Progression Free Survival, Overall Survival, and Relapse Rate in Endometrioid Ovarian Cancer and Synchronous Endometrial-Ovarian Endometrioid Cancer (SEO-EC): Results from a Large Retrospective Analysis.

Background and Objectives: We aimed to evaluate Progression Free Survival (PFS), Overall Survival (OS), and relapse rate in women affected by endometrioid ovarian cancer and synchronous endometrial-ovarian endometrioid cancer (SEO-EC). As secondary outcome, we assessed whether systematic pelvic and para-aortic lymphadenectomy could be considered a determinant of relapse rate in this population. Materials and Methods: We performed a retrospective analysis of women with diagnosis of endometrioid ovarian cancer or SEO-EC between January 2010 to September 2020, and calculated PFS, OS and relapse rate. Results: In almost all the patients (97.6%) who underwent systematic pelvic and para-aortic lymphadenectomy, there were no lymph node metastases confirmed by histology. We did not find a significant difference (p = 0.6570) for the rate of relapse in the group of women who underwent systematic pelvic and para-aortic lymphadenectomy (4/42; 9.5%) compared with the group of women who did not undergo the same procedure (1/21; 4.8%). During a median follow-up was 23 months, both PFS and OS were excellent. Conclusions: Women affected by early-stage low-grade endometrioid cancer and SEO-EC without apparent lymph node involvement at pre-operative imaging showed a very low rate of lymph node metastasis and similar relapse rate with or without lymphadenectomy.

Prognostic factors and surgical treatment in vulvar carcinoma: Single center experience.

AIM: Vulvar carcinoma represents 3-5% of all female genital cancers; the main surgical treatment is radical vulvectomy and inguinal lymphadenectomy. The aim of this study is to analyze prognostic factors in the patients underwent to primary surgery for vulvar carcinoma. METHODS: One hundred and eighteen cases of vulvar carcinoma underwent surgery between 2006 and 2016 at Operative Unit of Gynecology and Obstetrics of Cannizzaro Hospital (Catania, Italy) were retrospective analyzed. Risk factors for relapse (age, tumor size, FIGO stage, type of surgery, lymphadenectomy, margins status, metastatic nodes and radiotherapy) were evaluated by logistic regression. Univariate analysis of prognostic factors (age, tumor size, FIGO stage, metastatic inguinal nodes and type of surgery) was obtained by Cox proportional hazard model. Overall survival was calculated by Kaplan-Meier curves either for the entire population and for comparison between positive and negative variables (margin status, nodes and radiotherapy) with log-rank test to determine significance. Statistical significance was reached for P < 0.05. RESULTS: Type of surgery (radical local excision vs. radical vulvectomy) and positive inguinal nodes were identified as risk factors for relapse. Positive inguinal nodes and positive margins were identified as prognostic factors either for overall survival and disease specific survival; tumor size greater than 4 cm was identified as prognostic factors for overall survival. Overall survival was 38.4% and it was significantly higher in the patients with negative margins and nodes. CONCLUSIONS: Nodes status, resection margins, age and type of surgery represent prognostic factors have to be considered for adjuvant treatment in the patients affected from vulvar carcinoma.

Children Learn to Read: How Visual Analysis and Mental Imagery Contribute to the Reading Performances at Different Stages of Reading Acquisition.

Reading in alphabetic orthography requires analysis and recognition of specific attributes of visual stimuli, and generation, reactivation, and use of mental images of letters and words. This study evaluated the role of visual analysis and mental imagery in reading performances of students at different stages of reading acquisition. Reading "comprehension," "accuracy," and "speed," were analyzed. Participants were 90 children who attended primary school. Children were assessed in the first and third grade. The results highlighted that mental imagery and visual analysis influenced reading acquisition. These abilities are differently involved in the three dimensions of reading skill. The issues of this study have practical and educational applications. The early assessment of visual analysis and mental imagery skills and specific training on these abilities could contribute to facilitate reading acquisition. Strategies of intervention centered on visual imagery could increase reading performances in typically developing children and children at risk of learning difficulties.

Ultrasound examination with color power Doppler to assess the early response of apical periodontitis to the endodontic treatment.

OBJECTIVES: The purpose of this study was to assess the possibility to detect early vascular changes in apical periodontitis (AP) using ultrasound examination with color power Doppler (US-CPD) and to establish a correlation between the early response of AP to treatment and its potential healing. MATERIALS AND METHODS: Twenty-one apical lesions were visualized with US-CPD before endodontic treatment, 1 week after the first access to endodontic system and 4 weeks after root canal obturation. A differential diagnosis between cystic lesions (CLs) and granulomatous lesions (GLs) was attempted. The vascular modifications were then correlated with long-term radiographic follow-up using Fisher's exact test. RESULTS: The decrease or disappearance of vascular flow observed in AP 4 weeks after root canal obturation was significantly related to a healing trend (p = 0.0206) of the lesions. Combining the data with preoperative US-CPD diagnosis showed a reproducibility for GLs only (p = 0.0022). CONCLUSIONS: This study showed the possibility to detect early vascular changes in AP using US-CPD, correlating them with a healing trend after endodontic treatment. Future investigations should be conducted and more attention should be dedicated to the potential of this alternative and biologically safe imaging technique. CLINICAL RELEVANCE: US-CPD in endodontics may be a helpful tool to identify healing processes after endodontic treatment and to understand the behavior of different forms of AP.

A 10-year evaluation on adolescents with anxiety disorders: are they at risk of bipolarity?

OBJECTIVE: Anxiety disorders are the most frequent disorders comorbid with bipolar disorder (BD) often preceding the BD onset. The presence of comorbid anxiety in patients diagnosed with BD is associated with worsening of their BD symptoms, increased risky behaviour, decreased response to pharmacological treatment and deterioration in their quality of life and global functioning. The aim of this study was to investigate if anxiety disorders in adolescence could be considered as predictors of BD. METHODS: Adolescents with a primary anxiety disorder were recruited consecutively from the Mood and Anxiety Disorders Unit, Department of Neuroscience, University of Turin. Subjects were evaluated for Axis I psychiatric disorders, family history and global functioning, and followed up on average 10 years later. RESULTS: A total of 29 patients (59.2%) were male and the mean age at the onset of anxiety disorder was 16.3 (±0.8). Ten years following recruitment, 11 (22.4%) patients fulfilled the criteria for BD. Of them, 10 (90.9%) had a family history of BD and four (36.4%) presented a comorbid substance use disorder. CONCLUSIONS: Our study shows that both family history of BD and substance use disorder, in adolescent patients with a primary anxiety disorder, should be considered as potential predictors of BD onset.

The Buccal Fat Pad for Closure of Oroantral Communication.

The buccal fat pad (BFP) is a well-established tool in oral and maxillofacial surgery and its use has proved of value for the closure of oroantral communications. Oroantral communication may be a common complication after sequestrectomy in "bisphosphonate-related osteonecrosis of the jaws."The authors report a clinical case of a 70-year-old female patient in bisphosphonate therapy presented with right maxillary sinusitis and oroantral communication after implants insertion.The BFP was used to close the defect. The patient had an uneventful postoperative healing without dehiscence, infection, and necrosis.The authors postulate that the primary closure of the site with BFP may ensure a sufficient blood supply and adequate protection for an effective bone-healing response to occur.

Viral gene transfer rescues arrhythmogenic phenotype and ultrastructural abnormalities in adult calsequestrin-null mice with inherited arrhythmias.

RATIONALE: Catecholaminergic polymorphic ventricular tachycardia is an inherited disease that predisposes to cardiac arrest and sudden death. The disease is associated with mutations in the genes encoding for the cardiac ryanodine receptor (RyR2) and cardiac calsequestrin (CASQ2). CASQ2 mutations lead to a major loss of CASQ2 monomers, possibly because of enhanced degradation of the mutant protein. The decrease of CASQ2 is associated with a reduction in the levels of Triadin (TrD) and Junctin (JnC), two proteins that form, with CASQ2 and RyR2, a macromolecular complex devoted to control of calcium release from the sarcoplasmic reticulum. OBJECTIVE: We intended to evaluate whether viral gene transfer of wild-type CASQ2 may rescue the broad spectrum of abnormalities caused by mutant CASQ2. METHODS AND RESULTS: We used an adeno-associated serotype 9 viral vector to express a green fluorescent protein-tagged CASQ2 construct. Twenty weeks after intraperitoneal injection of the vector in neonate CASQ2 KO mice, we observed normalization of the levels of calsequestrin, triadin, and junctin, rescue of electrophysiological and ultrastructural abnormalities caused by CASQ2 ablation, and lack of life-threatening arrhythmias. CONCLUSIONS: We have proven the concept that induction of CASQ2 expression in knockout mice reverts the molecular, structural, and electric abnormalities and prevents life-threatening arrhythmias in CASQ2-defective catecholaminergic polymorphic ventricular tachycardia mice. These data support the view that development of CASQ2 viral gene transfer could have clinical application.

The professional background of a referring physician predicts the diagnostic yield of small bowel capsule endoscopy in suspected small bowel bleeding.

Background and study aims The diagnostic yield of small-bowel capsule endoscopy (SBCE) in suspected small bowel bleeding (SSBB) is highly variable. Different reimbursement systems and equipment costs also limit SBCE use in clinical practice. Thus, minimizing non-diagnostic procedures is advisable. This study aimed to assess the SBCE diagnostic yield and identify factors predicting diagnostic findings in a cohort of patients with SSBB. Patients and methods In this retrospective cohort study, we analyzed the medical records of patients who consecutively underwent SBCE for SSBB over 9 years. By logistic regression, we identified covariates predicting diagnostic findings at SBCE. Finally, we performed a post-hoc cost analysis based on previous gastroenterologist or endoscopist consultations versus direct SBCE ordering by other specialists. Results The final analysis included 584 patients. Most SBCEs were ordered by a gastroenterologist or endoscopist (74%). The number of SBCEs without any finding was significantly lower in the gastroenterologist/endoscopist group P <0.001). The SBCE diagnostic yield ordered by a gastroenterologist or endoscopist was significantly higher than that by other specialists (63% vs 52%, odds ratio [OR] 1.57; 95% confidence interval [CI] 1.07-2.26, P =0.019). At multivariate analysis, older age (OR 1.7, 95%CI 1.2-2.4, P =0.005), anemia (OR 4.9, 95%CI 1.9-12, P =0.001), small bowel transit time (OR 1, 95%CI 1-1.02, P =0.039), and referring physician (OR 1.8, 95%CI 1.1-2.7, P =0.003) independently predicted diagnostic findings. Implementing prior gastroenterologist or endoscopist referral vs direct SBCE ordering would reduce medical expenditures by 16%. Conclusions The professional background of referring physicians significantly improves the diagnostic yield of SBCE and contributes to controlling public health costs.

Awake laparoscopic cholecystectomy: A case report and review of literature.

BACKGROUND: Laparoscopic cholecystectomy (LC) is one of the most widely practiced surgical procedures in abdominal surgery. Patients undergo LC during general anaesthesia; however, in recent years, several studies have suggested the ability to perform LC in patients who are awake. We report a case of awake LC and a literature review. CASE SUMMARY: A 69-year-old patient with severe pulmonary disease affected by cholelithiasis was scheduled for LC under regional anaesthesia. We first performed peridural anaesthesia at the T8-T9 level and then spinal anaesthesia at the T12-L1 level. The procedure was managed in total comfort for both the patient and the surgeon. The intra-abdominal pressure was 8 mmHg. The patient remained stable throughout the procedure, and the postoperative course was uneventful. CONCLUSION: Evidence has warranted the safe use of spinal and epidural anaesthesia, with minimal side effects easily managed with medications. Regional anaesthesia in selected patients may provide some advantages over general anaesthesia, such as no airway manipulation, maintenance of spontaneous breathing, effective postoperative analgesia, less nausea and vomiting, and early recovery. However, this technique for LC is not widely used in Europe; this is the first case reported in Italy in the literature. Regional anaesthesia is feasible and safe in performing some types of laparoscopic procedures. Further studies should be carried out to introduce this type of anaesthesia in routine clinical practice.

CeO2-rGO Composites for Photocatalytic H2 Evolution by Glycerol Photoreforming.

The interaction between CeO2-GO or CeO2-rGO and gold as co-catalysts were here investigated for solar H2 production by photoreforming of glycerol. The materials were prepared by a solar photoreduction/deposition method, where in addition to the activation of CeO2 the excited electrons were able to reduce the gold precursor to metallic gold and the GO into rGO. The presence of gold was fundamental to boost the H2 production, whereas the GO or the rGO extended the visible-light activity of cerium oxide (as confirmed by UV-DRS). Furthermore, the strong interaction between CeO2 and Au (verified by XPS and TEM) led to good stability of the CeO2-rGO-Au sample with the evolved H2 that increased during five consecutive runs of glycerol photoreforming. This catalytic behaviour was ascribed to the progressive reduction of GO into rGO, as shown by Raman measurements of the photocatalytic runs. The good charge carrier separation obtained with the CeO2-rGO-Au system allowed the simultaneous production of H2 and reduction of GO in the course of the photoreforming reaction. These peculiar features exhibited by these unconventional photocatalysts are promising to propose new solar-light-driven photocatalysts for green hydrogen production.

Autoimmune liver diseases and SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), can trigger autoimmunity in genetically predisposed individuals through hyperstimulation of immune response and molecular mimicry. Here we summarise the current knowledge about auto-immune liver diseases (AILDs) and SARS-CoV-2, focusing on: (1) The risk of SARS-CoV-2 infection and the course of COVID-19 in patients affected by AILDs; (2) the role of SARS-CoV-2 in inducing liver damage and triggering AILDs; and (3) the ability of vaccines against SARS-CoV-2 to induce autoimmune responses in the liver. Data derived from the literature suggest that patients with AILDs do not carry an increased risk of SARS-Cov-2 infection but may develop a more severe course of COVID-19 if on treatment with steroids or thiopurine. Although SARS-CoV-2 infection can lead to the development of several autoimmune diseases, few reports correlate it to the appearance of de novo manifestation of immune-mediated liver diseases such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) or AIH/PBC overlap syndrome. Different case series of an AIH-like syndrome with a good prognosis after SARS-CoV-2 vaccination have been described. Although the causal link between SARS-CoV-2 vaccines and AIH cannot be definitively established, these reports suggest that this association could be more than coincidental.

Fosfomycin Pharmacokinetic Profile in Plasma and Urine and Quantitative Estimation in Prostate and Seminal Vesicles after One and Two Consecutive Doses of Oral Fosfomycin Trometamol in Healthy Male Volunteers.

The present Phase I study investigated, for the first time, fosfomycin pharmacokinetics in humans after two 3 g doses of fosfomycin trometamol administered 27 h apart, according to the dose regimen recommended for the prophylactic indication for transrectal prostate biopsy in adult men. Plasma, urine and seminal plasma concentrations were measured after one and two consecutive doses in 24 healthy men, representative of the target population of the prophylactic indication. Prostate and seminal vesicle concentrations were estimated based on seminal plasma concentrations using a one-step regression method. The exposure to fosfomycin was very similar in rate (Cmax, tmax) after one and two doses. The AUC showed a minimal increment. On average, the apparent volume of distribution was high (>100 L), and the mean clearance had an intermediate value. The total amount and dose fraction of fosfomycin excreted in urine showed a small increment after two doses. The renal clearance was about 5 L/h. The fosfomycin concentration in the prostate and seminal vesicles showed that the antibiotic increased on average after two consecutive doses. This result confirmed the ability of fosfomycin to distribute into the prostate and into seminal vesicles after one single dose and that a two consecutive dose regimen increases the antibiotic availability inside these peripheral tissues.

Pharmacokinetics and Safety of Single and Multiple Doses of Oral N-Acetylcysteine in Healthy Chinese and Caucasian Volunteers: An Open-Label, Phase I Clinical Study.

INTRODUCTION: Few studies have evaluated whether the pharmacokinetics of N-acetyl-cysteine (NAC) are different in Chinese and Caucasian individuals. METHODS: This single- and multiple-dose, single-centre, open-label, phase I clinical study was conducted in healthy adult volunteers. All participants received oral NAC 600-mg uncoated tablets, which were administered first as a single dose and, following a 48-h wash-out period, twice daily for 3 days. Blood and urine were collected after single- and multiple-dose NAC administration. Adverse event (AE) data were collected throughout the study. RESULTS: Fifteen Chinese and 15 Caucasian (mostly Italian) individuals (males 66.7%, mean age 36.8 years) participated in the study. Pharmacokinetic characteristics of NAC were similar in the two cohorts. Following both single- and multiple-dose administration, plasma concentration of NAC increased rapidly, reaching a peak at approximately 1.0 h. Maximum plasma concentration and extent of exposure were higher after multiple doses than after a single dose. The accumulation ratio was relatively consistent in both Chinese (mean ± standard deviation 1.5 ± 0.4) and Caucasian (1.4 ± 0.2) participants. The half-life was 15.4 h in Chinese and 18.7 h in Caucasian participants, and the fraction of NAC excreted in urine in the 36 h following administration was 3.7% in Chinese and 3.8% in Caucasian participants. Two Caucasian participants had a total of 3 AEs (headache, presyncope and dysmenorrhoea). No AEs occurred in Chinese participants. CONCLUSIONS: The pharmacokinetic characteristics of NAC are similar in healthy Chinese and Caucasian individuals after single and repeated administration. NAC has a favourable tolerability profile.

Pharmacokinetics and Safety of Rifamycin SV after Single and Multiple Doses of MMX® Modified Release Tablets in Healthy Male and Female Volunteers.

The primary objective of this single- and multiple-dose pharmacokinetic study was the investigation of rifamycin SV's pharmacokinetic profile in plasma and urine. All the 18 enrolled healthy men and post-menopausal women received modified release tablets containing 600 mg of the oral non-absorbable antibiotic, rifamycin SV, according to a multiple dose regimen: one tablet three times a day (daily intake: 1800 mg) for 14 consecutive days. Blood sampling and urine collection were performed up to 24 h post-dose after the first dose on Days 1 and 7. On average, on Day 1, Cmax,0-24 was 5.79 ± 4.24 ng/mL and was attained in a median time of 9 h. On Day 7, all the subjects had quantifiable levels of rifamycin SV in plasma at each sampling time. After a peak concentration attained 2 h post-dose (mean ± SD concentration: 10.94 ± 16.41 ng/mL), rifamycin SV decreased in plasma to levels similar to those of Day 1. The amounts of rifamycin SV excreted in urine paralleled the plasma concentration at the corresponding times. On Day 1, the total amount excreted in urine was 0.0013%, and was 0.0029% on Day 7. The study results confirmed those of the previous Phase I study: the systemic absorption of rifamycin SV was also proved negligible after 7 days of the 600 mg t.i.d. dose regimen of the newly formulated tablets, currently under development for the treatment of several small and large intestinal pathologies, including diarrhea-predominant irritable bowel syndrome, hepatic encephalopathy, and others. Registered at ClinicalTrials.gov with the identifier NCT02969252, last updated on 26JAN18.

One-Pot Synthesis of TiO2-rGO Photocatalysts for the Degradation of Groundwater Pollutants.

A non-conventional approach to prepare titanium dioxide-reduced graphene oxide (TiO2-rGO) nanocomposites based on solar photoreduction is here presented. The standard hydro-solvothermal synthesis of the TiO2-rGO composites requires high temperatures and several steps, whereas the proposed one-pot preparation allows one to obtain the photocatalysts with a simple and green procedure, by exploiting the photocatalytic properties of titania activated by the solar irradiation. The TiO2-rGO catalysts were tested in the solar photodegradation of a widely adopted toxic herbicide (2,4-Dichlorophenoxyacetic acid, 2,4-D), obtaining the 97% of degradation after 3 h of irradiation. The as-prepared TiO2-rGO composites were more active compared to the same photocatalysts prepared through the conventional thermal route. The structural, optical, and textural properties of the composites, determined by Raman, Photoluminescence, Fourier Transform InfraRed (FTIR), UV-vis diffuse reflectance (DRS) spectroscopies, and N2 absorption-desorption measurements, showed as the solar irradiation favors the reduction of graphene oxide with higher efficiency compared to the thermal-driven synthesis. Furthermore, the possible toxicity of the as-synthesized composites was measured exposing nauplii of microcrustacean Artemia sp. to solutions containing TiO2-rGO. The good results in the 2,4-D degradation process and the easiness of the TiO2-rGO synthesis allow to consider the proposed approach a promising strategy to obtain performing photocatalysts.

Early surgical treatment in unilateral coronoid hyperplasia and facial asymmetry.

Unilateral coronoid hyperplasia is a rare condition in the pediatric age. It may be an unrecognized cause of restricted mouth opening in children.The limited jaw movement is due to the enlargement of the coronoid process of the mandible that impinges on the zygomatic arch during mouth opening. This pathologic condition is still unknown and often misdiagnosed.Although in the past the term osteochondroma has been used to describe most of the unilateral and a few of the bilateral cases, there is no histologic evidence that the process has a neoplastic origin.Microscopic examination of the removed coronoid process has revealed hyperplastic compact bone covered with a thin layer of normal cartilage.There are multiple causes of mandibular hypomobility, each of them associated with different anatomic structures and etiologies, and a large number of cases, mostly bilateral, are idiopathic in nature.Several theories of pathogenesis have been proposed: temporomandibular joint dysfunctions, mandibular hypomobility, temporalis hyperactivity, hormonal stimulus, persistent cartilage growth center, genetic inheritance, and family factors.Unilateral coronoid hyperplasia is usually due to a trauma or a pathologic condition and is associated with facial asymmetry, being more frequently seen in women with histologic chondromatous or neoplastic changes. A thorough clinical history should include information about the onset and progression of pain and other subjective symptoms.In this study, we present a case of unilateral hyperplasia of the coronoid process in a 3 year-old female who, to the best of our knowledge, is the youngest patient so far reported with such anomaly.Our findings support the recommendation that early surgical treatment and aggressive postoperative physical therapy should be taken into account to allow for recovery of morphology and growth function in children.

The Role of Membrane Capacitance in Cardiac Impulse Conduction: An Optogenetic Study With Non-excitable Cells Coupled to Cardiomyocytes.

Non-excitable cells (NECs) such as cardiac myofibroblasts that are electrotonically coupled to cardiomyocytes affect conduction velocity (θ) by representing a capacitive load (CL: increased membrane to be charged) and a resistive load (RL: partial depolarization of coupled cardiomyocytes). In this study, we untangled the relative contributions of both loading modalities to NEC-dependent arrhythmogenic conduction slowing. Discrimination between CL and RL was achieved by reversibly removing the RL component by light activation of the halorhodopsin-based hyperpolarizing membrane voltage actuator eNpHR3.0-eYFP (enhanced yellow fluorescent protein) expressed in communication-competent fibroblast-like NIH3T3 cells (3T3 HR cells) that served as a model of coupled NECs. Experiments were conducted with strands of neonatal rat ventricular cardiomyocytes coated at increasing densities with 3T3 HR cells. Impulse conduction along preparations stimulated at 2.5 Hz was assessed with multielectrode arrays. The relative density of 3T3 HR cells was determined by dividing the area showing eYFP fluorescence by the area covered with cardiomyocytes [coverage factor (CF)]. Compared to cardiomyocytes, 3T3 HR cells exhibited a depolarized membrane potential (-34 mV) that was shifted to -104 mV during activation of halorhodopsin. Without illumination, 3T3 HR cells slowed θ along the preparations from ∼330 mm/s (control cardiomyocyte strands) to ∼100 mm/s (CF = ∼0.6). Illumination of the preparation increased the electrogram amplitudes and induced partial recovery of θ at CF > 0.3. Computer simulations demonstrated that the θ deficit observed during illumination was attributable in full to the CL represented by coupled 3T3 HR cells with θ showing a power-law relationship to capacitance with an exponent of -0.78 (simulations) and -0.99 (experiments). The relative contribution of CL and RL to conduction slowing changed as a function of CF with CL dominating at CF ≤ ∼0.3, both mechanisms being equally important at CF = ∼0.5, and RL dominating over CL at CF > 0.5. The finding that RL did not affect θ at CFs ≤ 0.3 is explained by the circumstance that, at the respective moderate levels of cardiomyocyte depolarization, supernormal conduction stabilized propagation. The findings provide experimental estimates for the dependence of θ on membrane capacitance in general and suggest that the myocardium can absorb moderate numbers of electrotonically coupled NECs without showing substantial alterations of θ.

Relative bioavailability and pharmacokinetics of two oral formulations of docosahexaenoic acid/eicosapentaenoic acid after multiple-dose administration in healthy volunteers.

OBJECTIVES: To assess the comparative pharmacokinetic profile and bioavailability of docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) after multiple-dose administration of a new oral formulation (test formulation) and a commercially available reference formulation in healthy subjects. METHODS: Forty-eight healthy subjects received a 28-day oral treatment with DHA/EPA in the form of either the test or the reference product according to an open-label, randomized, parallel-group design. Both formulations were given t.i.d. at 8-h intervals at a dose of 3.0 g/day. Steady-state DHA and EPA concentrations in plasma and lysed whole blood were measured by gas-liquid chromatography at baseline and after 7, 14, 21 and 28 days of treatment. Kinetic parameters were compared both after subtraction of baseline concentrations and by using baseline concentrations as a covariate. RESULTS: For both DHA and EPA, plasma and RBC concentrations measured from day 7 to day 28 were significantly higher than at baseline and did not differ significantly between the two products. On day 28 the plasma DHA concentration on average doubled the baseline level after administration of test and reference product, while there was a 10-fold increase in EPA plasma concentration. When the assessment was performed using baseline values as covariate, test-to-reference ratios for area under the curve (AUCss(0-8)) and for peak concentration (Css(max)) after the last administration on day 28 met bioequivalence criteria (i.e., 90% confidence intervals within 0.80-1.25 for AUCss(0-8) ratios, and within 0.75-1.33 for Css(max) ratios). When the assessment was conducted after subtraction of baseline values, the 90% confidence intervals for Css(max) ratios were within the bioequivalence range, whereas the intervals for AUCss(0-8) ratio were borderline for bioequivalence. CONCLUSION: The two formulations tested were similarly effective in increasing DHA and EPA concentrations in plasma and lysed whole blood, and showed comparable bioavailability for both active components.

Laparo-endoscopic "Rendezvous" to treat cholecysto-choledocolithiasis: Effective, safe and simplifies the endoscopist's work.

AIM: To investigate our clinical experience with combined laparo-endoscopic Rendezvous (RV) for the treatment of patients affected by gallstones and common bile duct (CBD) stones and especially to study the never evaluated opinion of the endoscopist concerning the difficulty of the intraoperative endoscopic procedure during the RV in comparison with standard endoscopic retrograde cholangio-pancreatography (ERCP). METHODS: Eighty consecutive patients affected by cholecystolithiasis and diagnosed or suspected CBD stones were treated with a standardized "tailored" RV. The relevant technical features, the feasibility, the effectiveness in stone clearance, the safety but also the simple evaluation of difficulty and agreement of the endoscopist were analyzed with a questionnaire. RESULTS: The feasibility was 97.5% and the effectiveness 100% concerning CBD clearance and solution of coexisting problems at the papilla. Minor morbidity was 3.3%, the operating time was prolonged by a mean of 14 min, the mean hospital stay was 3.8 d and only one stone's recurrence occurred. The endoscopist evaluated the procedure to be simpler than standard ERCP-ES in 81.2% of the cases. CONCLUSION: Simultaneous RV carries high effectiveness and safety at least comparable to those reported for other options. The endoscopist is very often satisfied with this approach because of the minimization of some steps of the endoscopic procedure and avoidance of relevant iatrogenic risk factors. If the mandatory collaboration between surgeons and endoscopists is guaranteed, this approach can often be preferable for the patient, the surgeon, the endoscopist and the hospital.

Pharmacokinetics and Pharmacodynamics of Follicle-Stimulating Hormone in Healthy Women Receiving Single and Multiple Doses of Highly Purified Human Menotrophin and Urofollitrophin.

BACKGROUND AND OBJECTIVE: Highly purified human menotrophin and urofollitrophin preparations obtained from human urine via a novel patented purification method have been tested over a timeframe of 14 years in the studies presented in this article. The objective of the studies was to investigate the pharmacokinetics and the pharmacodynamics of follicle-stimulating hormone (FSH) after single subcutaneous and intramuscular doses and multiple subcutaneous doses of the tested preparations in healthy fertile pituitary-suppressed women. DESIGNS: We performed five open, randomised, crossover, single-dose bioequivalence and/or bioavailability studies and one open, multiple-dose, pharmacokinetics and pharmacodynamics study. STUDY SUBJECTS AND TREATMENTS: The six studies included 121 healthy fertile women taking their usual combined oral contraceptives for 3 months before the study: Study 1: 300 international units (IU) of highly purified menotrophin as single subcutaneous and intramuscular doses. Study 2: 300 IU of highly purified menotrophin (test formulation vs. comparator) as single subcutaneous doses. Study 3: 300 IU of highly purified urofollitrophin (hp-FSH) (test formulation vs. comparator) as single subcutaneous doses. Study 4: 300 IU (2 × 150 IU vs. 4 × 75 IU) of hp-FSH as single subcutaneous doses. Study 5: 225 and 445 IU of hp-FSH as single subcutaneous doses. Study 6: daily 225 IU of hp-FSH as subcutaneous doses for 5 consecutive days. MAIN OUTCOME MEASURES: The main outcome measures were the FSH pharmacokinetic parameters, estradiol concentrations, and the number and size of the follicles. RESULTS: FSH after single subcutaneous and intramuscular injections of menotrophin or urofollitrophin attained a systemic peak (maximum) concentration (C max) that was on average consistent throughout the first four studies and ranged from 4.98 to 7.50 IU/L. The area under the plasma concentration-time curve (AUC) from administration to the last observed concentration time t (AUCt) ranged from 409.71 to 486.16 IU/L·h and the elimination half-life (t ½) ranged from 39.02 to 53.63 h. After multiple doses of urofollitrophin (225 IU) for 5 days, FSH attained a mean C max of 14.93 ± 2.92 IU/L and had an AUC during the time interval τ between two consecutive doses at steady state (AUCτ) of 322.59 ± 57.92 IU/L·h, which was similar to the mean AUCt after a single subcutaneous dose of 225 IU of urofollitrophin in study 5 (306.82 ± 68.37 IU/L·h). CONCLUSIONS: In our studies, the intramuscular and subcutaneous routes of menotrophin were equivalent; both menotrophin and urofollitrophin were bioequivalent to their marketed reference; FSH kinetic parameters following injection of urofollitrophin were dose proportional and independent from the administered concentration; and multiple doses of FSH increased estradiol levels and enhanced growth of follicles with a good dose-response correlation. Local tolerability was excellent throughout the six studies.