Blood-oxygen-level-dependent magnetic resonance signal and cerebral oxygenation responses to brain activation are enhanced by concurrent transient hypertension in rats.

Neuronal activation results in increases in blood-oxygen-level-dependent (BOLD) signal increases in magnetic resonance images, increases in cerebral blood flow (CBF), and changes in tissue oxygenation. We hypothesized that transient hypertension concurrent with neuronal activation would interfere with the normal physiological responses to neuronal activation potentially leading to additive responses. Anesthetized rats were prepared for functional magnetic resonance imaging studies in which increases in BOLD signal were measured in response to: (1) electrical forepaw stimulation, (2) different graded levels of transient hypertension produced with norepinephrine, and both 1 and 2. In other experiments with a similar protocol, changes in CBF and cortical oxyhemoglobin (oxyHb) and deoxyhemoglobin (deoxyHb) were measured using Laser Doppler Flowmetry and near-infrared (IR) spectroscopy. BOLD signal within the sensory-motor cortex increased during forepaw stimulation. These matched increases in CBF and oxyHb and decreases in deoxyHb. During moderate or severe transient hypertension, there was a blood pressure-dependent increase in BOLD signal, CBF, and oxyHb; and a decrease in deoxyHb. When transient hypertension and forepaw stimulation were combined, the responses of oxyHb, deoxyHb, or BOLD signal were generally a summation of each response. In contrast, the CBF response to forepaw stimulation was relatively unaffected by transient hypertension. We conclude that during stimulation with concurrent hypertension, the normal changes in tissue oxygenation that accompany neuronal activation are enhanced by the increases produced by hypertension despite an excellent autoregulation of CBF. The latter could reflect highly transient decreases in oxygen consumption or likely a redistribution of flow through more nonexchange vessels.     

Myocardial infarction in patient with variant angina

We present a case of a 49-year-old male with myocardial infarction in a course of variant angina. He was treated successfully with streptokinase, calcium antagonist and nitrates. Coronary angiography showed spasm of the left coronary artery, proximal spasm of the right coronary artery and myocardial bridging of the left anterior descending artery. He has been stable and symptom-free on a treatment with long acting calcium antagonist, nitrates and statin for 3-years.     

Therapy with infliximab decreases the CD4+CD28− T cell compartment in peripheral blood in patients with rheumatoid arthritis

Chronic inflammatory syndromes such as rheumatoid arthritis (RA) are associated with high frequencies of CD4+CD28– T cells. The number of these cells is genetically determined and may also be a consequence of chronic exposure to tumor necrosis factor-alpha (TNF). The aim of this study was to examine whether the reported efficacy of anti-TNF therapy in RA involves a resurgence of T cell populations that re-express CD28. After 36-week therapy with infliximab, a significant decrease in CD4+CD28– T cells in RA patients was observed in comparison with baseline. The results suggest that TNF-neutralizing therapy may restore T cell homeostasis and reduce expansion of the CD28– T cells, which are cytotoxic and may contribute to organ manifestations in RA.     

Relationships between myocardial perfusion, myocardial necrosis, and technetium--99m pyrophosphate uptake in dogs subjected to sudden coronary occlusion.

The quantitative relationship between abnormalities seen on technetium-99m pyrophosphate (99mTc-PYP) infarct scintigrams and the size of the myocardial infarction is unclear. We evaluated two possible determinants of 99mTc-PYP accumulation: myocardial perfusion measured with 7-10 mu microspheres and the extent of necrosis determined histologically. Hemodynamics and myocardial perfusion to small segments of the left ventricle were measured prior to, 5-10 min, and 44-48 hours following sudden occlusion of the left anterior descending coronary artery in ten awake dogs. 99mTc-PYP was injected i.v. following the third injection of microspheres and the animals were killed 2 hours later. The important findings were as follows: 1) there is a close relationship between the extent of myocardial necrosis observed and the perfusion of segments 5-10 min following coronary occlusion; and 2) that segmental myocardial perfusion is an important determinant of 99mTc-PYP accumulation by myocardial segments which contain areas of necrosis. Although the present data preclude statistical analysis of the relationship between the level of necrosis in a segment and the accumulation of 99mTc-PYP by that segment, the two do not appear to be related, a finding which would discourage use of intensity of 99mTc-PYP images for infarct size. The distribution of an abnormality on the scintigram may provide an estimate of infarct size. However, the geometry of the infarct and the resolving power of the scanning equipment will significantly limit this in many clinical situations.     

Polyphosphate-dependent synthesis of ATP and ADP by the family-2 polyphosphate kinases in bacteria

Inorganic polyphosphate (polyP) is a linear polymer of tens or hundreds of phosphate residues linked by high-energy bonds. It is found in all organisms and has been proposed to serve as an energy source in a pre-ATP world. This ubiquitous and abundant biopolymer plays numerous and vital roles in metabolism and regulation in prokaryotes and eukaryotes, but the underlying molecular mechanisms for most activities of polyP remain unknown. In prokaryotes, the synthesis and utilization of polyP are catalyzed by 2 families of polyP kinases, PPK1 and PPK2, and polyphosphatases. Here, we present structural and functional characterization of the PPK2 family. Proteins with a single PPK2 domain catalyze polyP-dependent phosphorylation of ADP to ATP, whereas proteins containing 2 fused PPK2 domains phosphorylate AMP to ADP. Crystal structures of 2 representative proteins, {"type":"entrez-protein","attrs":{"text":"SMc02148","term_id":"1174172212","term_text":"SMC02148"}}SMc02148 from Sinorhizobium meliloti and PA3455 from Pseudomonas aeruginosa, revealed a 3-layer α/β/α sandwich fold with an α-helical lid similar to the structures of microbial thymidylate kinases, suggesting that these proteins share a common evolutionary origin and catalytic mechanism. Alanine replacement mutagenesis identified 9 conserved residues, which are required for activity and include the residues from both Walker A and B motifs and the lid. Thus, the PPK2s represent a molecular mechanism, which potentially allow bacteria to use polyP as an intracellular energy reserve for the generation of ATP and survival.     

Serum neutrophil gelatinase-associated lipocalin as a marker of renal function in non-diabetic patients with stage 2-4 chronic kidney disease

The current Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines advocate creatinine-based equations for estimating GFR to identify patients with potential kidney disease and classify them into different stages due to the fact that serum creatinine is very insensitive to changes in the glomerular filtration rate. Very few biomarkers exist for monitoring chronic kidney disease. The aim of the study was to assess whether NGAL could represent a novel, sensitive marker of kidney function in adult patients with CKD. The study was performed on 92 non-diabetic patients with CKD stages 2-4. Serum and urinary NGAL as well as serum cystatin C were measured using commercially available kits. Serum NGAL was related, in univariate analysis, to serum creatinine, urinary NGAL, hemoglobin, hematocrit, leukocyte count, eGFR, and cystatin C. Urinary NGAL correlated with age, hemoglobin, hematocrit, serum creatinine, and eGFR. In multiple regression analysis, predictors of serum NGAL were creatinine (beta value = 0.97, p = 0.005), cystatin C (beta = 0.34, p = 0.01), and eGFR (beta value = 1.77, p = 0.001). In the healthy volunteers, serum NGAL correlated with age, serum creatinine, eGFR, leukocyte count, and cystatin C. Taking into consideration the fact that the recent DOQI (Dialysis Outcomes Quality Initiative) states that individuals with reduced GRF (glomerular filtration rate) are at greater risk for CVD and cardiac deaths, precise evaluation of renal function is important in order to select the appropriate strategy to reduce the cardiovascular risk. NGAL should be investigated as a potential early and sensitive marker of kidney impairment/injury.     

Association of urinary inflammatory markers and renal decline in microalbuminuric type 1 diabetics

Progressive renal function decline begins in one third of patients with microalbuminuria and type 1 diabetes. This study examined whether this decline is associated with elevated excretion of inflammatory markers in urine. Five inflammatory markers (IL-6, IL-8, monocyte chemoattractant protein-1, interferon-gamma-inducible protein (IP-10), and macrophage inflammatory protein-1delta) were measured in urine samples from the First Joslin Study of the Natural History of Microalbuminuria in Type 1 Diabetes, a cohort recruited in 1991. Samples were obtained from 43 participants with microalbuminuria and stable renal function (nondecliners), from 28 with microalbuminuria and early progressive renal function decline (decliners), and from 74 with normoalbuminuria and stable renal function (reference). Urinary concentrations of all five inflammatory markers were significantly higher in decliners than in nondecliners, who were similar to the reference group. Multivariate analysis revealed that those with more than two markers elevated were more than five times as likely to have early progressive decline of renal function. In contrast, serum concentrations of C-reactive protein, IL-8, and macrophage inflammatory protein-1delta did not differ between decliners and nondecliners. These results support the hypothesis that inflammatory processes in the kidney contribute to the progression of nephropathy in patients with type 1 diabetes.     

Ferric-reducing ability power of selected plant polyphenols and their metabolites: implications for clinical studies on the antioxidant effects of fruits and vegetable consumption

Undeniably, low sensitivities in the ferric-reducing ability power (FRAP) is evident in the detection of the augmentation of plasma antioxidant activity, relative to the rise in circulating polyphenols after ingestion of fruits and vegetables. We investigated in vitro the FRAP of 17 plant polyphenols and their metabolites at submicromolar concentrations commensurate in human plasma. We then explored the in vitro effects of polyphenols and purified apple quercetin glycosides on plasma FRAP. We found that apple quercetin glycosides along with various polyphenols observed this distinct power at submicromolar concentrations. The presence of a catechol structure in the compound molecule was positively associated with FRAP (r = 0.60, P < 0.05). An aliphatic substitute at a catechol ring and a double bond in an aliphatic substitute conjugated with an aromatic ring of catechol contributed to 37% of the variance in the FRAP of compounds with catechol in the backbone structure (n = 11). Plasma supplementation with 0.2 microM mixtures of seven of the most active compounds (catechin, 3,4-dihydroxycinnamic acid, 3,4-dihydroxyhydrocinnamic acid, 3,4-dihydroxyphenylacetic acid, ferulic acid, gallic acid and quercetin) initiated a placid rise in FRAP (23.3 +/- 1.2 versus 28.1 +/- 1.3 nmol of Fe(3+), P < 0.05). Apple quercetin glycosides at 0.5 microM did not elevate plasma FRAP. Plasma alone had 30 times higher power than quercetin glycosides at 0.5 microM. Abounding of FRAP exhibited in human plasma as compared to polyphenols at submicromolar concentrations, may offer elucidation to previous incongruities implicated in insignificant rises of plasma FRAP several days after ingestion of fruits or vegetables. This suggests that intake of food products and/or supplements rich in polyphenols containing a catechol ring with an aliphatic substitute augments the plasma FRAP in human beings.