IL SEGNALAMENTO DEL DELINQUENTE BY SALVATORE OTTOLENGHI: THE STUDY OF DERMATOGLYPHICS IN ANTHROPOMETRIC CABINETS / IL SEGNALAMENTO DEL DELINQUENTEDI SALVATORE OTTOLENGHI: LO STUDIO DEI DERMATOGLIFI NEI GABINETTI ANTROPOMETRICI

The dermatoglyphics are signs of the human variety, as they are absolutely different from one human being to another. For this reason, and for their characteristics of uniqueness, classification, and inalterability, the papillary ridges on the fingertips represent elements of a sure differentiation between one person and another. Fingerprints are, therefore, very helpful in identifying a human being. Salvatore Ottolenghi was the first to utilize the fingerprinting system to identify individuals, and he introduced this system in his "Cartellino di riconoscimento (identification card)" in 1902. He was sure about the scientific validity of this method, which he considered to be free from potential personal interpretation. According to hi definition, "fingerprints, by their nature, form special drawings from birth; these will not change throughout life and will be absolutely different from one human being to another". This fingerprint identification method was immediately refined by Giovanni Gasti, whom Salvatore Ottolenghi had chosen as his personal assistant at the Scuola di Polizia Scientifica (School of Forensic Science). Gasti, adapting the classification method of Francis Galton and Edward Henry, developed the "Sistema Gasti (Gasti System)", which was in use throughout the 1900s.

[BOOSTING CITIZENS'AWARENESS: THE ANATOMICAL COLLECTIONS FOR TEACHING PAST AND PRESENT]. / PER UNA CITTADINANZA ATTIVA E CONSAPEVOLE: LE COLLEZIONI ANATOMICHE PER LA DIDATTICA DI IERI E DI OGGI.

The challenge of eight museums of the University Museum System of the University of Siena for years has been that of annually offering to Siena schools a course of learning on the themes of science. The learning workshop is articulated in a frontal lesson, followed by a visit of the class in the proponent museum to better expound the chosen theme by the teacher. The fundamental role for such a didactic proposal is sustained by the conserved collections in the museum, used in the past to facilitate the university professor in their lessons, and that continue to show a strong didactic value helping the young student to "enter" in a captivating and easy manner into the world of science. In particular, the Anatomical Museum "L. Comparini" has now organized for some years a course of learning using historical instruments, models in terracotta and wax, plastinates, and tables that consent the operator to confront, with young children, the theme of the history of anatomy and the ways and means for research, formation, and the distribution of the anatomical sciences.

Evaluation of corticospinal tract impairment in the brain of patients with amyotrophic lateral sclerosis by using diffusion tensor imaging acquisition schemes with different numbers of diffusion-weighting directions.

Amyotrophic lateral sclerosis is characterized by degeneration of upper and lower motor neurons. Diffusion tensor imaging (DTI) indexes obtained along the corticospinal tracts distinguish ALS patients and control subjects. Diffusion tensor imaging can be estimated from at least 6 diffusion-weighted images; however an acquisition scheme with a higher number of diffusion directions allows a more robust estimation of DTI indexes. The aim of the study was to establish if a higher number of diffusion encoding gradients increases the diagnostic accuracy of DTI in ALS. We studied 18 patients and 16 control subjects acquiring 2 DTI data sets with 6 and 31 gradient orientations. The mean diffusivity and fractional anisotropy values were measured along the corticospinal tract. Mean diffusivity in ALS was significantly increased (P = 0.026) with respect to control subjects in acquisition scheme with 31 but not (P = 0.214) with 6 diffusion-weighting directions. Fractional anisotropy was significantly lower in patients both with 6 (P = 0.0036) and with 31 (P = 0.0004) diffusion-weighting directions (0.538 vs 0.588 and 0.530 vs 0.594). Fractional anisotropy receiver operating characteristic curve analysis showed a higher diagnostic accuracy by using 31 diffusion-weighting direction (85.76%) with respect to 6 directions (79.86%). Diffusion tensor imaging confirms its potentials in diagnosing ALS with a good accuracy; the acquisition scheme with a higher diffusion-weighting directions seems to better discriminate between ALS patients and control subjects.

[The female population of the S. Niccolò mental village in Siena]. / La popolazione femminile del villaggio manicomiale di Siena.

The author deals with the population in the Sienese mental hospital (1810-1999) according to the various female presences. So, not only the patients, poor and rich, but also the attendants, the nurses, the matrons, the teachers, the nuns: a complex and never studied female universe.

Vasovagal reactions in CT colonography.

We describe the occurrence of vasovagal reaction in two patients who underwent CT colonography (CTC). The patients, asymptomatic, were submitted to CTC in one case after right colectomy and in one case for screening purposes. The vasovagal symptoms occurred after pneumocolon and acquisition in the prone decubitus, and included headache, hypotension, bradycardia, cold sweat and pallor, nausea, and diaphoresis. Abdominal pain was also referred. All symptoms resolved within 30 min to 3 h from their onset. In all cases the vasovagal reaction occurred after prone decubitus. CTC images showed a significant distension of the small bowel. Vasovagal reactions are potential complications of CTC.

Suicide gene therapy with the yeast fusion gene cytosine deaminase/uracil phosphoribosyltransferase is not enough for pancreatic cancer.

OBJECTIVES: Suicide gene therapy with FCY1 gene, encoding cytosine deaminase (CD), together with FUR1, encoding uracil phosphoribosyltransferase (UPRT), has been proposed for pancreatic cancer therapy in vivo. We ascertained whether gene therapy with FCY1-FUR1 is effective in killing pancreatic cancer cells after 5-fluorocytosine (5-FC) treatment. METHODS: AsPC1, BxPC3, Capan1, MIA PaCa2, and Panc1 cell lines were transfected using 2 plasmid vectors expressing CD only (pRSV-CD) or the chimera CD-UPRT (pRSV-CD-UPRT). Control and pRSV-CD- or pRSV-CD-UPRT-transfected cell lines were treated with 0, 0.1, 0.5, 1, 5, and 10 mM of 5-FC for 1, 3, 6, 8, 10, and 13 days. RESULTS: FCY1 alone did not confer sensitivity to 5-FC. The CD-UPRT-transfected BxPC3 and Panc1 were sensitive to very low 5-FC doses (0.1 mM). 5-Fluorocytosine-sensitive transfected cell lines rapidly converted 5-FC into 5-fluorouracil, whereas the 5-FC resistant cell lines had an impaired 5-FC conversion. CONCLUSIONS: Suicide gene therapy with the FCY1 gene alone was ineffective in the treatment of pancreatic cancer in vitro. The pRSV-CD-UPRT construct conferred 5-FC sensitivity to some pancreatic cancer cell lines. Therefore, the application in vivo of suicide gene therapy with FCY1 alone or in combination with the FUR1 gene is probably destined to fail.

[A wide-ranging project to the best use of S. Niccolo Psychiatric Hospital]. / Un'operazione culturale per la salvaguardia del S. Niccolò di Siena.

The S. Niccolò Psychiatric Hospital was one of the most important health institutions not only for Siena but for the entire Tuscan district and beyond. It was known to serve all the catchment area for mentally ill patients coming from other cities. At a national level, it is also one of the most beautiful models of hospital architecture of the "village" type, the expression of a late nineteenth-century tendency to perceive mental disorders as illnesses that could be improved and cured through "moral treatment", with work and distraction as the principal therapeutic instruments. The closure of the psychiatric hospital in Siena provided for by the Italian psychiatric reform of 1978 actually took place over an extremely long period of time. It was definitively closed only on 30 September 1999 and was the last psychiatric hospital in Tuscany to cease its activity. Its history, the importance it had for the considerable number of committed patients, the extension of the area of the hospital over 183,574 m2 and its organization in 16 edifices, mean that S. Niccolò is now an architectonic complex of great value and interest but also subject to progressive deterioration. This reality, together with the urgency of salvaging the collections of books from its very rich library and its archives of administrative documents and medical records, has led the author to prepare a wide-ranging and extremely complex project that aims at the best use of S. Niccolò. Thanks to the collaboration of a group of experts from various Faculties of the University of Siena, and beginning with a multidisciplinary study of S. Niccolò's history, the project proceeds to the identification of concrete actions of cultural policy as well.

Thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase expression in colorectal cancer and normal mucosa in patients.

OBJECTIVE: To compare thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP) gene polymorphism and expression in colorectal cancer (CRC), and normal mucosa in chemotherapy-naïve patients. METHODS: TS, DPD and TP mRNA expression was analysed by real-time reverse-transcription polymerase chain reaction in primary CRC and adjacent normal tissues from 53 patients with glyceraldehyde-3-phosphate dehydrogenase as housekeeping gene. TS promoter (TSER and C/G SNP) and DPD IVS14+1G>A genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism assays. Moreover, the correlation between TS, DPD and TP expression and cytotoxicity of 5-fluorouracil was evaluated in Colo 320, HT-29, CaCo-2 and SW620 human CRC cell lines. RESULTS: TP and DPD mRNA expression was significantly different in tumour and normal tissue (7.51+/-13.50 vs. 1.10+/-0.57, P<0.05 and 0.60+/-0.63 vs. 1.17+/-0.55, P<0.0001, respectively), whereas no differences were observed in TS mRNA levels. High-grade, undifferentiated tumours (WHO grade 3) had significantly higher mRNA levels of TS with respect to moderately differentiated (WHO grade 2) carcinomas (0.38+/-0.37 vs. 0.00+/-0.44, respectively; P<0.05). Noteworthy, TS mRNA expression was significantly decreased (P<0.05) in homozygous TSER*3G/3G (-0.35+/-0.35) with respect to pooled homozygous TSER*2/2 and heterozygous TSER*2/3 genotypes (0.14+/-0.41). In-vitro results showed a higher sensitivity to 5-FU of cell lines with the lowest TS expression. CONCLUSIONS: The present results demonstrated significant differences in DPD and TP gene expression between normal mucosa and tumour samples, while TSER*3G/3G and high-grade histology were associated with significant variation in TS gene expression in tumour samples.

A pharmacokinetic-based test to prevent severe 5-fluorouracil toxicity.

BACKGROUND AND OBJECTIVES: Dihydropyrimidine dehydrogenase (DPD) plays a key role in the catabolism of 5-fluorouracil (5-FU) to 5-fluoro-5,6-dihydrouracil (5-FDHU), and as such, an impairment of DPD has been recognized as an important factor for altered 5-FU and 5-FDHU pharmacokinetics, predisposing patients to the development of severe 5-FU-associated toxicity. Our objectives were to avoid severe 5-FU toxicities in patients with greatly impaired 5-FU and 5-FDHU pharmacokinetics after the administration of a reduced test dose of 5-FU and to investigate possible 5-FU or 5-FDHU pharmacokinetic parameters of the test dose related to the most common drug toxicities that affect patients after the first cycle of 5-FU chemotherapy. METHODS: Pharmacokinetics of 5-FU/5-FDHU and DPD activity in peripheral blood mononuclear cells (PBMCs) were examined in 188 gastrointestinal cancer patients given a test dose of 5-FU, 250 mg/m2, 2 weeks before starting the planned 5-FU treatment of 370 mg/m2 plus l-folinic acid, 100 mg/m2, for 5 days every 4 weeks. Drug levels were examined by HPLC, and toxicities were graded according to World Health Organization criteria. RESULTS: The 5-FU test dose was well tolerated in all patients. Of 188 patients, 3 (1.6%) had marked alterations of 5-FU/5-FDHU pharmacokinetics (ie, 5-FU half-life [t(1/2 beta)] >5 hours, 5-FU total body clearance [CL(TB)] <1 L x h(-1) x m(-2), and 5-FDHU time to reach maximum plasma concentration [t max] > or = 45 minutes); they were excluded from 5-FU treatments and treated with irinotecan, which was well tolerated. The plasma disposition of 5-FU in the remaining 185 patients revealed an area under the curve (AUC) of 3.73 +/- 2.18 h x microg/mL (mean +/- SD), maximum plasma concentration (Cmax) of 16.78 +/- 8.61 microg/mL, and t(1/2 beta) of 0.16 +/- 0.15 hour, whereas the CL(TB) was 65.67 +/- 31.86 L x h(-1) x m(-2). The 5-FDHU plasma profile showed a Cmax value of 3.64 +/- 1.94 microg/mL, whereas the t max value was 26.63 +/- 10.06 minutes, with an AUC value of 3.71 +/- 1.90 h x microg/mL. The PBMC DPD activity was 202.15 +/- 141.14 pmol 5-FDHU x min(-1) x mg(-1) protein (95% confidence interval, 165-239.3 pmol 5-FDHU x min(-1) x mg(-1) protein). A significant correlation between 5-FU AUC and 5-FDHU AUC was found (r = 0.5492, P < .0001), whereas a weaker correlation between PBMC DPD activity and both 5-FDHU AUC (r = 0.328, P = .0121) and 5-FDHU Cmax (r = 0.369, P = .0044) was found. Interestingly, no relationships between PBMC DPD activity and common toxicities were found, whereas 5-FDHU t max values greater than 30 minutes were associated with the risk of moderate to severe neutropenia and diarrhea (P = .0323 and P = .0138, respectively; chi-square test). CONCLUSIONS: This study suggests a successful approach for preventing severe or life-threatening toxicities in gastrointestinal cancer patients who are candidates for standard 5-FU treatment by analyzing the 5-FU and 5-FDHU pharmacokinetic parameters after the administration of a reduced 5-FU test dose.

Time efficiency of CT colonography: 2D vs 3D visualization.

We aimed to compare the time efficiency of three visualization methods in CT colonography and to identify the colonic factors influencing the time for interpretation. Twenty CT colonographic examinations were prospectively analysed. Three reading methods were adopted: method 1, primary 2D analysis with the use of virtual endoscopy as problem solver, method 2, primary standard virtual endoscopy with semiautomatic navigation through the colon and use of 2D images as problem solver; method 3, primary virtual endoscopy with automatic navigation and the use of 2D images as problem solver. In method 1, time for 2D analysis ranged between 6 and 18min (mean 12) for evaluation of both supine and prone decubitus with a synchronization method. In method 2, time for 3D manual navigation in supine plus prone ranged between 9 and 24min (mean 17). In method 3, time for automated navigation ranged between 6 and 20min (mean 12) for evaluation of both supine and prone decubitus. A statistically significant difference was found between time efficiency of methods 1 and 2 (p=0.009, t-test, unequal variances). Methods 2 and 3 showed a tendency to significant differences (p=0.054, t-test, unequal variances). Faecal or fluid residuals were reported as major drawbacks in 3D navigations, requiring constant correlation with 2D images; tortuous folds influenced mostly the 2D analysis; diverticula were reported as influencing factor in all three methods. No differences in sensitivity and specificity were observed between the three viewing methods. The 3D semiautomatic navigation method* tended to increase the time for interpretation in almost all cases. There is, in particular, greatest time efficiency for 2D analysis as compared with 3D manual analysis. Two-dimensional and automated 3D navigation reading have comparable time efficiencies in a routine clinical setting.

Improved analysis of 5-Fluorouracil and 5,6-dihydro-5-Fluorouracil by HPLC with diode array detection for determination of cellular dihydropyrimidine dehydrogenase activity and pharmacokinetic profiling.

Administration of 5-fluorouracil (5-FU) may be associated with severe toxicities in patients who are deficient of dihydropyrimidine dehydrogenase (DPD) activity. For this reason, a sensitive HPLC method for the analysis of 5-FU and 5-fluoro-5,6-dihydrouracil (5-FDHU) was developed in the present study for the determination of DPD activity in nucleated cells of peripheral blood and pharmacokinetic analysis of 5-FU and 5-FDHU in humans. 5-FU and 5-FDHU were extracted from biologic matrices by adding sodium acetate, sodium sulfate, and diethyl ether/propanol. Dried samples were reconstituted in a mobile phase (KH2PO4 35 mmol/L, pH 4.0), isocratically eluted with a Hypersil C18 stationary phase (25 cm x 4.6 mm, 10 microm), and detected by a diode array detector (measurement and reference wavelengths, 215 and 360 nm, respectively). 5-Fluorocytosine (internal standard), 5-FDHU, and 5-FU were eluted within 13 minutes of the injection without interferences. Recoveries ranged between 81% to 85% for all compounds, and the method proved to be linear, with a coefficient of linearity of 0.999. The limits of detection and quantification were 3.2 and 16 ng/mL, respectively, and the within-day and between-day CV were less than 10% for both 5-FU and 5-FDHU. The present assay proved to be sufficiently sensitive and specific to evaluate cellular DPD activity and measure 5-FU and 5-FDHU plasma concentrations in cancer patients, thus allowing therapeutic 5-FU monitoring in patients and identification of DPD-deficient subjects at major risk of severe toxicities.

[Ancient instruments, tables, models for a modern education]. / Strumenti, tavole, modelli di ieri per una didattica di oggi.

The article put a series of actual proposal of scientific education, using historical collections, instruments, tables and models, preserved in Siennese Scientific Museums, as "tools" for the teaching of science.

Drug therapeutic failures in emergency department patients. A university hospital experience.

Drug therapeutic failure (DTF) could be considered as an adverse drug reaction in which the expected drug effects do not occur following a prescribed pharmacological treatment, including any clinical event that could be related to a low prescribed dose or lack of compliance. DTFs are responsible for increasing disease length, hospitalisation time and social costs, with the worsening of patient quality of life. The aims of the present study are: (1) to estimate the frequency of DTFs among cases of adverse drug events referred to the emergency department; (2) to identify drug classes implicated in DTFs; (3) to analyse the putative causes underlying DTFs. Data presented in this paper were obtained from the Pronto Soccorso and Adverse Drug Events (PSADE) study carried out to analyse drug-related emergency department admissions in several Italian hospitals. Patients, admitted to the emergency department throughout two periods of 10 days each, were interviewed to gain information on their medical status and drug intake during the last two weeks. The present study analysed the patient questionnaires collected in the emergency department of Pisa University Hospital. Among 123 recorded cases of adverse drug event, 41 cases (19:22 male:female ratio; age range: 17-98 years, median age: 75 years) were identified as suspect DTF, resulting in a frequency of 33.33%. A statistical analysis was performed to evaluate the influence of two variables, class of patient age and number of drugs assumed, on DTFs. In accordance with the present findings, showing that the number of drugs assumed by a patient may increase the risk of DTF more than advanced age (odds ratio: 1.371, P<0.02; 1.295, P<0.03, respectively), the prescription of pharmacological combinations might be proposed as a main risk factor for DTF occurrence. In conclusion, our results suggest that DTFs represent an important cause of emergency department admission, particularly in elderly subjects treated with pharmacological associations.

Limited sampling model for the analysis of 5-fluorouracil pharmacokinetics in adjuvant chemotherapy for colorectal cancer.

BACKGROUND: Administration of 5-fluorouracil may be associated with life-threatening toxicities, resulting from a reduced drug biotransformation to the inactive metabolite 5-fluoro-5,6-dihydrouracil. Patients with severe toxicities display significant alterations of 5-fluorouracil pharmacokinetics, the monitoring of which may be made easier by the availability of a limited sampling model (LSM). METHODS: LSMs for 5-fluorouracil and 5-fluoro-5,6-dihydrouracil therapeutic monitoring have been developed in 80 patients with colorectal cancer (training set) given 5-fluorouracil, 370 mg/m(2) per day as an intravenous bolus, plus leucovorin, 100 mg/m(2) per day, for 5 days every 4 weeks. Pharmacokinetic analysis was performed on plasma levels of 5-fluorouracil and 5-fluoro-5,6-dihydrouracil obtained on day 1 of the first cycle of chemotherapy, and backward stepwise regression analysis was used to determine the optimal LSM on the basis of bias (percentage mean prediction error [MPE]) and precision (percentage root mean square prediction error [RMSE]). RESULTS: An optimal model based on 2 time points was obtained (percentage MPE = 1.99% +/- 1.41%; percentage RMSE = 12.70% +/- 1.27%), and the predicted area under the time versus plasma concentration curve (AUC) was calculated as follows: predicted AUC (h x microg/mL) = 0.119 x C(5) + 1.436 x C(45) + 2.066, in which C(5) and C(45) are plasma concentrations of 5-fluorouracil at 5 and 45 minutes after drug administration, respectively. The application of this algorithm to pharmacokinetic analysis of plasma levels of 5-fluorouracil in 80 patients (test set) allowed a precise estimation of AUC (percentage MPE = -0.09% +/- 1.37%; percentage RMSE = 12.17% +/- 1.23%). The best LSM for 5-fluoro-5,6-dihydrouracil was characterized by a percentage MPE of -0.64% +/- 0.86% and a percentage RMSE of 7.64% +/- 0.81%, and the optimal sampling time points were 45 and 180 minutes. CONCLUSION: The current LSM allows a reliable assessment of drug exposure and improves the use of therapeutic drug monitoring for treatment optimization of 5-fluorouracil in patients with cancer.

Relationship between plasma concentrations of 5-fluorouracil and 5-fluoro-5,6-dihydrouracil and toxicity of 5-fluorouracil infusions in cancer patients.

This study investigated the relationship among the pharmacokinetics of 5-fluorouracil (5-FU) and 5-fluoro-5,6-dihydrouracil (5-FDHU); the activity of dihydropyrimidine dehydrogenase (DPD) in peripheral blood mononuclear cells; and treatment-related toxicity in 26 patients with surgically resected colorectal cancer treated with short daily infusions of 5-FU adjuvant chemotherapy, each cycle consisting of 5 consecutive days every 4 weeks. After the first chemotherapeutic cycle, severe stomatitis and diarrhea occurred in 5 patients and were related to the variations in the systemic disposition of the drug rather than to DPD activity. These patients showed a significant decrease in 5-FU clearance, and an increase in the 5-FU/5-FDHU area under the time-concentration curve (AUC) ratio, as compared with patients who experienced mild toxicities, whereas a low DPD activity was observed in only 2 patients. In conclusion, the results of this study demonstrate that the alterations in 5-FU and 5-FDHU pharmacokinetics are related to severe toxicities in patients treated with short intravenous infusion of 5-FU.