High prevalence of adrenal cortical adenomas in patients with cerebral meningiomas.

PURPOSE: Adrenal cortical adenomas (ACAs) represent one of the most common endocrine neoplasms. Recently, a genetic syndrome, characterized by tumor-suppressor ARMC5-gene mutations and causing primary macronodular bilateral adrenal hyperplasia with concomitant meningiomas of the central nervous system, has been described. Apart from this rare disorder and despite the well-known influence of steroid hormones on meningiomas, no data are available about the association between ACAs and meningiomas. METHODS: We investigated the prevalence of ACAs in a group of patients with cerebral meningioma undergoing unenhanced chest CT scans before attending surgical treatment. Patients with meningioma were age- and sex-matched in a 1:3 ratio with hospitalized patients for COVID-19. RESULTS: Fifty-six patients with meningioma were included and matched with 168 control patients with COVID-19. One-hundred forty-four (66.1%) were female and the median age was 63 years. Twenty ACAs were detected in the overall population (8.9% of the subjects): 10 in patients with meningioma (18%) and the remaining 10 (6%) in the control group (p = 0.007). Multivariate analysis showed that age and presence of meningioma were statistically associated with the presence of ACAs (p = 0.01, p = 0.008). CONCLUSION: We report, for the first time, a higher prevalence of ACAs in patients with meningioma as compared to age- and sex-matched controls. Larger studies are needed to confirm our data and to clarify the characteristics of the ACAs in patients with meningioma. Whether the detection of ACAs should prompt a neuroimaging evaluation to exclude the presence of meningiomas needs also to be considered.

Hemostatic abnormalities in patients with Ehlers-Danlos syndrome.

Essentials Ehlers-Danlos Syndrome (EDS) is a rare heterogeneous group of inherited collagen disorders. A cohort of EDS patients was investigated for bleeding tendency and hemostatic abnormalities. EDS is associated with an increased risk of bleeding. EDS patients have platelet function abnormalities, whose severity correlates with bleeding risk. SUMMARY: Background Ehlers-Danlos syndrome (EDS) includes a heterogeneous group of connective tissue disorders affecting skin, bones, vessels, and other organs. Patients with EDS have an increased risk of bleeding, but a comprehensive study of hemostasis in EDS patients is lacking. Objective To investigate the bleeding tendency of a cohort of patients with EDS by using the Bleeding Assessment Tool of the ISTH, the bleeding severity score (BSS). Methods The BSS was defined as abnormal when it was ≥ 4 in men and ≥ 6 in women. Patients with a bleeding tendency were compared with those without in terms of type and number of hemostatic abnormalities. Results Fifty-nine of 141 patients with EDS (41.7%) had an abnormal BSS. Prothrombin time and activated partial thromboplastin time were slightly prolonged in 10 patients (7.1%) because of mild coagulation factor deficiencies, which were not responsible for the bleeding diathesis. von Willebrand factor antigen, ristocetin cofactor, endogenous thrombin potential and platelet count were normal in all patients. At least one platelet function abnormality was found in 53 patients (90%) with an abnormal BSS and in 64 (78%) with a normal BSS (adjusted odds ratio [OR] 2.55, 95% confidence interval [CI] 0.87-7.48). The risk of bleeding progressively increased with the number of platelet function abnormalities, reaching an OR of 5.19 (95% CI 1.32-20.45) when more than three abnormalities were detected. Conclusions Our results show that nearly half of patients with EDS have an abnormal BSS, which, in 90% of cases, appear, at least in part, to be attributable to platelet function abnormalities. Abnormalities of primary hemostasis may contribute to the risk of bleeding in patients with EDS.

[Correction of thoraco-mammary deformity of Poland syndrome]. / Correction de la déformation thoracomammaire du syndrome de Poland.

Breast deformity of Poland syndrome is a malformation known to be difficult to treat. Numerous descriptions of surgical corrections have been published but none achieved to correct severe cases before description of lipomodeling technique. The aim of this article is to present thoraco-mammary deformity of Poland syndrome, corrections techniques already available and therapeutical indications in primary and secondary cases. Constant anomaly of Poland syndrome is agenesis of sternocostal part of pectoralis major muscle but other muscular anomalies can be associated. Skin and glandular anomalies present with a fine skin and an absent or hypoplasic subcutaneous fat with a glandular hypoplasia of various degree. Osteo-cartilaginous anomalies can be associated in very severe cases. Clinical sign of Poland syndrome is forced adduction maneuver highlighting pectoralis major agenesis. Functional impact of the deformity is low but psychological and psychosocial implications can be very important, supporting an early surgical correction. Therapeutic means are various and accurate descriptions are given in this article: thoracic bony reconstruction, thoracic implant made of silicone elastomer, breast implant, skin expansion, latissimus dorsi pedicled flap, free flaps, breast lipomodeling, breast-pectoralis flap. Principles of each technique are described and balanced with their actual use in this malformation. Indications have been completely modified these last years due to lipomodeling contribution which represented a huge step in this deformity treatment. In our practice, if autologous reconstruction with lipomodeling is possible, we choose this solution at first. In case of severe thoracic deformity, a silicone elastomer implant made with the help of computed assisted conception can be an important adjunct, mainly by thin young man. In secondary cases, if implant is well tolerated, we found logical to stay in the same reconstruction path and do one or two sessions of lipomodeling in order to improve reconstruction. If implant tolerance is low and skin very thin at risk of exposure, we do recommend a conversion of implant reconstruction to autologous reconstruction. In conclusion, thoraco-mammary deformities of Poland syndrome are rare and hard to treat and should be managed by well trained and experimented surgeons. Breast lipomodeling is a huge step in the treatment of these deformities and should be regarded, in our opinion, as first line treatment if fat deposits are sufficient. In case of low fat provisions or in the thin young man, composite techniques should be used with silicone elastomer implant.

[Fat grafting to improve severe tuberous breast]. / Apport du transfert graisseux dans les formes sévères de seins tubéreux.

INTRODUCTION: Tuberous breast is a rare malformation that has major, negative physical and psychological impacts during puberty. A range of surgical techniques has been used to correct breast shape and volume in this context. Most techniques are based on a combination of skin plasty and mammary gland remodelling, in order to redistribute volumes. Prostheses and local-regional flaps can also be used to correct the missing volume. Fat grafting to the breast has been used in our department since 1998 as a complementary technique in breast reconstruction; it constitutes a natural way of providing volume and modifying the shape of the breast. Since 2000, we have extended this lipomodelling technique to the correction of thorax malformations in general and tuberous breasts in particular. Here, we describe our experience of the correction of severe tuberous breasts by fat grafting. PATIENTS AND METHODS: Over an 11-year period, we performed a retrospective study on tuberous breast patients treated solely with fat grafting (i.e. without using an implant). Each breast deformation was graded according to the Grolleau classification. After aspiration, the fat was centrifuged and then transferred with a specific cannula. Using an 18-G trocar, we sometimes also performed fasioctomies to free up fibrous bridges and mammary gland remodelling. We evaluated the lipofilling for each case (number of sessions and mean fat transfer volume). Technical efficacy was evaluated in terms of patient's satisfaction and the surgeon's opinion. Safety was evaluated by screening for recipient site complications. RESULTS: We performed a retrospective study of 31 cases of tuberous breasts treated between January 2000 and December 2010. The severe tuberous breasts were type 3 in 10 cases. The mean patient age was 21 and the mean body mass index was 21.5. Two session (mean transfer volume: 380 cc) were required in every case. The mean follow-up period after the last fat transfer session was 6 years (range: 1-11). The patients were very satisfied in 90% of cases (n=9) and satisfied in 10% of cases (n=1). No complications were observed. Imaging performed before surgery and one year afterwards did not reveal any anomalies, other than oil cysts. CONCLUSION: The treatment of severe tuberous breast with fat grafting is a reliable technique that produces excellent results and high levels of patient satisfaction. The aesthetic outcome is natural, implant-free and long-lasting. Fat grafting decreases local fibrosis and helps (along with fasciotomies and mammary gland remodelling) modify the shape of the breast. The technique corrects the missing volume in a precise, personalized manner. Lipomodelling efficacy and absence of complications have made it our reference treatment for the correction of severe tuberous breasts (as long as the patient has sufficient adipose reserves).

Predictors of von Willebrand disease diagnosis in individuals with borderline von Willebrand factor plasma levels.

BACKGROUND: In individuals with borderline von Willebrand factor (VWF) plasma levels, second-level tests are required to confirm or exclude von Willebrand disease (VWD). These tests are time-consuming and expensive. OBJECTIVE: To assess which parameters can predict VWD diagnosis in individuals with borderline VWF levels (30-60 IU dL(-1) ). METHODS: Nine hundred and fifty individuals with bleeding episodes or abnormal coagulation test results were investigated with first-level tests (blood count, prothrombin time, activated partial thromboplastin time, blood clotting factor VIII, VWF ristocetin cofactor activity [VWF:RCo], and VWF antigen), and 93 (62 females and 31 males; median age, 28 years; interquartile range 15-44) had borderline VWF:RCo levels. All underwent second-level investigations to confirm or exclude VWD. A multivariable logistic regression model was fitted with sex, age, bleeding score, family history, VWF:RCo and ABO blood group as predictors, and used to predict VWD diagnosis. RESULTS: Forty-five of the 93 individuals (48%) had VWD (84% type 1). A negative linear relationship between VWF:RCo levels and risk of VWD diagnosis was present, and was particularly evident with blood group non-O [adjusted odds ratio 7.00 (95% confidence interval [CI] 1.48-33.11) for every 5 IU dL(-1) decrease in VWF:RCo]. The other variable clearly associated with VWD diagnosis was female sex (adjusted odds ratio 5.76 [95% CI 1.47-22.53]). The area under the receiver operating characteristic curve of the full logistic model was 0.89 (95% CI 0.82-0.95). CONCLUSIONS: In individuals with borderline VWF, the two strongest predictors of VWD diagnosis are low VWF:RCo levels (particularly in those with blood group non-O) and female sex. This predictive model has a promising discriminative ability to identify patients with borderline VWF levels who are likely to have VWD.

[Tolerance and efficacy of lipomodelling as an element of breast symmetry in breast reconstruction]. / Tolérance et efficacité du lipomodelage comme élément de symétrisation en reconstruction mammaire: à propos de 150 patientes.

AIM OF THE STUDY: Fat transfer significantly improved results in breast reconstruction. Final breast symmetry is very important in breast reconstruction, but sometimes, the result is not perfect with usual techniques. The aim of this study is to evaluate the tolerance and efficacy of lipomodelling as a complementary technique for breast symmetrisation. MEANS AND METHODS: In this study, 150 patients had controlateral breast symmetrisation after breast reconstruction, using or completed with fat transfer. Patients were clinically evaluated one year after surgery. Age, BMI, harvested, purified and transferred fat volumes, and postoperatory complications were recorded. Morphological outcomes were evaluated by the surgeon as: very good, good, average or bad. Patients rated their degree of satisfaction as: very satisfying, satisfying, poor or bad. RESULTS: We found out that 98.6 % of morphological results were good or very good, and 86.6 % of the patients were satisfied or very satisfied with the result. Complications were rare (2 % of cytosteatonecrotic lesions). CONCLUSION: Lipomodelling in native breast symmetrisation after reconstruction is a powerful technique because it allows to increase volume of a hypoplastic controlateral breast, to ameliorate its shape, and to finally enhance mammoplasty result by correcting persisting localized volume defects. It definitively is a major therapeutic tool for enhancing breast reconstruction outcomes.

A two-centre comparative evaluation of new automated assays for von Willebrand factor ristocetin cofactor activity and antigen.

von Willebrand disease (VWD) is caused by a quantitative and/or qualitative deficiency of the von Willebrand factor (VWF). The laboratory diagnosis of VWD is dependent on the measurement of VWF antigen (VWF:Ag) and ristocetin cofactor activity (VWF:RCo). The aim of this study was to undertake a two-centre evaluation of two new automated VWF:Ag and VWF:RCo assays systems from Instrumentation Laboratory (Bedford, USA). Using the two new analytical systems that operated with different detection principles: immunoturbidimetric (TOP500 analyser) and chemiluminescent (AcuStar analyser), VWF:Ag and VWF:RCo levels were determined in samples from 171 healthy normal subjects, 80 VWD patients (16 type 1, 58 type 2 and 6 type 3) and 7 acquired von Willebrand syndrome patients. With commercial lyophilized normal and pathological plasmas VWF: Ag and VWF:RCo assays performed on both analysers exhibited low levels of inter-assay imprecision (AcuStar: CV% range 3.3-6.9; TOP500: CV% range 2.6-6.3). Samples from normal healthy subjects (range: VWF:Ag 44.6-173.9 IU dL(-1) ; VWF:RCo 43.1-191.5 IU dL(-1)) and patients (range: VWF:Ag <0.3-115.1 IU dL(-1) ; VWF:RCo <0.5-57.2 IU dL(-1)) showed a good correlation between the two VWF:Ag and VWF:RCo methods (rs = 0.92 and 0.82 respectively), with only a few inconsistent cases among the patients' samples evaluated. The chemiluminescent assays had a lower limit of detection for both VWF:Ag and VWF:RCo compared to immunoturbidimetric tests (0.3 IU dL(-1) vs. 2.2 IU dL(-1) and 0.5 IU dL(-1) vs. 4.4 IU dL(-1) respectively). The TOP500 and AcuStar VWF:Ag and VWF:RCo assays were precise and compare well between centres, making these systems suitable for the diagnosis of VWD in non-specialized and reference laboratories.

A synonymous (c.3390C>T) or a splice-site (c.3380-2A>G) mutation causes exon 26 skipping in four patients with von Willebrand disease (2A/IIE).

INTRODUCTION: We characterized four unrelated patients with von Willebrand disease type 2A/IIE, sharing the same von Willebrand factor (VWF) in-frame deletion (p.[P1127_G1180delinsR];[=]) resulting from exon 26 skipping (Δ26). OBJECTIVES: To identify the VWF mutations and how they caused the mRNA splicing alteration, to evaluate the deletion by in vitro expression studies, and to assess whether or not the heterogeneity of the patients' phenotype might be related to a different degree of expression of the deleted subunit in patient plasma VWF. METHODS: Sequence analysis was performed with patient genomic DNA and platelet mRNA. Semiquantitative RT-PCR was also carried out to compare the expression of the wild-type (WT) and Δ26 alleles in the four patients. In silico analysis was performed with prediction splicing programs. Expression studies were performed to evaluate mutant recombinant VWF (rVWF) (Δ26 and Δ26/WT) as compared with WT rVWF. RESULTS: Three patients shared the synonymous single-nucleotide substitution (SSS) c.[3390C>T];[=], whereas the novel mutation c.[3380-2A>G];[=] was present in the fourth patient. Semiquantitative RT-PCR of platelet mRNA revealed a different ratio of the WT and Δ26 alleles in the patients, consistent with the different VWF:FVIIIB values present in patient plasma. Expression studies confirmed reduced VWF-FVIII binding of rVWF-Δ26/WT. CONCLUSIONS: SSS can induce alternative splicing, and those like c.3390C>T, which impact on the poorly conserved splicing regulatory elements, are difficult to predict, so that their role can be evaluated only by mRNA analysis. Moreover, these mutations seem to have different effects on the efficiency of alternative splicing, producing heterogeneous VWF variants among the four patients.

[Reconstruction of elbow defect by perforator propeller flap of the brachial region--clinical observation]. / Reconstruction des pertes de substance du coude par lambeau perforant en hélice de la région brachial--observation clinique.

INTRODUCTION: The elbow defects can raise problem to plastic surgeon. Indeed, this region is characterized by thin and mobile tissues; its reconstruction must be long-lasting, resistant to movements, to shear forces and to external support. Perforator propeller flaps beings appear an interesting option in the reconstruction of elbow defects. In this report, we describe a patient having benefited from the excision of a melanoma of the region of the elbow. After multidisciplinary meeting and resection of new margins, a reconstruction by perforator propeller flap was realized. A perforator pedicle of the lateral brachial region was located and used. The postoperative result in term of cover and function was considered very satisfactory. The perforator propeller flaps appear a reliable and interesting solution in the coverage of elbow defect.

[Treatment of Poland syndrome thorax deformity with the lipomodeling technique: about ten cases]. / Correction de la déformation thoraco-mammaire du syndrome de Poland par la technique du lipomodelage : à propos de dix cas.

The correct management, with the classic techniques, of the thoracic deformity in Poland's syndrome is difficult, with often insatisfactory results. The current surgical treatment involves the use of prothetic material and/or different flaps with their own complications and scares. The experience of our team with fat grafting (we named lipomodeling) in breast reconstruction helped us to propose the correction of the thoracic and mammary deformity by repeated fat transfer sessions. Fat grafting is commonly used in our team since 1998 in various indication of breast surgery. We reviewed retrospectively our ten first cases of thoracic deformity in Poland's syndrome treated with only fat grafting. Patients had repeated procedures until obtaining a satisfactory result. The fat was harvested from the thigh, buttocks, and abdomen. There were young patients with a mean age of 16years old (from 12 to 24). The mean follow-up was 51months. An average of 2.9 procedures (1 to 5) with 255cm(3) of fat injection at each procedure was needed to obtain symetry. Hundred percent of the patients were satisfied. No complication was noted. As reported, the reconstruction of the thoracic deformity and the mammary shape can be obtained by fat grafting. The absence of a flap donor site sequelae and the absence an implant allow this technique to be simple, reproductible, and without great complication. These criteria match well the surgical management of this deformity, which is mainly aesthetic. Moreover, the secondary benefit of liposuction of disgracious steatomery helps the acceptance of the procedure. Therefore in our hands, fat grafting to the breast (lipomodeling) is now our first choice treatment in thoracic Poland syndrome deformity. Given the rarity of this syndrome, we recommend a treatment by an operator who makes the learning curve of lipomodeling, and who often deals with Poland syndrome.

Lipomodelling: an important advance in breast surgery.

Based on long-term experiences, the authors consider lipomodelling to be a major advance in plastic, reconstructive and aesthetic surgery of the breast. The technique is now well established and the complication rate is very low. The risk of focal fat necrosis is around 3%. Oncological follow-up (now 14 years for the first patients) shows no increased risk of local recurrence or development of a new cancer. 30-40% of the injected fat is absorbed. Volume of the breast becomes stable in 3 to 4 months and remains definitive if the patient maintains constant weight. Because of very good results obtained and excellent acceptance of the procedure by the patients, this technique has completely modified our indications. In breast reconstruction, lipomodelling with autologous latissimus dorsi flap enables obtaining an entirely autologous breast in the majority of the patients. Analogically, lipomodelling can improve results of implant reconstructions, especially if the expander or the implant is planned to be exchanged. Lipomodelling is an effective tool for correction deformities especially in the décolleté after breast reconstruction with abdominal flap (DIEP, SIEA and TRAM). Lipomodelling is also progressively used in the correction of breast and chest wall deformities. In Poland syndrome, this technique appears to be a major advance that will probably revolutionize the treatment of severe cases. This is mainly due to its ability to achieve previously unachievable quality of reconstruction with minimal scaring. The application of lipomodelling in the treatment of pectus excavatum deformities is promising. Lipomodelling represents an advanced therapeutic alternative for tuberous breasts without the need to use an implant, as well as for breast asymmetry due to unilateral hypoplasia. Lipomodelling is an ideal option for cosmetic breast augmentation in patients who wish to achieve moderate, natural enlargement of breasts and who have considerable fat deposits.

Different bleeding risk in type 2A and 2M von Willebrand disease: a 2-year prospective study in 107 patients.

BACKGROUND: Type 2A and 2M von Willebrand disease (VWD2A and VWD2M) are characterized by the presence of a dysfunctional von Willebrand factor (VWF) and a variable bleeding tendency. So far, a head-to-head comparison of the clinical history and bleeding risk between VWD2A and VWD2M has never been provided in a prospective manner. AIM OF THE STUDY: We assessed the bleeding incidence rate and clinical characteristics in two cohorts of 17 families (46 patients) with VWD2A and 15 families (61 patients) with VWD2M prospectively followed-up for 24 months. VWF gene mutations were characterized in all of them. RESULTS: Mean bleeding score (BS) and VWF antigen at enrollment were significantly higher in VWD2A patients (P = 0.007). No correlation between VWF activity or factor VIII levels and the severity of BS was observed. The incidence rate of spontaneous bleeding requiring treatment was 107/100 patient-years (95% CI, 88.3-131) in VWD2A compared with 40/100 patient-years (95% CI, 30-53) in VWD2M (P < 0.001). The risk of bleeding was significantly higher in patients with BS ≥ 10 at enrollment compared with those with BS 0-2. Furthermore, 54 episodes of gastrointestinal bleeding occurred in 17/46 (36.9%) VWD2A patients and seven in 2/61 (3.3%) VWD2M patients (P < 0.0001). CONCLUSION: Bleeding tendency in VWD2A is greater than that of VWD2M, is not explained by factor VIII or VWF levels and is mainly due to an increased incidence of gastrointestinal bleeding.

Type 2A (IIH) von Willebrand disease is due to mutations that affect von Willebrand factor multimerization.

BACKGROUND: Type IIH von Willebrand disease was reported 20 years ago as a novel variant characterized by the loss of the largest multimers in plasma and platelets and absence of the typical triplet structure. OBJECTIVES AND METHODS: The propositus and his daughter have been reinvestigated and characterized at the molecular level. The identified mutations were expressed in COS-7 cells to evaluate the mechanism of this variant. RESULTS AND DISCUSSION: The propositus had normal von Willebrand factor (VWF):ristocetin cofactor activity (RCo) and high VWF antigen (VWF:Ag) values, with a low VWF:RCo/VWF:Ag ratio (0.51). No abnormalities were found in his daughter, except for the reduced triplet structure in plasma VWF and diminished ultralarge VWF (ULVWF) multimers in platelets. Three mutations were identified in the propositus: 604C>T (R202W), 4748G>A (R1583Q), and 2546G>A (C849Y). The amounts of secreted recombinant VWF (rVWF) were apparently increased for R202W (130%), R202W-R1583Q (131%), and R202W-R1583Q/WT (121%), reduced for C849Y (72%) and C849Y/WT (83%), and normal for R1583Q (107%) and R202W-R1583Q/C849Y (102%). In cell lysates, higher values were found in association with the C849Y mutation. A normal multimeric pattern was found in R1583Q rVWF, mainly dimers in R202W rVWF, and intermediate molecular weight multimers in C849Y rVWF. Hybrid R202W-R1583Q/WT and C849Y/WT rVWFs had a nearly normal multimeric pattern, whereas in hybrid R202W-R1583Q/C849Y rVWF there was a loss of large/intermediate multimers. CONCLUSIONS: The propositus phenotype seems to be due to mutations R202W and C849Y, both affecting the VWF multimerization process and, for C849Y rVWF, intracellular survival. The absent triplet multimeric structure in the propositus and its reduction in his daughter appears to be related to the lack of ULVWF multimers, which mainly contribute to the formation of satellite bands.

Expression studies of missense mutations p.D141Y, p.C275S located in the propeptide of von Willebrand factor in patients with type 3 von Willebrand disease.

Missense mutations are not considered a common cause of type 3 von Willebrand's disease (VWD), the most severe defect of von Willebrand factor (VWF) characterized by undetectable levels of this protein in plasma and platelets. Nevertheless, several missense mutations have been identified in these patients. In this study, we report the cases of two Italian patients with type 3 VWD, both compound heterozygotes for different missense mutations and null alleles, p.D141Y/c.2016_2019del and p.C275S/p.W222X. We performed in vitro expression studies of the candidate missense mutations, both located in the D1 domain of VWF propeptide, to confirm their link with the disease and to understand the mechanisms of type 3 VWD responsible in these patients. Mutant and wild-type (WT) expression vectors were used for transient transfection and co-transfection studies in COS-7 cells. Single construct transfections of both missense mutations showed a strongly reduced but detectable secretion of recombinant (r)VWFs (approximately 15% of WT), with essentially only dimers being visualized on multimeric analysis. As expected, expression of a single construct of either mutation with the WT, showed mildly reduced secretion (approximately 40% of WT) and a full set of multimers. These expression studies indicate that the two amino acids D141 and C275 are key residues in the tertiary structure of the VWF propeptide. Their replacement with a tyrosine and a serine, respectively, might compromise propeptide folding, affecting both its intracellular survival and its capacity to mediate multimerization. Co-expression of hybrid rVWFs confirmed the recessive inheritance pattern of these missense mutations.

[The treatment of benign laryngeal pathologies using CO2 laser in direct microlaryngoscopy with propofol-induced endovenous anesthesia in spontaneous respiration without intubation]. / Il trattamento delle lesioni benigne della laringe in micro-laringoscopia diretta con il laser CO2 mediante anestesia endovenosa con Propofol in respiro spontaneo senza intubazione orotracheale.

Direct microlaryngoscopy is an endoscopic technique with considerable diagnostic and surgical potentialities, which are increased when carbon-dioxide Laser is used, but often limited by the anaesthesiologic methods employed. In fact, the traditional anaesthesiologic technique, which uses small bore oral-tracheal tubes and provides good ventilation, has significant disadvantages: the tube often impedes surgical activity especially in the posterior regions of the larynx; stenoses of the larynx impede oral-thacheal intubation and thus require pre-operatory thacheotomy; administration of succinylcholine often induces diffused myalgia in the following 12-24 hours; administration of traditional narcotics always requires hospitalization. Jet-ventilation used by the Freach School as an alterative, while offering a more ample operatory space, is also accompanied by many disadvantages: vocal cords vibration; spray expulsion of smoke, blood, etc.; as with the traditional method, it cannot be employed in cases of laryngeal stenoses; succinylcholine often induces diffused myalgia; it cannot be used on out-patients. Introduction of Propofol, a new endovenous anaesthetic, the anaesthetologic pratice has permitted total endovenous anaesthesia to be achieved, in spontaneous respiration, without intubation. This method is indicated even in cases where the previously mentioned approaches are shown to be inadequate or impracticable. Narcosis with Propofol was used in 70 patients with benign laryngeal pathologies, belonging to the ASA risk classes I-II who underwent surgery via CO2 Laser during Microlaryngoscopy. The pharmacologic protocol of this narcosis require intravenous premedication with atropine and phentanyl, induction and continuation with Propofol and pharyngolaryngeal local anaesthesia with lidocaine spray. The advantages offered by this method are considerable: a completely free operative space; the possibility of being used in cases of laryngeal stenosis; a rapid return to consciousness; the absence of myalgia after surgery; the possibility of treating the disease on an out-patient basis. The absence of significant complications and the good results obtained lead us to propose this anaesthesiologic method as a valid alternative to anaesthesia by the traditional oral-tracheal intubation and to Jet ventilation.

Cognitive and EEG recovery following bolus intravenous administration of anesthetic agents.

Bolus intravenous (IV) administration of commonly used IV anesthetic agents such as fentanyl and the fentanyl analogues, alfentanil, remifentanil, and sufentanil, etomidate and propofol, produced anesthesia in rats as measured by the loss of righting (LOR) with calculated ED150 doses of 0.06, 0.09, 0.037, 0.007, 2.51 and 6.12 mg/kg, respectively. Animals trained in an eight arm radial maze (RAM) were assessed for cognitive recovery, as measured by response efficiency (percentage of correct arm entries within 10 min), immediately, 15 min and 30 min following IV administration of the calculated ED150 dose of each of these agents, and the subsequent return of righting (ROR). Animals administered fentanyl or sufentanil were unable to successfully complete the maze throughout the testing periods. Animals receiving remifentanil showed cognitive recovery within the first testing interval (immediately following the return of righting), while animals receiving alfentanil, etomidate or propofol showed recovery at the 15-min testing interval following ROR. In a separate experiment, bolus IV administration of the ED150 dose of these agents was evaluated in an acute rat EEG model. Following ROR, return to baseline EEG levels occurred at 0.30, 2.88, 5.06, 16.25, 31.29 and 43.98 min for remifentanil, propofol, alfentanil, etomidate, fentanyl and sufentanil, respectively. These data show that the return to efficient cognitive functioning corresponds to the return to normal baseline EEG waveforms.

Single versus multiple infusions of fentanyl analogues in a rat EEG model.

Administration of anesthetic agents to rats produces a loss of righting (LOR) which is predictive of clinical anesthesia. Following bolus i.v. administration of fentanyl, sufentanil, alfentanil, and remifentanil, the ED100 doses for LOR were 0.035, 0.003, 0.05, and 0.020 mg/kg, respectively. For the EEG infusion studies, rats were implanted with jugular catheters and 5 cortical electrodes on the surface of the dura mater. Each agent was infused at a rate of 0.02 ml/min such that each animal received the ED100 dose every 60 seconds until LOR was observed and the infusion was stopped. Following a single infusion to LOR, the difference in time from the return of righting (ROR) to baseline EEG for fentanyl, sufentanil, alfentanil, and remifentanil was 30.9, 35.3, 14.9, and 1.3 minutes, respectively. Following a three hour washout period, multiple infusions (three successive infusions to LOR) were administered. Following ROR (after the third LOR) the return to baseline EEG for fentanyl, sufentanil, alfentanil, and remifentanil was 56.1, 58.5, 13.6, and 2.9 minutes, respectively. There were no statistically significant differences between the single and multiple infusions for the return to baseline EEG for alfentanil and remifentanil, but there were significant increases in time to return to baseline following multiple infusions of fentanyl and sufentanil. These results show that there was no cumulation of alfentanil and remifentanil with respect to EEG effects but cumulation was observed for fentanyl and sufentanil.

The alpha-2 antagonists idazoxan and rauwolscine but not yohimbine or piperoxan are anxiolytic in the Vogel lick-shock conflict paradigm following intravenous administration.

The alpha 2 agonist clonidine has been shown to be anxiolytic in a number of preclinical anxiety models. Interestingly, intravenous infusion of the alpha 2 antagonists idazoxan at 10 mg/kg and rauwolscine at 2.24 mg/kg significantly disinhibited lick-shock conflict responding in rats similar to the alpha 2 agonist clonidine (0.022 mg/kg) and the benzodiazepine diazepam (0.5 mg/kg). However, the alpha 2 antagonists yohimbine and piperoxan, the alpha 2 agonists medetomidine, guanfacine, and guanabenz, the non-specific alpha antagonist phentolamine, and the alpha 1 antagonist prazosin did not disinhibit conflict responding in the Vogel lick-shock paradigm. In fact, yohimbine has been shown to be anxiogenic in both animals and man. This may be due to yohimbine's lack of specificity and its ability to inhibit GABAergic release. In addition, all of these agents, except idazoxan, did not increase water consumption in water deprived rats. Idazoxan (10 mg/kg) significantly decreased water consumption by 45%. Therefore, idazoxan increased conflict responding for water reward at a dose (10 mg/kg) which also decreased water consumption in a non-conflict paradigm. These data suggest that agents with selective antagonism at the alpha 2 receptor site may be anxiolytic while agents with less specificity at this site such as yohimbine, piperoxan, and phentolamine are not anxiolytic.

[Various aspects of dopaminergic function in patients with prolactin-secreting hypophyseal adenoma]. / Vari aspetti della funzione dopaminergica in pazienti affetti da adenoma ipofisario PRL-secernente.

Controversial data have been published in these last years on the dopaminergic tonus of tubero infundibular (TIDA) neurons in hyperprolactinemic subjects. Some authors retain that L-Dopa (LD) stimulation test after pretreatment with Carbidopa (CD), a dopa decarboxylase inhibitor substance, may reveal the presence of a central Dopamine (DA) defect in patient with prolactinoma. To elucidate the reason of so different activity of DA central tonus in subjects with prolactinoma, the effects of Nomifensine (NOM), an indirect DA agonist, DOM, Carbidopa/L-Dopa (CD/LD) and LD, were studied in 26 prolactinoma patients, (basal Prl levels 50 to 280 ng/ml). The patients (24-39 years) were characterized by secondary amenorrhea with sella turcica enlargement at hypocicloidal polytomography. The NOM administration resulted unable to reduce Prl plasma levels in all the patients. On the basis of Prl response to CD/LD administration the patients were subdivided in two groups: group A, which showed a significant decrease of Prl plasma levels and group B, who did not show any significant change. LD test induced a significant Prl decrease in all patients with more evident response in these of group A. DOM administration induced a Prl rise in patients of group A, but failed to change significantly Prl levels in group B subjects. These results confirming the high validity of NOM inhibiting test in the diagnosis of tumoural hyperprolactinemic states, reveal contradictory responses to CD/LD, LD and DOM, with sustain the existence of 2 sub-group of Prolactinomas: with or without a maintained DA central tonus supporting the possibility of different etiopathogenetical factors in inducing a tumoural hyperprolactinemic states.