Self-monitoring of Blood Pressure in Patients With Hypertension-Related Multi-morbidity: Systematic Review and Individual Patient Data Meta-analysis.

BACKGROUND: Studies have shown that self-monitoring of blood pressure (BP) is effective when combined with co-interventions, but its efficacy varies in the presence of some co-morbidities. This study examined whether self-monitoring can reduce clinic BP in patients with hypertension-related co-morbidity. METHODS: A systematic review was conducted of articles published in Medline, Embase, and the Cochrane Library up to January 2018. Randomized controlled trials of self-monitoring of BP were selected and individual patient data (IPD) were requested. Contributing studies were prospectively categorized by whether they examined a low/high-intensity co-intervention. Change in BP and likelihood of uncontrolled BP at 12 months were examined according to number and type of hypertension-related co-morbidity in a one-stage IPD meta-analysis. RESULTS: A total of 22 trials were eligible, 16 of which were able to provide IPD for the primary outcome, including 6,522 (89%) participants with follow-up data. Self-monitoring was associated with reduced clinic systolic BP compared to usual care at 12-month follow-up, regardless of the number of hypertension-related co-morbidities (-3.12 mm Hg, [95% confidence intervals -4.78, -1.46 mm Hg]; P value for interaction with number of morbidities = 0.260). Intense interventions were more effective than low-intensity interventions in patients with obesity (P < 0.001 for all outcomes), and possibly stroke (P < 0.004 for BP control outcome only), but this effect was not observed in patients with coronary heart disease, diabetes, or chronic kidney disease. CONCLUSIONS: Self-monitoring lowers BP regardless of the number of hypertension-related co-morbidities, but may only be effective in conditions such obesity or stroke when combined with high-intensity co-interventions.

Sensitivity of 2H NMR spectroscopy to motional models: proteins and highly viscous liquids as examples.

In order to study to what extent mechanisms of molecular motion can be unambiguously revealed by (2)H NMR spectroscopy, (2)H spectra for proteins (chicken villin protein headpiece HP36, selectively methyl-deuterated at leucine-69, C(δ) D(3)) and binary systems of high viscosity (benzene-d(6) in tricresyl phosphate) have been carefully analyzed as illustrative examples (the spectra are taken from the literature). In the first case, a model of restricted diffusion mediated by jumps between rotameric orientations has been tested against jump- and free diffusion models which describe rotational motion combined with jump dynamics. It has been found that the set of (2)H spectra of methyl-deuterated at leucine-69 chicken villin protein headpiece HP36 can be consistently explained by different motional models as well as by a gaussian distribution of correlation times assuming isotropic rotation (simple brownian diffusion model). The last finding shows that when the possible distribution of correlation times is not very broad one might not be able to distinguish between heterogeneous and homogenous (but more complex) dynamics by analyzing (2)H lineshapes. For benzene-d(6) in tricresyl phosphate, the dynamics is heterogeneous and it has been demonstrated that a gaussian distribution of correlation times reproduces well the experimental lineshapes, while for a Cole-Davidson distribution the agreement is somewhat worse. For inquires into the sensitivity of quadrupolar NMR spectral analysis (by "quadrupolar NMR spectroscopy we understand NMR spectroscopy of nuclei possessing quadrupole moment), the recently presented theoretical approach [Kruk et al., J. Chem. Phys. 135, 224511 (2011)] has been used as it allows simulating quadrupolar spectra for arbitrary motional conditions by employing the stochastic Liouville equation.

1H NMR relaxation in glycerol solutions of nitroxide radicals: effects of translational and rotational dynamics.

(1)H spin-lattice relaxation rates in glycerol solutions of selected nitroxide radicals at temperatures between 200 K and 400 K were measured at 15 MHz and 25 MHz. The frequency and temperature conditions were chosen in such a way that the relaxation rates go through their maximum values and are affected by neither the electron spin relaxation nor the electron-nitrogen nucleus hyperfine coupling, so that the focus could be put on the mechanisms of motion. By comparison with (1)H spin-lattice relaxation results for pure glycerol, it has been demonstrated that the inter-molecular electron spin-proton spin dipole-dipole interactions are affected not only by relative translational motion of the solvent and solute molecules, but also by their rotational dynamics as the interacting spins are displaced from the molecular centers; the eccentricity effects are usually not taken into account. The (1)H relaxation data have been decomposed into translational and rotational contributions and their relative importance as a function of frequency and temperature discussed in detail. It has been demonstrated that neglecting the rotational effects on the inter-molecular interactions leads to non-realistic conclusions regarding the translational dynamics of the paramagnetic molecules.

Nuclear quadrupole resonance lineshape analysis for different motional models: stochastic Liouville approach.

A general theory of lineshapes in nuclear quadrupole resonance (NQR), based on the stochastic Liouville equation, is presented. The description is valid for arbitrary motional conditions (particularly beyond the valid range of perturbation approaches) and interaction strengths. It can be applied to the computation of NQR spectra for any spin quantum number and for any applied magnetic field. The treatment presented here is an adaptation of the "Swedish slow motion theory," [T. Nilsson and J. Kowalewski, J. Magn. Reson. 146, 345 (2000)] originally formulated for paramagnetic systems, to NQR spectral analysis. The description is formulated for simple (Brownian) diffusion, free diffusion, and jump diffusion models. The two latter models account for molecular cooperativity effects in dense systems (such as liquids of high viscosity or molecular glasses). The sensitivity of NQR slow motion spectra to the mechanism of the motional processes modulating the nuclear quadrupole interaction is discussed.

Variable Coupling Scheme for High Frequency Electron Spin Resonance Resonators Using Asymmetric Meshes.

The sensitivity of a high frequency electron spin resonance (ESR) spectrometer depends strongly on the structure used to couple the incident millimeter wave to the sample that generates the ESR signal. Subsequent coupling of the ESR signal to the detection arm of the spectrometer is also a crucial consideration for achieving high spectrometer sensitivity. In previous work, we found that a means for continuously varying the coupling was necessary for attaining high sensitivity reliably and reproducibly. We report here on a novel asymmetric mesh structure that achieves continuously variable coupling by rotating the mesh in its own plane about the millimeter wave transmission line optical axis. We quantify the performance of this device with nitroxide spin-label spectra in both a lossy aqueous solution and a low loss solid state system. These two systems have very different coupling requirements and are representative of the range of coupling achievable with this technique. Lossy systems in particular are a demanding test of the achievable sensitivity and allow us to assess the suitability of this approach for applying high frequency ESR to the study of biological systems at physiological conditions, for example. The variable coupling technique reported on here allows us to readily achieve a factor of ca. 7 improvement in signal to noise at 170 GHz and a factor of ca. 5 at 95 GHz over what has previously been reported for lossy samples.

In vitro expanded human CD4+CD25+ regulatory T cells suppress effector T cell proliferation.

Regulatory T cells (Tregs) have been shown to be critical in the balance between autoimmunity and tolerance and have been implicated in several human autoimmune diseases. However, the small number of Tregs in peripheral blood limits their therapeutic potential. Therefore, we developed a protocol that would allow for the expansion of Tregs while retaining their suppressive activity. We isolated CD4+CD25 hi cells from human peripheral blood and expanded them in vitro in the presence of anti-CD3 and anti-CD28 magnetic Xcyte Dynabeads and high concentrations of exogenous Interleukin (IL)-2. Tregs were effectively expanded up to 200-fold while maintaining surface expression of CD25 and other markers of Tregs: CD62L, HLA-DR, CCR6, and FOXP3. The expanded Tregs suppressed proliferation and cytokine secretion of responder PBMCs in co-cultures stimulated with anti-CD3 or alloantigen. Treg expansion is a critical first step before consideration of Tregs as a therapeutic intervention in patients with autoimmune or graft-versus-host disease.

A physician-pharmacist model for the surveillance of blood pressure in the community: a feasibility study.

Hypertension is poorly managed. Hospital-based pharmacists working with physicians have been shown to improve the rate of achievement of "target" blood pressure in selected patients. It is unknown if such schemes can operate in the community and to what extent they would attract volunteers with poorly managed blood pressure. We assessed the feasibility of pharmacists to provide community-based, open-access, blood pressure monitoring. In addition, we describe the blood pressure profile of the group in comparison to that of the 1994 Health Survey of England (HSE). Pharmacists from six pharmacies were trained to deliver the service. Adults living within the postal districts of the pharmacies were invited, through an advertising campaign, to volunteer to have their blood pressure measured. Blood pressure data and information on treatment for hypertension and/or diabetes were collected on 263 registrants. Patients were advised to have their blood pressure managed by the general practitioner immediately (category 1), re-measured within 2-3 months (category 2) or in 12 months time (category 3). The mean (s.d.) blood pressure of patients in categories 1 (n = 16), 2 (n = 117) and 3 (n = 130) was 186(16)/97(29), 151(13)/94(9) and 139(22)/86(13) mm Hg respectively; P < 0.001. Ninety-one patients (35%) were in receipt of antihypertensive therapy. Forty-five percent of the treated group had controlled blood pressure (<160/95 mm Hg) compared with 30% in the HSE dataset. A large proportion of known hypertensive patients with poor blood pressure control who had visited their general practitioner within the previous 6 months were detected by the pharmacist-led service. Pharmacists operating an open-access blood pressure monitoring service may be of value in improving the management of hypertension.

Electron spin resonance in studies of membranes and proteins.

We provide a review of current electron spin resonance (ESR) techniques for studying basic molecular mechanisms in membranes and proteins by using nitroxide spin labels. In particular, nitroxide spin label studies with high-field/high-frequency ESR and two-dimensional Fourier transform ESR enable one to accurately determine distances in biomolecules, unravel the details of the complex dynamics in proteins, characterize the dynamic structure of membrane domains, and discriminate between bulk lipids and boundary lipids that coat transmembrane peptides or proteins; these studies can also provide time resolution to studies of functional dynamics of proteins. We illustrate these capabilities with recent examples.

Lipid hydroperoxide and markers of renal disease susceptibility in African-Caribbean and Caucasian patients with Type 2 diabetes mellitus.

AIMS: The reasons for the increased incidence of diabetic nephropathy in African-Caribbean compared with Caucasian subjects are poorly understood. Increased oxidative stress is linked to the development of endothelial dysfunction and histological abnormalities associated with diabetic renal disease. Therefore, it was assessed whether a marker of oxidative stress, lipid hydroperoxide (LOOH) and endothelial damage, von Willebrand factor (vWF) varied according to ethnic origin in the presence or absence of early diabetic nephropathy. METHODS: Eighty-eight patients with Type 2 diabetes mellitus of African-Caribbean or Caucasian origin without a history of cardiovascular disease or clinical proteinuria were studied. Patients were classified as having microalbuminuria or normal albumin excretion. Fasting plasma vWF and LOOH were measured by an inhouse enzyme-linked immunoassay and ferrous oxidation with xylenol orange (FOX) assay, respectively. The relationship of LOOH to urinary albumin status, the metabolic disturbances of diabetes, blood pressure and ethnic origin were assessed using multivariate analysis. RESULTS: Compared with Caucasian patients those of African-Caribbean origin had higher systolic blood pressure and HDL-cholesterol (157.8 +/- 17.0 vs. 147.8 +/- 24.4, P = 0.041 and 1.6 +/- 0.4 vs. 1.3 +/- 0.5, P = 0.018) but lower total triglycerides (1.3 +/- 0.8 vs. 1.9 +/- 1.1, P = 0.008). LOOH was significantly higher in the African-Caribbean patients compared with Caucasians (5.98 +/- 2.49 vs. 4.49 +/- 2.19, P = 0.006). vWF tended to be higher in microalbuminuric patients but showed no variation with ethnicity. In logistic regression analysis, LOOH was the only independent predictor of a raised albumin excretion rate (P = 0.008). In multiple regression analysis, African-Caribbean ethnicity (P = 0.020) HDL-cholesterol (P = 0.036), total triglycerides (P = 0.002) and a raised albumin excretion rate (P = 0.002) were independent predictors of LOOH. CONCLUSIONS: In this group of Type 2 diabetic patients an increase in LOOH is associated with abnormal urinary albumin excretion. African-Caribbean origin was a determinant of LOOH independently of microalbuminuria. It is postulated that increased oxidative stress is of pathophysiological significance in accelerating the development of renal disease in African-Caribbean patients.

Variation in the progression of diabetic nephropathy according to racial origin.

BACKGROUND: In the United Kingdom, diabetic nephropathy is a leading cause of end-stage renal disease. There is a higher incidence amongst subjects of Indo-Asian and African-Caribbean origin compared with Caucasians that is not wholly explained by the differences in the prevalence of diabetes. Therefore, we postulated that this observation could be related to variations in the rate of progression of renal disease according to racial origin. METHODS: We conducted a retrospective case-note review of 1684 adult attendees of the diabetes clinic. Forty-five patients were found with renal impairment (serum creatinine > or = 170 micromol/l) due to diabetic nephropathy. The patients were of Indo-Asian (n=10), African-Caribbean (n=11), and Caucasian (n=24) origin. Progression of nephropathy was assessed by analysing (i) the doubling of serum creatinine through construction of Kaplan-Meier curves and (ii) the slope (beta) of the rate of change in serum creatinine using linear regression analysis in relation to demographic variables, putative risk factors for nephropathy and antihypertensive drug therapy. RESULTS: There were no statistically significant differences between systolic and diastolic blood pressure, glycaemic control, smoking habit, baseline proteinuria, and usage of angiotensin-converting enzyme inhibitors between the three groups. The proportion of patients doubling their creatinine was significantly higher in the Indo-Asian compared with the African-Caribbean and Caucasian groups (100, 45 and 50%; P=0.025 respectively). In addition, the mean (95% CI) of beta (micromol/l/month) was highest in the Indo-Asian (5.36 (2.21-8.52)) compared with the African-Caribbean (3.14 (0.82-5.46)) and Caucasian (2.22 (1.31-3.14)) groups (P=0.035). The mean ranks of beta were highest in the Indo-Asian group (P=0.038) after adjusting for marginal differences in blood pressure age, gender, baseline proteinuria, anti-hypertensive treatment, and smoking habit. CONCLUSIONS: In this small cohort of type 2 diabetic subjects with established renal disease, the rate of decline in renal function is accelerated in Indo-Asian subjects. This observation could be related to differences in renoprotection from antihypertensive therapy.

QT dispersion in microalbuminuric Type 1 diabetic patients without myocardial ischemia.

Microalbuminuria is associated with an increased risk of cardiac death. We assessed whether urinary albumin excretion is related to abnormalities of the QT interval independently of myocardial ischemia. Thirty-four patients with type 1 diabetes who were free from ischemic heart disease on the basis of normal stress electrocardiography and echocardiography were studied. Maximal QT interval and dispersion were significantly greater in the group with microalbuminuria (n=17) compared to controls (n=17) with normal urinary albumin excretion (394 [26.1] vs. 373.8 [27.8] ms; P=.044 and 62.4 [21.8] vs. 42.7[11.6] arbitrary units; P=.009). Autonomic function was similar between the groups. Urinary albumin excretion correlated positively with QT dispersion (P=.023). These data suggest that in type 1 diabetic patients, QT abnormalities can occur independently of autonomic dysfunction or myocardial ischemia and may be related to the processes which increase urinary albumin leakage.

Pattern of angiogenic cytokine release from human vascular smooth muscle cells programmed by amino acid deprivation.

Vascular smooth muscle cells (VSMC) may be programmed by nutrient deprivation. We found that after 2 and 12 h exposure to 75% reduced amino acids, the release of basic fibroblast growth factor (bFGF) and transforming growth factor beta1 (TGF beta 1) from VSMC was significantly greater than that from cells maintained in control medium [2572.0 (546.3) vs 602.1 (241.7), P=0.001 and 16 028.0 (2192. 4) vs 13 027.3 (1233.5) pg/10(6)cells, P=0.022 respectively]. These differences were magnified after two passages of exposure for both bFGF (P=0.0001) and TGF beta 1 (P=0.0001). The stimulated release of VEGF by hypoxia and bFGF was unaffected. Amino acid deprivation of human VSMC is associated with a patterned release of angiogenic cytokines which could be relevant to the programmed changes in VSMC phenotype.

Bail-out rotational atherectomy to ablate stent struts after treatment of a LAD bifurcation lesion with the Trousers technique.

We present a previously unreported complication of the "trousers" stent procedure used for treatment of a bifurcation lesion in the left anterior descending artery and the first diagonal branch. Closure of the main vessel occurred. A balloon, however, could not be advanced across the side-branch stent to open the struts toward the main branch. Therefore, a bailout rotational atherectomy was performed to ablate the stent that then allowed a further dilatation with a PTCA balloon. This procedure resolved a potentially lethal outcome for the patient who subsequently underwent uneventful coronary by-pass grafting.

Jones matrix formalism for quasioptical EPR.

The Jones matrix formalism that has been used to analyze quasioptical millimeter-wave circuits is extended for specific application to high-frequency electron paramagnetic resonance (EPR). A survey of general expressions for Jones matrices of elements commonly used in quasioptical EPR spectrometers is given. The Jones matrix representations of quasioptical transmission and reflection cavities are derived, and their relationship to the equivalent circuit and transmission line representations used for conventional EPR cavities is demonstrated. The formalism is applied to selected quasioptical EPR spectrometer designs and experimental tests of the formalism are presented for two configurations of a quasioptical spectrometer operating at 220 GHz.

Growing kittens require less dietary calcium than current allowances.

We previously demonstrated that a purified diet containing 3.125 microg of cholecalciferol/kg was adequate to maintain plasma concentrations of 25-hydroxyvitamin D in growing kittens. With the use of this concentration of cholecalciferol, the response of growing kittens to varying levels of calcium in purified diets was measured. Five groups (treatments 1-5), each comprised of seven weaned kittens, were given diets containing 3.8, 5.0, 6.0, 7.2 or 8. 1 g calcium/kg diet (Ca:P ratio of 1:1.25) from 9 to 18 wk of age. Two further groups of kittens (treatments 6 and 7) received similar diets containing 6.0 g Ca/kg diet, with Ca:P ratios of 1:1.55 and 1:2.61, respectively. No clinical signs of calcium deficiency were observed, i.e., growth rate, energy intake and plasma total calcium were not affected by the treatments. However, ionized calcium was significantly lower in kittens in treatment 7. Plasma phosphorus was lower in kittens in treatment 7 than in kittens in treatments 1, 2, 3 and 4, and there was a negative relationship between dietary and plasma phosphorus concentrations. Kittens in treatment 7 had a significantly higher alkaline phosphatase concentration in plasma than kittens in treatments 1, 2, 3 and 5. Kittens in treatment 1 had a lower percentage of bone minerals measured by dual-energy X-ray absorptiometry than kittens in treatments 2-6. These results indicate that the calcium requirement of growing kittens is not >6.0 g/kg diet, (calculated metabolizable energy approximately 20 kJ/g) and that kittens are not very sensitive to inverse Ca:P ratios up to 1:1.55.

Synergistic effect of formulated plasmid and needle-free injection for genetic vaccines.

PURPOSE: A plasmid-based gene expression system was complexed with protective, interactive, and non-condensing (PINC) polymer system and administered with Medi-Jector, a needle-free injection device (NFID), to achieve high and sustained levels of antigen-specific antibodies in blood circulation. METHODS: Human growth hormone (hGH) or bacterial beta-galactosidase gene expression plasmids driven by a cytomegalovirus (CMV) promoter were formulated in saline or complexed with a PINC polymer, polyvinylpyrrolidone (PVP), and intramuscularly or subcutaneously administered into dogs and pigs using a 22-gauge needle or a NFID. The hGH-specific IgG titers in serum were measured by an ELISA. Beta-galactosidase expression was measured in injected muscles by an enzymatic assay or immunohistochemistry. The effect of NFID on DNA stability and topology was assessed by gel electrophoresis. RESULTS: Intramuscular (i.m.) or subcutaneous (s.c.) injection of a hGH expression plasmid pCMV-hGH (0.05-0.5 mg/kg) in dogs and pigs elicited antigen-specific IgG antibody titers to expressed hGH. With both routes of injection, pDNA delivery by a NFID was superior to pDNA injection by needle. The magnitude of hGH-specific IgG titers with NFID was 15-20-fold higher than needle injection when pDNA was complexed with PVP, and only 3-4-fold higher with pDNA in saline. The transfection efficiency in the injected muscle, as measured by beta-galactosidase expression, following i.m. injection of pCMV-betagalactosidase/PVP, was not significantly different between needle and NFID-injected groups. CONCLUSIONS: These data demonstrate that the combination of pDNA/ PVP complexes and a NFID act synergistically to achieve high and sustained levels of antigen-specific IgG response to expressed antigen. This gene delivery approach may offer advantage over needle injection of naked DNA for the development of genetic vaccines.

Plasma 25-hydroxyvitamin D in growing kittens is related to dietary intake of cholecalciferol.

Vitamin D synthesis by growing kittens exposed to ultraviolet light is ineffective. Concentration of 25-hydroxyvitamin D (25-OHD) in plasma (the most useful index of vitamin D status) was measured in six groups each of seven kittens given a purified diet (12 g calcium and 8 g phosphorus/kg, calculated metabolizable energy = 20 kJ/g) that contained either 0.0, 3.125, 6.25, 12.5, 18.75 or 25 microg of cholecalciferol/kg diet. All kittens received these diets from 9 to 22 wk of age, and the two groups given the 0.0 and 3.125 microg cholecalciferol/kg treatments continued to receive the diets until they were 34 wk old. Total and ionizable calcium and phosphorus in plasma were not affected by treatments. No adverse clinical changes were observed or found on radiographic examination of the kittens at 22 or 34 wk of age. Plasma concentration of 25-OHD was linearly related (r2 = 0.99, P < 0.001) to dietary intake of cholecalciferol. Plasma concentration of 25-OHD in kittens given the diet without added vitamin D was significantly less at 22 wk than at 9 wk, whereas kittens receiving the diet containing 3.125 microg cholecalciferol/kg had significantly higher 25-OHD concentrations at 22 and 34 wk than at 9 wk of age. Kittens given the 6.25 microg cholecalciferol/kg diet had plasma 25-OHD concentrations at 22 wk > 50 nmol/L which is considered replete for humans. An allowance of 6. 25 microg (250 IU) of cholecalciferol/kg diet is suggested to provide a margin of safety.