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The accumulation of anthocyanin pigments is one of the most important traits that turn strawberry fruit attractive to consumers. During ripening, strawberry fruit color development is associated to anthocyanin synthesis through the phenylpropanoid pathway. Phenylalanine ammonia-lyase (PAL) is a key enzyme in this pathway, having a determining role in strawberry fruit quality. In this work, we studied the level of anthocyanins during fruit ripening of two cultivars that differ in color development (Camarosa and Toyonoka). Toyonoka showed a lower anthocyanin accumulation that was limited to external fruit tissue, while Camarosa accumulated higher amount of anthocyanins in both internal and external sections. In addition, we cloned a full-length gene (FaPAL6) and analyzed its expression in different strawberry plant tissues. The expression of this gene is fruit specific, and increases during fruit ripening in both cultivars along with anthocyanin accumulation. The mRNA level of FaPAL6 was higher in Camarosa. PAL enzyme activity increased at similar rates in both cultivars at early ripening stages, but at the end of ripening PAL activity diminished in Toyonoka while it rose markedly in Camarosa. PAL activity was higher in internal fruit tissue, showing no correlation with anthocyanin level of the same section in both cultivars. The higher FaPAL6 expression and activity detected in Camarosa could be associated to the enhanced anthocyanin accumulation found in this cultivar., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: There are several known autosomal genes responsible for Ras/MAPK pathway syndromes, including Noonan syndrome (NS) and related disorders (such as LEOPARD, neurofibromatosis type 1), although mutations of these genes do not explain all cases. Due to the important role played by the mitochondrion in the energetic metabolism of cardiac muscle, it was recently proposed that variation in the mitochondrial DNA (mtDNA) genome could be a risk factor in the Noonan phenotype and in hypertrophic cardiomyopathy (HCM), which is a common clinical feature in Ras/MAPK pathway syndromes. In order to test these hypotheses, we sequenced entire mtDNA genomes in the largest series of patients suffering from Ras/MAPK pathway syndromes analyzed to date (n = 45), most of them classified as NS patients (n = 42)., Methods/principal Findings: The results indicate that the observed mtDNA lineages were mostly of European ancestry, reproducing in a nutshell the expected haplogroup (hg) patterns of a typical Iberian dataset (including hgs H, T, J, and U). Three new branches of the mtDNA phylogeny (H1j1, U5b1e, and L2a5) are described for the first time, but none of these are likely to be related to NS or Ras/MAPK pathway syndromes when observed under an evolutionary perspective. Patterns of variation in tRNA and protein genes, as well as redundant, private and heteroplasmic variants, in the mtDNA genomes of patients were as expected when compared with the patterns inferred from a worldwide mtDNA phylogeny based on more than 8700 entire genomes. Moreover, most of the mtDNA variants found in patients had already been reported in healthy individuals and constitute common polymorphisms in human population groups., Conclusions/significance: As a whole, the observed mtDNA genome variation in the NS patients was difficult to reconcile with previous findings that indicated a pathogenic role of mtDNA variants in NS.

We report a case of congenital hypothyroidism (CH) with neurological and respiratory alterations due to a heterozygotic c.374-1G > A mutation of TITF1/NKX2-1. The hypothyroidism was detected using a neonatal screening protocol in which the thyroid stimulating hormone (TSH) threshold is re-set each day on the basis of within-day variability and between-day variation. In this case, the threshold on the day of the initial analysis was 8.2 mIU/L, and the measured TSH level in heel-prick blood was 8.3 mIU/L.

Introduction and Objectives: An abnormal ankle-braquial index (ABI) has been related to a higher vascular mortality in the general population. People with HIV infection have a higher prevalence of abnormal ABI than general population. Our aim was to study that prevalence in a cohort of patients with HIV chronic infection and associated factors with an abnormal ABI., Methods: ABI was calculated consecutively in all the patients who agreed to participate. Abnormal ABI was defined as that lower than 0.9 or higher than 1.3. Demographic variables and those related to vascular risk, HIV infection status and antiretroviral therapy were assessed., Results: 231 patients collaborated in the study, and 25% of them had abnormal ABI (<0.9 in only 3 patients). Age, hypertension, lipid lowering agents use, vascular risk using Framingham equation, proportion of AIDS, CD4 nadir, years with the infection and protease inhibitors use were greater in the group with abnormal ABI. In logistic regression, lipid lowering agents use (OR: 0.39, CI95%: 0.16-0.94) and protease inhibitors use (OR: 2.59, CI95%: 1.33-5.05) remained in the model., Conclusion: Protease inhibitors use is associated with abnormal ABI, overall with an ABI greater than 1.3., (Copyright © 2010 Elsevier España, S.L. All rights reserved.)

The purpose of this article is to analyze the incidence, demographic distribution, type, and etiology of all facial fractures treated by the Department of Oral and Maxillofacial Surgery in A Coruña University Hospital (Spain) from 2001 to 2008. A descriptive and analytic retrospective study evaluated 643 patients treated for facial fracture (excluding nasal and dento-alveolar) by the Department of Oral and Maxillofacial Surgery in A Coruña University Hospital from January 2001 to December 2008. Five parameters were studied: year of the injury, gender, age, fracture type, and etiology. Six hundred and forty-three patients with 793 fractures were included. Of these, 83.2% were males and 16.8% were females. The patients' age ranged between 18 months and 89 years, with a mean of 37.6 and a median of 33. The major cause of injury was traffic accidents (27%), followed by assaults (20.5%), accidental traumas (20.1%), sports (11%), syncopes (7.8%), rural accidents (6.1%), industrial accidents (5.1%), and suicide attempts (0.3%). In 1.1% of the patients, it was impossible to verify the etiology. The etiology of facial fractures varies from one country to another, depending on the cultural, environmental, and socioeconomic factors. In our study, the most common cause was traffic accidents, closely followed by assaults. The number of fractures due to traffic accidents has decreased in the last 3 years. Rural accidents accounted for a significantly higher percentage of fractures than that observed in other series. The number of fractures receiving a surgical treatment from 2005 to 2008 has progressively decreased.

Context: Steroid 11beta-hydroxylase (CYP11B1) deficiency (11OHD) is the second most common form of congenital adrenal hyperplasia (CAH). Cases of nonclassic 11OHD are rare compared with the incidence of nonclassic 21-hydroxylase deficiency., Objective: The aim of the study was to analyze the functional consequences of seven novel CYP11B1 mutations (p.M88I, p.W116G, p.P159L, p.A165D, p.K254&#95;A259del, p.R366C, p.T401A) found in three patients with classic 11OHD, two patients with nonclassic 11OHD, and three heterozygous carriers for CYP11B1 mutations., Methods: We conducted functional studies employing a COS7 cell in vitro expression system comparing wild-type (WT) and mutant CYP11B1 activity. Mutants were examined in a computational three-dimensional model of the CYP11B1 protein., Results: All mutations (p.W116G, p.A165D, p.K254&#95;A259del) found in patients with classic 11OHD have absent or very little 11beta-hydroxylase activity relative to WT. The mutations detected in patients with nonclassic 11OHD showed partial functional impairment, with one patient being homozygous (p.P159L; 25% of WT) and the other patient compound heterozygous for a novel mild p.M88I (40% of WT) and the known severe p.R383Q mutation. The two mutations detected in heterozygous carriers (p.R366C, p.T401A) also reduced CYP11B1 activity by 23 to 37%, respectively., Conclusion: Functional analysis results allow for the classification of novel CYP11B1 mutations as causative for classic and nonclassic 11OHD, respectively. Four partially inactivating mutations are predicted to result in nonclassic 11OHD. These findings double the number of mild CYP11B1 mutations previously described as associated with mild 11OHD. Our data are important to predict phenotypic expression and provide important information for clinical and genetic counseling in 11OHD.

Proximal hamstring avulsions from the ischium are becoming more frequently recognized, secondary to their disability when treated nonoperatively. The acute repair of these injuries is becoming prevalent given the improved outcomes reported in the literature. Anatomic studies have recently been conducted on the proximal hamstring origin; however, there are few reports on surgical techniques for repair in the setting of injury. The present article describes the technique for proximal hamstring avulsion repair, as performed by the senior author. More than 30 cases have been performed based on this technique, with excellent results.

Background: Hypochondroplasia (HCH) is a skeletal dysplasia inherited in an autosomal dominant manner due, in most cases, to mutations in the fibroblast growth factor receptor 3 (FGFR3). Acanthosis nigricans (AN) is a velvety and papillomatous pigmented hyperkeratosis of the skin, which has been recognized in some genetic disorders more severe than HCH involving the FGFR3 gene., Objective and Design: After initial study of the proband, who had been consulted for short stature and who also presented AN, the study was extended to the patient's mother and to 12 additional family members., Methods: Clinical, biochemical and radiological studies were performed on the family. In addition, exons 11 and 13 of FGFR3 were analyzed., Results: The proband and ten relatives presented HCH plus AN and the analysis of FGFR3 showed the p.Lys650Thr mutation. The members with normal phenotypes were non-carriers of the mutation., Conclusion: This is the first report of a large pedigree with the clinical phenotype of HCH plus AN due to a FGFR3 mutation, p.Lys650Thr. This finding demonstrates the coexistence of both conditions due to the same mutation and it might represent a true complex, which should be further established by searching for AN in mild HCH patients or for HCH in patients with AN.

Context: Several endocrine disorders that share resistance to PTH are grouped under the term pseudohypoparathyroidism (PHP). PHP type I, associated with blunted PTH-induced nephrogenous cAMP formation and phosphate excretion, is subdivided according to the presence or absence of additional endocrine abnormalities, Albright's hereditary osteodystrophy (AHO), and reduced Gsalpha activity caused by GNAS mutations., Objective: We sought to identify the molecular defect in four unrelated patients who were thought to have PHP-Ia because of PTH and TSH resistance and mild AHO features., Methods: Gsalpha activity and mutation analysis, and assessment of GNAS haplotype, methylation, and gene expression were performed for probands and family members., Results: Two patients showed modest decreases in erythrocyte Gsalpha activity. Instead of Gsalpha point mutations, however, all four patients showed methylation defects of the GNAS locus, a feature previously described only for PHP-Ib. Furthermore, one patient with an isolated loss of GNAS exon A/B methylation had the 3-kb STX16 deletion frequently identified in PHP-Ib patients. In all but one of the remaining patients, haplotype analysis excluded large deletions or uniparental disomy as the cause of the observed methylation changes., Conclusions: Our investigations indicate that an overlap may exist between molecular and clinical features of PHP-Ia and PHP-Ib. No current mechanisms can explain the AHO-like features of our patients, some of which may not be linked to GNAS. Therefore, patients with hormone resistance and AHO-like features in whom coding Gsalpha mutations have been excluded should be evaluated for epigenetic alterations within GNAS.

Objective: To detect common as well as rare and novel CYP21A mutations in 21-hydroxylase deficiency patients. To estimate the distribution of mutations and compare them with other European studies. To construct haplotypes linked to a recurrent novel mutation., Design: Genetic analysis by sequencing the entire CYP21A2 gene plus Southern blot., Patients: A total of 138 unrelated Spanish patients: 122 nonclassical forms (NCF) and 16 classical forms (CF) were studied., Results: Among the 266 nonrelated mutated alleles; CYP21A2 deletions/conversions and a spectrum of 27 different mutated alleles were found: 15 different single point mutations, 8 nucleotide deletions in exon 3, 3 mutation clusters in exon 6, 9 alleles with more than one mutation, one 21-nucleotide duplication in exon 10, and one allele with CYP21A2 duplicated and both copies mutated. The most frequent mutation in NCF alleles is V281L (71.8%). Among CFs, the most common is I2 g (20%) and Q318X (16%) and rare alleles (21.9%). Six novel causative mutations were found, four associated with CF: I46+1nt, R444X, P463L and M473&#95;R479dup and two associated with NCF: W302 and D322G. The R444X mutation was found in seven unrelated patients and it appeared only once in an ancestral haplotype. In addition, we found a novel single nucleotide polymorphism with a 31.5% frequency for the rare allele., Conclusion: A great diversity of haplotypes with a large spectrum of mutated alleles was found. The frequency of the V281L mutation was the highest reported and the relatively high frequency of R444X was the result of a founder effect.

Growth in humans is a complex process controlled by many genetic and non-genetic factors. It is influenced by endogenous factors like genetics, hormones and metabolism as well as exogenous ones like nutrition, physical activity and psychosocial status. Growth is one of the most sensitive markers of children's health, their nutritional status and genetic background. Besides, deviation from normality may be the first manifestation of an underlying congenital or acquired pathology. Thus, it is important to know the growth process and the disorder that can disturb it. Short stature is defined as a condition in which the height of an individual is more than 2 SD below the corresponding mean height for a given age, sex and population group. This disorder is a major concern for patients and their parents, and represents a diagnostic challenge to the clinician. A correct diagnosis is particularly important in view of the availability of effective, but costly, therapy in a small subset of cases. Cytogenetic and molecular analysis can be of great value in this diagnostic process. Emphasis can be made on the advances of molecular genetics, which have characterized human genes involved in the hypothalamus-pituitary-GH axis such as GH, POU1F1, PROP1, GHRHR, GHR, IGF, IGFR, HESX1, LHX3, LHX4, among others. Our current line of investigation is related to the study of some of these genes and the genotype-phenotype relation with the aim of identifying features that add some more light on the genetic origins of short stature.

Mixed connective tissue disease (MCTD), undifferentiated connective tissue disease and overlap syndromes are autoimmune systemic diseases that must be differentiated. Antibodies against the U1-ribonucleoprotein complex --spliceosome-- allows the diagnosis of mixed connective tissue disease. Links between the immunologic and clinical phenomena are emerging. Longitudinal studies of patients with MCTD highlight the impact of pulmonary hypertension and contribute to define the disease. Immunogenetic studies hold MCTD as an independent disease.

The potency test for the anthrax vaccine currently licensed for human use in the United States (Anthrax Vaccine Adsorbed) involves the protection of actively immunized guinea pigs from a lethal challenge with a virulent strain of Bacillus anthracis. Lethal challenge tests entail the use of specialized containment facilities for the safe and secure handling of the challenge strain. This potential difficulty, plus humane considerations, have prompted us to investigate non-lethal, alternative immunogenicity assays that could be considered as potency tests not only for the current vaccine, but also for vaccines under development. Immunogenicity tests will require suitable measurement of an antibody response to relevant antigens, by methods such as enzyme linked immunosorbent assay (ELISA) or a toxin neutralization assay. Any assay chosen for this purpose should be adequately validated and reproducible by other laboratories. Validation of an analytical procedure requires the demonstration that the assay is suitable for its intended purpose. The objective of this work was to study the performance of an anti-PA-ELISA designed to assess the antibody response to anthrax vaccines in mice. Validation studies were performed according to the guidelines of the International Conference of Harmonization (ICH), and we have established the working range of the assay (37-1159 EU/mL) on the bases of the following parameters: linearity (20-1159 EU/mL; r2=0.99; p-value=0.21), accuracy (91-118% recovery), precision (< or =20%CV, repeatability; < or =9 and < or =21%CV, intermediate precision per day and per analyst, respectively), detection limit (5 EU/mL), and quantification limit (37 EU/mL). We believe that assay specificity and the above characteristics are adequate to allow this ELISA to be considered for use in a mouse immunogenicity (potency) test of anthrax vaccines, and for the standardization of reagents.

More than 40 years after the introduction of growth hormone (GH) treatment, many questions remain unanswered. Clearly, with the availability of rhGH and with current treatment protocols, treatment efficacy has improved. However, it still remains unclear whether current treatment protocols are the best possible. Before GH deficiency was recognized as a chronic disease, children only received treatment until normal adult height had been reached. However, it has recently been shown that not all GH-dependent body structures and functions normalize in parallel with height. Furthermore, in adolescents with GH deficiency, the interruption of GH substitution leads to severe hormone deficiency symptoms in adulthood. In the case of an adolescent who meets the biochemical criteria for GH deficiency in adulthood, but does not show alterations of metabolism, body structure, or emotional state, should GH treatment be started in adolescence, or only if and when the clinical syndrome becomes apparent? This is a difficult question to which there is not yet any clear answer, and we suggest that there is a need for further studies in this area. Furthermore, it will be necessary to re-evaluate the situation of patients who have completed their growth, and definitive conclusions will require controlled studies.

The pulsatile release of growth hormone (GH) from anterior pituitary gland is regulated by the interplay of at least two hypothalamic hormones, GH-releasing hormone (GHRH) and somatostatin, via their engagement with specific cell surface receptors on the anterior pituitary somatotroph. Furthermore, release of GH in vivo may also be controlled by a third type of receptor, the growth hormone secretagogue receptor, a G-protein-coupled receptor, called GHS receptor type 1a (GHSR1a), which was identified in the pituitary and the hypothalamus in humans using a nonpeptidyl growth hormone secretagogue (MK-0677). Ghrelin, the endogenous ligand for the GHS-R1a, is a 28-amino-acid peptide isolated from human stomach that is modified by a straight chain octanoyl group covalently linked to Ser3, which is essential for its endocrine activity. This hormone, predominantly expressed and secreted by the stomach, has a dual action on GH secretion and food intake, showing interdependency between these actions. The finding that fasting and food intake, respectively, increase and decrease the secretion of ghrelin suggests that this hormone may be the bridge connecting somatic growth and body composition with energy metabolism, and appears to play a role in the alteration of energy homeostasis and body weight in pathophysiological states such as hypothyroidism and hyperthyroidism. Despite this, little is known about the intracellular signaling through which ghrelin exerts its regulatory actions. Activation of intracellular calcium mobilization is one of the earliest known cellular signals elicited by ghrelin. In HEK- 293 cells expressing the GHS-R1a, ghrelin induces a biphasic cytosolic calcium elevation characterized by a spike phase of the response, which reflects Ins(1,4,5)P3- dependent calcium mobilization of intracellular stores, and a sustained phase of the response, which is due to calcium influx across the plasma membrane triggered by aperture of capacitative calcium channels (store-operated calcium channels). Upon repeated administration, ghrelin showed a marked suppression of ghrelin-mediated elevations of intracellular calcium. This homologous desensitization represents an important physiological mechanism that modulates receptor responsiveness and acts as an information filter for intracellular signaling system. The discovery of ghrelin adds a new component to the complex machinery responsible for regulation of GH secretion in connection with the regulation of appetite and energy homeostasis.

Acute coronary embolism is rarely diagnosed and it may explain why normal coronary arteries are found after or even before an acute coronary event in patients with thromboembolic risk factors. Emergency coronary angiography was performed in three patients with prior normal coronary arteries and an acute myocardial infarction, followed by primary angioplasty with low-pressure balloon inflations plus stenting and combined antiaggregation with aspirin, clopidogrel, and abciximab to disrupt the thrombi and protect distal circulation from microemboli. Angiographic success was achieved in 100%, and 6-month follow-up has been uneventful on oral anticoagulation and antiaggregation., (Copyright 2002 Wiley-Liss, Inc.)

Endocarditis due to Mycobacterium fortuitum complex is a rare entity generally linked to the hospital environment. Only 18 cases have been published since 1966. Here we present a case of a female who developed an endocarditis due to Mycobacterium chelonae after valve replacement as well as a review of the literature. The course of this kind of endocarditis is generally subacute and the outcome is usually fatal. Blood cultures were positive in 75% of cases of metallic valve endocarditis, versus 20% in bioprostheses. The treatment must include antibiotics that have shown activity against these mycobacteria, such as amikacin, imipenem, cefoxitin, fluorinated quinolones and macrolides (especially clarithromycin). Surgical removal is recommended. Although the prognosis for the patient is poor, we should expect better outcomes with the use of new antibiotic regimens.

Objective: Although thoracotomy for removal of pulmonary metastasis is well documented in a wide variety of solid tumors, data are sparse regarding management of patients with gynecologic malignancies metastatic to the lung., Methods: We retrospectively reviewed the Roswell Park Cancer Institute experience between 1982 and 1999. Of 82 eligible patients with gynecologic tumors metastatic and confined to the lung, 25 underwent pulmonary resection., Results: There were 60 uterine and 22 cervix cancer patients with pulmonary metastases. Among patients with uterine cancer primaries undergoing pulmonary resection (n = 19) median survival was 26 months. Uterine cancer patients who underwent surgical resection for leiomyosarcomas (n = 11) had a median survival of 25 months compared to 46 months in patients with adenocarcinoma (n = 6, P = 0.02). Median survival in cervix cancer patients undergoing resection for pulmonary metastases (n = 6) was 36 months., Conclusions: Pulmonary resection may provide a survival advantage for selected patients with uterine and cervical malignancies with metastases isolated to the lung., ((c)2001 Elsevier Science.)

Growth hormone secretion by the somatotroph cells depends upon the interaction between hypothalamic regulatory peptides, target gland hormones and a variety of growth factors acting in a paracrine or autocrine fashion. This review will be focused on recent data regarding the mechanism by which growth hormone-releasing hormone (GHRH) influences somatotroph cell function and the physiological role played by Ghrelin and leptin in the regulation of growth hormone (GH) secretion. It is well established that binding of GHRH to its receptor leads to activation of protein kinase A (PKA). More recently, it was found that GHRH can also activate mitogen-activated protein (MAP) kinase both in pituitary cells and in a cell line overexpressing the GHRH receptor. Whether somatotroph adenomas, either with or without a GS-alpha mutation, have alterations in some of the components of the activation of the MAP kinase pathway remains to be known. The recent isolation of Ghrelin, the endogenous ligand of the growth hormone secretagogue receptor, can be considered a landmark in the GH field, which opens up the possibility of gaining greater insight into our understanding of the mechanisms involved in the regulation of GH secretion and somatic growth. Indeed, preliminary evidences indicate that this peptide exerts a marked stimulatory effect on plasma GH levels in both rats and humans. Finally, it is well known that GH secretion is markedly influenced by nutritional status. Leptin has emerged as an important adipose tissue-generated signal that is involved in the regulation of GH secretion, thus providing an integrated regulatory system of growth and metabolism. Although the effects of leptin on GH secretion in humans remain to be clarified, indirect evidences indicate that it may play an inhibitory role., (Copyright 2001 S. Karger AG, Basel.)

Purpose: We evaluated the role of a patent processus vaginalis for cryptorchidism as well as inguinal herniography as a predictor of the efficacy of human chorionic gonadotropin (HCG) treatment., Materials and Methods: We studied 244 boys with unilateral and 66 with bilateral cryptorchidism. All patients underwent inguinal herniography and received HCG. Nonresponders to treatment subsequently underwent orchiopexy, when processus vaginalis status, testicular position and epididymal characteristics were assessed., Results: HCG was effective for 139 of 281 testes (49.5%) with an obliterated and 0 of 95 with a patent processus vaginalis on herniography. We further evaluated herniography in accordance with orchiopexy findings of persistent unilateral and bilateral cryptorchidism in 206 boys (237 testes) after HCG. Herniography findings of processus vaginalis morphology revealed a close correlation with that reported by the surgeon after orchiopexy (p<0.000005). The incidence of a patent processus vaginalis increased as testicular position became more caudal. The processus vaginalis was obliterated in all cases of anorchia. The incidence of more severe epididymal anomalies decreased as the testicular position became more caudal. Epididymal abnormalities were more common when the processus vaginalis was patent., Conclusions: Pretreatment herniography assessment of processus vaginalis morphology is of prognostic value for predicting the efficacy of hormone treatment, the presence or absence of testes when they are nonpalpable and future fertility.

Objective: Children with diabetes mellitus are prone to develop obesity and to experience a delay in onset of the pubertal process. In order to understand the role of leptin in these abnormalities, serum leptin levels were analysed in children with type 1 diabetes mellitus., Subjects: Twenty diabetic girls, 23 diabetic boys and 66 healthy children (selected from a reference population of 706 normal children), age-, sex- and BMI-matched with diabetic patients, were studied., Measurments: Standing height, weight and BMI were determined in each child. Serum testosterone, oestradiol and leptin were measured by specific radioimmunoassays, and HBA1c by high performance liquid chromatography., Results: Both diabetic girls and boys showed higher leptin levels than the normative healthy population and a group of age-, sex- and BMI-matched normal children. In an age-related analysis, leptin levels in diabetic girls rose from 7.4 +/- 1.2 and 8.1 +/- 2.1 microg/l for the 5-7.99 and 8-10.99 year groups, to 12.6 +/- 2.4 microg/l for the 11-13.99 year group, and to 15.6 +/- 4.0 microg/l in the 14-15.99 year group in parallel with body weight. Leptin concentrations were parallel but higher (P < 0.05) than those of healthy girls. Diabetic boys had lower leptin levels than girls and, in contrast with normal boys, did not show a drop after the 10-year period. Leptin levels were 4.9 +/- 2.2, 3.9 +/- 0.2, 5.5 +/- 0.6 and 5.1 +/- 0.9 microg/l for the 5-7.99, 8-10. 99, 11-13.99 and 14-15.99 year groups, respectively. When divided by pubertal stage, leptin levels in the prepuberty stage of diabetic girls (8.6 +/- 1.0 microg/l) were higher (P < 0.05) than those in the controls (4.1 +/- 0.4 microg/l). In overt puberty girls, leptin was higher (P < 0.05) for diabetic (15.9 +/- 2.9 microg/l) than for healthy girls (9.2 +/- 1.1 microg/l). In prepubertal boys, differences were observed in leptin levels (4.9 +/- 0.5 microg/l for diabetic boys and 3.4 +/- 0.6 microg/l for healthy boys). In the overt puberty stage, diabetic boys showed higher (P < 0.05) levels of leptin (5.2 +/- 0.7 microg/l) than the healthy matched controls (2.1 +/- 0.2 microg/l). A multiple step regression analysis in the diabetic children revealed no associations between leptin and other relevant variables such as glycosylated haemoglobin, daily insulin dose, or years of suffering from the disease., Conclusion: Serum leptin levels were higher in diabetic than in healthy children. These differences were not attributable to age, adiposity or stage of pubertal development, and were probably conditioned by the metabolic perturbation intrinsic to the diabetic state, or the chronic hyperinsulinemia.

The neuroregulation of growth hormone (GH) secretion and the state of the adipose tissue reserves are closely related. GH exerts lipolytic actions on the adipose tissue and low body weight enhances secretion of GH while obesity is associated with reduced levels of GH and blocked release of GH when challenged by all stimuli. The mediators of the regulation exerted by the adipose tissue on the GH/insulin-like growth factor-I axis are not fully understood, but in the last few years two relevant factors have emerged--free fatty acids (FFA) and the adipocyte-produced hormone leptin. FFA and GH integrate a classical feedback loop and a rise in FFA blocks GH secretion. This action is rapid, dose-related and exerted at the pituitary level with no evident hypothalamic participation. A pharmacological reduction in FFA enhances secretion of GH and eliminates the GH blockade of obesity and Cushing's syndrome. The discovery of leptin has expanded our knowledge of the way in which the adipose tissue participates in some neuroendocrine actions. Obesity is associated with elevated levels of serum leptin while undernutrition and fasting lead to low leptin. In fasted rats, the pattern of GH pulsatility is eliminated with a near absence of spontaneous peaks, but the administration of leptin by the intracerebroventricular (i.c.v.) route restores the altered pattern. When fed rats receive antileptin antibodies i.c.v the normal pattern is reversed to an absence of pulses, reminiscent of the fasting state. These results are the first demonstration that, at least in experimental animals, leptin is a relevant factor in GH regulation. Leptin has no direct pituitary action and its action at the hypothalamic level appears to be mediated by neuropeptide Y, being the final step in a reduction in the somatostatin tone. On the other hand, the action of GH on leptin levels seems to be tenuous in humans, but in the near future it will be possible to investigate the action of leptin on human GH. As the hypothalamic neuroregulation of GH secretion in humans is unlike that in the rat, a crucial point for elucidation will be the actions, if any, and the mechanisms by which leptin participates in GH regulation in humans, as well as its alterations in disease states.

Growth hormone (GH) releasing hexapeptide (GHRP)-6 and other peptidergic and non-peptidergic compounds collectively designated GH secretagogues (GHS) are potent releasers of GH in man. Their clinical future may be envisioned in three areas: therapy of GH-deficient (GHD) states, diagnosis of GHD, and non-endocrinological actions. As therapeutic agents and compared with GH itself, GHS have the disadvantage of lower potency but have a more physiological and safer profile of GH secretion. GHS administration could be indicated for states in which medium GH doses have been shown to be effective. As a diagnostic tool, the combined administration of GH releasing hormone plus GHRP-6, both at saturating doses, is currently the most powerful releaser of GH, devoid of side effects and convenient for the patient; it may also be an alternative to the insulin tolerance test for the diagnosis of GHD in adult patients. Their potential action at cardiovascular level is highly promising. Although the clinical future of GH releasing substances is appealing, probably the most relevant contribution has yet to be discovered. Once the endogenous ligand of the GHS receptor is identified, we will have an insight into the real hypothalamic control of GH secretion in man. With this knowledge it is likely that some diagnostic and therapeutic actions that are commonly undertaken will significantly change., (Copyright 1999 S. Karger AG, Basel)

Growth hormone (GH)-releasing hormone (GHRH) and somatostatin have a dominant role in regulating GH secretion. However, results of studies using the new class of GH secretogogues, particularly GHRP-6, indicate that there may also be other, as yet undefined, hypothalamic mechanisms involved. Studies in adults with hypothalamopituitary disconnection (functional pituitary stalk transection), show GHRP-6-mediated GH release to be completely blocked, indicating a main action at the hypothalamic rather than the pituitary level. The synergistic effect of GHRH plus GHRP-6 administration on GH release seen in normal adults (and virtually unaffected by age, obesity, or sex) is also absent in these patients, providing further support for this conclusion. Studies of the effects of GHRP-6 in children with GH deficiency due to perinatal pituitary stalk transection have produced similar findings. It is suggested that the combined GHRH plus GHRH-6 test should be a promising tool for diagnosing GH deficiency states in both children and adults, and may identify a subgroup of patients with GH deficiency caused by interruption of the hypothalamopituitary connection.

Pituitary GH reserve can be assessed by substances that act directly at the somatotroph, such as GHRH, or by a variety of metabolic and neuropharmacological tests acting at the hypothalamic level, such as hypoglycemia, clonidine or L-Dopa. In order to evaluate GHRP-6 as a test of pituitary GH reserve, we studied GH responses of i.v. administered GHRP-6 in a group of short-statured children, as well as in a group of adults diagnosed with growth hormone deficiency (GHD) by conventional GH testing. Although we found that the GH response to GHRP-6 was lower in patients with GHD than in normal children, on an individual basis a considerable degree of overlap was observed between the two groups. In contrast, we found an almost complete blockade of GH response to either GHRP-6 or GHRH plus GHRP-6 in patients with pituitary stalk transection, suggesting that this could be a cost-effective test for the diagnosis of this condition. A similar finding was also obtained in GH response to the combined administration of GHRH plus GHRP-6 in patients with GHD of adult onset; this test may well prove valuable in the diagnosis of this clinical entity.

Elevated glucocorticoid (GC) levels produce a marked impairment in somatic growth in both rodents and primates. In addition, GC play an important role in the regulation of growth hormone (GH) synthesis and secretion. Blunted GH response to stimulation tests in conditions of chronic exposure to excessive cortisol secretion or administration are well documented. In contrast, acute administration of GC to normal human subjects induces a transient increase in plasma GH levels. This dual action of GC on GH secretion is probably due to the fact that they act at different loci; i.e. in the regulation of GH transcription and GHRH and somatostatin receptors at the pituitary level as well as GHRH, somatostatin and GH receptor gene expression at the hypothalamic level.

Serous cystadenoma of the pancreas are rare tumors and have little or no malignant potential. We report our experience in the management of eight cases of these tumors in the last 22 years. All the patients were women with a mean age of 59 years. All the cysts caused symptoms. Ultrasound and CT-scan were useful in the diagnosis of the pancreatic cystic tumor out not in determining the nature of these lesions clear. FNA-biopsy was performed in 6 cases but in only case was the diagnosis confirmed. All tumors were resected. Four radical pancreatoduodenectomies, two distal pancreatectomies and two cystectomies were performed. Mean followup was 83.5 months. All patients are alive and with no signs of recurrence. Complications include an external pancreatic fistula, an acute cholangitis and a case of delayed gastric emptying. In all cases the histological diagnosis was serous cystadenoma of the pancreas. We conclude that resection of these tumors is mandatory although they are supposed to be benign, in order to avoid complications and because malignant transformations has been related to nonresective treatment.

We report the case of a male patient with a carcinoma of the upper third of the esophagus who presented a tracheal rupture during a transhiatal esophagectomy. The clinical picture was characterized by a severe alteration of the ventilatory function that required selective intubation and, later on, a right thoracotomy for repairing the tracheal lesion. After surgery the patient was treated at the Recovery Unit. He received high-frequency mechanic ventilation (jet ventilation type) during nine days in a attempt to decrease the risk for dehiscence of the tracheal suture and to ensure an adequate oxygenation and hemodynamic control. The clinical course was favourable.

The C-reactive protein, leukocytes count and erythrocyte sedimentation rate, were determined in 32 hydrocephalus children treated with shunt, on the 1st day, 5th day and 10th day postintervention. C-reactive protein was positive on the 5th day postintervention in the 66.6% of the patients with infection and the 100% of these patients on the 10th day. In three patients C-reactive protein was the first sign of infection. In 33.3% of the patients with infectious complications, C-reactive protein positive was earlier than leukocytes and erythrocyte sedimentation rate abnormalities. From these findings, authors suggest C-reactive protein as valuable test in the postoperative control of the hydrocephalus children and should alert to the possibility of a infectious complication.

Authors make a report concerning a male patient who presents microcephaly, oculocutaneus albinism, hypoplasia of the distal phalanx of the 1st, 3rd and 4th finger of the right hand, 1st, 3rd, 4th and 5th finger of the left hand and agenesia of the distal end of the big toe of the right foot. They think it is a new dysmorphic syndrome. Because of patient's sister presented a similar picture they suggest that it may be an autosomal recessive inheritance pattern.

104 patients with (UI) non-complicated urinary infection, diagnosed at the emergency department of a third level hospital, are presented. The median age (x +/- DE) was of 58.12 +/- 20, 48 years; 78 were female (73%) and 22 male. 81 had fever and/or micturitional syndrome, the rest of the patients were without symptoms. The most frequent germ was escherichia coli, which was isolated in 80 patients (84.6%) followed by proteus mirabilis in 9 patients (8.6%) and enterococo in 2 patients (1.9%), other differing germs were also isolated, one for each remaining case. The only active antibiotic "in vitro" for all the germs isolated was gentamicin; other showed varying resistance. The best effectivity "in vivo" was also obtained with gentamicin followed by cotrimoxazole, despite the resistance which was superior to cefalexin. There were no deaths reported during the ambulatory treatment. We concluded that non-complicated UI can be treated in an ambulatory regimen. The most effective antibiotic is gentamicin, cotrimoxazole being a valid alternative.

A new case of factor VII congenital deficiency is presented in a four year old girl, with a factor VII level of 3.9%. The patient had no history of bleeding and her coagulation disorder was a casual finding. Clinical features of the disease and its therapeutic guidelines are discussed. It seemed appropriate to continue the study in order to evaluate the factor VII capacity of inhibiting an specific antibody, to confirm heterozygosity of partents and to prove that this case is a genetic variant of factor VII deficiency with good prognosis.