Quercetin 3,7,3',4'-tetrasulphated isolated from Flaveria bidentis inhibits tissue factor expression in human monocyte.

Sulphated esters of the flavonoids sulphated quercetin 3,7,3',4'-tetrasulphated (QTS) and quercetin 3-acetyl-7,3,4'-trisulphate (ATS), isolated from Flaveria bidentis, have demonstrated anticoagulant and antiplatelet properties. In this study, we examined if both compounds affected the expression of the procoagulant tissue factor (TF) induced by lipopolysaccharide (LPS) on human monocyte. Monocytes were pretreated with different concentrations of each flavonoid (0.1-500 µM), followed by a 4h incubation with LPS in order to induce TF expression. Results of the TF expression showed different behaviors for the two flavonoids studied. A slight inhibitory effect on the TF expression was detected at a QTS concentration of 0.1 µM, but from 1 µM onwards a significant inhibitory effect that remained up to 500 µM could be observed. In contrast, ATS induced a poor inhibitory effect on TF expression at all concentrations tested. These results suggest that QTS has another antithrombotic property, to be added to its already renowned ability as an anticoagulant and antiplatelet compound.

Growth and pubertal disorders in neurofibromatosis type 1.

The first textbook of Pediatric Endocrinology in the early 1950s reported an association of neurofibromatosis type 1 (NF1) and precocious puberty (PP) and/or short stature. Recent studies have indicated that children with NF1 grow normally until puberty; thereafter height velocity and relative height (SDS or percentiles) decreases with respect to healthy peers, reaching a mean adult height close to the 25th percentile for the general population. Moreover, the percentage of patients with true short stature (<3rd percentile) increases from childhood (5%) to late puberty (20-30% in literature, 18% in our study), and final height is significantly below the genetic target and predicted adult height calculated just before or at the beginning of puberty. Finally, among the shortest patients (<10th percentile) there is a high incidence of severe complications, such as CNS tumors, huge plexiform neurofibromas and severe scoliosis. Precocious puberty is a frequent complication of NF1, and occurs mainly in association with optic pathway tumors (OPT); however, occasionally it has been reported in the absence of optic gliomas, probably with a similar incidence as in the general population. GnRH agonist therapy must be decided individually as in some patients further growth could be normal and/or treatment would not improve final height. In the presence of early pubertal signs, an OPT must be ruled out. In addition to PP, delayed puberty has been frequently reported in NF1. In a study of 123 girls with NF1, we found that the mean age at menarche (13.0 +/- 1.9 yr) was later than in their mothers (12.7 +/- 1.4 yr) and in the general population (12.4 +/- 1.2 yr; p <0.05), with a very high incidence of delayed menarche (>2 SD): 16% vs 6.8% (mothers) vs 3.4% (controls) (p <0.01). In conclusion, growth and puberty present unusual patterns in NF1, often with true pathological findings increasing medical and psychological problems.

Lethal neonatal presentation of carnitine palmitoyltransferase I deficiency.

A neonate subsequently diagnosed with carnitine palmitoyltransferase I deficiency died at 34 h of untreatable bradycardia. There was fatty infiltration of the liver and increased free carnitine and reduced acylcarnitines in the blood.

Neurofibromatosis type 1 and precocious puberty.

Since neurofibromatosis type 1 (NF1) is a well known cause of precocious puberty (PP), we reviewed 412 NF1 pediatric patients to evaluate the prevalence of PP, the association with optic pathway tumors (OPT), and other clinical, auxological and hormonal data. Thirty-one of 412 patients had OPT (7.5%), 10/412 PP (2.4%), and in seven of these PP was associated with OPT (7/31, 22.6%). OPT in patients with PP involved the chiasm in four patients, and the optic nerves alone in three patients. The age at the onset of puberty (or better at diagnosis) ranged from 5.2 to 7.5 yr in girls (n=6) and from 7.9 to 8.9 yr in boys (n=4). LHRH agonist therapy was used in only three children because in the others the predicted height at diagnosis was good, treatment was refused or the patients were referred to us too late. The three treated patients attained a final height within the familial range. In the untreated patients the progression of puberty was not too rapid and final height was slightly below the genetic target in four patients; however, three patients had a final height markedly below the familial range. In conclusion, the prevalence of PP is increased in children with NF1, and frequently but not exclusively is associated with OPT. Moreover, sexual precocity does not seem to be necessarily bound to chiasmatic OPT. Treatment seems to be useful in the children with younger age at the onset of puberty or with a progressive decline in predicted final height.

Ulnar deviation of the thumb: an exceptional finding in Rubinstein-Taybi syndrome.

A 2-year-old girl with Rubinstein-Taybi syndrome and the unusual finding of ulnar deviation of the thumb is described. Possible modes of inheritance are discussed.

Marden-Walker syndrome: case report, nosologic discussion and aspects of counseling.

The Marden-Walker syndrome is characterized by a mask-like face with blepharophimosis, micrognathia, cleft or high-arched palate, low-set ears, congenital joint contractures, decreased muscular mass, failure to thrive and psychomotor retardation. We report a boy with a phenotype mostly resembling the condition named Marden-Walker syndrome, with many of the criteria proposed for diagnosing this particular phenotype. In addition he had hypoplastic corpus callosum, cerebellar vermis hypoplasia, enlarged cisterna magna and vertebral abnormalities. During pregnancy there were reduced fetal movements. In the present patient the fetal hypokinesia sequence, due to central nervous system malformation, is most compatible with the diagnosis of Marden-Walker syndrome. The etiology is probably heterogeneous, but the possibility of autosomal recessive inheritance should be considered in genetic counseling.

[Care recommendations for type 1 neurofibromatosis]. / Raccomandazioni assistenziali per la neurofibromatosi tipo 1.

Neurofibromatosis type 1 (NF1) is a progressive, multisystem disorder affecting about 1:3000 individuals. About one third of patients show serious complications and about one half are mildly affected. Since the original National Institutes of Health Consensus Conference in 1987, that established the clinical criteria for the diagnosis of NF1, there has been significant progress toward a more complete understanding of the molecular bases for NF1, and our knowledge of the natural history and management of the NF1 has significantly improved. Despite these advances, the diagnosis of NF1 is still based largely on clinical criteria and no individual prognostic evaluation or definitive medical therapy are available. The recommendations for the care of NF1 patients and their families are constantly changing: according to the new guidelines, the mainstay of management is anticipatory guidance and surveillance for treatable complications; surveillance usually includes annual follow-up visits, unless symptoms call for more frequent visits or more accurate diagnostic evaluation.

[Genetics of type 1 neurofibromatosis]. / Genetica della neurofibromatosi tipo 1 (NF1).

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterised by cafè au lait spots, multiple neurofibromas and Lisch nodules of the iris, with marked variability of expression. The NF1 gene is located at 17q11.2, spans 350 kb genomic DNA and comprises 60 exons encoding a 11-13 kb transcript (Viskochil et al.). Four alternatively spliced NF1 transcripts have been identified and they show differential expression in various tissues. NF1 gene is a member of the tumor suppressor gene family. The protein encoded by NF1, neurofibromin, has a domain homologous to the GTPase activating protein (GAP) family, and downregulates ras activity. Neurofibromin is involved in the control of cellular growth and differentiation and germline mutation analysis has shown that around 82% of all the fully characterised NF1 specific mutations so far predict severe truncation of neurofibromin. The current demand for molecular diagnosis of NF1 is low. Many couples would probably request a prenatal diagnosis if it could predict disease severity. Molecular prediction of disease severity and prognosis may either be very complicated or even impossible. Presymptomatic DNA diagnosis is probably not going to be in huge demand because the clinical diagnosis of NF1 is usually straightforward, even in early childhood. Further knowledge of the gene function may also lead to the development of new therapy for the disease.

Oculo-auriculo-vertebral spectrum in Klinefelter syndrome.

We report a boy with classical 47,XXY Klinefelter syndrome (KS) and oculo-auriculo-vertebral spectrum (OAV). Two patients with KS and OAV were reported previously. Also, the combination of bilateral aplasia of the mandibular ramus and condyle and KS has been documented. The present observation supports the view that the cause of hemifacial microsomia appears heterogeneous and that OAV may be part of the spectrum of craniofacial anomalies associated with KS.

Time-course study of cellular immune response and testosterone metabolism in an autoimmune model for chronic prostatic inflammation.

PURPOSE: Little is known of the etiology and pathogenesis of chronic inflammatory prostate diseases of noninfectious origin. In our experimental autoimmune rat model for chronic prostatic inflammation (CPI) we evaluated, in a time-course study, the specific cellular immune response to male accessory glands (MAG) and metabolic activity in the prostate gland. Results obtained in CPI rats were compared with data from rats immunized with kidney homogenate as well as from non-treated rats. MATERIALS AND METHODS: Specific cellular immune response against MAG antigen(s) was studied by delayed type hypersensitivity (DTH) and lymphocyte proliferation tests. The prostate 5alpha-reductase activity was studied in prostate homogenates by thin layer chromatography (TLC). RESULTS: DTH values were positive in MAG treated rats sacrificed at days 7 and 28 after first immunization (FI) (p < or = 0.05) in relation to kidney treated and non-treated rats. When we analyzed the proliferative responses to MAG antigen(s), an antigen specific proliferation, as shown by the mean [3H]thymidine uptake (cpm), was observed in rats sacrificed on days 14 and 28 (p < or = 0.05) after FI. The metabolic studies indicated that the 5alpha-reductase activity decreased slightly in MAG treated groups at day 14 after FI and diminished significantly at the end of CPI development. CONCLUSION: These data reveal that the prostatic endocrine cell destruction during CPI could be a consequence of immune/inflammatory cell mediated processes.

Thymoma associated with syndrome of inappropriate antidiuretic hormone secretion and myasthenia gravis.

We describe the association of malignant thymoma with the syndrome of inappropriate antidiuretic hormone secretion and myasthenia gravis. Hyponatremia has not been reported associated with those tumors and our case should alert physicians about the potential for a life-threatening complication.

Inflammatory cells and MHC class II antigens expression in prostate during time-course experimental autoimmune prostatitis development.

The degree of lymphocytic infiltration alongside the phenotype of the infiltrating cells and MHC class II expression were studied in rats during a time-course experimental autoimmune prostatitis (EAP) development. Inflammatory foci per square millimeter were scarce at day 7 after first immunization (FI) and were composed of few mononuclear cells. The number of inflammatory foci per square millimeter increased at day 14 and remained with slight variations at days 21 and 28 after FI. The number of mononuclear cells per square millimeter increased on day 14, diminished slightly on day 21 and reached the highest level on day 28. All these infiltrates were constituted by CD4 and CD8 T cells whereas only few macrophages were present. Mast cells were also present reaching maximum levels on day 7 after FI and then decreased. MHC class II antigens were found in epithelial cells during EAP development. IA showed a similar pattern in all periods analyzed whereas IE showed a modulating behavior, reaching the highest expression on day 21 after FI. In this experimental model, the differential expression of MHC class II antigens could modulate the immune response during EAP development.

Time course of reactive oxygen intermediates release and histopathological findings during experimental autoimmune prostatitis development.

Spontaneous and stimulated reactive oxygen intermediates (ROI) release by peritoneal exudate cells (PEC) and histopathological findings in the prostate gland were assessed during experimental autoimmune prostatitis (EAP) development. Results in EAP rats were compared with data from rats immunized with kidney homogenate, BSA, and CFA, as well as nontreated rats. At 28 days of first immunization (FI), EAP rats spontaneously released significantly more ROI than occurred in the cells from control rats. A similar response was found when ROI release was analyzed after in vitro stimulus. In time course studies, an increased spontaneous O2- production was observed at day 7 after FI, and remained the same during all period studied, (14, 21, and 28 days after FI). The stimulated O2- production showed elevated levels at 7 days after FI and fell afterward to levels similar to those of nontreated rats and increased again at 28 days. Spontaneous or stimulated H2O2 release showed a progressive increase during the study periods. ROI release was correlated with infiltrate formation in the prostate gland. This differential responsiveness could indicate that, during the autoimmune process, the autoantigen(s) amplify the inflammatory response triggered by them.

Hypertension in children with neurofibromatosis.

Hypertension in neurofibromatosis is mostly a consequence of a stenosis of the renal artery or is due to phaeochromocytoma. Riccardi pointed out primary hypertension in patients with several cervical neurofibromas in the absence of phaeochromocytoma and he noticed that the elevation of BP was often already present in children. Nine (15.8%) of 57 neurofibromatosis patients (age from 1.5 to 23 years) examined, presented BP levels above the 95th percentile on several occasions and three in particular had severe hypertension with compromised target organs. Two of them had a stenosis of the renal artery, in the third an organic origin of hypertension was not demonstrated, but there was an asymptomatic glioma of the hypothalamus. The other six children had a labile or borderline hypertension and two of them had, respectively, a glioma of the thalamus and of the optical chiasm. Elevation of the catecholamine metabolites or other causes of hypertension were not found in any of these patients. These preliminary data show a high incidence of hypertension in neurofibromatosis, primary or due to organic causes and overall they point out a possible correlation between hypertension and cerebral neoplasia.

Determination of type I transglutaminase in differentiating normal and neoplastic human keratinocytes by an in situ radioimmunoassay.

The presence of type I transglutaminase was determined in the neoplastic human keratinocyte line SqCC/Y1 and in normal human epidermal keratinocytes (NHEK) by an in situ radioimmunoassay which corresponded directly with the measurement of type I transglutaminase enzymatic activity. Dexamethasone induced differentiation of SqCC/Y1 cells caused a marked increase in transglutaminase immunoreactivity and enzymatic activity over non-steroid treated cells in a concentration-related and a time-related fashion. Retinoic acid suppressed the dexamethasone induced increase in type I transglutaminase immunoreactivity in differentiating SqCC/Y1 cells. The type I transglutaminase radioimmunoassay should be useful in studies focusing on the regulation of transglutaminase activity in normal and neoplastic keratinocytes, and for rapidly screening agents for their effects on squamous cell differentiation.

Periaqueductal gliosis causing hydrocephalus in a patient with neurofibromatosis type 1.

We present a case of primary nontumoral aqueductal stenosis associated with neurofibromatosis type 1 (NF-1) in an asymptomatic 11-year-old boy. The diagnosis of hydrocephalus followed the finding of bilateral papilledema at an ocular assessment and the diagnosis of NF-1 was made during hospitalization for the papilledema. Periaqueductal gliosis was suspected on cerebral T2-weighted magnetic resonance imaging (MRI). We believe that the incidence of hydrocephalus due to nontumoral aqueductal stenosis has been underestimated in NF-1. We emphasize the importance of early diagnosis of NF-1 and prompt evaluation in order to recognize this complication. In this regard MRI scanning offers more diagnostic advantages over other investigations. Forty-seven previously described cases have been collected from the literature.