High Blood Pressure States in Children, Adolescents, and Young Adults Associate Accelerated Vascular Aging, with a Higher Impact in Females' Arterial Properties.

The aims of the study were to determine (1) whether the presence of High blood pressure (HBP) states in the youth associate a steeper rate of age-related change in arterial geometrical and wall properties with respect to subjects with no previous cardiovascular risk factor (CRF) exposure, (2) in which parameters and in what magnitude, and (3) the existence of a gender-related difference in the impact of this condition on arterial properties. 300 individuals (mean/range: 15/4-29 years; 133 females) were included. Two groups were assembled: (1) Reference: nonprevious exposure to traditional CRF and (2) HBP: subjects with arterial hypertension and/or elevated blood pressure (BP) levels during the study. Additionally, HBP subjects were separated in BP-related subgroups. Measured parameters were (1) central (aortic) arterial BP and aortic pulse wave analysis parameters, (2) carotid and femoral artery local (pressure-strain elastic modulus) and regional (pulse wave velocity; PWV) stiffness, and (3) arterial diameters and carotid intima-media thickness (CIMT). Age-related changes in these parameters (absolute values and z-scores) were explored by obtaining simple linear regression models for each group. HBP presented a steeper rate of change (accelerated vascular aging; VA) for most of the parameters assessed, mainly in central (aortic) hemodynamics. VA increased as the HBP level got higher. Both males' and females' aging rates were affected by this condition, but females presented a more marked relative age-related increase with HBP exposure. HBP states in the youth gradually associate accelerated VA, with a progressive hemodynamic-structural-functional onset of damage, with females presenting a more marked relative HBP-associated arterial repercussion.

Systems for Paediatric Sepsis: A Global Survey.

OBJECTIVES: To evaluate the resources available for early diagnosis and treatment of paediatric sepsis at hospitals in developing and developed countries. METHODS: This was a voluntary online survey involving 101 hospitals from 41 countries solicited through the World Federation of Pediatric Intensive and Critical Care Societies contact list and website. The survey was designed to assess the spectrum of sepsis epidemiology, patterns of applied therapies, availability of resources and barriers to optimal sepsis treatment. RESULTS: Ninety per cent of respondents represented a tertiary or general hospital with paediatric intensive care facilities, including 63% from developed countries. Adequate triage services were absent in more than 20% of centres. Insufficiently trained personnel and lack of a sepsis protocol was reported in 40% of all sites. While there were specific guidelines for sepsis management in 78% of centres (n = 100), protocols for assessing sepsis patients were not applied in nearly 70% of centres. Lack of parental recognition of sepsis and failure of referring centres to diagnose sepsis were identified as major barriers by more than 50% of respondents. CONCLUSIONS: Even among centres with no significant resource constraints and advanced medical systems, significant deficits in sepsis care exist. Early recognition and management remain a key issue and may be addressed through improved triage, augmented support for referring centres and public awareness. Focussed research is necessary at the institutional level to identify and address specific barriers.

[Assessment and management of chronic cough in adults]. / Toux chronique de l'adulte: evaluation et prise en charge.

Chronic cough is one of the most common symptoms for which outpatient care is sought. The most frequent causes are upper airway cough syndrome, asthma, and gastroesophageal reflux. It is often difficult to determine the origin of chronic cough based on the medical history and physical examination. Empirical treatment directed at the three aforementioned etiologies is thus of considerable value in the initial workup. Treatment failure is most commonly due to insufficient treatment (dosage or duration) or to the coexistence of several causes needing simultaneous use of different drugs.

[Bronchiectasis: diagnostic workup]. / Bronchiectasies chez l'adulte: recherche d'une étiologie.

Bronchiectasis is a condition defined by permanent dilation of the bronchi, either idiopathic or associated with other disease states. Diagnostic workup for bronchiectasis is essential in determining management and treatment. For diffuse bronchiectasis, we propose a workup plan that includes testing for humoral immunodeficiency by measuring serum IgG and anti-pneumococcal antibodies, looking for primary ciliary dyskinesia by exhaled nasal NO and cytologic brush biopsy of the nasal mucosa, looking for cystic fibrosis by chloride sweat testing and genotyping, evaluation for allergic bronchopulmonary aspergillosis, and testing for alpha-1-antitrypsin deficiency. Workup studies should be guided by the patient's history and clinical context.

Increased oxidative stress in children with post infectious Bronchiolitis Obliterans.

BACKGROUND: There is increasing evidence that oxidative stress is involved in the development and severity of bronchiolitis obliterans occurring in post-transplant patients. In developing countries, the most common form of bronchiolitis obliterans occurs after severe lung infection, mainly caused by adenovirus. However, the oxidative status in the lungs of children with post infectious bronchiolitis obliterans is unknown. METHODS: The aim of this study was to measure the oxidant (8-isoprostane and protein carbonyls) and antioxidant (catalase and glutathione peroxidase) activity in the bronchoalveolar lavage fluid of 21 children with post-infectious bronchiolitis obliterans, and to correlate oxidant/antioxidant level with lung function. Lung function was assessed by spirometry and plethysmography, one week prior to fiberbronchoscopy. RESULTS: There was a markedly increased oxidative stress (lipid and protein oxidation) in the bronchoalveolar lavage fluid, and a notorious impairment of lung function demonstrating moderate-severe distal airway narrowing. There was not a significant correlation between the level of oxidants or antioxidants and lung function. There was a consistent antioxidants/oxidants pattern characterised by markedly increased 8-isoprostane and carbonyls, increased GPx and normal catalase activity. CONCLUSION: The present study shows for the first time that children with post-infectious bronchiolitis obliterans have a markedly increased oxidative stress in their lungs.

Differential regulation of prohormone convertase 1/3, prohormone convertase 2 and phosphorylated cyclic-AMP-response element binding protein by short-term and long-term morphine treatment: implications for understanding the "switch" to opiate addiction.

Drug addiction is a state of altered brain reward and self-regulation mediated by both neurotransmitter and hormonal systems. Although an organism's internal system attempts to maintain homeostasis when challenged by exogenous opiates and other drugs of abuse, it eventually fails, resulting in the transition from drug use to drug abuse. We propose that the attempted maintenance of hormonal homeostasis is achieved, in part, through alterations in levels of processing enzymes that control the ratio of active hormone to pro-hormone. Two pro-hormone convertases, PC1/3 and PC2 are believed to be responsible for the activation of many neurohormones and expression of these enzymes is dependent on the presence of a cyclic-AMP response element (CRE) in their promoters. Therefore, we studied the effects of short-term (24-h) and long-term (7-day) morphine treatment on the expression of hypothalamic PC1/3 and PC2 and levels of phosphorylated cyclic-AMP-response element binding protein (P-CREB). While short-term morphine exposure down-regulated, long-term morphine exposure up-regulated P-CREB, PC1/3 and PC2 protein levels in the rat hypothalamus as determined by Western blot analysis. Quantitative immunofluorescence studies confirmed these regulatory actions of morphine in the paraventricular and dorsomedial nucleus of the hypothalamus. Specific radioimmunoassays demonstrated that the increase in PC1/3 and PC2 levels following long-term morphine led to increased TRH biosynthesis as evidence by increased TRH/5.4 kDa C-terminal proTRH-derived peptide ratios in the median eminence. Promoter activity experiments in rat somatomammotrope GH3 cells containing the mu-opioid receptor demonstrated that the CRE(s) in the promoter of PC1/3 and PC2 is required for morphine-induced regulation of PC1/3 and PC2. Our data suggest that the regulation of the prohormone processing system by morphine may lead to alterations in the levels of multiple bioactive hormones and may be a compensatory mechanism whereby the organism tries to restore its homeostatic hormonal milieu. The down-regulation of PC1/3, PC2 and P-CREB by short-term morphine and up-regulation by long-term morphine treatment may be a signal mediating the switch from drug use to drug abuse.

Polymerized-type I collagen for the treatment of patients with rheumatoid arthritis. Effect of intramuscular administration in a double blind placebo-controlled clinical trial.

OBJECTIVE: To determine the efficacy, tolerance and safety of intramuscular injections of porcine type I collagen-PVP in patients with RA in a long term-therapy. METHODS: The study was a double blind placebo-controlled and included 30 patients with active RA (ACR). Patients were treated with intramuscular injections of 2 ml of collagen-PVP (3.4 mg of collagen) or 2 ml of placebo during 6 months. The follow up was done during the next 6 months. The primary endpoints included the Ritchie index (RI), swollen joint count, disease activity score (DAS), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). The secondary endpoints included morning stiffness, pain intensity on a visual analogue scale (VAS), and Spanish-health assessment questionnaire (HAQ-DI). Improvement was determined using American College of Rheumatology response criteria (ACR20, 50 and 70). RESULTS: Collagen-PVP was safe and well tolerated. There were no adverse events. Patients had a statistically significant improvement (p < 0.05) in collagen-PVP-treated vs. placebo at 6 months of treatment in: swollen joint count (7.1 +/- 0.8 vs. 16.0 +/- 1.6), RI (8.1 +/- 0.8 vs. 15.2 +/- 1.5), morning stiffness (9.2 +/- 3.1 vs. 29.1 +/- 5.9 min), HAQ-DI (50.0 +/- 10.8 vs. 22.9 +/- 10.3), DAS (3.0 +/- 0.2 vs. 4.9 +/- 0.3), ACR20 (78.6 vs. 71.4%), ACR50 (57.1 vs. 0%) and ACR70 (7.1 vs. 0%) and CRP (1.1 +/- 0.4 vs. 2.5 +/- 0.7). Patients treated with collagen-PVP required lower doses of methotrexate vs. placebo (12.6 +/- 0.6 vs. 14.2 +/- 0.7 at 6 months and 12.3 +/- 0.8 vs. 15.4 +/- 0.6 at 12 months; p < 0.05). Serological or haematological parameters remained unchanged. CONCLUSION: Collagen-PVP has been shown to be a safe and well-tolerated drug for the long-term treatment of RA. Combination of collagen-PVP plus methotrexate was more efficacious than methotrexate alone. This biodrug can be useful in the treatment of RA.

Growing-Related Changes in Arterial Properties of Healthy Children, Adolescents, and Young Adults Nonexposed to Cardiovascular Risk Factors: Analysis of Gender-Related Differences.

The aims of our work were to determine normal aging rates for structural and functional arterial parameters in healthy children, adolescents, and young adults and to identify gender-related differences in these aging rates. Methods. 161 subjects (mean: 15 years (range: 4-28 years), 69 females) were studied. Subjects included had no congenital or chronic diseases, nor had they been previously exposed to traditional cardiovascular risk factors. Arterial parameters assessed were (1) central blood pressure (BP) and aortic pulse wave analysis, (2) arterial local (pressure-strain elastic modulus) and regional (pulse wave velocity, PWV) stiffness, and (3) arterial diameters and carotid intima-media thickness (CIMT). Simple linear regression models (age as the independent variable) were obtained for all the parameters and the resulting rates of change were compared between genders. Results. No gender-related differences were found in mean values of arterial structural and functional parameters in prepubertal ages (4-8 years), but they started to appear at ~15 years. Boys showed a greater rate of change for central systolic BP, central pulse pressure, CIMT, and carotid-femoral PWV. Conclusion. Gender-related differences in arterial characteristics of adults can be explained on the basis of different growing-related patterns between boys and girls, with no existing differences in prepubertal ages.

Potato tuber isoapyrases: substrate specificity, affinity labeling, and proteolytic susceptibility.

Apyrase/ATP-diphosphohydrolase hydrolyzes di- and triphosphorylated nucleosides in the presence of a bivalent ion with sequential release of orthophosphate. We performed studies of substrate specificity on homogeneous isoapyrases from two potato tuber clonal varieties: Desiree (low ATPase/ADPase ratio) and Pimpernel (high ATPase/ADPase ratio) by measuring the kinetic parameters K(m) and k(cat) on deoxyribonucleotides and fluorescent analogues of ATP and ADP. Both isoapyrases showed a broad specificity towards dATP, dGTP, dTTP, dCTP, thio-dATP, fluorescent nucleotides (MANT-; TNP-; ethene-derivatives of ATP and ADP). The hydrolytic activity on the triphosphorylated compounds was always higher for the Pimpernel apyrase. Modifications either on the base or the ribose moieties did not increase K(m) values, suggesting that the introduction of large groups (MANT- and TNP-) in the ribose does not produce steric hindrance on substrate binding. However, the presence of these bulky groups caused, in general, a reduction in k(cat), indicating an important effect on the catalytic step. Substantial differences were observed between potato apyrases and enzymes from various animal tissues, concerning affinity labeling with azido-nucleotides and FSBA (5'-p-fluorosulfonylbenzoyl adenosine). PLP-nucleotide derivatives were unable to produce inactivation of potato apyrase. The lack of sensitivity of both potato enzymes towards these nucleotide analogues rules out the proximity or adequate orientation of sulfhydryl, hydroxyl or amino-groups to the modifying groups. Both apyrases were different in the proteolytic susceptibility towards trypsin, chymotrypsin and Glu-C.

Self-pulsing dynamics of ultrasound in a magnetoacoustic resonator.

A theoretical model of parametric magnetostrictive generation of ultrasound is considered, taking into account magnetic and magnetoacoustic nonlinearities. The stability and temporal dynamics of the system is analyzed with standard techniques revealing that, for a given set of parameters, the model presents a homoclinic or saddle-loop bifurcation, which predicts that the ultrasound is emitted in the form of pulses or spikes with arbitrarily low frequency.

Interleukin-1beta regulates phospholipase D-1 expression in rat pancreatic beta-cells.

The cytokine interleukin (IL)-1beta induces a biphasic effect in rat pancreatic islets, with an early and transitory stimulation of insulin release followed by progressive functional suppression. To clarify the mechanisms involved in these effects, we have recently performed a differential display of messenger RNA (mRNA) by RT-PCR (DDRT-PCR) on rat beta-cells exposed for 6 or 24 h to IL-1beta. Among the different IL-1beta-induced genes, there was an early and transient increase in phospholipase D-1 (PLD1) expression. PLD1 can induce phosphatidic acid formation and subsequent activation of protein kinase C, a process which stimulates insulin release. In the present study, we characterized the regulation of PLD isoforms by IL-1beta in pancreatic beta-cells. By using different combinations of primers and RT-PCR, we observed that IL-1beta induces an early increase (2 and 6 h) in the expression of both alternatively spliced isoforms of PLD1 (PLD1alpha and 1b). Prolonged exposure to IL-1beta (12 and 24 h) caused a decrease of PLD1a mRNA expression compared with control beta-cells, and lead to a return of PLD1b mRNA to basal level. NG-methyl-L-arginine (LMA), a blocker of the inducible form of nitric oxide synthase (iNOS), prevented this late inhibitory effect of IL-1beta, suggesting that IL-1beta-induced decrease in PLD1a expression is NO-mediated. IL-1beta induced an early (2-6 h) and sustained (16-24 h) increase in PLD1a mRNA expression in insulin-producing RINm5F cells. This was paralleled by a cytokine-induced increase in PLD1 protein expression and enzyme activity. RINm5F cells, but not primary beta-cells, expressed PLD2, and the expression of this gene was not affected by IL-1beta. In conclusion, we have shown that the cytokine IL-1beta regulates PLD1 expression in primary and clonal beta-cells. The early induction of PLD1 probably contributes to the early stimulatory effects of IL-1beta on islet insulin release.

Differences in nucleotide-binding site of isoapyrases deduced from tryptophan fluorescence.

Comparative studies of intrinsic and extrinsic fluorescence of apyrases purified from two potato tuber varieties (Pimpernel and Desirée) were performed to determine differences in the microenvironment of the nucleotide binding site. The dissociation constants (K(d)) of Pimpernel apyrase for the binding of different fluorescent substrate analogs: methylanthranoyl (MANT-), trinitrophenyl (TNP-), and epsilon -derivatives of ATP and ADP were determined from the quenching of Trp fluorescence, and compared with K(d) values previously reported for Desirée enzyme. Binding of non-fluorescent substrate analogues decreased the Trp emission of both isoapyrases, indicating conformational changes in the vicinity of these residues. Similar effect was observed with fluorescent derivatives where, in the quenching effect, the transfer of energy from tryptophan residues to the fluorophore moiety could be additionally involved. The existence of energy transfer between Trp residues in the Pimpernel enzyme was demonstrated with epsilon -analogues, similar to our previous observations with the Desirée. From these results we deduced that tryptophan residues are close to or in the nucleotide binding site in both enzymes. Experiments with quenchers like acrylamide, Cs(+) and I(-), both in the presence and absence of nucleotide analogues, suggest the existence of differences in the nucleotide binding site of the two enzymes. From the results obtained in this work, we can conclude that the differences found in the microenvironment of the nucleotide binding site can explain, at least in part, the kinetic behaviour of both isoenzymes.

Fluorescence studies of ATP-diphosphohydrolase from Solanum tuberosum var. Desirée.

Chemical modification of potato apyrase suggests that tryptophan residues are close to the nucleotide binding site. Kd values (+/- Ca2+) for the complexes of apyrase with the non-hydrolysable phosphonate adenine nucleotide analogues, adenosine 5'-(beta,gamma-methylene) triphosphate and adenosine 5'-(alpha,beta-methylene) diphosphate, were obtained from quenching of the intrinsic enzyme fluorescence. Other fluorescent nucleotide analogues (2'(3')-O-(2,4,6-trinitrophenyl) adenosine 5'-triphosphate, 2'(3')-O-(2,4,6-trinitrophenyl) adenosine 5'-diphosphate. 1,N6-ethenoadenosine triphosphate and 1,N6-ethenoadenosine diphosphate) were hydrolysed by apyrase in the presence of Ca2+, indicating binding to the active site. The dissociation constants for the binding of these analogues were calculated from both the decrease of the protein (tryptophan) fluorescence and enhancement of the nucleotide fluorescence. Using the sensitised acceptor (nucleotide analogue) fluorescence method, energy transfer was observed between enzyme tryptophans and ethene-derivatives. These results support the view that tryptophan residues are present in the nucleotide-binding region of the protein, appropriately oriented to allow the energy transfer process to occur.

Studies on ATP-diphosphohydrolase nucleotide-binding sites by intrinsic fluorescence.

Potato apyrase, a soluble ATP-diphosphohydrolase, was purified to homogeneity from several clonal varieties of Solanum tuberosum. Depending on the source of the enzyme, differences in kinetic and physicochemical properties have been described, which cannot be explained by the amino acid residues present in the active site. In order to understand the different kinetic behavior of the Pimpernel (ATPase/ADPase = 10) and Desirée (ATPase/ADPase = 1) isoenzymes, the nucleotide-binding site of these apyrases was explored using the intrinsic fluorescence of tryptophan. The intrinsic fluorescence of the two apyrases was slightly different. The maximum emission wavelengths of the Desirée and Pimpernel enzymes were 336 and 340 nm, respectively, suggesting small differences in the microenvironment of Trp residues. The Pimpernel enzyme emitted more fluorescence than the Desirée apyrase at the same concentration although both enzymes have the same number of Trp residues. The binding of the nonhydrolyzable substrate analogs decreased the fluorescence emission of both apyrases, indicating the presence of conformational changes in the neighborhood of Trp residues. Experiments with quenchers of different polarities, such as acrylamide, Cs+ and I- indicated the existence of differences in the nucleotide-binding site, as further shown by quenching experiments in the presence of nonhydrolyzable substrate analogs. Differences in the nucleotide-binding site may explain, at least in part, the kinetic differences of the Pimpernel and Desirée isoapyrases.

Comparison of the biochemical properties, regulation and function of ATP-diphosphohydrolase from human placenta and rat kidney.

ATP-diphosphohydrolase (apyrase. EC 3.6.1.5) has both ATPase and ADPase activity that are stimulated by bivalent metals, with Ca2+ being the most effective. The possible physiological function of this enzyme, associated with placental and renal microvilli, is related to the extracellular metabolism of nucleotides. A comparison of the biochemical properties of human placenta and rat kidney apyrase is presented, showing similarities in Mr. bivalent metal stimulation, nucleotide nonspecificity, insensitivity towards specific ATPase inhibitors, and lack of essential sulfhydryl and aliphatic hydroxyl groups. We describe the treatment of membrane preparations from both tissues with different detergents and the isoelectric focusing of the solubilized proteins to partially purify apyrase. An ectoenzyme localization is assigned both in microvillus membranes and in the vasculature on the basis of organ perfusion experiments with nucleotides in the presence of antibodies. Placental and kidney microvillus membranes inhibited ADP-induced platelet aggregation, in agreement with an extracellular role. Initial studies on enzyme regulation suggested the existence of at least two types of modulatory proteins: an activating protein in the cytosol of both tissues, and an inhibitory protein associated with placental microsomes. Possible hormonal regulation was investigated in kidneys using in vivo estradiol treatment, but only slight changes in total apyrase activity were observed.

[Diagnosis and treatment of osteoporosis. Position of the Mexican College of Orthopedics and Traumatology]. / Diagnóstico y tratamiento de la osteoporosis. Posición del Colegio Mexicano de Ortopedia y Traumatología.

Our current in Mexico is that it represents a serious health problem not yet recognized as low-energy fractures in older adults account for approximately 10% of subjects over 65 years (compared with 29% in Japan) about 4.4 million fractures in patients over 70 years, taking into account that we are a nation of 112 million, the problem is minor compared with other diseases in this and other population groups. In the Mexican health system, orthopedic services instead share with other health priorities, so that the authorities do not understand osteoporosis as a health problem, not observe increased morbidity and mortality that implicitly leads, there are few centers to support the diagnosis of osteoporosis (densitometers do not have), and recruitment, diagnosis and management of patients who have suffered a broken ground mechanically compromised. Have increased the frequency of fractures in osteoporotic ground, and institutional level has only treatments based on calcitriol and calcium to maintain bone mineral density. In the Mexican health system, orthopedic services instead share with other health priorities, so that the authorities do not understand osteoporosis as a health problem, not observe increased morbidity and mortality that implicitly leads, there are few centers to support the diagnosis of osteoporosis (we don't count with densitometers), and recruitment, diagnosis and management of patients who have suffered a broken ground mechanically compromised. Have increased the frequency of fractures in osteoporotic ground, and institutional level has only treatments based on calcitriol and calcium to maintain bone mineral density.

Expectant management of severe preeclampsia remote from term: a structured systematic review.

OBJECTIVE: To compare outcomes associated with expectant vs. interventionist care of severe preeclampsia in observational studies. DATA SOURCES: Medline (01/1980-07/2007), bibliographies of retrieved papers, personal files, Cochrane Database of Systematic Reviews. STUDY SELECTION: Expectant or interventionist care of preeclampsia at <34 wk. TABULATION, INTEGRATION, RESULTS: Data abstraction independently by two reviewers. Median [IQR] of clinical maternal/perinatal outcomes presented. RESULTS: 72 publications, primarily from tertiary care centres in Dutch and developed world sites. Expectant care of severe preeclampsia <34 wk (39 cohorts, 4,650 women), for which 40% of women are eligible, is associated with pregnancy prolongation of 7-14 d, and few serious maternal complications (median <5%), similar to interventionist care (2 studies, 42 women). Complication rates are higher with HELLP <34wk (12 cohorts, 438 women) and severe preeclampsia <28wk (6 cohorts, 305 women), similar to interventionist care (6 cohorts, 467 women and 2 cohorts, 70 women, respectively). Expectant care of HELLP <34 wk (12 cohorts, 438 women) is associated with fewer days gained (median 5), but more serious maternal morbidity (e.g., eclampsia, median 15%). More than half of women have at least temporary improvement of HELLP. In the developed world, expectant (vs. interventionist) care of severe preeclampsia or HELLP <34 wk is associated with reduced neonatal death and complications. Stillbirth is higher in Dutch and developing world sites where viability thresholds are higher. For preeclampsia <24wk (4 cohorts), perinatal mortality is >80%. No predictors of adverse maternal/perinatal outcomes were identified (13 studies). CONCLUSIONS: Future research should establish the best maternal/fetal monito regimen and indications for delivery with expectant care. A definitive RCT is needed.