Self-regulation of the head-inducing properties of the Spemann organizer

The Spemann organizer stands out from other signaling centers of the embryo because of its broad patterning effects. It defines development along the anteroposterior and dorsoventral axes of the vertebrate body, mainly by secreting antagonists of growth factors. Qualitative models proposed more than a decade ago explain the organizer’s region-specific inductions (i.e., head and trunk) as the result of different combinations of antagonists. For example, head induction is mediated by extracellular inhibition of Wnt, BMP, and Nodal ligands. However, little is known about how the levels of these antagonists become harmonized with those of their targets and with the factors initially responsible for germ layers and organizer formation, including Nodal itself. Here we show that key ingredients of the head-organizer development, namely Nodal ligands, Nodal antagonists, and ADMP ligands reciprocally adjust each other’s strength and range of activity by a self-regulating network of interlocked feedback and feedforward loops. A key element in this cross-talk is the limited availability of ACVR2a, for which Nodal and ADMP must compete. By trapping Nodal extracellularly, the Nodal antagonists Cerberus and Lefty are permissive for ADMP activity. The system self-regulates because ADMP/ACVR2a/Smad1 signaling in turn represses the expression of the Nodal antagonists, reestablishing the equilibrium. In sum, this work reveals an unprecedented set of interactions operating within the organizer that is critical for embryonic patterning.     

Influence of enamel matrix derivative (Emdogain®) and sodium fluoride on the healing process in delayed tooth replantation: histologic and histometric analysis in rats

Abstract – Although it has already been shown that enamel matrix derivative (Emdogain^®) promotes periodontal regeneration in the treatment of intrabony periodontal defects, there is little information concerning its regenerative capacity in cases of delayed tooth replantation. To evaluate the alterations in the periodontal healing of replanted teeth after use of Emdogain^®, the central incisors of 24 Wistar rats (Rattus norvegicus albinus) were extracted and left on the bench for 6 h. Thereafter, the dental papilla and the enamel organ of each tooth were sectioned for pulp removal by a retrograde way and the canal was irrigated with 1% sodium hypochlorite. The teeth were assigned to two groups:in group I, root surface was treated with 1% sodium hypochlorite for 10 min (changing the solution every 5 min), rinsed with saline for 10 min and immersed in 2% acidulated‐phosphate sodium fluoride for 10 min; in group II, root surfaces were treated in the same way as described above, except for the application of Emdogain^® instead of sodium fluoride. The teeth were filled with calcium hydroxide (in group II right before Emdogain^® was applied) and replanted. All animals received antibiotic therapy. The rats were killed by anesthetic overdose 10 and 60 days after replantation. The pieces containing the replanted teeth were removed, fixated, decalcified and paraffin‐embedded. Semi‐serial 6‐μm‐thick sections were obtained and stained with hematoxylin and eosin for histologic and histometric analyses. The use of 2% acidulated‐phosphate sodium fluoride provided more areas of replacement resorption. The use of Emdogain^® resulted in more areas of ankylosis and was therefore not able to avoid dentoalveolar ankylosis. It may be concluded that neither 2% acidulated‐phosphate sodium fluoride nor Emdogain^® were able to prevent root resorption in delayed tooth replantation in rats.     

Multiple lentiginosis and hypertrophic obstructive cardiomyopathy

Two patients with Multiple Lentiginosis (ML) had hypertrophic cardiomyopathy with severe obstruction of the right and left ventricular outflow tracts. ML is a rare syndrome in which there is a typical skin pigmentation disorder together with various other abnormalities like slight mental retardation, sensorineural deafness, genital and skeletal anomalies and sometimes a characteristic facies. Obstruction of the right ventricular outflow tract is frequent in such patients. The association of ML and obstructive hypertrophic cardiomyopathy has been recently reported. A critical examination of the literature in addition to our clinical observations suggests that the biventricular obstructive hypertrophic cardiomyopathy may play a major role in the clinical feature of ML syndrome.     

A high body mass index and female gender are associated with an increased risk of nodular hyperplasia of parathyroid glands in chronic uraemia.

BACKGROUND: A persistent hyperphosphataemia represents one of the most important factors in the development of secondary hyperparathyroidism (sHPTH). The present prospective study was designed in order to test the hypothesis that a higher body mass index (BMI) may predispose to a larger body burden of phosphate (P), influencing by that way the severity of sHPTH. METHODS: Histological studies were performed on 168 parathyroid glands of 42 consecutive adult Caucasian haemodialysis patients (20 males and 22 females) referred for first parathyroidectomy (PTx): each parathyroid gland was graded as 0, when only or mainly diffuse hyperplasia was found, or as 1, when only or mainly nodular hyperplasia was found. Thus, parathyroid histology was scored on a 5-point scale: 0 = diffuse hyperplasia in the four glands; 1 = nodular hyperplasia in one gland; 2 = nodular hyperplasia in two glands; 3 = nodular hyperplasia in three glands; 4 = nodular hyperplasia in the four glands. For sake of simplicity, the three less severe histological gradings, i.e. scores 0-2 were grouped together and indicated as score group 2. RESULTS: The distribution of the patients was the following: 28.6% were in the score group 2, 23.8% in the score group 3 and 47.6% in the score group 4 (20 patients, 14 of whom were females). The output of the one-way ANOVA with the histological scores as grouping variable and age, dialysis duration, BMI and pre-PTx serum iPTH, alkaline phosphatase (ALP), calcium (Ca) and P as predictors showed that only BMI was different among the three histological scores (P = 0.001). By stratifying the analysis by gender, the relationship between BMI and histological scores was confirmed only in females (P = 0.006). The stratification of the entire cohort into two groups according to the cut-off value of BMI = 25 kg/m(2) showed that: (i) score 4 was more prevalent in the high-BMI group and score 2 in the normal-BMI group (P = 0.01); (ii) female gender was more represented in the high-BMI group (12 out of 18 patients, P = 0.04); and (iii) the pre-PTx serum P levels were significantly higher in the high-BMI group (P = 0.008). The output of the linear multiple regression analysis with pre-PTx serum P as dependent variable and BMI, pre-PTx serum ALP and Ca as independent variables (selected according to the statistical significance in the bivariate correlations) showed that only serum Ca and BMI were statistically significant predictors of serum P levels. CONCLUSIONS: A high BMI and female gender are associated with an increased risk of nodular hyperplasia of parathyroid glands in adult Caucasian haemodialysis patients. The two risk factors, above all if combined in the same patient, appear to predispose to a larger body burden of P, increasing by that way the severity of sHPTH.     

Is there a role for double-contrast radiology in the characterization of patients with non-ulcer dyspepsia?]

Nun-ulcer dyspepsia (NUD) is a very common disorder: about 30% of subjects may suffer from this syndrome, with a subsequent increase in sanitary cost. NUD is diagnosed by means of both an accurate anamnesis and instrumental investigations like double-contrast upper gastrointestinal X-rays, endoscopy, and US of the biliary tract. Our study was aimed at evaluating the actual capabilities of double-contrast radiology in the characterization of NUD patients. One-hundred consecutive outpatients (53 males and 47 females, age range 15-84 years) with clinical symptoms of NUD were submitted to double-contrast gastric radiological examination. X-rays were performed without pharmacological hypotonicity to better depict functional disorders (i.e., impaired esophageal motility, gastroesophageal and duodenogastric reflux, gastric hypotonicity, and delayed gastric emptying) even though this prevented the though evaluation of morphological features, which are better identified by gastrointestinal endoscopy. 42% of patients, especially middle-aged ones, exhibited only functional disorders. Double-contrast X-rays might therefore be suggested as a useful investigation technique in young patients with clinical symptoms of NUD: it is capable of showing functional disorders and therefore can support upper gastrointestinal tract endoscopy in the pathophysiological characterization of NUD patients.     

Expert systems as a diagnostic aid in otoneurology

Expert systems (ES) are a new tool for information processing developed by the branch of computer science known as artificial intelligence. ES are capable of solving problems in a given domain by using the knowledge and emulating the behaviour of specialists in that field. ES can be used as powerful tools for education since they are able to justify their own conclusions and to make the underlying reasoning explicit. This paper presents 'Vertigo', an ES aimed at the classification and diagnosis of different forms of dizziness. It has been conceived mainly as a teaching tool in otoneurological departments. The rationale of this project, its development, the structure and the use of the system are described. So far, 'Vertigo' has been tested on more than 200 cases of dizziness and is presently being used by ENT residents during their otoneurology stage.     

Pharmacokinetics and effects of propranolol in terminal uraemic patients and in patients undergoing regular dialysis treatment.

Propranolol blood and plasma levels were measured after a single oral dose of 40 mg in patients with chronic renal failure, in patients undergoing regular dialysis treatment, and in healthy volunteers. Peak levels were observed in all cases within 1.5 to 3 hours. However, peak blood and plasma concentrations of propranolol in the chronic renal failure group were 2- to 3-fold higher (161 +/- 41 ng/ml) than those observed in the dialysis patients (47 +/- 9 ng/ml) and in the healthy volunteers (26 +/- 1 ng/ml). The apparent plasma clearance was also significantly reduced in the patients with chronic renal failure. The data suggest a reduced hepatic extraction in chronic renal failure patients. A significant increase in the fraction of the dose available to the systemic circulation was also found, together with a modification of apparent plasma half-life and volume of distribution in regular dialysis patients during the dialysis day as compared with the after-dialysis day. No extraction of propranolol by the dialyzer was noticed. Marked fluctuations in propranolol blood concentrations were also observed in patients on regular dialysis following continuous propranolol treatment. The suppressive effect of propranolol on plasma renin activity did not fully correlate with the hypotensive effect of the drug. On the basis of the reported data, propranolol should be used with great caution and at low doses in chronic renal failure.