In a registry study of 63,910 adults, 24-hour ambulatory BP was a stronger predictor of mortality than BP measured in the clinic. Masked hypertension (normal BP in the clinic but elevated ambulatory ...BP) was associated with a greater risk of death than sustained hypertension.
Ribosomes are the highly complex macromolecular assemblies dedicated to the synthesis of all cellular proteins from mRNA templates. The main principles underlying the making of ribosomes are ...conserved across eukaryotic organisms and this process has been studied in most detail in the yeast Saccharomyces cerevisiae. Yeast ribosomes are composed of four ribosomal RNAs (rRNAs) and 79 ribosomal proteins (r-proteins). Most r-proteins need to be transported from the cytoplasm to the nucleus where they get incorporated into the evolving pre-ribosomal particles. Due to the high abundance and difficult physicochemical properties of r-proteins, their correct folding and fail-safe targeting to the assembly site depends largely on general, as well as highly specialized, chaperone and transport systems. Many r-proteins contain universally conserved or eukaryote-specific internal loops and/or terminal extensions, which were shown to mediate their nuclear targeting and association with dedicated chaperones in a growing number of cases. The 60S r-protein Rpl4 is particularly interesting since it harbours a conserved long internal loop and a prominent C-terminal eukaryote-specific extension. Here we show that both the long internal loop and the C-terminal eukaryote-specific extension are strictly required for the functionality of Rpl4. While Rpl4 contains at least five distinct nuclear localization signals (NLS), the C-terminal part of the long internal loop associates with a specific binding partner, termed Acl4. Absence of Acl4 confers a severe slow-growth phenotype and a deficiency in the production of 60S subunits. Genetic and biochemical evidence indicates that Acl4 can be considered as a dedicated chaperone of Rpl4. Notably, Acl4 localizes to both the cytoplasm and nucleus and it has the capacity to capture nascent Rpl4 in a co-translational manner. Taken together, our findings indicate that the dedicated chaperone Acl4 accompanies Rpl4 from the cytoplasm to its pre-60S assembly site in the nucleus.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The development of collagen hydrogels with tailored properties for improved applications in biomedicine represents an area of opportunity for materials science. The collagen can form ...semi‐interpenetrated networks (semi‐IPN) with various natural and/or synthetic polymers. This work aims the preparation of novel hydrogels generated from a collagen matrix cross‐linked with polyurethane (PU), and the subsequent inclusion of polysaccharide chains to form semi‐IPN systems with improved properties. The choice of polysaccharides for this purpose is related to their ability to modulate the biocompatibility and the antibacterial capacity in various biomedical strategies. The work contemplates to study the effect of the chemical structure of polysaccharide (hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC) or starch (Alm)) on the properties of these novel hydrogels. The results indicate that the semi‐IPN hydrogels that include Alm exhibit the formation of stronger intermolecular interactions promoted by hydrogen bonds than HEC and HPMC, significantly improving the mechanical properties and their degradation rate in acidic, alkaline, and proteolytic media; also showing high capacity to inhibit the growth of E. colli. The semi‐IPN hydrogels based on HEC and HPMC exhibit excellent improvement in both thermal and proteolytic degradation, compared with the collagen‐PU matrix. On the other hand, this semi‐IPN system does not present cytotoxic character for monocytes and fibroblasts growing for up to 48 h of culture. Therefore, these innovative 3D matrices will be excellent candidates with potential application in biomedical strategies such as wound healing dressings.
There are limited data on the quality of treated blood pressure (BP) control during normal daily life, and in particular, the prevalence of 'masked uncontrolled hypertension' (MUCH) in people with ...treated and seemingly well-controlled BP is unknown. This is important because masked hypertension in 'treatment naïve' patients is associated with a high risk of cardiovascular events. We therefore conducted the first study to define the prevalence and characteristics of MUCH among a large sample of hypertensive patients in routine clinical practice in whom BP was treated and controlled to recommended clinic BP goals.
We analysed data from the Spanish Society of Hypertension ambulatory blood pressure monitoring (ABPM) Registry and identified patients with treated and controlled BP according to current international guidelines (clinic BP <140/90 mmHg). Masked uncontrolled hypertension was diagnosed in these patients if despite controlled clinic BP, the mean 24-h ABPM average remained elevated (24-h systolic BP ≥130 mmHg and/or 24-h diastolic BP ≥80 mmHg). From 62 788 patients with treated BP in the Spanish registry, we identified 14 840 with treated and controlled clinic BP, of whom 4608 patients (31.1%) had MUCH according to 24-h ABPM criteria (mean age 59.4 years, 59.7% men). The prevalence of MUCH was significantly higher in males, patients with borderline clinic BP (130-9/80-9 mmHg), and patients at high cardiovascular risk (smokers, diabetes, obesity). Masked uncontrolled hypertension was most often because of poor control of nocturnal BP, with the proportion of patients in whom MUCH was solely attributable to an elevated nocturnal BP almost double that solely attributable to daytime BP elevation (24.3 vs. 12.9%, P < 0.001).
The prevalence of masked suboptimal BP control in patients with treated and well-controlled clinic BP is high. Clinic BP monitoring alone is thus inadequate to optimize BP control because many patients have an elevated nocturnal BP. These findings suggest that ABPM should become more routine to confirm BP control, especially in higher risk groups and/or those with borderline control of clinic BP.
We aimed to estimate the prevalence of resistant hypertension through both office and ambulatory blood pressure monitoring in a large cohort of treated hypertensive patients from the Spanish ...Ambulatory Blood Pressure Monitoring Registry. In addition, we also compared clinical features of patients with true or white-coat-resistant hypertension. In December 2009, we identified 68 045 treated patients with complete information for this analysis. Among them, 8295 (12.2% of the database) had resistant hypertension (office blood pressure ≥140 and/or 90 mm Hg while being treated with ≥3 antihypertensive drugs, 1 of them being a diuretic). After ambulatory blood pressure monitoring, 62.5% of patients were classified as true resistant hypertensives, the remaining 37.5% having white-coat resistance. The former group was younger, more frequently men, with a longer duration of hypertension and a worse cardiovascular risk profile. The group included larger proportions of smokers, diabetics, target organ damage (including left ventricular hypertrophy, impaired renal function, and microalbuminuria), and documented cardiovascular disease. Moreover, true resistant hypertensives exhibited in a greater proportion a riser pattern (22% versus 18%; P<0.001). In conclusion, this study first reports the prevalence of resistant hypertension in a large cohort of patients in usual daily practice. Resistant hypertension is present in 12% of the treated hypertensive population, but among them more than one third have normal ambulatory blood pressure. A worse risk profile is associated with true resistant hypertension, but this association is weak, thus making it necessary to assess ambulatory blood pressure monitoring for a correct diagnosis and management.
Phenylcapsaicin (PC) is a new capsaicin analog which has exhibited a higher bioavailability. This sudy assessed the effects of a low dose (LD) of 0.625 mg and a high dose (HD) of 2.5 mg of PC on ...aerobic capacity, substrate oxidation, energy metabolism and exercise physiological variables in young males.
Seventeen active males (age = 24.7 ± 6.0 years) enrolled to this randomized, triple-blinded, placebo-controlled, crossover trial. Participants attended the laboratory on 4 sessions separated by 72-96 h. A submaximal exercise test to determine maximal fat oxidation (MFO) and the intensity at MFO (FATmax) followed by a maximal incremental test (to determine VO2
) were performed in a preliminary session. The subsequent sessions only differed in the supplement ingested LD, HD or placebo (PLA) and consisted of a steady-state test (60 min at FATmax) followed by a maximal incremental test. Energy metabolism, substrate oxidation, heart rate, general (gRPE) and quadriceps (RPEquad) rate of perceived exertion, skin temperature and thermal perception were tested.
Clavicle thermal perception was lower in HD compared to PLA and LD (
= 0.04) across time. HD reduced maximum heart rate in comparison to PLA and LD (
= 0.03). LD reported higher general RPE (RPEg) values during the steady-state test compared to PLA and HD across time (
= 0.02). HD and LD elicited higher peak of fat oxidation during the steady-state test compared with PLA (
= 0.05). Intra-test analyses revealed significant differences for fat oxidation (FATox) in favor of HD and LD compared to PLA (
0.002 and 0.002, respectively), and for carbohydrate oxidation (CHOox) (
0.05) and respiratory exchange ratio (RER) (
0.03) for PLA. In the incremental test, only general RPE at 60% of the maximal intensity (W) differed favoring HD (
≤ 0.05).
Therefore, PC may contribute to increase aerobic capacity through the improvement of fat oxidation, maximum heart rate and perceptual responses during exercise.
Nighttime blood pressure (BP) and albuminuria are two important and independent predictors of cardiovascular morbidity and mortality. Here, we examined the quantitative differences in nighttime ...systolic BP (SBP) across albuminuria levels in patients with and without diabetes and chronic kidney disease.
A total of 16,546 patients from the Spanish Ambulatory Blood Pressure Monitoring Registry cohort (mean age 59.6 years, 54.9% men) were analyzed. Patients were classified according to estimated glomerular filtration rate (eGFR), as ≥60 or <60 mL/min/1.73 m(2) (low eGFR), and urine albumin-to-creatinine ratio, as normoalbuminuria (<30 mg/g), high albuminuria (30-300 mg/g), or very high albuminuria (>300 mg/g). Office and 24-h BP were determined with standardized methods and conditions.
High albuminuria was associated with a statistically significant and clinically substantial higher nighttime SBP (6.8 mmHg higher than with normoalbuminuria, P < 0.001). This association was particularly striking at very high albuminuria among patients with diabetes and low eGFR (16.5 mmHg, P < 0.001). Generalized linear models showed that after full adjustment for demographic, lifestyles, and clinical characteristics, nighttime SBP was 4.8 mmHg higher in patients with high albuminuria than in those with normoalbuminuria (P < 0.001), and patients with very high albuminuria had a 6.1 mmHg greater nighttime SBP than those with high albuminuria (P < 0.001). These differences were 3.8 and 3.1 mmHg, respectively, among patients without diabetes, and 6.5 and 8 mmHg among patients with diabetes (P < 0.001).
Albuminuria in hypertensive patients is accompanied by quantitatively striking higher nighttime SBP, particularly in those with diabetes with very high albuminuria and low eGFR.
Ribosomal protein L3 is an evolutionarily conserved protein that participates in the assembly of early pre-60S particles. We report that the rpl3W255C allele, which affects the affinity and function ...of translation elongation factors, impairs cytoplasmic maturation of 20S pre-rRNA. This was not seen for other mutations in or depletion of L3 or other 60S ribosomal proteins. Surprisingly, pre-40S particles containing 20S pre-rRNA form translation-competent 80S ribosomes, and translation inhibition partially suppresses 20S pre-rRNA accumulation. The GTP-dependent translation initiation factor Fun12 (yeast eIF5B) shows similar in vivo binding to ribosomal particles from wild-type and rpl3W255C cells. However, the GTPase activity of eIF5B failed to stimulate processing of 20S pre-rRNA when assayed with ribosomal particles purified from rpl3W255C cells. We conclude that L3 plays an important role in the function of eIF5B in stimulating 3' end processing of 18S rRNA in the context of 80S ribosomes that have not yet engaged in translation. These findings indicate that the correct conformation of the GTPase activation region is assessed in a quality control step during maturation of cytoplasmic pre-ribosomal particles.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVE:Increased BP-variability predicts cardiovascular morbidity and mortality in hypertensives. This study aimed to examine short-term BP-variability according to renal function stage.
...METHODS:We included 16 546 patients 10 270 (62.1%) without/6276 (38.9%) with CKD Stage 1–5 from the Spanish Ambulatory-Blood-Pressure Monitoring (ABPM) Registry. Stages of CKD were defined according to K/DIGO criteria, based on estimated glomerular filtration rate calculated with the CKD-EPI equation and albumin-to-creatine ratio. BP-variability was assessed with standard deviation (SD), weighted SD (wSD), coefficient of variation (CV), and average real variability (ARV).
RESULTS:Compared with those without CKD, a lower proportion of CKD patients were dippers (51.9 versus 39.6%; P < 0.001). Across CKD stages, a progressive decrease in dipper (from 39.1 to 20.4%; P < 0.001) and increase in riser proportion (from 12.3 to 36.7%; P < 0.001) were noted. Patients with CKD had significantly higher SBP SD, wSD, CV and ARV and lower DBP SD compared with those without CKD (P < 0.001). Within CKD Stages, an increasing trend from Stage 1 towards Stage 5 was observed for SBP SD (from 13.8 ± 3.7 to 15.6 ± 5.4 mmHg), wSD (from 12.0 ± 3.2 to 13.9 ± 5.1 mmHg), CV (from 10.4 ± 2.7 to 11.5 ± 4.1%), ARV (from 9.9 ± 2.3 to 11.4 ± 3.2 mmHg); P < 0.001 for all comparisons. DBP SD (P < 0.001), wSD and ARV (P = 0.002) were slightly decreasing, whereas DBP CV increased from Stage 1 to Stage 4 (P < 0.001). In multivariate analysis, male gender, older age, abdominal obesity, diabetes, number of antihypertensive medications, and clinic SBP were independent factors for higher SBP 24-h ARV in CKD.
CONCLUSION:An increase in short-term SBP-variability was present with advancing CKD stages in a large cohort. This increased SBP-variability may be involved in the sharp elevation of cardiovascular risk with worsening renal function.
Patients with coronary heart disease (CHD) can be particularly susceptible to the adverse effects of excessive blood pressure (BP) lowering by antihypertensive treatment. The identification of ...hypotension is thus especially important. This study estimated the prevalence of hypotension among CHD-treated hypertensive patients undergoing ambulatory blood pressure monitoring (ABPM) in routine clinical practice. We performed a cross-sectional study with 2892 CHD-treated hypertensive patients from the Spanish ABPM Registry. Based on previous studies, hypotension was defined as systolic/diastolic BP < 120 and/or 70 mmHg according to office measurements, <115 and/or 65 mmHg according to daytime ABPM, <100 and/or 50 mmHg according to nighttime ABPM, and <110 and/or 60 mmHg according to 24 h ABPM. The participants' mean age was 67.1 years (69.8% men). A total of 19.6% of the patients had office hypotension, 26.5% had daytime hypotension, 9.0% had nighttime hypotension, and 16.1% had 24-hr ABPM hypotension. Low diastolic BP values were responsible for most cases of hypotension. Fifty-eight percent of the cases of hypotension detected by daytime ABPM did not correspond to hypotension according to office BP. The variables independently associated with daytime ambulatory systolic/diastolic hypotension and diastolic hypotension (the latter being the most frequent type of ambulatory hypotension) were age, female sex, and the number of antihypertensive medications. In conclusion, in a large ABPM registry, one out of every four CHD-treated hypertensive patients was potentially at risk because of hypotension according to daytime ABPM, and more than half of them were not identified if office BP was relied on alone. We suggest that ABPM should be performed in these patients.
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