Delia Garrido

Gene expression profiling of the hedgehog signaling pathway in human meningiomas

The Hedgehog (Hh) signaling pathway has an important role during embryogenesis and in adult life, regulating proliferation, angiogenesis, matrix remodeling and stem-cell renewal. Deregulation of the Hh pathway is involved in tumor development, since mutations in several components of this pathway were found in patients with basal cell carcinoma, medulloblastoma and other tumors; however, the role of Hh in meningiomas has not been studied yet. Meningiomas represent 30% of primary cranial tumors, are mostly benign and prevail in the second half of life. Novel therapies for meningiomas such as targeted molecular agents could use Hh pathway components. To provide information concerning molecular alterations, by use of real-time RT-PCR, we studied expression at the mRNA level of 32 Hh pathway and target genes in 36 meningioma specimens of different grades. mRNA levels of 16 genes, involved mainly in Hh pathway activation and cell proliferation, increased in meningiomas in comparison with normal tissue, whereas those of 7 genes, mainly related to Hh pathway repression, decreased. The most significant changes occurred in signal transduction (SMO) and GLI-transcription factor genes, and the target FOXM1 mRNA attained the highest values; their overexpression was found in aggressive and in benign tumors. Some proliferation-related genes (SPP1, IGF2) were overexpressed in higher meningioma grades. A correlation in expression between genes with a similar function was also found. Our results show a marked activation of the Hh pathway in meningiomas, which may be important for their biological and clinical characterization and would be useful for gene therapy.

Long-Term Effects of Parathyroidectomy on Hypertension Prevalence and Circadian Blood Pressure Profile in Primary Hyperparathyroidism

Our aims were to evaluate the prevalence and outcome of hypertension in patients with primary hyperparathyroidism (PHPT), previously and after follow-up of parathyroidectomy. A group of 46 consecutive patients with sporadic PHPT due to adenoma undergoing surgery were followed an average of 3.5 years (range 36 to 53 months). In 16 nonselected, consecutive parathyroidectomized patients, with normalized biochemical measurements, circadian rhythm of blood pressure was evaluated with ambulatory blood pressure monitoring (ABPM). Prevalence of hypertension in PHPT was 54.35%, and there was no significant association of PTH, total and ionic calcium levels with SBP and DBP. During follow-up, none of the patients with presurgical hypertension became normotensive and five of the normotensive patients developed clinical hypertension. In ABPM, 6/11 hypertensive and 3/5 normotensive subjects showed nondipper behavior. Serum total calcium was significantly related to night-time systolic blood pressure (SBP) (r = 0.620, P < 0.02), and night-time diastolic blood pressure (DBP) (r = 0.758, P < 0.002). In dippers, creatinine clearance was significantly higher (91.3 ± 18.5 vs. 64.3 ± 11.5 ml/min, P < 0.01), while serum total calcium was lower (2.42 ± 0.13 vs. 2.23 ± 0.17 mmol/L, P < 0.04) than in nondippers. In conclusion, our results suggest that parathyroidectomy has little effect on hypertension prevalence. Renal impairment, a condition that did not improve after parathyroidectomy, may be a causal factor of hypertension in PHPT. Also, the high prevalence of nondipper behavior in hypertensive and normotensive subjects after parathyroidectomy, suggests that target organ risk persists. We hypothesized that slight elevations of serum total calcium even in the normal range could be involved in the alteration of the circadian rhythm of blood pressure.

Gene Expression Profiling of ErbB Receptors and Ligands in Human Meningiomas

ErbB family receptors mediate major cellular functions implied in tumorigenesis, though their role in meningiomas was not thoroughly studied. Meningiomas represent 30% of primary cranial tumors, are mostly benign, and prevail in the second half of life. Tumor therapy requires information about molecular alterations, thus we studied expression of ErbB receptor and ligand genes by real-time RT-PCR in different meningioma grades. Receptors were overexpressed (ErbB1, ErbB2) or underexpressed (ErbB3, ErbB4). Ligands EGF, TGFA, AREG, DTR, BTD were underexpressed and the neuregulins were overexpressed or underexpressed. A strong ErbB1–ErbB2 correlation was found. These data might be useful for gene therapy.

Blood sugar, serum insulin and serum free fatty acid responses to slow graded glucose in thyroxine-treated dogs

SummaryThe effects of short-term (10 days) thyroxine administration (100 µg/kg body weight/die) on the BS, serum IRI and circulating FFA responses to slow, graded glucose stimulation were studied in dogs. The experiments reported demonstrated that the mean basal BS value in thyroxine-treated dogs is higher than that found in untreated controls, and that non-parallel mean BS responses to glucose infusion were observed during the test: the higher curve was found in the thyroxine-treated group. Mean basal serum IRI was similar in both groups, and parallel insulinemic responses to hyperglycemia were observed. Mean serum IRI responses as a function of time from the start of infusion in hyperthyroid dogs were lower than those observed in untreated controls. Mean basal serum FFA levels in both groups did not differ, and parallel serum FFA curves were found during the test. Thyroxine treatment caused a better lipogenic response to combined hyperglycemia/hyperinsulinemia and a steep subsequent rebound of serum FFA, as compared to untreated controls. We conclude that dogs with recently induced hyperthyroidism show an impairment in the net glucose uptake by tissues, a poor insulinemic response to glucose, a good lipogenic response and a sharp subsequent rebound of serum FFA. The high BS curve, the high tissue FFA response to insulin antagonists and the high mean BS level in the fasting condition might be accounted for by a thyroxine-induced active production of cAMP in body cells, but the low insulin secretion evidently is due to other mechanisms.

Association between nondipper behavior and serum calcium in hypertensive patients with mild-to-moderate chronic renal dysfunction.

A nondipping BP pattern has been shown to be predictive of end-organ damage, cardiovascular events, and mortality. The mechanisms of blunted nocturnal BP fall are multifactorial. We assessed whether total corrected serum calcium and ionic calcium (iCa) are associated with a blunted nocturnal BP fall in both treated and untreated hypertensive patients with stages 1–3 of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI). Clinical data and 24-hour ambulatory blood pressure monitoring were obtained in a cohort of 231 essential hypertensive patients. Among the entire cohort, 107 were nondippers and 124 were dippers. Only in nondippers, we found significant correlations between iCa and 24-hour systolic blood pressure (SBP; r = 0.21, P < .03), diurnal SBP (r = 0.21, P < .03), and 24-hour pulse pressure (PP; r = 0.23, P < .02). The ambulatory arterial stiffness index (AASI) was significantly related with 24-hour PP in both dippers and nondippers after adjusting for age. Both AASI and 24-hour PP were higher in nondippers than in dippers. In addition, in nondippers, the prevalence of estimated glomerular filtration rate (eGFR) <60 mL/minute/1.73 m2 was higher than in dippers (50% vs. 33.7%, P < .02). Logistic regression showed that patients with eGFR ≥60 mL/minute/1.73 m2 had lower risk of nondipper status than patients with eGFR <60 mL/minute/1.73 m2 (odds ratio = 2.445; 95% confidence interval = 1.398–4.277, P < .002). In conclusion, serum iCa could participate in the pathogenesis of nondipping pattern. Increased large artery stiffness may be a mechanism of the deleterious influence of nondipping on cardiovascular outcome. Hypertensive subjects with stage 3 of NKF KDOQI had a greater loss of circadian BP rhythm than those in stages 1 and 2.

Relationship between Hyperinsulinemia and Ambulatory Blood Pressure Monitoring of Lean and Overweight Male Hypertensives

Objective To elucidate the role of hypertension as part of a state of insulin resistance. Methods Thirty-one uncomplicated hypertensive men not receiving antihypertensive treatment or who had been without treatment for a 4-week washout period and 10 lean normotensive controls were compared. Hypertensive men were divided according to their body mass index into three groups. All subjects came to the clinic for measurements of height, weight, hip and waist circumferences, and sitting blood pressure, and to begin 24 h ambulatory blood pressure monitoring. Plasma glucose and insulin levels were measured during a 2 h oral glucose (75 g)-tolerance test. For the hypertensive population as a whole, behaviors of studied variables among dippers (n= 18) and nondippers (n= 13) were determined. Results During oral glucose-tolerance testing blood glucose levels after 60 min and 120 min were significantly higher (P < 0.05) in members of the high body mass index group than they were in members of the low body mass index group. insulin levels of members of the high and middle body mass index groups were higher than those of members of the low body mass index group after 60 min (P < 0.05 for both comparisons) and 120 min (P < 0.05 for both comparisons). The mean serum insulin level in members of the low body mass index group was significantly higher than that in normotensives after 30 min, 60 min and 120 min (P < 0.05 for all three comparisons). The mean serum insulin: Plasma glucose ratio for men in the low BMI group was significantly higher than that for normotensives after 60 min and 120 min (P < 0.05 for both comparisons). Correlations of blood pressure and insulin levels were not significant. Levels of high-density lipoprotein cholesterol and triglycerides were lower in members of the group with high body mass index than they were in members of the group with low body mass index. Total cholesterol: High-density lipoprotein cholesterol ratio was higher for members of the high body mass index group than it was for members of the middle body mass index group. Weight, body mass index, casual systolic blood pressure, 24 h average systolic blood pressure and diastolic blood pressure, 0700-2300 h systolic blood pressure, and 24 h average heart rate-systolic blood pressure product of dippers were significantly lower than those of nondippers. Conclusions These results suggest that hypertension and being overweight have additive effects increasing insulinemia and that being overweight is associated with a significantly lower nocturnal fall in blood pressure. J Cardiovasc Risk 5: 25-30

Blood sugar, serum insulin and serum free fatty acid responses to graded glucose pulses in hypothyroid dogs

SummaryThe actions of hypothyroidism on BS, serum IRI and circulating FFA profiles observed in response to single glucose pulses at three levels of stimulation (1.00, 0.66 and 0.33 g/kg body weight) in male dogs were studied. Hypothyroidism modified neither of the mean basal values of these variables. There were different mean BS responses for every time and dose with significant interaction between the two. The BS curves at different doses were not parallel. There was a different time effect for every dose of glucose, and normal and hypothyroid dogs did not differ in this respect. The mean serum IRI responses found in normal and hypothyroid dogs were different; the mean responses at different times also differed, and there were significant normality-time and dose-time interactions. If the hypothyroid dogs and the euthyroid controls received a particular dose of glucose, a significant time effect on the serum IRI level was observed. In the normal dogs receiving glucose dose 1.00, a significant serum IRI response between 5 and 25 min was observed; in the hypothyroid dogs receiving a similar treatment, the significant response lasted from 5 to 45 min. In the normal dogs receiving glucose dose 0.66, the response was significant only at 5 min, and the serum IRI levels were below baseline between 60 and 90 min, while in the hypothyroid dogs the IRI response lasted from 5 to 25 min. In both normal and hypothyroid dogs receiving the 0.33 dose, the responses were significant between 5 and 25 min. As for the mean serum FFA responses to glucose, they were different at every time, and a significant normality-time interaction was found. In the euthyroid controls, the response lasted from 5 to 60 min, while it was longer in the hypothyroid dogs, lasting from 5 min after glucose injection until the end of the test.

Primary care survey of awareness and control of hypertension: a hospital-based study.

The objectives of this cross-sectional study were to determine awareness degree, treatment status, and control of hypertension and its predictors in a consecutive group of attendees at a Buenos Aires University School Hospital primary care setting from April 2003 to May 2006. Results for 1733 hypertensive subjects, all of them white (578 men and 1155 women), were available for analyses. Mean age of hypertensive subjects was 66.61 ± 12.34 years. Eighty-seven percent of hypertensive patients knew their diagnosis. Prevalence of hypertension was consistently higher in overweight-obese than in normal weight subjects (P < 0.001). Overall prevalence of hypertension treatment was 62%, and blood pressure (BP) control rate was 30%. Among knowledgeable treated hypertensive patients, 80.4% used only one antihypertensive drug, 17.6% used two, and 2% used three (P < 0.001). Only 8% of hypertensive patients carried out consensus-recommended dietarian guidelines. A prevention index performed with periodic general prevention measures during the past 5 years was calculated. Logistic regression model showed that independent variables more likely to be associated with poor BP control were being overweight (odds ratio [OR] 1.53, 95% confidence interval [CI] 1.057-2.208), obesity (OR 2.1, 95% CI 1.307-3.286), and previous stroke (OR 2.9, 95% CI 1.099-7.652). Conversely, the higher the prevention index, the less odds of uncontrolled BP (OR 0.841, 95% CI 0.725-0.975). These results highlight the consistency of general primary care prevention measures with achieving BP control. The poor control rates of BP found in patients who already suffered from stroke suggest that, after hospital discharge for that event, antihypertensive therapy was inadequate and document the challenge that these situations impose on primary care physicians.

Effects of short-term thyroxine treatment on pancreatic cytology and responses of blood sugar, serum insulin and serum free fatty acids to epinephrine infusion

The influence of short-term treatment with l-thyroxine on pancreatic histology and on the responses of glycemia, insulinemia and serum free fatty acids to a continuous l-epinephrine infusion in the absence or presence of alpha- and beta-adrenergic blockade was studied in male dogs. l-Epinephrine dosage: 0.06 microgram/kg body weight/min for 55 min. Two experimental groups were studied, one treated for 10 days with sodium l-thyroxine, one daily dose of 100 micrograms/kg body weight, the other of untreated controls. Three alternative treatments were applied to dogs of both groups: 1) no treatment; 2) alpha-adrenergic blockade with phentolamine (2.0 mg/kg body weight, 35 min before starting the l-epinephrine infusion); 3) beta-adrenergic blockade with propranolol (0.3 mg/kg body weight, 20 min before starting the l-epinephrine infusion). Body weight, rectal temperature, heart and respiratory rates were used as guidelines to assess experimental hyperthyroidism. Insulin immunocytolocalization was also studied in the Langerhans islets of T4-treated and control dogs. Body weight decreased and rectal temperature did not vary as a result of thyroxine administration which had no significant effect on respiratory and heart rate. The mean number of breaths from 0 to 120 min from the start of l-epinephrine infusion decreased in both T4-treated and control dogs submitted to propranolol blockage compared to non-blocked animals; phentolamine had no effect on the respiratory rate. Thyroxine treatment did not modify the number of heart beats, but phentolamine blockade had a different effect in T4-treated compared to control dogs whereas propranolol had similar effects in these two groups. Histological examination of the Langerhans islets of dogs submitted to short-term thyroxine treatment showed degranulation though no vacuolation. Most of the beta-granules contained in the B-cells of these islets were found near the cell membrane, thus forming a dark brown line after the immunochemical reaction. Since negative images of B-cell nuclei and vascular spaces were predominant in these specimens, the pancreas of T4-treated dogs presented a mesh structure. In dogs submitted to short-term thyroxine treatment, the hyperglycemic response to l-epinephrine was enhanced and prolonged as compared to untreated controls. In normal dogs, this response is mainly mediated by alpha-adrenergic receptors while beta-receptors hardly influence this response.(ABSTRACT TRUNCATED AT 400 WORDS)

Primary care role in awareness and control of hypertension: a hospital-based study

To the Editor: Based on survey data, it has been estimated that the prevalence of hypertension in Latin America and the Caribbean countries ranges from 8% to 43% (1–4) and is affected by ethnicity and cultural facts. Yet, little is known about the relationship between general preventive medicine measures taken by the sample population studied and its impact on treatment and control of hypertension. Also, there is a lack of information about the validity of the data conveyed by hypertensive patients about their adherence to consensus dietary guidelines and the real complying. We performed a cross-sectional study in a primary care setting of the Hospital de Clı́nicas, Universidad de Buenos Aires aiming to assess the degree of awareness, treatment status, compliance to dietary recommendations, control rate of hypertension in the whole sample, associated cardiovascular risk factors, and blood pressure (BP) control rate (<140 mm Hg systolic BP and <90 mm Hg diastolic BP) in hypertensive subjects who had previously suffered stroke or myocardial infarction. Also, we intended to test our hypothesis that a calculated general prevention index (PI) based on representative preventive medicine measures and regular physical exercise individually carried out in the last 5 years could serve as a predictor of BP control. Results for 1733 hypertensive subjects, all of them white (578 men and 1155 women, mean age 66.61 ± 12.34 years) consecutively attended were available for analyses. Eightyseven per cent of hypertensive subjects knew their diagnosis, and the prevalence of hypertension was consistently higher in overweight obese than in normal weight subjects (p < 0.001). Overall, the prevalence of pharmacologic treatment of hypertension was 62% but the BP control rate was only 30%. Among knowledgeable-treated hypertensive subjects 80.4% used only one antihypertensive drug; 17.6% used two and 2% used three (p < 0.001). Only 8% of hypertensives carried out consensus recommended dietarian guidelines while 79% asserted that they did. The PI considered patients’ answers about chest x-rays, flu vaccines and faecal occult blood test, digital rectal examination and prostate ultrasonography or prostate-specific antigen level in men, and mammography and papanicolaou in women, performed during the past 5 years. A numeric value was assigned for each variable, zero if answer was negative and one if affirmative, and PI was calculated as summation of the five variables, for each gender. Regular physical activity executed at least once a week during the same period of time was also recorded. Logistic regression model showed that independent variables more likely to be associated with poor BP control were: overweight (OR 1.53, 95% CI: 1.057–2.208), obesity (OR 2.1, 95% CI: 1.307–3.286) and previous stroke (OR 2.9, 95% CI: 1.099– 7.652). Previous myocardial infarction was not associated with poor BP control, whilst the less odds of poor controlled BP were high PI (OR 0.841, 95% CI: 0.725–0.975) and regular physical activity (OR 0.67, 95% CI: 0.449– 0.989). Using a validated index to assist with clinical decision making could help care for hypertensive patients. However, before implementation as a predictor, the model should be validated externally using a different patient population and clinical setting. The poor control rates of BP found in patients who already suffered from stroke suggest that after hospital discharge for that event antihypertensive therapy was inadequate and document the need of a more stringent surveillance.