Suprapubic versus transurethral catheterization for bladder drainage in male rectal cancer surgery (GRECCAR10), a randomized clinical trial.

BACKGROUND: Bladder drainage is systematically used in rectal cancer surgery; however, the optimal type of drainage, transurethral catheterization (TUC) or suprapubic catheterization (SPC), is still controversial. The aim was to compare the rates of urinary tract infection on the fourth postoperative day (POD4) between TUC and SPC, after rectal cancer surgery regardless of the day of removal of the urinary drain. METHODS: This randomized clinical trial in 19 expert colorectal surgery centers in France and Belgium was performed between October 2016 and October 2019 and included 240 men (with normal or subnormal voiding function) undergoing mesorectal excision with low anastomosis for rectal cancer. Patients were followed at postoperative days 4, 30, and 180. RESULTS: In 208 patients (median age 66 years [IQR 58-71]) randomized to TUC (n = 99) or SPC (n = 109), the rate of urinary infection at POD4 was not significantly different whatever the type of drainage (11/99 (11.1%) vs. 8/109 (7.3%), 95% CI, - 4.2% to 11.7%; p = 0.35). There was significantly more pyuria in the TUC group (79/99 (79.0%) vs. (60/109 (60.9%), 95% CI, 5.7-30.0%; p = 0.004). No difference in bacteriuria was observed between the groups. Patients in the TUC group had a shorter duration of catheterization (median 4 [2-5] vs. 4 [3-5] days; p = 0.002). Drainage complications were more frequent in the SPC group at all followup visits. CONCLUSIONS: TUC should be preferred over SPC in male patients undergoing surgery for mid and/or lower rectal cancers, owing to the lower rate of complications and shorter duration of catheterization. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02922647.

Assessment of arterial elasticity among HIV-positive participants with high CD4 cell counts: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.

OBJECTIVES: Both HIV infection and antiretroviral therapy (ART) may increase cardiovascular disease (CVD) risk. Assessments of vascular function and structure can be used to study the pathogenesis and progression of CVD, including the effects of ART and other interventions. The objective of this report is to understand methods to assess vascular (dys)function and report our experience in the Arterial Elasticity Substudy in the Strategic Timing of AntiRetroviral Treatment (START) trial. METHODS: We review literature and analyze baseline data from the Arterial Elasticity Substudy, which estimated vascular (dys)function through analysis of the diastolic blood pressure (BP) waveform. Linear regression was used to study cross-sectional associations between baseline clinical factors and small or large arterial elasticity. RESULTS: Arterial elasticity measurement was chosen for its improved measurement reproducibility over other methodologies and the potential of small arterial elasticity to predict clinical risk. Analysis of baseline data demonstrates that small artery elasticity is impaired (lower) with older age and differs by race and between geographical regions. No HIV-specific factors studied remained significantly associated with arterial elasticity in multivariate models. CONCLUSIONS: Longitudinal analyses in this substudy will provide essential randomized data with which to study the effects of early ART initiation on the progression of vascular disease among a diverse global population. When combined with future biomarker analyses and clinical outcomes in START, these findings will expand our understanding of the pathogenesis of HIV-related CVD.

Baseline cardiovascular risk in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.

OBJECTIVES: The Strategic Timing of AntiRetroviral Treatment (START) trial has recruited antiretroviral-naïve individuals with high CD4 cell counts from all regions of the world. We describe the distribution of cardiovascular disease (CVD) risk factors, overall and by geographical region, at study baseline. METHODS: The distribution of CVD risk factors was assessed and compared by geographical region among START participants who had a baseline electrocardiogram (n = 4019; North America, 11%; Europe/Australia/Israel, 36%; South America, 26%; Asia, 4%; Africa, 23%; median age 36 years; 26% female). RESULTS: About 58.3% (n = 2344) of the participants had at least one CVD risk factor and 18.9% (n = 761) had two or more. The most common CVD risk factors were current smoking (32%), hypertension (19.3%) and obesity (16.5%). There were significant differences in the prevalence of CVD risk factors among geographical regions. The prevalence of at least one risk factor across regions was as follows: North America, 70.0%; Europe/Australia/Israel, 65.1%; South America, 49.4%; Asia, 37.0%; Africa, 55.8% (P-value < 0.001). Significant regional differences were also observed when risk factors were used as part of the Framingham and Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) risk scores or used to define a favourable risk profile. CONCLUSIONS: CVD risk factors are common among START participants, and their distribution varies by geographical region. Better understanding of how and why CVD risk factors develop in people with HIV infection and their geographical distributions could shed light on appropriate strategies for CVD prevention and may inform the interpretation of the results of START, as CVD is expected to be a major fraction of the primary endpoints observed.

Serum vitamin C concentration is low in peripheral arterial disease and is associated with inflammation and severity of atherosclerosis.

BACKGROUND: Peripheral arterial disease (PAD) is a severe atherosclerotic condition frequently accompanied by inflammation and oxidative stress. We hypothesized that vitamin C antioxidant levels might be low in PAD and are related to inflammation and disease severity. METHODS AND RESULTS: We investigated vitamin C (L-ascorbic acid) levels in 85 PAD patients, 106 hypertensives without PAD, and 113 healthy subjects. Serum L-ascorbic acid concentrations were low among PAD patients (median, 27.8 micromol/L) despite comparable smoking status and dietary intake with the other groups (P<0.0001). Subclinical vitamin C deficiency (<11.4 micromol/L), confirmed by low serum alkaline phosphatase activity, was found in 14% of the PAD patients but not in the other groups. Serum C-reactive protein (CRP) concentrations were significantly higher in PAD patients (P<0.0001) and negatively correlated with L-ascorbic acid levels (r=-0.742, P<0.0001). In stepwise multivariate analysis, low L-ascorbic acid concentration in PAD patients was associated with high CRP level (P=0.0001), smoking (P=0.0009), and shorter absolute claudication distance on a standardized graded treadmill test (P=0.029). CONCLUSIONS: Vitamin C concentrations are lower in intermittent claudicant patients in association with higher CRP levels and severity of PAD. Future studies attempting to relate vitamin C levels to disease occurrence should include in their analysis an inflammatory marker such as CRP.

Paraxis is expressed in myoblasts during their migration and proliferation in the chick limb bud.

The Paraxis gene encodes a basic helix-loop-helix (bHLH) transcription factor expressed in paraxial mesoderm and whose mutant displays an inability to form epithelial somites. We analyzed the later expression pattern of Paraxis transcripts in the chick limb. Paraxis transcripts are located in the Pax3-expressing myoblasts migrating from the somites and persist in proliferating myoblasts in the limb bud. Moreover, the QH1 antibody, which recognizes quail endothelial cells, reacts with a subset of the Paraxis/Pax3 expressing cells in the quail limb. Paraxis is then down-regulated during muscle differentiation.

Fgf8 transcripts are located in tendons during embryonic chick limb development.

Fibroblast growth factor 8 (Fgf8) is a secreted growth factor involved in the initiation, outgrowth and patterning of vertebrate limbs (Genes Dev. 12 (1998) 1571). In this paper, we present a new site of expression of Fgf8 in the chick limb. Fgf8 transcripts are localised close to the muscle fibres, at the same level as the tendon-associated molecules, tenascin and scleraxis. Fgf8 is expressed in a sub-region of the tendons during limb development; its location being restricted to the area near the muscle. In addition, the restricted Fgf8 expression in the tendons allowed us to observe that the myogenic determination factor (MyoD) is not detected at the myotendinous junction.

BMP-2 induces ectopic expression of cardiac lineage markers and interferes with somite formation in chicken embryos.

In Drosophila induction of the homeobox gene tinman and subsequent heart formation are dependent on dpp signaling from overlying ectoderm. In order to define vertebrate heart-inducing signals we screened for dpp-homologues expressed in HH stage 4 chicken embryos. The majority of transcripts were found to be BMP-2 among several other members of the BMP family. From embryonic HH stage 4 onwards cardiogenic mesoderm appeared to be in close contact to BMP-2 expressing cells which initially were present in lateral mesoderm and subsequently after headfold formation in the pharyngeal endoderm. In order to assess the role of BMP-2 for heart formation, gastrulating chick embryos in New culture were implanted with BMP-2 producing cells. BMP-2 implantation resulted in ectopic cardiac mesoderm specification. BMP-2 was able to induce Nkx2-5 expression ectopically within the anterior head domain, while GATA-4 was also induced more caudally. Cardiogenic induction by BMP-2, however remained incomplete, since neither Nkx2-8 nor the cardiac-restricted structural gene VMHC-1 became ectopically induced. BMP-2 expressing cells implanted adjacent to paraxial mesoderm resulted in impaired somite formation and blocked the expression of marker genes, such as paraxis, Pax-3, and the forkhead gene cFKH-1. These results suggest that BMP-2 is part of the complex of cardiogenic signals and is involved in the patterning of early mesoderm similar to the role of dpp in Drosophila.

Sonic hedgehog (SHH) specifies muscle pattern at tissue and cellular chick level, in the chick limb bud.

Development of the musculature in chick limbs involves tissue and cellular patterning. Patterning at the tissue level leads to the precise arrangement of specific muscles; at the cellular level patterning gives rise to the fibre type diversity in muscles. Although the data suggests that the information controlling muscle patterning is localised within the limb mesenchyme and not in the somitic myogenic precursor cells themselves, the mechanisms underlying muscle organisation have still to be elucidated. The anterior-posterior axis of the limb is specified by a group of cells in the posterior region of the limb mesenchyme, called the zone of polarizing activity (ZPA). When polarizing-region cells are grafted to the anterior margin of the bud, they cause mirror-image digit duplications to be produced. The effect of ZPA grafts can be reproduced by application of retinoic acid (RA) beads and by grafting sonic hedgehog (SHH)-expressing cells to the anterior margin of the limb. Although most previous studies have looked at changes of the skeletal patterning, ZPA and RA also affect muscle patterning. In this report, we investigated the role of SHH in tissue and cellular patterning of forearm wing muscles. Ectopic application of a localised source of SHH to the anterior margin of the wing, leading to complete digit duplication, is able to transform anterior forearm muscles into muscles with a posterior identity. Moreover, the ectopic source of SHH induces a mirror image duplication of the normal posterior muscles fibre types in the new posterior muscles. The reorganisation of the slow fibres can be detected before muscle mass cleavage has started; suggesting that the appropriate fibre type arrangement is in place before the splitting process can be observed.

Overexpression of BMP-2 and BMP-4 alters the size and shape of developing skeletal elements in the chick limb.

Bone morphogenetic proteins are members of the transforming growth factor beta (TGF beta) superfamily which are involved in a range of developmental processes including modelling of the skeleton. We show here that Bmp-2 is expressed in mesenchyme surrounding early cartilage condensations in the developing chick limb, and that Bmp-4 is expressed in the perichondrium of developing cartilage elements. To investigate their roles during cartilage development, BMP-2 and BMP-4 were expressed ectopically in developing chick limbs using retroviral vectors. Over-expression of BMP-2 or BMP-4 led to a dramatic increase in the volume of cartilage elements, altered their shapes and led to joint fusions. This increase in volume appeared to result from an increase in the amount of matrix and in the number of chondrocytes. The latter did not appear to be due to increased proliferation of chondrocytes, suggesting that it may result from increased recruitment of precursors. BMP-2 and BMP-4 also delayed hypertrophy of chondrocytes and formation of the osteogenic periosteum. These data provide insights into how BMP-2 and BMP-4 may model and control the growth of skeletal elements during normal embryonic development, suggesting roles for both molecules in recruiting non-chondrogenic precursors to chondrogenic fate.

Expression of Frzb-1 during chick development.

We cloned the chick homolog of Xenopus and mouse Frzb-1, a secreted Wnt antagonist and performed in situ hybridizations to determine the pattern of cFrzb-1 expression in the developing chick embryo. At early stages, cFrzb-1 transcripts are located exclusively in the ectodermal layer corresponding to the neural plate. The labelling continues in the neural tube, but is always excluded from the floor plate. cFrzb-1 mRNA is expressed by migrating cephalic and truncal neural crest cells. Later, cFrzb-1 transcripts are found in a subset of neural crest derivatives such as cephalic cartilage, nerves and spinal ganglia. In addition to ectodermal derivatives, cFrzb-1 transcripts were also observed in mesodermal derivatives such as vertebral and limb cartilage, the adrenal cortex, the gonads, and a subpopulation of blood cells.

Relationship between C-reactive protein and arterial stiffness in an asymptomatic population.

Plasma concentration of high sensitive C-reactive protein (hsCRP) is used as a marker for inflammatory states and is directly correlated with the risk for coronary heart disease. Evidence concerning the role of inflammation in atheroma formation has been derived from several models of atherosclerosis. Inflammation should exert its adverse vascular effects by structural changes in the artery wall and consequently alterations in arterial elasticity, which could be detected already in asymptomatic early vascular disease. We hypothesized that CRP is related to large artery elasticity, but not to small artery elasticity in early vascular disease. Therefore, we examined the association between arterial stiffness of large and small arteries and inflammation in an asymptomatic population referred for primary prevention cardiovascular screening. Studies were performed in 391 subjects (age 21-82 years; 254 men, 137 women) who underwent screening at the Cardiovascular Disease Prevention Center. Large artery (C1) and small artery (C2) elasticity indices were obtained by the CVProfiler 2000 (HDI, Eagan, MN, USA). After overnight fasting, venous samples were taken for measurement of hsCRP, lipids, glucose. There was a significant inverse correlation between hsCRP (0.29 +/- 0.40 mg/dl) and C1 (16.7 +/- 5.8 ml/mmHg), r = -0.133, P = 0.01; there was no significant correlation between hsCRP and C2 (6.6 +/- 3.2 ml/mmHg). C2, but not hsCRP, was inversely correlated with age, abnormal lipids and glucose, whereas C1, but not hsCRP, was inversely correlated with age and systolic blood pressure (SBP). In multiple regression analysis, the relationship between hsCRP and C1 was not affected by age, body mass index, SBP, serum glucose or lipids. In conclusion, these findings support the hypothesis that hsCRP, a marker for acute and low-grade inflammation, is associated with large artery but not with small artery elasticity in asymptomatic individuals undergoing primary prevention cardiovascular screening.

Localization of RIHB (retinoic acid-induced heparin-binding factor) transcript and protein during early chicken embryogenesis and in the developing wing.

Previously, we isolated an avian protein which we named retinoic acid induced heparin binding factor (RIHB). RIHB is a 121 amino acid secreted polypeptide, rich in basic and cysteine residues (Vigny et al., Eur. J. Biochem. 186: 733-740, 1989). Northern blot analysis indicates that the RIHB gene is transiently expressed during embryogenesis (Urios et al., Biochem. Biophys. Res. Com. 175:617-624, 1991). Here we present an investigation of RIHB expression during early chicken embryogenesis by in situ hybridization and immunofluorescence studies. In the 3-day embryo (stage 20-21), the RIHB transcript is observed throughout the embryo, with the notable exception of the neural tube. At this stage the protein can be visualized in almost all of the basement membranes and around many types of cells. The localization of the RIHB protein does not strictly parallel that of its messenger. Between days 3 and 11 we focused our attention on wing development. The level of both the mRNA and protein decreases during this period but the disappearance is not uniform. The level of both the mRNA and protein decreases during this period but the disappearance is not uniform. The transcript becomes progressively restricted to epithelia and regions surrounding the forming cartilage. In contrast to the transcript, the protein accumulates in the epithelial basement membrane and, interestingly, in the central part of the embryonic cartilage (diaphysis) but not in the distal parts (epiphysis). These data are discussed in relation to the putative role(s) of RIHB in development.

HB-GAM/pleiotrophin: localization of mRNA and protein in the chicken developing leg.

The heparin-binding growth-associated molecule HB-GAM (also named pleiotrophin) is a developmentally-regulated protein that belongs to a new family of heparin-binding molecules with putative functions during cell growth and differentiation. In order to study the localization of HB-GAM during chicken embryogenesis, we produced specific monoclonal antibodies to this factor. HB-GAM protein is first observed at stage 23 in the developing nervous system and later in the forming cartilage. We present an investigation of the HB-GAM mRNA expression and HB-GAM protein distribution in the developing leg by in situ hybridization and immunocytochemical studies. We focused our attention on the development of the tibia, where the HB-GAM protein appears at stage 27-28, i.e., just after the condensation of the mesodermal precursor cells of the chondrocytes. The protein then progressively accumulates in the central part of the embryonic cartilage (diaphysis). It persists until stage 42-44 in the regions where hypertrophic cartilage is being replaced by bone marrow. In contrast to the protein, the transcript is first detected at stage 26-27 and later expressed essentially in the epiphysis until stage 37. Therefore the localization of the mRNA does not parallel that of the protein and our data suggest a long half-life of the protein in the hypertrophic cartilage. In addition, the layer of stacked cells surrounding the cartilage core (usually considered as the osteoprogenitor cells) clearly expresses the HB-GAM message between stages 30-37 whereas differentiated osteoblasts do not. Furthermore, the distribution of HB-GAM protein in the osteoblast/osteoid layer suggests an involvement of this protein in early steps of osteogenesis. HB-GAM is absent from the newly formed bone.

Changes in N-terminal pro-B-type natriuretic peptide and incidence of diabetes: The Multi-Ethnic Study of Atherosclerosis (MESA).

AIMS: This study looked at whether the inverse association of circulating N-terminal pro-B-type natriuretic peptide (NT-proBNP) with incident diabetes is modified by changes in NT-proBNP (ΔNT-proBNP) levels. METHODS: Plasma NT-proBNP was assayed at baseline and 3.2 years later (visit 3) in the Multi-Ethnic Study of Atherosclerosis (MESA). ΔNT-proBNP was calculated as NT-proBNP visit3-NT-proBNP baseline. A Poisson distribution was fitted to determine the incidence density of diabetes, adjusted for age, race, gender, educational attainment, antihypertensive medication, total intentional exercise and plasma IL-6 levels. In the primary analysis (n=3236 without diabetes up to visit 3, followed for a mean of 6.3 years), incidence density was regressed for the following categories of baseline NT-proBNP: (1)<54.4 pg/mL; (2) 54.4-85.9 pg/mL; and (3) 86-54.2 pg/mL. This was crossed with categories of ΔNT-proBNP as medians (ranges): (1) -6.2 (-131-11.7) pg/mL; (2) 19.8 (11.8-30.1) pg/mL; (3) 44.0 (30.2-67.9) pg/mL; and (4) 111.2 (68.0-3749.9) pg/mL. RESULTS: The incidence density of diabetes followed a U-shaped association across categories of ΔNT-proBNP within categories of baseline NT-proBNP after adjusting for other covariates (P=0.02). At each level of baseline NT-proBNP, the incidence density of diabetes was lowest for small-to-moderate increases in NT-proBNP. CONCLUSION: This analysis suggests that NT-proBNP has a biphasic association with diabetes in which the risk of incident diabetes decreases within a 'physiological range' of ΔNT-proBNP, and plateaus or increases as NT-proBNP concentrations increase, probably in response to pathophysiological conditions leading to high levels of NT-proBNP.

Alcohol-induced hypertension: an important healthcare target in Belgium.

Excessive alcohol intake is one of the leading causes of premature death in Europe and particularly in Belgium. Belgian people are consuming more alcohol per year than the European average. It is well established that excessive alcohol consumption is a significant predictor of the development of hypertension (HTN). Two million adults in Belgium suffer from HTN and this number will increase to three million by 2025. Less than 50% of Belgian people treated for HTN are well-controlled. Alcohol reduction in patients with HTN can significantly lower systolic and diastolic blood pressure. After reviewing the epidemiology of HTN and alcohol disorders in Belgium, this paper will focus on the rationale for alcohol screening and brief intervention in primary care. It will also describe the barriers to alcohol screening, and what could be the benefits of alcohol screening for our healthcare system. The authors believe that early identification through alcohol screening and brief intervention in general practice can help to improve the management of patients with HTN, to reach the targets of the WHO Global Action Plan, i.e., a 25% relative reduction in the risk of premature mortality from cardiovascular diseases, cancer, diabetes or chronic respiratory diseases. They are also convinced that this would allow achieving major healthcare savings.

Circulatory changes in muscle and skin arteries in primary hypertension.

This review deals with circulatory adjustments occurring in the limb arteries of hypertensive patients. Measurements of regional blood flow are mandatory, because conclusions drawn from calculated total peripheral resistance often are not applicable to local vascular beds. Limb arteries, which can be followed by easy and noninvasive methods, often are the first choice for study of regional circulation. In this discussion, a few historic studies are cited first; next, the data available on skeletal muscle (forearm and calf) and skin (finger) circulation are reviewed, to show that flow through both muscle and skin is increased in mild and moderate hypertension, while there is a trend to lower values in more severe hypertension. Our own data are derived from 51 untreated patients showing mild to moderate hypertension, matched to 23 normotensive subjects. Flow is measured simultaneously with an ECG-triggered venous occlusion plethysmograph at calf and finger. At rest, calf and finger blood flows are significantly higher and calculated resistance is lower in hypertensive subjects; during reactive hyperemia, blood flow remains higher in hypertensive subjects but calculated resistance increases up to values that are higher, compared to normotensive control subjects; these data are compatible with structural changes in the vascular wall.

Haptoglobin polymorphism and peripheral arterial occlusive disease.

Haptoglobin (Hp) 2-2 phenotype is a genetic risk factor in coronary atherosclerosis. In this study, haptoglobin phenotypes were determined in 141 patients with peripheral arterial occlusive disease (PAOD) and compared to a reference population (n = 1000). The relative Hp1 allele frequency was decreased among PAOD patients (0.294 vs. 0.403 for the reference population, P < 0.01) due to an overrepresentation of the Hp 2-2 phenotype (50%, odds ratio 1.82 (95% C.I. 1.28-2.60), P < 0.001). This finding was even more pronounced in non-diabetic and in non-smoking PAOD patients (Hp1 allele frequencies: 0.265 and 0.228, respectively). Serum lipids, inflammatory parameters, and blood pressure levels were comparable among the Hp phenotypes, but serum levels of the antioxidant vitamin C were lower in Hp 2-2 patients than in patients with another phenotype (P < 0.05). In PAOD patients with severe atherosclerotic lesions, maximal walking distance of patients carrying a Hp 2-2 phenotype (225-525 m) exceeded that of other Hp phenotypes (50-242 m) (interquartile ranges) (P < 0.05). The findings demonstrate that, despite an increased risk for developing PAOD, the Hp 2-2 phenotype is associated with a longer maximal walking distance which might be attributed to the earlier reported in vitro angiogenic properties of the Hp 2-2 molecule.

Impaired microcirculation in mild-to-moderate essential arterial hypertension.

OBJECTIVE: The aim of this study was to correlate capillary morphology and erythrocyte velocity to blood pressure in mild-to-moderate essential arterial hypertension. DESIGN: Ambulatory blood pressure measurement may provide more precise information about a patient's mean blood pressure than office measurements. METHODS: Fifteen patients with recently diagnosed, previously untreated mild-to-moderate essential hypertension underwent 24-h ambulatory blood pressure recording and a capillaroscopic examination of finger microcirculation. Erythrocyte velocity was determined by the flying spot technique. RESULTS: Both mean 24-h ambulatory systolic blood pressure (SBP) and mean 24-h ambulatory diastolic blood pressure (DBP) were significantly inversely correlated with capillary erythrocyte velocity. However, the correlation between erythrocyte velocity and office SBP and office DBP was less significant. Capillary length was related to 24-h ambulatory DBP but not to office DBP. Capillary number was not related to any blood pressure parameter. CONCLUSIONS: These results indicate that, in patients with mild-to-moderate essential hypertension, erythrocyte velocity is significantly lower than for matched controls. It is also inversely related to mean 24-h ambulatory SBP and 24-h ambulatory DBP.