An alpha-adrenergic blocker titrated by self-measured blood pressure recordings lowered blood pressure and microalbuminuria in patients with morning hypertension: the Japan Morning Surge-1 Study

BACKGROUND: The impact on microalbuminuria of strict treatment aimed at lowering of self-measured morning blood pressure using an adrenergic blockade is unclear. METHODS: We conducted an open-label multicenter trial, the Japan Morning Surge-1 Study, that enrolled 611 hypertensive patients, whose self-measured morning systolic blood pressure levels were more than 135 mmHg while taking antihypertensive drugs. These were randomly allocated to an experimental group, whose members received bedtime administration of 1-4 mg doxazosin (doxazosin group) or a control group whose members continued without any add-on medication (control group). The urinary albumin/creatinine ratio was investigated at the baseline and 6 months after the randomization. RESULTS: Both the morning and evening blood pressures and urinary albumin/creatinine ratio (-3.4 vs. 0.0 mg/gCr for urinary albumin/creatinine ratio; P < 0.001) were more markedly reduced in the doxazosin group than in the control group. This difference in the urinary albumin/creatinine ratio between the two groups was more marked in the patients with microalbuminuria (n = 238, -27.9 vs. -8.1 mg/gCr, P < 0.001). The reduction of urinary albumin/creatinine ratio was significantly associated with the use of doxazosin, and the change in all self-measured blood pressures (morning, evening, the average morning-evening), and these associations were independent of each other (P < 0.001). CONCLUSION: Adding a bedtime dose of an alpha-adrenergic blocker titrated by self-measured morning blood pressure in treated hypertensive patients with uncontrolled morning hypertension significantly reduced blood pressure and urinary albumin excretion rate, particularly in those with microalbuminuria.     

Morning blood pressure surge and hypertensive cerebrovascular disease: role of the alpha adrenergic sympathetic nervous system

BACKGROUND: The morning surge of blood pressure (BP) is associated with alpha-adrenergic activity. We studied the association between the alpha-adrenergic morning surge in BP and silent cerebrovascular disease in elderly patients with hypertension. METHODS: We conducted ambulatory BP monitoring three times (twice at baseline and after nighttime dosing of the alpha1-blocker doxazosin) in 98 elderly hypertensive patients in whom the presence of silent cerebral infarcts (SCI) was assessed by brain magnetic resonance imaging. The morning BP surge (MBPS) was calculated as the mean systolic BP during the 2 h after waking minus the mean systolic BP during 1 h that included the lowest sleep BP. The alpha-adrenergic MBPS was calculated as the reduction of MBPS by doxazosin. RESULTS: The prevalence of multiple SCI was higher in the Surge group (top quartile: MBPS > or = 45 mm Hg, n = 24) than in the Nonsurge group (MBPS < 45 mm Hg, n = 74) (54% v 31%, P = .04), and in the higher alpha-adrenergic surge group (top quartile: alpha-adrenergic MBPS > or = 28 mm Hg, n = 25) than in the lower alpha-adrenergic surge group (< 28 mm Hg, n = 73) (68% v 26%, P < .0001). In the Surge group, subjects with higher alpha-adrenergic surge (n = 17) had a markedly higher frequency of multiple SCI, whereas none in the lower alpha-adrenergic surge group had multiple SCI (n = 7) (77% v 0%, P = .001). The alpha-adrenergic MBPS was closely associated with multiple SCI (10 mm Hg increase: OR = 1.96, P = .006), independently of age, MBPS, 24-h systolic BP, and other confounding factors. CONCLUSION: The morning BP surge, particularly that dependent on alpha-adrenergic activity, is closely associated with advanced silent hypertensive cerebrovascular disease in elderly individuals.     

Elevated blood viscosity in patients with borderline essential hypertension

In patients with borderline hypertension, total peripheral resistance (TPR) is either elevated or abnormally related to cardiac output. Since blood viscosity is one determinant of TPR, we compared various components of blood viscosity in 25 patients with borderline hypertension and 25 normal subjects. Under all experimental blood flow conditions examined, blood viscosity directly correlated with systolic and diastolic blood pressure (p less than 0.05 or better) and was greater in the hypertensive than in normal subjects. Venous hematocrit and plasma viscosity were higher in the hypertensive patients. These latter rheologic abnormalities accounted for the increased blood viscosity at higher shear rates. At lower shear rates, increased red cell aggregation, primarily mediated by elevated fibrinogen concentration, accounted for the higher blood viscosity in the hypertensive subjects. We conclude that even relatively small elevations in arterial pressure are associated with increased viscous resistance of blood to flow, and that the increased blood viscosity is a consequence of increased hematocrit, plasma viscosity, and red cell aggregation.     

Ultra‐deep T cell receptor sequencing reveals the complexity and intratumour heterogeneity of T cell clones in renal cell carcinomas

The recognition of cancer cells by T cells can impact upon prognosis and be exploited for immunotherapeutic approaches. This recognition depends on the specific interaction between antigens displayed on the surface of cancer cells and the T cell receptor (TCR), which is generated by somatic rearrangements of TCR α‐ and β‐chains (TCRb). Our aim was to assess whether ultra‐deep sequencing of the rearranged TCRb in DNA extracted from unfractionated clear cell renal cell carcinoma (ccRCC) samples can provide insights into the clonality and heterogeneity of intratumoural T cells in ccRCCs, a tumour type that can display extensive genetic intratumour heterogeneity (ITH). For this purpose, DNA was extracted from two to four tumour regions from each of four primary ccRCCs and was analysed by ultra‐deep TCR sequencing. In parallel, tumour infiltration by CD4, CD8 and Foxp3 regulatory T cells was evaluated by immunohistochemistry and correlated with TCR‐sequencing data. A polyclonal T cell repertoire with 367–16 289 (median 2394) unique TCRb sequences was identified per tumour region. The frequencies of the 100 most abundant T cell clones/tumour were poorly correlated between most regions (Pearson correlation coefficient, –0.218 to 0.465). 3–93% of these T cell clones were not detectable across all regions. Thus, the clonal composition of T cell populations can be heterogeneous across different regions of the same ccRCC. T cell ITH was higher in tumours pretreated with an mTOR inhibitor, which could suggest that therapy can influence adaptive tumour immunity. These data show that ultra‐deep TCR‐sequencing technology can be applied directly to DNA extracted from unfractionated tumour samples, allowing novel insights into the clonality of T cell populations in cancers. These were polyclonal and displayed ITH in ccRCC. TCRb sequencing may shed light on mechanisms of cancer immunity and the efficacy of immunotherapy approaches. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Hyperspectral imaging and spectral unmixing for improving whole-body fluorescence cryo-imaging

Whole-animal fluorescence cryo-imaging is an established technique that enables visualization of the biodistribution of labeled drugs, contrast agents, functional reporters and cells in detail. However, many tissues produce endogenous autofluorescence, which can confound interpretation of the cryo-imaging volumes. We describe a multi-channel, hyperspectral cryo-imaging system that acquires densely-sampled spectra at each pixel in the 3-dimensional stack. This information enables the use of spectral unmixing to isolate the fluorophore-of-interest from autofluorescence and/or other fluorescent reporters. In phantoms and a glioma xenograft model, we show that the approach improves detection limits, increases tumor contrast, and can dramatically alter image interpretation.     

Genetic deficiency of the second component of complement (C2) associated with systemic lupus erythematosus. Relation of the complement abnormality and disease manifestations.

Systemic lupus erythematosus (SLE) was documented in a patient with genetic deficiency of the second complement component (C2). A review of disease manifestations in this patient and in others with SLE and genetic C2 deficiency previously reported on suggest that many findings such as fever, skin lesions, central nervous system involvement, the presence of autoantibodies and leukopenia occur in patients with SLE independent of whether or not they have C2 deficiency. However, renal disease appears mild in patients with genetic C2 deficiency despite the presence of immunoglobulins and complement components demonstrated in glomeruli by immunofluorescent microscopy. Electron microscopic study of glomeruli from the patient we describe showed electron-dense deposits consistent with the immunofluorescent findings. Tubuloreticular inclusion bodies identical to those previously seen in patients with SLE were also observed. Analysis of serum complement components and tissue deposition of complement components suggests activation of both the classic and alternative complement pathways in patients with C2 deficiency. The clinical, pathologic and complement findings in this group of patients support the hypothesis that although SLE is similar in patients with and without C2 deficiency, renal disease remains mild when this classic pathway component is not present. Histocompatibility antigen analysis of the family of the propositus confirmed the association of C2 deficiency with an A10, B18 haplotype, and with a haplotype not previously associated with C2 deficiency, AW32, BW40. One sibling with this latter haplotype has normal C2 levels, presumably as a result of recombination.