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Intrauterine and perinatal life are critical periods for programming of cardiometabolic diseases. However, their relative role remains controversial. We aimed to assess, at weaning, sex-dependent alterations induced by fetal or postnatal nutritional interventions on key organs for metabolic and cardiovascular control. Fetal undernutrition was induced by dam food restriction (50 % from mid-gestation to delivery) returning to ad libitum throughout lactation (Maternal Undernutrition, MUN, 12 pups/litter). Postnatal overfeeding (POF) was induced by litter size reduction from normally fed dams (4 pups/litter). Compared to control, female and male MUN offspring exhibited: 1) low birth weight and accelerated growth, reaching similar weight and tibial length by weaning, 2) increased glycemia, liver and white fat weights; 3) increased ventricular weight and tendency to reduced kidney weight (males only). Female and male POF offspring showed: 1) accelerated growth; 2) increased glycemia, liver and white fat weights; 3) unchanged heart and kidney weights. In conclusion, postnatal accelerated growth, with or without fetal undernutrition, induces early alterations relevant for metabolic disease programming, while fetal undernutrition is required for heart abnormalities. The progression of cardiac alterations and their role on hypertension development needs to be evaluated. The similarities between sexes in pre-pubertal rats suggest a role of sex-hormones in female protection against programming.

Uterine cervical cancer is the second most frequent gynecological malignancy worldwide. The assessment of the extent of disease is essential for planning optimal treatment. Imaging techniques are increasingly used in the pre-treatment work-up of cervical cancer. Currently, MRI for local extent of disease evaluation and PET-scan for distant disease assessment are considered as first-line techniques. Notwithstanding, in the last few years, ultrasound has gained attention as an imaging technique for evaluating women with cervical cancer. In this paper, current knowledge about the use of ultrasound for assessing uterine cervical cancer will be reviewed and discussed.

Objective: Albuminuria has been recently described in hypertensive patients under chronic renin-angiotensin system (RAS) suppression. We investigated whether this fact could be related to an increase in oxidative stress., Methods: We examined normoalbuminuric and albuminuric patients in stage 2 chronic kidney disease, both with more than 2 years of RAS blockade. The relationship between albuminuria and circulating biomarkers for both oxidative damage, that is carbonyl and malondialdehyde, as well as antioxidant defense, that is reduced glutathione, thiol groups, uric acid, bilirubin, or catalase, and superoxide scavenging activity, was assessed., Results: We found that only patients with albuminuria showed an important increase in carbonyls (P < 0.001) and malondialdehyde (P < 0.05) compared to normoalbuminuric patients. This increase in oxidative damage was also accompanied by a rise in catalase activity (P < 0.05) and low-molecular-weight antioxidants only when they were measured as total antioxidant capacity (P < 0.01). In order to establish the specific oxidative status of each group, new indexes of oxidative damage and antioxidant defense were calculated with all these markers following a mathematical and statistical approach. Although both pro-oxidant and antioxidant indexes were significantly increased in patients with albuminuria, only the oxidative damage index positively correlated with the increase of albumin/creatinine ratio (P = 0.0024)., Conclusions: We conclude that albuminuria is accompanied by an amplified oxidative damage in patients in early stages of chronic kidney disease. These results indicate that chronic RAS protection must be directed to avoid development of albuminuria and oxidative damage.

The cardinal symptoms of attention deficit hyperactivity disorder (ADHD)--inattention, hyperactivity and impulsiveness--are not specific and may be found in the general population and in other disorders. These symptoms are present in over 50% of patients with autism spectrum disorders (ASD). It thus seems quite clear that both problems can coexist in these patients. The usual pharmacological treatments for ADHD, methylphenidate and atomoxetine, appear to be useful in reducing the above-mentioned symptoms in patients with ADHD and ASD. Effectiveness seems to be lower in patients with ASD and tolerance is slightly poorer. This may be conditioned by a number of variables, including: the complexity of ASD, association with mental retardation, polypharmacotherapy, and so on. Given the long-term tolerance profile of methylphenidate and atomoxetine, these treatments appear to be a good alternative with which to improve the problems of attention and self-control these patients have. Nevertheless, further controlled studies are needed to confirm this proposition.

Objective: Atomoxetine's tolerance and efficacy were studied in 24 patients with pervasive developmental disorder and symptoms of ADHD., Method: Prospective, open-label, 16-week study was performed, using the variables of the Clinical Global Impression Scale and the Conners' Scale, among others., Results: A significant difference was found between pre- and posttreatment scores as well as a significant reduction was found on the scales used. Only five patients presented adverse events., Conclusion: Atomoxetine therefore appears to be a useful drug, pointing to the need for larger, randomized, controlled, double-blind studies to confirm its efficacy versus placebo and in comparison with other treatment options.

Vulvar cancer is a rare malignancy; most tumors are squamous cell type while adenocarcinomas are rare. Primary adenocarcinomas of the vulva predominantly include extramammary Paget's disease and sweat gland carcinomas. Greene first described a rare form of adenocarcinoma in 1936, which was called adenocarcinoma of mammary-like glands of the vulva because of its morphologic and immunohistochemical resemblance to breast adenocarcinomas. In the management of this entity, varying combinations of surgery, radiation therapy, systemic chemotherapy and/or hormonal therapy may be used, as in patients with orthotopic breast carcinoma. However, hormonal therapy leads the way in patients with positive hormonal receptors, where other therapies cannot be used due to comorbidities or advanced age. We present the first reported case of an elderly patient with metastatic vulvar adenocarcinoma arising from mammary-like glands, successfully treated with a combination of surgery and hormonal therapy., (© 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology.)

Leptin causes vasodilatation both by endothelium-dependent and -independent mechanisms. Leptin is synthesized by perivascular adipose tissue (PVAT). The hypothesis of this study is that a decrease of leptin production in PVAT of spontaneously hypertensive rats (SHR) might contribute to a diminished paracrine anticontractile effect of the hormone. We have determined in aorta from Wistar-Kyoto (WKY) and SHR (i) leptin mRNA and protein levels in PVAT, (ii) the effect of leptin and PVAT on contractile responses, and (iii) leptin-induced relaxation and nitric oxide (NO) production. Leptin mRNA and protein expression were significantly lower in PVAT from SHR. Concentration-response curves to angiotensin II were significantly blunted in presence of PVAT as well as by exogenous leptin (10(-9) M) only in WKY. This anticontractile effect was endothelium-dependent. Vasodilatation induced by leptin was smaller in SHR than in WKY, and was also endothelium-dependent. Moreover, release of endothelial NO in response to acute leptin was higher in WKY compared to SHR, but completely abolished in the absence of endothelium. In conclusion, the reduced anticontractile effect of PVAT in SHR might be attributed to a reduced PVAT-derived leptin and to an abrogated effect of leptin on endothelial NO release probably due to an impaired activation of endothelial NO synthase.

Objective: We have analyzed social and leadership abilities in children with ADHD and their relationship with execution of tasks involving sustained attention and inhibitory control., Patients and Methods: A retrospective analysis of 170 patients with ADHD was performed. We evaluated leadership and social abilities, measured through the Behavior Assessment System for Children (BASC) and their relations with the results of different neuropsychological tests, including Wechsler scale for children (WISC-IV) and Conners' continuous performance (CPT II)., Results: In the differential analysis between the IQ, results of the tests and their relation to BASC scores, a statistically significant relation was observed between attentional capacity expected according to the patient's intelligence and social skills scores (according to BASC filled out by mothers and teachers) and leadership (according to all informants) sections., Conclusions: Attentional difficulties are closely related to social competence in patients with ADHD, either by a direct cause-effect relationship or a shared dysexecutive substrate of this disorder.

Attention deficit hyperactivity disorder (ADHD) is a remarkably heterogeneous neurobiological disorder. This characteristic is aetiologically mediated by genetic and environmental factors. Numerous studies have shown that different genes play a moderate but complex role in the aetiology of ADHD. Significant associations have been identified with several candidate genes for this disorder, including DAT1, DRD4, DRD5, 5HTT, HTR1B or SNAP25. The neurocognitive models of ADHD have been largely based on the findings from neuroimaging studies conducted in patients with ADHD, when establishing hypotheses capable of explaining the clinical features that are observed. From a neurobiological point of view, the genetic architecture of these patients or the interaction of the above-mentioned genes should at least partially account for the neuroanatomical and neuropsychological findings observed, which explains the axiomatic antithesis in the title. Nevertheless, the results of studies into the relationship between the genotyping and the neuroimaging or psychological findings are scarce and contradictory. The methodological differences in the volumetric analyses, the sizes of the populations studied, the neuropsychological batteries that are used, the presence of previous pharmacological treatment or comorbidity could account for these results.

Introduction: Numerous studies have documented that children with attention deficit hyperactivity disorder (ADHD) show a low social competence., Objective: To compare the symptomatic severity of ADHD, as well as associations to different subtypes, sex and comorbidities, with social functioning ("ability" and "leadership") estimated through a Behavior Assessment System for Children (BASC) for parents and teachers., Patients and Methods: We have retrospectively analyzed 170 patients with ADHD, diagnosed between 2007 and 2010. Social "ability," "leadership," "hyperactivity" and "attention deficit" sections of BASC and cardinal symptoms of ADHD measured through a Spanish scale for de evaluation of DHD (E-DHD) were registered. Results of these variables are analyzed according to the normative data by age and sex, and processed in Z values., Results: The ratings for social skills were significantly lower in patients with conduct disorder or oppositional defiant disorder as informed by parents (p<0.05). Symptomatic intensity of ADHD showed significant (p<0,001) and inverse relation with social "ability" as parents. "Attention-deficit" scores were related with social "ability" and "leadership" as parents and teachers., Conclusions: Intensity of attention deficit was the only variable that showed a significant relation with the social skills and leadership according to the BASC scores, independently of the informer.

Background: In April 2009, the World Health Organization declared the emergence of human cases by a new influenza virus H1N1 as a Public Health Emergency of International Importance. Our objective was to analyze the characteristics of the cases investigated and to assess the compliance of the subjects studied with the indications and recommendations of the Health Regional Ministry of Health Castilla y León., Methods: A descriptive epidemiological study of all positive cases and every requests made to Castilla y León, from epidemiological weeks 44 to 50, both included., Results: 588 requests were made to test for influenza A H1N1 (58% males). The mean age was 34.8 years (27.1% between 15 and 44 years). 42% fulfilled criteria for severity. Chronic respiratory disease was the most common risk factor found (18.9%). Antiviral treatment was found in 19.1% (54.5% within the first 48 hours). 27.4% of the requests were positive (53.4% males). The mean age of the positive cases was 34.52 years was positive (33.1% between 15 and 44 years). 47.8% of them fulfilled criteria for severity and chronic respiratory disease was also the most common risk factor found also in the positive (26.7%). Only 6.8% were morbidly obese. 28.9% of positives received antiviral treatment (61.4% within the first 48 hours)., Conclusion: Most cases did not fulfil severity criteria, which illustrates the low compliance of monitoring protocols in sanitary care system.

Perivascular adipose tissue (PVAT) plays a paracrine role in regulating vascular tone. We hypothesize that PVAT undergoes adaptative mechanisms during initial steps of diet-induced obesity (DIO) which contribute to preserve vascular function. Four-week-old male C57BL/6J mice were assigned either to a control [low-fat (LF); 10% kcal from fat] or to a high-fat diet (HF; 45% kcal from fat). After 8 wk of dietary treatment vascular function was analyzed in the whole perfused mesenteric bed (MB) and in isolated mesenteric arteries cleaned of PVAT. Relaxant responses to acetylcholine (10(-9)-10(-4) m) and sodium nitroprusside (10(-12)-10(-5) m) were significantly ameliorated in the whole MB from HF animals. However, there was no difference between HF and LF groups in isolated mesenteric arteries devoid of PVAT. The enhancement of relaxant responses detected in HF mice was not attributable to an increased release of nitric oxide (NO) from the endothelium nor to an increased sensitivity and/or activity of muscular guanilylcyclase. Mesenteric PVAT of HF animals showed an increased bioavailability of NO, detected by 4,5-diaminofluorescein diacetate (DAF2-DA) staining, which positively correlated with plasma leptin levels. DAF-2DA staining was absent in PVAT from ob/ob mice but was detected in these animals after 4-wk leptin replacement. The main finding in this study is that adaptative NO overproduction occurs in PVAT during early DIO which might be aimed at preserving vascular function.

Recent studies have demonstrated that the rat adipose tissue expresses some of the components necessary for the production of angiotensin II (Ang II) and the receptors mediating its actions. The aim of this work is to characterize the expression of the renin-angiotensin system (RAS) components in perivascular adipose tissue and to assess differences in the expression pattern depending on the vascular bed and type of adipose tissue. We analyzed Ang I and Ang II levels as well as mRNA levels of RAS components by a quantitative RT-PCR method in periaortic (PAT) and mesenteric adipose tissue (MAT) of 3-month-old male Wistar-Kyoto rats. PAT was identified as brown adipose tissue expressing uncoupling protein-1 (UCP-1). It had smaller adipocytes than those from MAT, which was identified as white adipose tissue. All RAS components, except renin, were detected in both PAT and MAT. Levels of expression of angiotensinogen, Ang-converting enzyme (ACE), and ACE2 were similar between PAT and MAT. Renin receptor expression was five times higher, whereas expression of chymase, AT(1a), and AT(2) receptors were significantly lower in PAT compared with MAT respectively. In addition, three isoforms of the AT(1a) receptor were found in perivascular adipose tissue. The AT(1b) receptor was found at very a low expression level. Ang II levels were higher in MAT with no differences between tissues in Ang I. The results show that the RAS is differentially expressed in white and brown perivascular adipose tissues implicating a different role for the system depending on the vascular bed and the type of adipose tissue.

Objective: Perivascular adipose tissue of normotensive rats releases a transferable factor that induces relaxation by opening voltage-dependent K+ (Kv) channels. The relevance of these observations to hypertension is unknown., Methods and Results: We characterized mesenteric perivascular adipose tissue from 3-month-old Wistar Kyoto rats (WKY) and aged-matched spontaneously hypertensive rats (SHR). Mesenteric bed (MB) weight and MB total lipid content were lower in SHR than in WKY. Freshly isolated MB adipocytes were smaller in SHR. Plasma triglycerides, glycerol, nonesterified free-fatty acids, and cholesterol were also lower in SHR. Plasma and mesenteric leptin were correlated with the quantity of mesenteric fat. To study vascular function, the MB was cannulated and perfused at a constant 2 mL/min flow. The Kv channel blocker 4-aminopyridine (4-AP; 2 mmol/L) increased perfusion pressure less in SHR MB than WKY and was directly correlated with the mesenteric fat amount. In isolated mesenteric artery rings, 4-AP (2 mmol/L) induced a contractile effect that was attenuated in SHR compared with WKY. The anticontractile effects of perivascular fat were reduced in SHR mesenteric artery rings compared with WKY., Conclusions: Differences in visceral perivascular adipose tissue mass and function may contribute to the increased vascular resistance observed in SHR.

Purpose: We determined if a third of the dose of intravesical bacillus Calmette-Guerin (BCG) has the same efficacy than a standard dose for decreasing the risk of recurrence and progression after transurethral resection in patients with superficial high risk (stages T1G3 and carcinoma in situ) bladder cancer. Also, we evaluated toxic side effects., Material and Methods: A total of 155 patients with a mean age +/- SD of 67 +/- 10.1 years with superficial bladder cancer, including stages T1G3 in 90, a Tis primary tumor in 23 and associated Tis disease in 42, were enrolled and randomly assigned to be treated after transurethral resection of all visible lesions with intravesical BCG, Connaught strain (weekly x 6 and fortnightly x 6 thereafter) with the standard dose of 81 mg or with the decreased dose of 27 mg., Results: Median followup was 61 months (range 3 to 102). Disease recurred in 32 patients (39%) treated with the standard dose and in 33 (45%) treated with the decreased dose. Median time to recurrence was not attained in the standard dose arm and it was 63 months in the decreased dose arm. Kaplan-Meier estimates for time to recurrence did not reveal differences between the 2 doses (p = 0.405). Tumor progressed in 20 patients (24.7%) with the standard dose and in 19 (26%) with the decreased dose. Four patients (6.1%) with Tis had local extension into the prostatic urethra and ducts, including 3 (8.3%) treated with the standard dose and 1 (3.4%) treated with the decreased dose. Median time to progression was not attained in either arm. Kaplan-Meier estimates for time to progression did not differ significantly (p = 0.7997). Deferred cystectomy for progression was performed in 7 patients (8.4%) treated with the standard dose and in 7 (9.5%) of those treated with the decreased dose. Subgroup analysis by patient age, tumor status, number, size and T stage (T1G3 vs Tis) did not differ significantly. The groups did not differ in disease specific mortality, which was 12.2% in the standard dose arm and 16.4% in the decreased dose arm. Mean disease specific survival +/- SE was 86.96 +/- 4.14 and 83.73 +/- 4.73 months, respectively., Conclusions: Our results suggest that a 3-fold decreased dose of intravesical BCG is as effective as the standard dose against progression in patients with high risk stages T1G3 and Tis superficial bladder carcinoma but with significantly less toxicity.

We have previously reported an adaptation of arterial wall elasticity in spontaneously hypertensive rats (SHR) that involves an increase in both fibronectin/alpha5beta1-integrin complexes and smooth-muscle elastic lamellae connections. We examined the mechanical strength (MS) of the carotid artery in relation to its elastic properties, its elastin/collagen content, and the structure of the internal elastic lamina. MS was defined as the in vitro intraluminal pressure and wall stress that produces rupture of the vascular wall. Intact carotid arteries from 3-month-old normotensive rats (Wistar-Kyoto, WKY) and SHR were cannulated on a specially designed device and adjusted to their in situ length. A slowly increasing static pressure was applied until wall rupture occurred to determine the static mechanical behavior and MS. Static elasticity was similar in SHR and WKY, as were the rupture pressure (2740+/-90 versus 2740+/-40 mm Hg) and wall stress at rupture (11.5+/-1.0 versus 12.8+/-0.4 MPa), indicating equivalent MS in both groups. Histological examination showed several wall ruptures and dissociation of lamellar units that did not differ significantly between the 2 groups. Confocal microscopy showed that the size of fenestrations of the internal elastic lamina and the fraction of area occupied by them were reduced 3-fold in SHR. We have demonstrated that static elasticity of the arterial wall and mechanical strength are similar in carotid arteries from SHR and WKY.

The aim of the present study was to determine whether the adventitia of large arteries modulates vascular function. We developed a method to obtain functional vascular rings devoid of adventitia. Carotid and iliac arteries from 3-mo-old Sprague-Dawley rats were denuded from adventitia after treatment with collagenase followed by gentle peeling. Adventitia removal and integrity of the media was demonstrated by optical and confocal microscopy. Arterial rings with or without adventitia and with or without endothelium were mounted in an organ bath for isometric tension recording. Responses to 75 mM KCl or norepinephrine (0.1 nM-1 microM) were significantly reduced in segments without adventitia. Acetylcholine-induced relaxation (0.1 microM-0.1 mM) was enhanced in arteries without adventitia, whereas sodium nitroprusside-induced responses were not modified. These results demonstrate that the combination of stripping with a previous collagenase treatment allows us to obtain functional rings devoid of adventitia and that this layer plays a role in contractile capacity and in endothelium-modulated responses.

Our aim was to determine the structural factors that determine the mechanical adaptation of the carotid arterial wall in stroke-prone hypertensive rats (SHRSP). Distensibility-pressure and elastic modulus-stress curves assessed by in vivo echo-tracking measurements indicated a reduction in arterial stiffness in 13-week-old SHRSP compared with Wistar-Kyoto rats (WKY). Elastin and collagen contents determined biochemically were not different between SHRSP and WKY. Confocal microscopy showed that the mean area of fenestrations and fraction of area occupied by fenestrations of the internal elastic lamina (IEL) were smaller in SHRSP than in WKY, which indicated a reduction in stress-concentration effects within the IEL. Immunohistologic staining of EIIIA fibronectin isoform and total fibronectin (also as determined by Western blot) was greater in SHRSP, which suggested increased cell-matrix interactions. We suggest that these structural modifications of the vascular wall play a synergistic role in the mechanical adaptation to a high level of stress in SHRSP.

Integral field optical spectroscopy with the INTEGRAL fiber-fed system and Hubble Space Telescope optical imaging are used to map the complex stellar and warm ionized gas structure in the ultraluminous infrared galaxy IRAS 12112+0305. Images reconstructed from wavelength-delimited extractions of the integral field spectra reveal that the observed ionized gas distribution is decoupled from the stellar main body of the galaxy, with the dominant continuum and emission-line regions separated by projected distances of up to 7.5 kpc. The two optical nuclei are detected as apparently faint emission-line regions, and their optical properties are consistent with being dust-enshrouded weak [O i] LINERs. The brightest emission-line region is associated with a faint (mI=20.4), giant H ii region of 600 pc diameter, in which a young ( approximately 5 Myr) massive cluster of about 2x107 M middle dot in circle dominates the ionization. Internal reddening toward the line-emitting regions and the optical nuclei ranges from 1 to 8 mag in the visual. Taking the reddening into account, the overall star formation in IRAS 12112+0305 is dominated by starbursts associated with the two nuclei and corresponds to a star formation rate of 80 M middle dot in circle yr-1.

Integral field optical spectroscopy with the INTEGRAL fiber-based system is used to map the extended ionized regions and gas flows in Mrk 273, one of the closest ultraluminous infrared galaxies. The Hbeta and [O iii] lambda5007 maps show the presence of two distinct regions separated by 4&arcsec; (3.1 kpc) along position angle (P.A.) 240 degrees. The northeastern region coincides with the optical nucleus of the galaxy and shows the spectral characteristics of LINERs. The southwestern region is dominated by [O iii] emission and is classified as a Seyfert 2. Therefore, in the optical, Mrk 273 is an ultraluminous infrared galaxy with a LINER nucleus and an extended off-nucleus Seyfert 2 nebula. The kinematics of the [O iii] ionized gas shows (1) the presence of highly disturbed gas in the regions around the LINER nucleus, (2) a high-velocity gas flow with a peak-to-peak amplitude of 2.4x103 km s-1, and (3) quiescent gas in the outer regions (at 3 kpc). We hypothesize that the high-velocity flow is the starburst-driven superwind generated in an optically obscured nuclear starburst and that the quiescent gas is directly ionized by a nuclear source, similar to the ionization cones typically seen in Seyfert galaxies.

The stroke-prone spontaneously hypertensive rat (SHRSP) is a strain with high incidence of cerebrovascular accidents increased by salt-rich diet and decreased by calcium-antagonist treatment. In the SHRSP rat basilar artery the authors have previously shown reduced contractility and altered structure including regions of smooth muscle cell (SMC) disorganization. The aims of this study have been to analyze (1) the morphology of these abnormal regions, (2) the structural modifications responsible for the reduced function, and (3) the effect of salt and calcium-antagonist treatment on vascular structure and function. Wistar Kyoto and SHRSP rats, untreated or treated from week 8 through 14 with 1% NaCl or 1% NaCl + 1 mg x kg(-1) x d(-1) lacidipine, were used. Function was studied with wire myography. Structure was analyzed in fixed intact arteries with confocal microscopy. Basilar arteries from SHRSP rat showed (1) reduced contractility, (2) discrete foci of SMC disarray with altered proportion of adventitia to SMC, and (3) decreased SMC and increased adventitial cell number. Arteries from salt-loaded SHRSP rats showed a higher degree of SMC disarray and further reduction in contractility. Lacidipine treatment of salt-loaded rats significantly improved structure and function. These data suggest that vascular remodeling can provide an explanation for the observed reduction in vascular contractility of SHRSP rat basilar arteries and might show light on the effects of salt load and calcium-channel blockers in life span and the incidence of cerebrovascular accidents in SHRSP rats.

The introduction of myographs was crucial for the study of structure and function of resistance arteries. The ability to support and maintain small blood vessels paved the way for true microscopic studies of the vascular cells. However, even after decades of study, we still do not know very much about the "normal" arrangement of smooth muscle cells in the vascular wall and how their distribution affects function. It was clearly time for the next technological step forward. We have shown here how the combination of myography and confocal microscopy creates a platform for the study of vascular structure at the cellular level and in 3D. In addition, the possibility of using live myograph-mounted vessels in combination with LSCM opens a new field of research to assess vascular remodeling from a physiological point of view and to study vascular function at a level not achieved by any other method at present. Now that the hardware is in place it is time to concentrate on the software and improve the methods of analysis. We have used 2D analysis of 3D data sets to describe differences in vascular structure and, at the same time, developed methods to semiautomate the process. The success of the 3D methods will ultimately depend on the reliability and accuracy of the analysis routines. There are still problems to overcome en route to finding a complete solution. However, we believe that the search for a robust fully (or semi-) automated method of 3D analysis will be more than worthwhile. We have defined vascular remodeling to include any changes in cellular arrangement or morphology. However, on a more subtle level, changes in receptors, enzymes, and proteins leading to altered functionality could also be regarded as remodeling. In that respect it may be interesting to map the distribution of the many receptors, channels, and proteins that regulate vascular growth, death, and function. Currently, there is a growing list of fluorescent ligands and antibodies that can be used in conjunction with confocal microscopy. It is possible that multiple stains could be used and imaged at different wavelengths with a view to constructing full 3D models of various structures and their colocalization. It is our belief that the confocal approach will prove to be a major tool in unraveling the complexities of cell-cell interactions and arrangements and will allow a better understanding of the process of vascular remodeling and function.

In this article we describe the decision making process used to choose the best alternative for bringing under control an epidemic of meningococcal C disease, which occurred in Galicia in 1996. In the decision making process, we used a methodology which consisted on the identification and definition of a problem, in order to identify alternative solutions and to select one, and finally implement and evaluate it. The health problem was detected studying the data obtained from a survey conducted following an outbreak of meningococcal C disease in february 1995 and from the active epidemiological surveillance system created thereafter. Because this was a new, complex and severe problem, with far-reaching social consequences, critical for our organization, and with long-term implications, and because it was considered important to take the decision as objectively as possible and to clearly explain it, the methodology chosen to solve the problem was a non-programmed, multicriteria making decision process, carried out by a working group using a criterion weighting approach. This working group was created within the General Directorate of Public Health, composed of specialist and of people responsible for the different areas involved. The working group put into practice the different steps of the methodology. The assessment criteria and their respective weights were: effect (efficacy measured by the number of cases we could have prevented if the alternatives were applied in the previous season) 40%; cost (in millions of pesetas) 15%; acceptability (acceptance of and response to each strategy from different groups: general population, health care professionals, other Administrations with competency in Public Health) 30%; and coherence (adherence to the currently accepted strategies for disease control in other countries)15%. When these criteria were applied to the ten alternatives considered, a score was obtained for each one of them. The highest scoring alternative corresponded to the massive vaccination of the total population of Galicia between 18 months and 19 years of age.

A substellar-mass object in orbit at about 300 astronomical units from the young low-mass star G 196-3 was detected by direct imaging. Optical and infrared photometry and low- and intermediate-resolution spectroscopy of the faint companion, hereafter referred to as G 196-3B, confirm its cool atmosphere and allow its mass to be estimated at 25-10+15 Jupiter masses. The separation between the objects and their mass ratio suggest the fragmentation of a collapsing cloud as the most likely origin for G 196-3B, but alternatively it could have originated from a protoplanetary disc that has been dissipated. Whatever the formation process was, the young age of the primary star (about 100 million years) demonstrates that substellar companions can form on short time scales.

1. We have studied the alpha 1-adrenoceptor-mediated responses in intact tail artery rings from 3-4 and 20-22 months old Sprague-Dawley rats, focusing on possible endothelial alterations. The influence of nitric oxide released by the endothelium, the number of alpha 1-adrenoceptors and the functional receptor reserve were evaluated to determine their contribution to the contractile response mediated by this receptor. The state of the endothelial layer was assessed by confocal microscopy. 2. Noradrenaline (1 nM-100 microM) induced concentration-dependent vasoconstriction. The maximum contractions to noradrenaline (P < 0.05) and to 75 mM KCl (P < 0.01) were higher in young than in old animals. 3. The density (Bmax) of alpha 1-adrenoceptors and the dissociation constant (KD) obtained in [3H]-prazosin binding experiments were unchanged by age. 4. The apparent affinity (pKA) and the percentage of functional receptors (qx 100) remaining after phenoxybenzamine (0.03 microM) were similar in both age groups. 5. After partial alpha 1-adrenoceptor inactivation with phenoxybenzamine, NG-nitro-L-arginine methylester (30 microM) significantly potentiated the E/[A] curve to noradrenaline in young rats. However, only responses to 0.1 to 1 microM noradrenaline were significantly potentiated in old animals. In addition, 94% of the vessels from young, but only 52% from old rats were relaxed by 80-100% of the noradrenaline (0.03 microM) contraction, with 1 microM acetylcholine. 6. No modifications in the area (micron2) or in the number of endothelial nuclei (per mm2) were observed between age groups. An elongation of the nuclei of endothelial cells was observed in the old animals. 7. These data suggest that the noradrenaline-induced contraction is decreased in old rats probably due to differences in either the contractile machinary or postreceptor mechanisms. These alterations may be accompanied by an impairment of the release or production of NO from endothelial cells.

The influence of vascular endothelium on ouabain-induced contractions and sodium pump activity in aortic segments of Wistar-Kyoto (WKY) and spontaneously hypertensive rat (SHR) was analyzed. De-endothelialization increased and reduced ouabain-induced contractions in WKY and SHR segments, respectively. The effects of de-endothelialization were not reproduced by pretreatment of the segments with NG-nitro-L-arginine methyl ester, indomethacin, or 5, 8, 11, 14-eicosatetraenoic acid, acetyl salicylic acid, dazoxiben, phosphoramidon, BQ-123, or superoxide dismutase. Bioassay experiments suggest that ouabain releases a diffusible factor from endothelial cells that inhibits or facilitates digitalis-induced contractions in WKY and SHR segments, respectively. In a potassium-free solution, potassium-induced relaxation in segments of both strains was abolished by ouabain in de-endothelialized aortas and reduced in intact ones. Ouabain-sensitive 86Rb+ uptake was significantly reduced by de-endothelialization both in WKY and in SHR. These results suggest that the vascular endothelium of WKY and SHR aortas releases a diffusible factor that stimulates the sodium pump and/or protects it from ouabain blockade. Ouabain also releases a diffusible endothelium-derived factor in SHR aortas that facilitates ouabain-induced contractions.

The structure and composition of living small blood vessels can be studied in great detail in three dimensions using confocal microscopy. Individual cells and their components can be visualised by vital dyes for the nucleus, cytoplasm or extracellular space. Specific ligands can then localise individual components such as membrane receptors with great precision. Cell function is unaffected, allowing the study, in real time, of the changing relation and contribution to vascular contraction or dilatation of different cell types particularly smooth muscle, endothelium and adventitia. This allows not only visualisation but quantification, using image analysis software. These techniques will be of particular value in assessing the contribution of form to function in pathological situations such as vascular remodelling in hypertension.

The muscarinic (M) receptors involved in the vasodilation elicited by acetylcholine (ACh) and in the carbachol inhibition in electrically induced [3H]noradrenaline (NA) release in cat cerebral arteries was investigated. For this, atropine, pirenzepine, AF-DX 116, 4-DAMP, non-specific, M1, M2 and M3 receptor antagonists, respectively, were used. ACh elicited concentration-dependent relaxations up to 10(-6) M which were attenuated by these antagonists; the order of potency (pA2 values) to inhibit the ACh-induced relaxation was: atropine (10.1) 4-DAMP (8.9) greater than pirenzepine (7.6) greater than AF-DX 116 (5.9). The electrical stimulation (200 mA, 0.3 ms, 2 Hz, during 1 min) of these arteries preincubated with [3H]NA caused tritium release which was inhibited by carbachol (10(-6) M). The 4 antagonists attenuated the action of the M agonist; the order of potency (pIC50 values) was: atropine (8.7) greater than 4-DAMP (8.1) greater than AF-DX 116 (7.9) greater than pirenzepine (5.8). The action of McN-A-343, a putative M1 agonist, was also investigated. This agent produced small vasodilator responses and elevated concentrations (5 x 10(-5) M) inhibited the stimulated NA release, which was partially antagonized by atropine (10(-7) M) and pirenzepine (10(-8) and 10(-7) M). These results suggest the existence of M3 and M2 receptors mediating the relaxation induced by ACh and the NA release inhibition evoked by carbachol, respectively.

The possible existence of a heterogeneous population of alpha 2-adrenoceptors (alpha 2A and alpha 2B, demonstrated by binding studies) in adrenergic nerve endings of cat and bovine cerebral arteries modulating noradrenaline release was investigated. Electrical field stimulation elicited an increase of tritium secretion from these vessels preincubated with (+/-)-[3H]noradrenaline, which was reduced by the alpha 2-agonists, clonidine (1 microM) and B-HT 920 (0.01 and 0.1 microM), in cat cerebral arteries but only by B-HT 920 in bovine cerebral arteries. This reduction was inhibited by the antagonist of the alpha 2B-subtype, prazosin, and the antagonists of alpha 2A- and alpha 2B-subtypes yohimbine and particularly rauwolscine. The effect of B-HT 920 was partially inhibited by clonidine in bovine, but not in cat cerebral arteries. In both types of arteries, prazosin, yohimbine and the alpha 1-agonist methoxamine (all at 1 microM) failed to modify the stimulated radioactivity liberation, whereas it was increased by 1 microM rauwolscine, and by yohimbine plus prazosin in cat cerebral arteries. The basal tritium release was enhanced by rauwolscine and prazosin in cat cerebral arteries but only by the latter in bovine cerebral arteries. These results suggest: (1) the existence of presynaptic alpha 2-adrenoceptors, mainly of the alpha 2B-subtype, in these vessels negatively modulating noradrenaline release, their activity being greater in cat than in bovine cerebral arteries, and (2) clonidine has no agonistic but a weak antagonistic action in the latter vessels.