     

Granulocyte colony-stimulating factor perturbs lymphocyte mitochondrial function and inhibits cell cycle progression

Sera from healthy subjects receiving recombinant human granulocyte colony-stimulating factor (rHuG-CSF) to mobilize CD34(+) peripheral blood progenitors (PBPC) have been recently shown to induce unresponsiveness of allogeneic lymphocytes to mitogenic challenge. In the present investigation, the effects of rHuG-CSF on the early stages of lymphocyte activation-induced apoptosis and on lymphocyte cell cycle entry were evaluated.Sera were obtained from HLA-identical donors receiving rHuG-CSF to mobilize CD34(+) PBPC for allogeneic transplantation. Normal peripheral blood mononuclear cells (PBMC) were challenged with phytohemagglutinin (PHA) in the presence of serum collected before (preG) or after rHuG-CSF administration (postG). Mitochondrial function, that is, incorporation of 3,3'-dihexyloxacarbocyanine iodide [DiOC(6)(3)] and generation of reactive oxygen species (ROS) as well as expression of c-Myc and Bcl-2 family members (Bcl-2, Bcl-X(L), Bax) were evaluated by multiparameter flow cytometry. The activation-induced fragmentation of genomic DNA was detected by highly sensitive LM-PCR assay.CD4(+)DiOC(6)(3)(low) and CD8(+)DiOC(6)(3)(low) T lymphocytes increased and reached 32% (range 27%-38%) and 20% (range 15%-23%) of circulating T cells, respectively, on day 4 of rHuG-CSF administration. Hypergeneration of ROS could be demonstrated in 65% (range 58%-82%) of CD4(+) T lymphocytes and in 0.4% (range 0.2%-0. 8%) of circulating CD8(+) T cells. rHuG-CSF determined no alteration of mitochondrial function if added to allogeneic PBMC in vitro, thus suggesting indirect effects mediated by soluble factors; on the contrary, when PBMC were challenged with PHA in the presence of postG serum, both perturbation of mitochondrial transmembrane potential (Deltapsi(m)) and hypergeneration of ROS were induced, and lymphocytes were predominantly arrested in a G(0) -like phase of the cell cycle and displayed genomic DNA fragmentation. Interestingly, the preincubation of PBMC with a blocking antibody directed against CD95 abrogated the perturbation of lymphocyte Deltapsi(m), suggesting that the CD95 signaling pathway might play a role in the induction of apoptosis after PHA stimulation in the presence of postG serum. Moreover, Bax protein was overexpressed in postG (median fluorescence intensity = 180, range 168-186) compared with preG cultures (median fluorescence intensity = 75, range 68-80; p < 0.01), while no differences in Bcl-2, Bcl-X(L), and c-Myc staining intensity were observed.Our findings demonstrate a humoral-mediated rHuG-CSF-induced dissipation of lymphocyte mitochondrial Deltapsi(m); these effects might be mediated by Bax overexpression, with imbalance between apoptosis-promoting and apoptosis-inhibiting Bcl-2 family members and with subsequent induction of mitochondrial permeability transition. Whether immune dysfunction will favorably impact on incidence and severity of acute graft vs host disease after allogeneic PBPC transplantation remains to be determined.     

Update on MALT lymphomas

Gastric mucosa associated lymphoid tissue (MALT) lymphoma is a histologically distinct tumour derived from MALT acquired as a result of Helicobacter pylori infection. Eradication of H. pylori causes clinical regression of the lymphoma in 75% of cases. In seeking to identify those cases resistant to this therapy, and in the interests of further understanding the biology of MALT lymphoma, genetic alterations of MALT lymphomas have been investigated. Three translocations, t(11;18)(q21;q21), t(1;14)(p22;q32) and t(14;18)(q32;q21) are specifically associated with MALT lymphoma and the genes involved have been identified. T(11;18) results in a chimeric fusion between the API2 and MALT1 genes and is specifically associated with gastric MALT lymphomas that do not respond to eradication of H. pylori. T(1;14) and t(14;18) deregulate BCL10 and MALT1 expression, respectively. These three chromosomal translocations that involve different genes appear to share common oncogenic properties by targeting the same nuclear factor kappa B (NF kappa B) oncogenic pathway.     

糖尿病对高血压患者动态血压及血压变异性的影响

目的 探讨2型糖尿病（T2DM）对原发性高血压（EH）患者动态血压（ambulatory blood pressure，ABP）及血压变异性（blood pressure variability，BPV）的影响。方法 选取36例单纯EH及33例合并T2DM的EH患者，行24hABP监测，对2组患者的ABP及BPV进行对比分析。结果 与单纯EH患者相比，合并T2DM的EH患者日间平均收缩压（dmSBP）（P〈0，05）、日间脉压（dmPP）（P〈0.01）、日间收缩压标准差（dSBPSD）（P〈0.01）及日间收缩压标准差变异系数（dSBPCV）（P〈0．05）显著增大。结论 T2DM加重EH患者心血管系统的结构与功能异常，引起ABP及BPV增大；改善其体内糖代谢状况，将有助于改善其心血管系统血流动力学，从而减少心血管并发症。     

Myeloid neoplasms with t(16;21)(q24;q22)/<Emphasis Type="Italic">RUNX1-RUNX1T3</Emphasis> mimics acute myeloid leukemia with <Emphasis Type="Italic">RUNX1-RUNX1T1</Emphasis>

Chromosome translocation t(16;21)(q24;q22)/RUNX1-RUNX1T3 is an infrequent but recurrent chromosomal abnormality identified in myeloid neoplasms, with only 25 cases have been reported to date. Here, we report eight cases (six women and two men) of myeloid neoplasms associated with t(16;21)(q24;q22): five with therapy-related myeloid neoplasms, two with relapsed acute myeloid leukemia (AML), and one with blast phase of chronic myeloid leukemia. Morphologic and immunophenotypic features include granulocytic dysplasia, blasts with prominent perinuclear hof, large orange-pink granules, long and slim Auer rods, and aberrant expression of CD19. Six patients received AML-based regimens, and five achieved complete remission after initial induction therapy. Our study suggests that myeloid neoplasm with t(16;21)/RUNX1-RUNX1T1 resembles AML with t(8;21)(q22;q22)/RUNX1-RUNX1T1, in regard to morphology, immunophenotype, and response to therapy. Therefore, the clinical management of AML with t(8;21) may provide the best model for patients with myeloid neoplasms with t(16;21).     

The effect of perchlorate, thiocyanate, and nitrate on thyroid function in workers exposed to perchlorate long-term

Perchlorate (ClO(4)(-)) and thiocyanate (SCN(-)) are potent and nitrate (NO(3)(-)) a weak competitive inhibitor of the thyroid sodium-iodide symporter. To determine the effects of long-term, high ClO(4)(-) exposure on thyroid function, we conducted a study of 29 workers employed for at least 1.7 yr (50% over 5.9 yr) in an ammonium ClO(4)(-) production plant in Utah. Serum ClO(4)(-), SCN(-), and NO(3)(-); serum T(4), free T(4) index, total T(3), thyroglobulin (Tg), and TSH; 14-h thyroid radioactive iodine uptake (RAIU); and urine iodine (I) and ClO(4)(-) were assessed after 3 d off (Pre) and during the last of three 12-h night shifts in the plant (During) and in 12 volunteers (C) not working in the plant. Serum and urine ClO(4)(-) were not detected in C; urine ClO(4)(-) was not detected in 12 of 29 and was 272 microg/liter in 17 Pre workers; serum ClO(4)(-) was not detected in 27 of 29 Pre; and serum and urine ClO(4)(-) were markedly elevated during ClO(4)(-) exposure to 868 microg/liter and 43 mg/g creatinine, respectively. Serum SCN(-) and NO(3)(-) concentrations were similar in all groups. Thyroid RAIUs were markedly decreased in During compared with Pre (13.5 vs. 21.5%; P < 0.01, paired t) and were associated with an increase in urine I excretion (230 vs. 148 microg I/g Cr; P = 0.02, paired t) but were similar to those in the C group (14.4%). Serum TSH and Tg concentrations were normal and similar in the three groups. Serum T(4) (8.3 vs. 7.7 microg/dl), free T(4) index (2.4 vs. 2.2), and total T(3) (147 vs. 134 ng/dl) were slightly but significantly increased in the During vs. Pre workers (P < 0.01, paired t). Thyroid volumes and patterns by ultrasound were similar in the 29 workers and 12 community volunteers. In conclusion, high ClO(4)(-) absorption during three nights work exposure decreased the 14-h thyroid RAIU by 38% in ClO(4)(-) production workers compared with the RAIU after 3 d off. However, serum TSH and Tg concentrations and thyroid volume by ultrasound were not affected by ClO(4)(-), suggesting that long-term, intermittent, high exposure to ClO(4)(-) does not induce hypothyroidism or goiter in adults.     

Neighborliness of randomly projected simplices in high dimensions

Let A be a d x n matrix and T = T(n-1) be the standard simplex in Rn. Suppose that d and n are both large and comparable: d approximately deltan, delta in (0, 1). We count the faces of the projected simplex AT when the projector A is chosen uniformly at random from the Grassmann manifold of d-dimensional orthoprojectors of Rn. We derive rhoN(delta) > 0 with the property that, for any rho < rhoN(delta), with overwhelming probability for large d, the number of k-dimensional faces of P = AT is exactly the same as for T, for 0 < or = k < or = rhod. This implies that P is left floor rhod right floor-neighborly, and its skeleton Skel(left floor rhod right floor)(P) is combinatorially equivalent to Skel( left floor rhod right floor)(T). We also study a weaker notion of neighborliness where the numbers of k-dimensional faces f(k)(P) > or = f(k)(T)(1-epsilon). Vershik and Sporyshev previously showed existence of a threshold rhoVS(delta) > 0 at which phase transition occurs in k/d. We compute and display rhoVS and compare with rhoN. Corollaries are as follows. (1) The convex hull of n Gaussian samples in Rd, with n large and proportional to d, has the same k-skeleton as the (n-1) simplex, for k < rhoN (d/n)d(1 + oP(1)). (2) There is a "phase transition" in the ability of linear programming to find the sparsest nonnegative solution to systems of underdetermined linear equations. For most systems having a solution with fewer than rhoVS(d/n)d(1 + o(1)) nonzeros, linear programming will find that solution.     

Short- and long-term effects of nisoldipine on cardiac function and exercise tolerance in patients with hypertrophic cardiomyopathy

Nisoldipine is a second generation dihydropyridine calcium antagonist having characteristics of strong coronary artery dilating effect and less negative inotropic action. The purpose of this study was to evaluate the effect of nisoldipine on the cardiac function (systolic and diastolic) and the exercise tolerance in patients with hypertrophic cardiomyopathy (HCM).Subjects: Twenty-three patients with HCM were studied.Methods: We measured the following indices using M-mode and pulsed wave Doppler echocardiography before and after nisoldipine therapy; left ventricular fractional shortening (LVFS), isometric relaxation time (IRT), deceleration half-time (DHT) of early diastolic mitral (E) flow, late diastolic mitral (A) flow and A/E ratio. Symptomlimited treadmill exercise test was performed. Exercise tolerance (EX) time was measured. Nisoldipine of 10mg/day was orally administered. Same tests were repeated on day 14 and after 6 months.Results: 1) Short-term effects; LVFS did not change (55.9±5.9%57.0±7.4%, NS) after 2 weeks. However, LV diastolic function significantly improved (IRT; 92.1±7.7 ms85.2±11.6 ms, p<0.05, DHT; 70.7±16.2 ms63.3±3.7 ms, p<0.05). EX time increased (8.9±2.6 min 10.0±3.3 min, p<0.05). 2) Long-term effects; LV diastolic function had a tendency toward improvement, but is statistically not significant (IRT; 91.1±7.683.8±11.6 ms, DHT; 73.1±23.461.0±11.4 ms, A/E; 1.26±0.291.11±0.36) after 6 months. EX time was significantly increased (9.4±1.7 10.1±1.7 min, p<0.05).Conclusions: Nisoldipine improved LV diastolic dysfunction and exercise tolerance in patients with HCM. These effects were similar to the first generation calcium antagonists. LV diastolic dysfunction may be improved due to the reduction of intracellular calcium concentration and the relief of myocardial ischemia by strong coronary artery dilating effect. However, nisoldipine did not affect the LV systolic function because of its less negative inotropic effect.     

Using TOF-SIMS Spectrometry to Study the Kinetics of the Interfacial Retro Diels–Alder Reaction

In this work, the use of Time of Flight Secondary Ion Mass Spectrometry (TOF-SIMS) was explored as a technique for monitoring the interfacial retro Diels–Alder (retro DA) reaction occurring on well-controlled self-assembled monolayers (SAMs). A molecule containing a Diels–Alder (DA) adduct was grafted on to the monolayers, then the surface was heated at different temperatures to follow the reaction conversion. A TOF-SIMS analysis of the surface allowed the detection of a fragment from the molecule, which is released from the surface when retro DA reaction occurs. Hence, by monitoring the decay of this fragment’s peak integral, the reaction conversion could be determined in function of the time and for different temperatures. The viability of this method was then discussed in comparison with the results obtained by ¹H NMR spectroscopy.     

“Polarizing” microplegia improves cardiac cycle efficiency after CABG for unstable angina

Background

Myocardial protection during coronary artery bypass grafting (CABG) for unstable angina (UA) still represents a major challenge, ought to the risk for further ischemia/reperfusion injury. Few studies investigate the biochemical, hemodynamic and echocardiographic results of microplegia (Mic) in UA.

Methods

Eighty UA-patients undergoing CABG were randomized to Mic (Mic-Group) or standard 4:1 blood Buckberg-cardioplegia (Buck-Group). Troponin-I and lactate were sampled from coronary sinus at reperfusion (T1), and from peripheral blood preoperatively (T0), at 6 (T2), 12 (T3) and 48 (T4) hours. Cardiac index (CI), indexed systemic vascular resistances (ISVR), Δp/Δt, cardiac cycle efficiency (CCE), and central venous pressure (CVP) were collected preoperatively (T0), and since Intensive Care Unit (ICU)-arrival (T1) to 24 h (T5). Echocardiographic E-wave (E), A-wave (A), E/A, peak early-diastolic TDI-mitral annular-velocity (Ea), and E/Ea investigated the diastolic function and Wall Motion Score Index (WMSI) the systolic function, preoperatively (T0) and at 96 h (T1).

Results

Mic-Group showed lower troponin-I and lactate from coronary sinus (p = .0001 for both) and during the postoperative course (between-groups p = .001 and .0001, respectively). WMSI improved only after Mic (time-p = .001). Higher CI Δp/Δt and CCE (between-groups p = .0001), with comparable CVP and ISVR (p = N.S.) were detected after Mic. Diastolic function improved in both groups, but better after Mic (between-groups p = .003, .001, and .013 for E, E/A, and Ea, respectively). Mic resulted in lower transfusions (p = .006) and hospitalization (p = .002), and a trend towards lower need/duration of inotropes (p = .04 and p = .041, respectively), and ICU-stay (p = .015).

Conclusion

Microplegia attenuates myocardial damage in UA, reduces transfusions, improves postoperative systo-diastolic function, and shortens hospitalization.     

How αβ T cells deal with induced TCRα ablation

On deletion of the gene encoding the constant region of the T cell antigen receptor (TCR)alpha chain in mature T cells by induced Cre-mediated recombination, the cells lose most of their TCR from the cell surface within 7--10 days, but minute amounts of surface-bound TCR beta chains are retained for long periods of time. In a situation in which cellular influx from the thymus is blocked, TCR-deficient naive T cells decay over time, the decay rates being faster for CD8(+) cells (t(1/2) approximately 16 days) than for CD4(+) cells (t(1/2) approximately 46 days). TCR(+) na?ve cells are either maintained (CD8(+)) or decay more slowly (CD4(+); t(1/2) approximately 78 days.) Numbers of TCR-deficient memory T cells decline very slowly (CD8(+) cells; t(1/2) approximately 52 days) or not at all (CD4(+) cells), but at the population level, these cells fail to expand as their TCR(+) counterparts do. Together with earlier data on T cell maintenance in environments lacking appropriate major histocompatibility complex antigens, these data argue against the possibility that spontaneous ligand-independent signaling by the alpha beta TCR contributes significantly to T-cell homeostasis.