[Implementation of a new gene therapy in ophthalmology: Regulatory and organizational issues]. / Mise en place d'une nouvelle thérapie génique en ophtalmologie : aspects réglementaires et organisationnels.

Voretigene neparvovec (VN) is the first gene therapy in ophthalmology for patients with RPE65-mediated hereditary retinal dystrophy. It has recently obtained European market approval, which is subject to strict regulatory and organizational conditions for its use. Here, we analyze the main studies supporting the authorization of this new therapy and describe the necessary steps to take at a hospital level for optimal administration to patients following current regulations.

[Drug interactions in an elderly population. Prospective assessment of their frequency and seriousness among 56 patients]. / Interactions médicamenteuses dans une population âgée.

OBJECTIVE: To assess the nature and the number of potential adverse drug interactions by analysis of outpatient prescriptions for elderly patients, of medications taken during the week before hospitalization in a general surgery department. METHOD: The study of 56 patients older than 65 years was conducted from November 2002 through February 2003. The outpatient prescriptions corresponding to medications taken during the 7 days before admission were analyzed by a pharmacy resident, who used data-processing tools and databases. RESULTS: Most patients (83%) knew the reason for their prescription. Thirteen (28%) reported using over-the-counter medication. Only 89% of the patients reported complete compliance with the prescription. The average age of the patients was 72.1 +/- 6.3 years and the median was 71 years [65-91]; 43% were women and 57% men. The 257 lines of prescriptions analyzed averaged 5.7 +/- 2.6 drugs (range: 2-10) per prescription. The average number of possible interactions was 3.1 +/- 2.8 per prescription for a total of 89 listed potential interactions. The levels observed were 3 warnings (3%), 37 precautions (42%) and 49 possible adverse interactions (55%). No contraindication was noted. The drugs mentioned most often were benzodiazepines, diuretics, conversion enzyme inhibitors, angiotensin II inhibitors, and beta-blockers. The potential risks most often found were hypotension, depression of the central nervous system, hypoglycemia and acute renal failure. The drug interactions were mainly due to the accumulation of the effects of separate drug classes. Deterioration in renal function was often noted as plasma concentration of the second drug increased. DISCUSSION: This exploratory study shows the reality of the iatrogenic risk for elderly patients. This analysis of outpatient prescriptions is consistent with findings in the literature. Analysis of interactions is conducted on a pairwise basis. It is thus difficult to envisage the consequences of the association of 5 or more drugs in patients with complex illnesses and diminished physiological and metabolic capacity. Patient files kept by the pharmacist could provide information about individual combinations ofthe prescription and over-the-counter drugs.

Stability of doxorubicin combined with Radioselectan, a contrast agent, for chemoembolization.

OBJECTIVE: To assess the stability of doxorubicin combined with Radioselectan. METHODS: Solutions of doxorubicin 5 mg/mL were prepared from commercially available 50 mg powder with 10 mL of Radioselectan. They were stored in glass syringes at 4, 25 and 45 degrees C. The concentrations of doxorubicin were determined using a stability-indicating high-performance liquid chromatography method. The initial and final pHs of solutions were compared. The times (t90) needed for doxorubicin to fall to 90% of its initial concentration were calculated by a linear regression analysis. RESULTS: The t90 [95% confidence limits] were 79 [75-83], 56 [53-59] and 22 [21-23] hours for the solutions stored at 4, 25 and 40 degrees C respectively. The initial pH of the solutions stored at 4, 25 and 40 degrees C were 6.52, 6.50 and 6.51 respectively. The final pH of solutions stored at 25 and 40 degrees C decreased significantly by 0.3 and 0.9 respectively. No change of pH solution stored at 4 degrees C was observed. CONCLUSION: Doxorubicin combined with Radioselectan stored at room temperature is stable for 48 h.

Screening of multidrug-resistance sensitive drugs by in situ brain perfusion in P-glycoprotein-deficient mice.

PURPOSE: This study was conducted to assess the influence of P-glycoprotein (P-gp) on brain uptake of multidrug resistance sensitive drugs using an in situ brain perfusion technique in P-gp-deficient (mdr1a[-/-]) and wild-type mice. METHODS: The blood-brain transport of radiolabeled vinblastine, vincristine, doxorubicin, colchicine, and morphine was evaluated in mdr1a(-/-) and wild-type CF-1 mice with the in situ brain perfusion technique. Brain uptake of drugs after intravenous pretreatment with P-gp reversal agents, (PSC 833, GF 120918, or (+/-)-verapamil), or vehicle also was studied in wild-type mice. In all experiments, cerebral vascular volume was determined by co-perfusion of sucrose. RESULTS: Cerebral vascular volume was preserved during perfusion, indicating maintenance of blood-brain barrier integrity in both types of mice within the concentration range of substrates in the perfusate. The apparent brain transport of colchicine. vinblastine, doxorubicin, and morphine was increased 3.0, 2.7, 1.5, and 1.4-fold, respectively, in mdr1a(-/-) mice compared with the wild-type: the brain uptake of vincristine was not affected by P-gp. Preadministration of PSC 833 or GF 120918 in wild-type mice led to a -3-fold increase in the brain transport of colchicine and vinblastine, but no effect was observed for the other compounds. Intravenous verapamil enhanced colchicine brain transport (1.8-fold), but failed to increase the brain uptake of vinblastine and morphine. CONCLUSION: The in situ brain perfusion technique appears to be a sensitive and powerful tool for medium throughput screening of the brain uptake of multidrug resistance sensitive drugs. The effect of P-gp is characterized more efficiently with mdr1a(-/-) mice than by using modulators of P-gp in wild-type mice.

[Laparoscopic appendectomy as first choice intervention in the treatment of inflammatory diseases of the appendix. Analysis of 397 laparoscopic interventions]. / L'appendicectomia laparoscopica come intervento di scelta nel trattamento delle malattie infiammatorie dell'appendice. Analisi di 397 interventi laparoscopici.

Despite the increasingly widespread use of laparoscopy, especially for gallbladder diseases, laparoscopic appendectomy has not yet met with universal acceptance. The aim of the present retrospective study was to illustrate the technical aspects and the results of 397 laparoscopic appendectomies carried out at the Surgical Department of the San Giovanni Battista Hospital in Zagarolo, Rome, from January 1993 to December 2000. The patients included 260 females with a mean age of 35.5 years and 137 males with a mean age of 38.5 years. All the appendectomies were carried out laparoscopically, with a conversion index of 0%, by two surgeons, utilising only three trocars and the Veress needle technique. Mean operating time was 22.5 min (range: 15-30 min). The mean postoperative hospital stay was 1.5 days. Morbidity was 1.76% (7 cases) and mortality nil. The authors emphasise the numerous advantages of laparoscopic techniques in their experience, including the excellent cosmetic results, reduced postoperative pain, rapid functional recovery, and lower incidences of adhesions, wound infections and laparocele, and believe that laparoscopic appendectomy is a reliable operation for treating all inflammatory diseases of the appendix.

[Videolaparoscopic treatment of varicocele: retrospective study of 165 cases]. / Trattamento videolaparoscopico del varicocele: studio retrospettivo su 165 casi.

Idiopathic varicocele is a common condition that is present in approximately 15% of the general male population. The mechanism by which varicocele exerts a deleterious effect on testicular function and semen quality remains unknown. Nevertheless, it is generally regarded as a significant factor in male infertility. Varicocelectomy is accomplished with a variety of approaches: the inguinal and high retroperitoneal procedures are still commonly accepted methods, but laparoscopic varicocelectomy is currently proving an increasingly popular procedure. The authors report the results of a retrospective study of 165 laparoscopic varicocelectomies performed from 1993 to 2000 and conclude that this approach is simple, safe and effective and should be recommended as the treatment of choice.

Population pharmacokinetics of methotrexate in the guinea pig.

The population pharmacokinetics of an antitumoral and antiinflammatory agent, methotrexate (MTX), a folic acid antagonist, was studied in guinea pigs. Animals received an acute intraperitoneal injection of 0.25, 1 or 5 mg/kg MTX. Blood sampling was carried out for 12 hrs. after MTX administration and plasma drug concentrations were measured by fluorescence polarization immunoassay. The pharmacokinetic (PK) parameters were computed using the bayesian population model. MTX reached the level of detection at 3 hrs. for the animals injected with the lowest dose (0.25 mg/kg), at 3.5 hrs. for those animals which had the intermediate dose (1 mg/kg) and more than 6 hrs. for animals having received the highest dose (5 mg/kg). Each kinetic parameter (half life, total clearance - CLt, volume of distribution at steady state - VDSS, mean residence time - MRT - and area under curve - AUC) didn't show any significant difference between doses. MTX kinetic was linear for the first two doses (0.25 and 1 mg/kg MTX) and non-linear thereafter. MTX presented a one compartment distribution.

[The use of the jejunum free flap in the reconstruction of the oral cavity]. / Il lembo rivascolarizzato di digiuno nella ricostruzione del cavo orale.

The rapid development of surgical techniques in the head and neck area has greatly assisted in enabling reconstructive surgery to bring about prompt positive results. Radical tumor excision alone is no longer an acceptable treatment. Through new reconstructive techniques, psychological and social isolation of the patients, due to difficulties in such vital functions as chewing, speech, swallowing and breathing, can be reduced remarkably. In the past numerous techniques which employed myocutaneous flaps in the reconstruction of the oropharynx have been described. During the last ten years, however, many Authors have proposed the use of free flaps for this reconstructive surgery. Our Department presents its personal experience in reconstruction of the oral cavity using the jejunal flap, which facilitates superior physiological and histological adaptation when compared to that had with other flaps. Our histological study shows metaplastic transformation of the columnar epithelium into squamous epithelium (similar to oral cavity epithelium), phenomenon already observed in "cervix uteri" and anorectal area. The primary reconstruction with a free revascularized jejunal loop associated with mandibular replacement offers certain significant advantages such as satisfactory reconstruction of large defects, high flexibility of the flap and a productions of mucous which cleans the surface of transplants. Furthermore, the mesenteric foot tissue serves as good transplant material for extended soft-tissue loss. In agreement with a Study begun by Carrel in 1906 and that of Reuther (1982), we believe that reconstruction of large defects in the oral cavity by means of transplantation of the mucosa is the ideal treatment.

[Magnetic resonance imaging of the esophagus with lumen opacification using a specific contrast agent]. / Studio dell'esofago con risonanza magnetica con opacizzazione del lume mediante impiego di un mezzo di contrasto specifico.

A new contrast agent has been developed for the opacification of the esophageal lumen in Magnetic Resonance (MR) Imaging. The contrast agent consists of an emulsion of low-density and high-viscosity barium paste employed for the CT study of the esophagus (E.Z.E.M., Westbury, USA) and a small amount of Gadolinium-DTPA (Magnevist, Schering, Germany), diluted in 3 ml of saline solution. In vitro evaluation of the contrast solution showed high-signal intensity on T1-weighted SE sequences. The study was subsequently performed on 5 healthy volunteers and 30 subjects with clinical indication for MR Imaging of the chest. The complete opacification of the esophagus was obtained in 12 of the 16 patients (75%) who presented no pathological involvement of the esophagus. The esophageal lumen was completely opacified in 8 patients with esophageal carcinoma and in 1 case of esophageal leiomyoma. In the cases with esophageal carcinoma, lumen opacification allowed the evaluation of tumor growth (concentric or eccentric), a more detailed definition of tumor extent, with assessment of neoplastic wall thickening, and the evaluation of the possible infiltration of adjacent organs. Lumen opacification was obtained in 8 of 10 patients (80%) affected with other chest conditions secondarily involving the esophagus. In these cases, lumen opacification helped to localize the esophagus and to evaluate its involvement by adjacent tumors.

[Magnetic resonance in the diagnosis of thyroid diseases]. / La Risonanza Magnetica nella diagnostica delle malattie della tiroide.

Previous clinical experience in the study of the soft tissues of the neck region has pointed out the accuracy of MRI in terms of high definition and contrast resolution. Seventy-seven patients with thyroid diseases were examined to define the possible role of MRI in the diagnosis of these conditions. In the patients affected with thyroiditis, MR findings were not specific, showing increased glandular volume and signal inhomogeneity. MR examinations of struma allowed an accurate evaluation of glandular size; furthermore, more information was obtained than with other imaging modalities in the cases with mediastinal involvement. On T2-weighted images, adenomas were always hyperintense, whereas variable signal intensity was seen on T1-weighted scans, with the exception of Hürthle cell adenomas, which were hyperintense on both T1- and T2-weighted sequences. MRI proved to be reliable in the depiction of tumor spread at both glandular and extraglandular levels. The distinction between scar fibrosis and relapse was also possible, in the cases undergoing postoperative follow-up. In conclusion, MRI emerges as a diagnostic tool complementary to other imaging techniques. However, in selected conditions--e.g., mediastinal struma and tumors--and in the postoperative follow-up, MRI can be considered the method of choice.

Arteriography in diagnosing hepatocellular carcinoma.

The diagnostic role of arteriography in the evaluation of hepatocellular carcinoma is pointed out. In the identification of large lesions angiography achieves a sensitivity of 100%. However, when evaluating small lesions (under 5 or 3 cm in diameter), the sensitivity is reported to be 82-89%. To increase the sensitivity, different special techniques have been developed which require angiographic placement of a catheter. These include CT arteriography, CT arterial portography and CT after intraarterial injection of iodized oil. Particularly with the two latter techniques, the sensitivity in identification of small hepatocellular carcinoma reaches a value of 91-95%. Angiography can also be proposed for the characterization of neoplastic lesions in cirrhotic livers. Its specificity is 72% in the differential diagnosis of hepatocellular carcinoma and adenomatous hyperplastic nodules. Small grade I hepatocellular carcinoma can simulate this benign lesion at angiography, as well as at histology. Finally, angiography may still play a role in the preoperative staging of hepatocellular carcinoma both for the diagnosis of satellite lesions and for the identification of vascular invasion.

Myxoid intraneural cysts of external popliteal ischiadic nerve. Report of 2 cases studied with ultrasound, computed tomography and magnetic resonance imaging.

Peripheral neuropathy of the external popliteal ischiadic nerve caused by intraneural cysts is a very rare and peculiar pathological phenomenon compared with diseases associated with extraneural cysts or colliquative phenomena of solid nervous lesions. Two cases of peripheral neuropathy of the external popliteal ischiadic nerve caused by intraneural cysts and evaluated with ultrasound, computed tomography and magnetic resonance are described. The diagnostic efficacy of these imaging modalities is also evaluated with particular reference to MR capability to define the morphology of such lesions and their relationships to the surrounding structures. It is not yet possible to obtain a correct diagnosis about histopathologic features by means of the imaging techniques currently available. Nevertheless, they do provide information about the involvement of the neighboring areas, which are useful indications for possible surgical treatment of the disease.

Sealed rupture of abdominal aortic aneurysms.

Sealed rupture of abdominal aortic aneurysms, even if uncommon, deserves particular attention for the possibility of misdiagnosis and for the deleterious effects of such a misdiagnosis. Sixteen patients (mean age 72 years; range 65 to 84 years) with chronic sealed rupture of abdominal aortic aneurysms are reported. Two patients had acute rupture of the aneurysm, and at operation chronic contained rupture was found along with the recent hemorrhage. One patient died after surgery. The remaining patients underwent successful resection with long-term survival and regression of symptoms. Consideration of sealed abdominal aortic aneurysm rupture should be included when examining elderly patients with history of unexplained back pain or femoral neuropathy. Computed tomography is a useful aid in the diagnosis of sealed rupture. Ultrasonography is less accurate; in three patients ultrasonography failed to diagnose the presence of the rupture.

Comparison of two techniques to isolate microvascular endothelial cells from the omentum.

The purpose of the study was to compare two different techniques for isolation of omental microvascular endothelial cells (ECs). Segments of unreinforced polytetrafluorethylene (PTFE) grafts, 9 cm long and 6 mm in diameter, were implanted in 22 dogs as an aortic interposition. Fourteen grafts were seeded with a mean of 7 x 10(5) viable ECs, derived from the microvessels of the omentum: eight grafts (group A) were seeded with ECs obtained by collagenase digestion and by filtration through a pore mesh; six grafts (group B) were seeded with ECs obtained by collagenase digestion and by Percoll gradient separation. In eight grafts (group C), the ECs were not added to the preclot mixture and served as a control. Animals were sacrificed 5 weeks after surgery. The percentage of thrombus-free area was 65 +/- 22% for group A grafts and 74 +/- 15% for group B grafts (NS). The subendothelial layer was 280 +/- 60 microns thick in group A and 220 +/- 30 microns thick in group B (P less than 0.05). Seeded grafts showed a higher production of 6-keto-PGF1 alpha after addition of sodium arachidonate than control grafts. Percoll gradient separation allows isolation of a more purified suspension of ECs. Refinements in omental EC procurement are still required to minimize contamination with other types of cells.

Magnetic resonance imaging of abdominal aortic grafts.

The widespread use of abdominal aortic grafting procedures and increasing awareness of related complications suggests the need for a reliable and non-invasive diagnostic technique which will allow early detection of both occlusive and non-occlusive complications. Ultrasound is generally used with satisfactory results, but has several limitations, whereas MRI has shown great promise in the study of cardiovascular disease, being non-invasive, multiplanar and multiparametric. The present research aims to evaluate MRI in the follow-up of abdominal aortic grafts, attempting to define its significance as a screening procedure in non-selected patients. MRI is reliable in ascertaining the normality of the graft as well as the complications, these being partial or total thrombosis, pseudoaneurysms and perigraft collections. The data obtained are highly satisfactory and are almost always superior to those achieved with ultrasound and CT.

Inflammatory aneurysms of the abdominal aorta: incidence, pathologic, and etiologic considerations.

Among 486 patients undergoing repair for abdominal aortic aneurysm (AAA) during a 12-year period, 30 (6.2%) had evidence of "inflammatory" AAA. One patient (3%) had acute rupture, and six patients (20%) had chronic contained rupture. Ureteral obstruction was evident in 20% of the patients. In the early period of the study there were two postoperative deaths and operative time and blood loss were significantly increased. In the last period of the study, no attempt was made to separate the duodenum and the ureters from the aneurysm; there was no operative mortality, and operative time and blood loss were similar to that of patients with atherosclerotic aneurysms. In 23 of 100 specimens of atherosclerotic AAA, microscopic findings resembling inflammatory AAA were found. On the basis of our study we conclude the following: (1) Inflammatory AAAs are simply atherosclerotic aneurysms that show an unusual accentuation of the chronic inflammation observed in relation to atherosclerotic aneurysms. (2) Operative technique should be modified to avoid excessive dissection and lysis of ureters and duodenum. (3) Excellent early and late results can be expected with proper surgical technique. (4) The causes of AAA are multiple, and chronic contained rupture of the aneurysm and reactive lymphatic hyperplasia might play a role of greater significance than previously thought.

[Surgical treatment of aneurysms of the abdominal aorta. Consecutive experience for 12 years]. / Il trattamento chirurgico degli aneurismi dell'aorta addominale. Una esperienza consecutiva di 12 anni.

The authors present their experience with abdominal aortic aneurysm during the last 12 years. From 1976 up to now they treated 70 patients with abdominal aortic aneurysms. Sixty-seven patients (96%) were male, while 3 (4%) female. Mean age was 65 years (S.D. +/- 7.97). 82% of the patients were heavy smokers. Sixty-five patients were treated by means of resection and vascular reconstruction. Their associated pathologies were: M.I. or severe heart ischemia 34 (52.3%), diabetes 13 (20%), hypertension 25 (38.4%), T.I.A. 6 (9.2%), renal insufficiency 13 (20%), and respiratory insufficiency 18 (27.6%). Results demonstrated a 12-year patency rate of 91.8%. Five high-risk patients were treated by means of "palliative" treatment. Associated pathologies and risk factors were: smoking 5 (100%), M.I. or severe heart ischemia 5 (100%), diabetes 2 (40%), hypertension 4 (80%), T.I.A. 2 (40%), renal insufficiency 2 (40%), respiratory insufficiency 3 (60%). Treatment consisted in the sac thrombosis by means of Gianturco-Wallace coils into the aneurysm (2 cases) and iliac artery ligation (3 cases). Both techniques allowed acute thrombosis of the aneurysm. Vascular supply to the lower limbs was performed by means of an axillo-bifemoral reconstruction in all cases. Long-term prognosis of these five patients was poor due to their general condition.