The tryptophan hydroxylase activation inhibitor, AGN-2979, decreases regional 5-HT synthesis in the rat brain measured with α-[C]methyl-l-tryptophan: An autoradiographic study

Many experimental conditions are stressful for animals. It is well known that stress induces tryptophan hydroxylase (TPH) activation, resulting in increased serotonin (5-HT) synthesis. In our experimental procedure to measure 5-HT synthesis using alpha-[(14)C]methyl-L-tryptophan (alpha-MTrp) autoradiographic method, the hind limbs of animals are restrained using a loose-fitted plaster cast such that the forelimbs of the animal remain free. The objective of the present investigation was to evaluate the changes, if any, in 5-HT synthesis, after injecting these restrained rats with the TPH activation inhibitor AGN-2979. The effect on regional 5-HT synthesis was studied using the alpha-MTrp autoradiographic method. The hypothesis was that the TPH activation inhibitor would reduce 5-HT synthesis, if TPH activation was induced by this restraint. The rats received injection of AGN-2979 (10 mg/kg, i.p.) or distilled water vehicle (1 mL/kg, i.p.) 1 h prior to tracer administration. The free- and total tryptophan concentrations were not significantly different between the treatment and control groups. The results demonstrate that 5-HT synthesis in AGN-2979 treated rats is significantly decreased (-12 to -35%) in both the raphe nuclei and their terminal areas when compared to the control rats. These findings suggest that restrained conditions, such as those used in our experimental protocol, induce TPH activation resulting in an increased 5-HT synthesis throughout the brain. The reduction in 5-HT synthesis in the AGN-2979 group is not related to a change in the plasma tryptophan. Because there was no activation in the pineal body, the structure having a different isoform of TPH, we can propose that it is only the brain TPH that becomes activated with this specific restraint.     

Origin of nasal polyps: an endoscopic autopsy study

OBJECTIVES/HYPOTHESIS: To further elucidate the natural history, etiology, and pathogenesis of nasal polyps, the present study of their anatomical site of origin was undertaken. The possibility for preferred areas or certain patterns in the places of origin was also considered. STUDY DESIGN: Autopsies were examined consecutively. METHODS: Endoscopic examination of the nasal cavity and paranasal sinuses, including endoscopic sinus surgery, was performed in 69 autopsies. The place of origin and attachment of each polyp was meticulously described. Polyps were photographically documented in situ and removed, together with the corresponding mucosa, for later histological examination. The cause of death of the patients was either cardiopulmonary disease or malignant diseases. Median age was 73 years (age range, 47-94 y). RESULTS: Nasal polyps were found in 22 of the 69 autopsies, corresponding to a frequency of 32%. In all, 54 polyps were found. Thirty-nine polyps were small (length, 2-5 mm), 10 were medium-sized, and 5 were large. No complaints of symptoms from the nasal polyps were registered. Most of the polyps (40 of 54 [74%]) originated in relation to sinus outlets. Most of these (34 of 54 [63%]) were found in the middle or superior meatus (13 of 54 [24%]). CONCLUSION: The results seemed to indicate that the frequency of nasal polyps is high and that most of the polyps originate from the mucosa of the ostia, clefts, and recesses in the ostiomeatal complex where the initial stage of sinonasal polyposis seems to take place. Continuous postmortem studies in autopsy materials and systematic endoscopic examinations for "silent," asymptomatic nasal polyps in various groups of patients will lead to a better understanding of the natural history of nasal polyps.     

Particle image velocimetry for flow analysis in longitudinal planes across a mechanical artificial heart valve

In the last decades a great number of in vitro studies have been conducted to improve the design and to understand the transvalvular flow patterns under steady-state and pulsating flow conditions. Steady-state tests are useful for studying the flow established upstream and downstream of the valve prosthesis in different flow conditions and, in particular, at the peak flow rate. In the present study, the particle image velocimetry (PIV) technique is employed to visualize the flow patterns in a precommercial model of a bi-leaflet mechanical heart valve prosthesis in a steady-state flow regime. The use of the PIV technique and a convenient test rig provide good conditions with which to investigate the whole flow field upstream and downstream of the valve. Velocity and vorticity maps are obtained for the flow passing through the prosthesis in different axial planes. A new and simple solution for the measurement test chamber is proposed. This innovative approach of observing the flow in staggered planes (other than diametrical planes) allows a flow analysis to be performed upstream and downstream of the valve in regions near the tube wall where it has the maximum potential for injury of the vessel's inner cell layer.     

Role of Computer Analysis in Gastric Cancer Surgery: Evaluation of the WinEstimate v. 2.5 Computer Program

To identify the group of patients with gastric cancer who can benefit from extensive lymphadenectomy and to offer a rational approach to lymph node dissection, it is important to know the incidence of metastases at each lymph node station. A computer program was developed for assessment of lymph node involvement and survival time in each individual case according to preoperative variables. In patients who have undergone R0 resection with D2 lymphadenectomy, differences between the individual results generated by the computer and the actual data were compared. A cutoff point of 10% in the prediction of metastases was used as a positive result. The computer program made false predictions in 9% of patients for the pN status (3% lower and 6% higher than the actual status). Computerized prediction of 5-year survival was close to the rate calculated by the Kaplan-Meier method (55.5% vs 56.1%). Preoperative computer analysis of patient data and tumor characteristics offers a rational approach to individualizing tumor therapy] where the extent of lymph node dissection is tailored to the type, site, and stage of the tumor, thereby minimizing the disadvantages (morbidity, mortality) associated with the extensive operative procedure.     

Detection of mutations in the cDNA of the proliferation marker Ki-67 protein in four tumor cell lines

The Ki-67 protein has an essential role in cell proliferation. It is present in all dividing cells of normal and tumor tissues, but absent in resting cells. At present, no data are available about any alterations in the gene of this protein that could contribute to its altered structure and function, resulting in tumor development. We therefore searched for mutations in the Ki-67 gene (MKI67). cDNAs from four tumor cell lines derived from carcinoma of the cervix (HeLa), colon (CXF94, SW480), and lung (A549) were prepared. Defined parts of the cDNA were amplified by specific primers, cloned into pCRII-Blunt-TOPO vector, and replicated in Escherichia coli. The sequence of the amplified products were determined by automated fluorescence sequencing. Eight different mutations were characterized in the four cell lines tested. One is a deletion of a single base at position 1496 causing a truncated protein, the second is a A433T exchange is a silent mutation, and the remaining six mutations result in an amino acid change that might alter the conformation of the protein. Our results show that several mutations exist within the Ki-67 protein's cDNA in four tumor cell lines. These mutations might provide a genetic basis for tumor development.     

Tau protein phosphorylated at threonine 181 in CSF as a neurochemical biomarker in Alzheimer’s disease

Cerebrospinal fluid (CSF) concentrations of total Tau and Tau phosphorylated at threonine (position 181 [pTau181]) were studied with ELISA in a group of carefully selected patients with a neurochemically supported diagnosis of Alzheimer's disease (AD, n = 9; age range, 51-89 yr) and in a group of sex- and age-matched nondemented controls (n = 9; age range, 52-81 yr). The concentration of both biomarkers is increased significantly in the AD group (total Tau, p < 0.0008; pTau181, p < 0.008). A significant correlation between CSF concentrations of both biomarkers is observed (R = 0.897; p < 0.001). Neither total Tau nor pTau181 correlates with age or degree of memory impairment, and only a tendency is observed between the concentrations of total Tau and Abeta42 in the CSF. Our results further confirm a possible role of pTau181 as a diagnostic tool in AD. The current literature regarding the physiological and pathological role of phosphorylated Tau proteins is reviewed, as well as the role of these proteins as promising biomarkers in the diagnosis of neurodegenerative disorders.     

Uptake of a cholesterol-rich emulsion by breast cancer

OBJECTIVE: Overexpression of low-density lipoprotein (LDL) receptors occurs in several cancer cell lines and offers a unique strategy for drug targeting by using LDL as vehicle. However, the native lipoprotein is difficult to obtain and handle. Previously, we showed that a lipidic emulsion (LDE) similar to the lipid structure of native LDL may bind to LDL receptors and be taken up by acute myelocytic leukemia cells. We also showed that LDE can also concentrate in ovarian cancer tissue. In this study, we tested whether LDE is taken up by breast carcinoma. METHODS: LDE labeled with (99m)Tc was injected into 18 breast cancer patients, and nuclear medicine images of the tumor and metastatic sites were acquired. Subsequently, LDE labeled with [3H]cholesteryl oleate was intravenously injected into 14 breast cancer patients 24-30 h before total mastectomy procedure. Fragments of normal and of breast cancer tissue excised during surgery were lipid extracted with chloroform/methanol and their radioactivity was measured in a scintillation solution. RESULTS: (99m)Tc-LDE images of the primary tumor and of metastasis sites were obtained in all 18 breast cancer patients. As directly measured in the tumor and in the normal mammary tissue, the amount of the emulsion radioactive label in the tumor was 4.5 times greater than in the normal tissue (range 1.2- to 8.8-fold). CONCLUSION: LDE concentrates much more in malignant breast tumor tissue than in the normal tissue. Thus it has potential to carry drugs or radionuclides directed against mammary carcinoma cells for diagnostic or therapeutic purposes.     

Surgical versus endovascular treatment of acute thoracic aortic rupture: a single-center experience

BACKGROUND: Surgical management of acute thoracic aortic ruptures is controversial, especially in patients with preexisting comorbidities; associated mortality and paraplegia rates remain high. It was our objective to evaluate whether treating these patients acutely with endovascular stent grafts would improve their outcome. METHODS: From November 1999 to February 2002 a total of 54 patients, age 28 to 83 years, were admitted to our institution with an acute rupture of the thoracic aorta (24 ruptured aneurysms, 14 perforated type B dissections, 16 traumatic ruptures). Twenty-eight patients were managed surgically using cardiopulmonary bypass (group 1), and 26 patients were treated acutely with an endovascular stent graft (group 2). The resuscitation protocol and interval from onset of symptoms to treatment was comparable in both groups. Medical records were reviewed for prehospitalization and emergency department data, operative findings, and outcomes. RESULTS: There were 5 of 28 deaths (17.8%) in the surgical group and 1 of 26 deaths (3.8%) in the endovascular group. In the surgical group 1 of 28 patients (3.6%) exhibited paraplegia; there were no cases of paraplegia in the endovascular group. There were 4 of 28 cases (14.3%) of renal failure in group 1 and 1 of 26 (3.8%) in group 2. In group 1, 8 patients (28.6%) required mechanical ventilation for more than 48 hours; there were 2 of 26 patients (7.7%) in group 2 with this ventilatory requirement. Three patients required a repeat thoracotomy for hemorrhage in the surgical group. There were two access failures in the endovascular group. CONCLUSIONS: In the treatment of acute ruptures of the thoracic aorta, the immediate outcome of patients treated with endovascular stent grafts appears to be better than with management by conventional surgical repair.