Screening for impulse control disorders in Parkinson's disease and dopamine agonist use: a study of pharmacokinetic and psychological risk factors.

INTRODUCTION: Dopamine agonist (DA) use is considered the main risk factor for impulse control disorder (ICD) development in Parkinson's disease (PD). Besides DAs, personality traits and cognitive features may represent risk factors for ICDs. The primary aim of this study was to investigate differences in DA plasma concentrations in PD patients with and without a positive screening for ICDs according to validated tools. The secondary aim was to compare the psychological profile between ICD positive and negative screened patients. METHODS: PD patients receiving chronic DA therapy were screened for ICDs according to the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP). Blood samples for measurement of DA (pramipexole, ropinirole, rotigotine) trough plasma concentrations were drawn in the morning, at mean 16-19 h from the last DA dose. Patients' psychological profile was investigated by Millon Clinical Multiaxal Inventory III and Barratt Impulsiveness Scale (BIS-11). RESULTS: One hundred and five PD patients were enrolled. Forty-one patients (39%) were QUIP positive, mainly for binge eating and hobbyism. Median plasma concentrations of pramipexole (n = 71, 66%), ropinirole (n = 21, 19%), and rotigotine (n = 16, 15%) were similar between QUIP positive and negative patients. QUIP positive patients showed higher motor impulsiveness (p = 0.04) and tended to higher total impulsiveness (p = 0.05). CONCLUSION: This is the first prospective study to evaluate the relationship between DA plasma concentrations and ICDs risk in PD patients. DA plasma levels were overlapping between QUIP positive and negative patients. BIS-11, particularly the motor impulsiveness subscale, might be a useful screening tool in PD patients eligible for DA therapy.

A Step-by-Step Procedure for Bone Regeneration Using Calcium Phosphate Scaffolds: From Site Preparation to Graft Placement.

Hydroxyapatite (HA) is the main mineral component of bone and teeth. HA is often used as a bone substitute and especially in its granular form it is osteoconductive and osseointegrating as shown by many investigations in animals and humans. HA granules are used for filling bone defects, but they have poor handling qualities and retention at the surgical site, leading to graft voids between the granules and bone tissue and resulting in mechanical instability. Furthermore HA implantation is not constantly followed by favorable results, especially when it is carried out for augmentation of the alveolar ridge. This article offers a protocol for bone reconstruction and predictable implant treatment outcomes. We provide a step-by-step description of both the recipient site and composite graft preparations using coralline HA granules (CHAG) and homologous fibrin glue (HFG). In the present study, 20 randomly selected patients (12 women and 8 men) underwent bone regeneration using CHAG-HFG before a dental implant procedure. Radiographic imaging, physical examination, and histological analysis were performed during a 2-year period. Biopsies were obtained at second-stage surgery before implant insertion using a 2.8-mm trephine bur. A morphological study of 20 bioptic human specimens was performed. Our results demonstrate that this surgical protocol for the preparation of the recipient site associated with a mixture of coralline HA granules with homologous fibrin glue provides reliable bone regeneration, thus reducing failures and minimizing risks of postoperative morbidity.

A Step-By-Step Technique for the Piezosurgical Removal of Fractured Implants.

With the increasing popularity of dental implants, the removal of fractured implants has become a major challenge for clinicians. Several tools can be used for the removal of osseointegrated implants; however, few of these have the characteristics of easy control, selective cutting, and rapid healing. In this study, the authors describe a step-by-step technique for the removal of osseointegrated fractured implants via multiple peri-implant osteotomies performed using a piezoelectric device and appropriate inserts. All patients ended with primary wound closure without any soft tissue dehiscence and no healing problems during the postoperative period. As the use of ultrasonic inserts enables precise and selective cuts, piezosurgical implant removal is an attractive alternative to trephine burs or rotary drills.

A phase II, randomized, multicenter study evaluating the combination of lapatinib and vinorelbine in women with ErbB2 overexpressing metastatic breast cancer.

Lapatinib is approved in combination with capecitabine for treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) who have progressed on prior trastuzumab in the metastatic setting. Vinorelbine is an important chemotherapy option for MBC. We evaluated efficacy and safety of lapatinib plus vinorelbine, compared with lapatinib plus capecitabine, in women with HER2-positive MBC. In this open-label, multicenter, phase II study, eligible patients (N = 112) were randomized 2:1 to lapatinib plus vinorelbine [(N = 75) 1,250 mg orally once daily (QD) continuously plus 20 mg/m(2)/day intravenously] or lapatinib plus capecitabine [(N = 37) 1,250 mg orally QD continuously plus 2,000 mg/m(2)/day orally, 2 doses]. The primary endpoint was progression-free survival (PFS). Other endpoints included overall survival (OS) and safety. Patients progressing within the study were given the option of crossover to the other treatment arm; time to second progression was an exploratory endpoint. Patient demographics, stratification, and prognostic factors were well balanced between treatments. Median PFS in both arms was 6.2 months [95 % confidence interval (CI) 4.2, 8.8 (lapatinib plus vinorelbine); 4.4, 8.3 (lapatinib plus capecitabine)]. Median OS on lapatinib plus vinorelbine was 24.3 months (95 % CI 16.4, NE) and 19.4 months (95 % CI 16.4, 27.2) on lapatinib plus capecitabine. In total, 42 patients opted to cross over; median PFS was 3.2 months (95 % CI 1.7, 5.1) on lapatinib plus vinorelbine and 4.0 months (95 % CI 2.1, 5.8) on lapatinib plus capecitabine. Lapatinib plus vinorelbine offers an effective treatment option for patients with HER2-overexpressing MBC, having displayed comparable efficacy and tolerability rates to lapatinib plus capecitabine.

Reconstruction of the Maxillary Sinus After Previous Major Sinus Elevation Failure: A Study with a 3-Year Follow-up.

Fourteen maxillary sinuses were reconstructed in 12 patients who presented with a previous sinus elevation failure. In all cases, large perforations of the sinus membrane occurred during removal of the failed graft from the sinus; the perforations were sealed with fibrin glue, then the site was grafted using homologous fibrin glue (HFG) mixed with a calcium phosphate scaffold (CPS). Histologic analyses revealed that the CPS-HFG graft was followed by an ossification process, with the formation of spongy bone similar to that of the normal skeleton. Twenty-four endosseous implants were successfully placed into the newly regenerated bone. All implants were successfully restored with ceramic crowns 6 months after placement. At the 3-year follow-up, no infections or implant failures were reported. The described technique offers several clinical advantages, as the removal of the failed graft, the sinus perforation repair, and the sinus elevation can be achieved in the same surgery without needing to postpone the regenerative surgery phase.

Metabolite Changes After Metabolic Surgery - Associations to Parameters Reflecting Glucose Homeostasis and Lipid Levels.

Aims: To test the hypothesis that adipose tissue gene expression patterns would be affected by metabolic surgery and we aimed to identify genes and metabolic pathways as well as metabolites correlating with metabolic changes following metabolic surgery. Materials and Methods: This observational study was conducted at the Obesity Unit at the Catholic University Hospital of the Sacred Heart in Rome, Italy. Fifteen patients, of which six patients underwent Roux-en-Y gastric bypass and nine patients underwent biliopancreatic diversion, were included. The participants underwent an oral glucose tolerance test and a hyperinsulinemic euglycemic clamp. Small polar metabolites were analyzed with a two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC×GC-TOFMS). Gene expression analysis of genes related to metabolism of amino acids and fatty acids were analyzed in subcutaneous adipose tissue. All procedures were performed at study start and at follow-up (after 185.3 ± 72.9 days). Results: Twelve metabolites were significantly changed after metabolic surgery. Six metabolites were identified as 3-indoleacetic acid, 2-hydroxybutyric acid, valine, glutamic acid, 4-hydroxybenzeneacetic acid and alpha-tocopherol. The branched chain amino acids displayed a significant decrease together with a decrease in BCAT1 adipose tissue mRNA levels. Changes in the identified metabolites were associated to changes in lipid, insulin and glucose levels. Conclusions: Our study has identified metabolites and metabolic pathways that are altered by metabolic surgery and may be used as biomarkers for metabolic improvement.

Mixed neuropathology in frontotemporal lobar degeneration.

Aim: Frontotemporal lobar degeneration (FTLD) is a significant cause of dementia in mid-life and older adults. The extent of interactions between FTLD and other neurodegenerative pathologies is unclear. We reviewed the occurrences of mixed pathology in cases of neuropathologically diagnosed FTLD from the UK Brain Bank Network. Materials and methods: Clinicopathological details of cases of FTLD were extracted from the UK Brain Bank Network database. Results: Of 515 cases, 30.10% had mixed neuropathology. Concordance between clinical and neuropathological diagnosis was lower in these cases (38.71% vs. 59.17%). Alzheimer's spectrum pathology was the commonest additional finding. Age at death was higher in mixed neuropathology cases (mean 76.7 years vs. 72.59.0 years, p < 0.005), increasing in tandem with the number of neuropathologies present. Conclusion: Mixed neuropathology is common in FTLD and associated with increased age at death. Our findings suggest that mixed neuropathology influences age at onset and clinical phenotype in FTLD and makes accurate antemortem diagnosis more difficult. Further investigation of interactions between neuropathologies and phenotype is warranted, particularly in view of the potential impact on clinical diagnosis and patient selection for clinical trials.Key pointsMixed neurodegenerative neuropathologies commonly occur with frontotemporal lobar degeneration.The likelihood of mixed neuropathology with FTLD increases with older age at death.Mixed neuropathology could influence the clinical phenotype of frontotemporal lobar degeneration.

Biliopancreatic Diversion Induces Greater Metabolic Improvement Than Roux-en-Y Gastric Bypass.

Diabetes remission is greater after biliopancreatic diversion (BPD) than Roux-en-Y gastric bypass (RYGB) surgery. We used a mixed-meal test with ingested and infused glucose tracers and the hyperinsulinemic-euglycemic clamp procedure with glucose tracer infusion to assess the effect of 20% weight loss induced by either RYGB or BPD on glucoregulation in people with obesity (ClinicalTrials.gov number: NCT03111953). The rate of appearance of ingested glucose into the circulation was much slower, and the postprandial increases in plasma glucose and insulin concentrations were markedly blunted after BPD compared to after RYGB. Insulin sensitivity, assessed as glucose disposal rate during insulin infusion, was ∼45% greater after BPD than RYGB, whereas ß cell function was not different between groups. These results demonstrate that compared with matched-percentage weight loss induced by RYGB, BPD has unique beneficial effects on glycemic control, manifested by slower postprandial glucose absorption, blunted postprandial plasma glucose and insulin excursions, and greater improvement in insulin sensitivity.

Improving memory following prefrontal cortex damage with the PQRST method.

We tested (1) whether the PQRST method, involving Preview (P), Question (Q), Read (R), State (S), and Test (T) phases, is effective in enhancing long-term memory in patients with mild memory problems due to prefrontal cortex lesions, and (2) whether patients also benefit from a more self-initiated version of the PQRST. Seven patients with prefrontal lesions encoded new texts under three different conditions: the Standard condition, requiring to read texts repeatedly, the PQRST-Other condition, in which the experimenter formulated questions about the text (Q phase), and the PQRST-Self condition, in which patients formulated the relevant questions on their own. Compared to the Standard condition, both the PQRST-Other and the PQRST-Self condition resulted in higher immediate and delayed recall rates, as well as a higher ability to answer questions about the texts. Importantly, the two PQRST conditions did not differ in efficacy. These results confirm that the PQRST method is effective in improving learning of new material in brain-injured populations with mild memory problems. Moreover, they indicate that the PQRST proves effective even under conditions with higher demands on patients' autonomy and self-initiation, which encourages its application to real-life situations.

Final overall survival analysis of a phase II trial evaluating vinorelbine and lapatinib in women with ErbB2 overexpressing metastatic breast cancer.

Lapatinib plus capecitabine (lap+cap) is approved as treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), who have progressed on prior trastuzumab in the metastatic setting. We previously reported progression-free survival (PFS), overall survival (OS) and safety results from this open-label, multicentre, phase II study (VITAL; NCT01013740) conducted in women with HER2 positive MBC, to evaluate the efficacy and safety of lap plus vinorelbine (lap+vin), an important chemotherapy option for MBC, compared with lap+cap. In total, 112 patients were randomised 2:1 to treatment with lap+vin (N = 75) or lap+cap (N = 37). Results showed that the median PFS (primary endpoint) and OS (secondary endpoint) post-randomisation were comparable between treatment arms, with no new safety signals detected. Here, we assessed the final OS in this study at 40 months post-randomisation. At the time of final analyses, 24 (32%) patients were ongoing in the lap+vin arm, compared with 14 (38%) patients in the lap+cap arm (92% in both arms had discontinued treatment). Median OS in the lap+vin arm was 23.3 months (95% confidence intervals [CI]: 18.5, 31.1), compared with 20.3 months (95% CI: 16.4, 31.8) in the lap+cap arm. The median follow-up in the lap+vin arm was 18.86 months (95% CI: 10.68, 26.02), compared with 19.38 (95% CI: 25.56) months in the lap+cap arm. Similar rates of death (56-57%) were observed in both arms. The final OS was consistent with the previously reported data and suggest that lap+vin offers an effective treatment option for women with HER2-positive MBC.

[Drug trafficking and international law]. / Il traffico di droga nel diritto internazionale.

The production, the commerce and the use of drugs and other substances are ruled by several conventions of international law, that, at first, have had as object the production and the commerce of drugs for lawful purposes, and the measures required to prevent and to repress, at certain conditions, abuses and unlawful traffics. Just more recently, following some solicitations noticed by the International Community, and according to the concept of "well-balanced approach" described in the text, the measures introduced in this way were supported by a more incisive international movement, fit for the repression of unlawful traffics of drugs and to the adoption of suitable measures of prevention, also to avoid, at national level, sanitary, social and economical implications of the criminal phenomenon.

Prevalence of tick-borne pathogens in an urban park in Rome, Italy.

INTRODUCTION: Limited information is available about the presence of tick-borne pathogens in urban parks in Italy. To fill this gap, ticks were collected in a public park in Rome over a 1-year period and screened by molecular methods for tick-borne pathogens. RESULTS AND CONCLUSION: The most abundant tick species were Rhipicephalus turanicus and Ixodes ricinus. The predominant pathogens detected were Borrelia. burgdorferi sensu lato (36%), Rickettsia spp. (36%), and Coxiella burnetii (22%). Among less frequently detected pathogens, Babesia microti was detected for the first time in Italy, with a prevalence of 4%. Neither Bartonella spp. nor Francisella tularensis were detected. With regard to co-infections, the most frequent double and triple infections involved Rickettsia spp., B. burgdorferi sl., and C. burnetii.. A positive correlation was detected between pathogens and I. ricinus. Further studies are needed in order to assess risk associated with tick-borne pathogens in urban areas.

Seasonal dynamics of tick species in an urban park of Rome.

Regular collections were obtained in the Natural Reserve of the Insugherata of Rome during 2011 in order to obtain the tick species composition and the respective seasonal dynamics of the area. A total of 325 ticks was collected in selected sites by means of drag sampling. Among the identified species, Rhipicephalus turanicus was the most abundant (72.3%), followed by Ixodes ricinus (19.7%), Dermacentor marginatus (6.5%), Haemaphysalis punctata (1.2%), and Rhipicephalus bursa (0.3%). R. turanicus occurred mainly in pastures, showing a mono-modal seasonal activity pattern from spring to early summer. Questing I. ricinus were prevalent in woodland from October to May, and the seasonal trend of specimens showed a weak peak in winter. Although adult D. marginatus exhibited seasonal dynamics similar to I. ricinus, with an activity period from October to April, this species occurred in a different environment (pasture) and with considerably lower densities. Haemaphysalis punctata and R. bursa were rare, with an apparent autumn and autumn-winter seasonal activity, respectively. While the species diversity recorded appears as an unequivocal consequence of the natural state of the park, the remarkable R. turanicus density could be a direct effect of the recent introduction of wild boar, as carriers, from the close Veio Park. The presence of the species, a proven vector of various diseases in humans and domestic animals, is discussed in the light of the possible risk of tick-bite exposure of park workers and visitors.

Preoperative chemotherapy plus trastuzumab, lapatinib, or both in human epidermal growth factor receptor 2-positive operable breast cancer: results of the randomized phase II CHER-LOB study.

PURPOSE: This is a noncomparative, randomized, phase II trial of preoperative taxane-anthracycline in combination with trastuzumab, lapatinib, or combined trastuzumab plus lapatinib in patients with human epidermal growth factor receptor 2 (HER2) -positive, stage II to IIIA operable breast cancer. The primary aim was to estimate the percentage of pathologic complete response (pCR; no invasive tumor in breast and axillary nodes). PATIENTS AND METHODS: In the three arms, chemotherapy consisted of weekly paclitaxel (80 mg/m(2)) for 12 weeks followed by fluorouracil, epirubicin, and cyclophosphamide for four courses every 3 weeks. The patients randomly assigned to arm A received a 4-mg loading dose of trastuzumab followed by 2 mg weekly; in arm B patients received lapatinib 1,500 mg orally (PO) daily; and in arm C, patients received trastuzumab and lapatinib 1,000 mg PO daily. RESULTS: A total of 121 patients were randomly assigned. Diarrhea and dermatologic and hepatic toxicities were observed more frequently in patients receiving lapatinib. No episodes of congestive heart failure were observed. The rates of breast-conserving surgery were 66.7%, 57.9%, and 68.9% in arms A, B and C, respectively. The pCR rates were 25% (90% CI, 13.1% to 36.9%) in arm A, 26.3% (90% CI, 14.5% to 38.1%) in arm B, and 46.7% (90% CI, 34.4% to 58.9%) in arm C (exploratory P = .019). CONCLUSION: The primary end point of the study was met, with a relative increase of 80% in the pCR rate achieved with chemotherapy plus trastuzumab and lapatinib compared with chemotherapy plus either trastuzumab or lapatinib. These data add further evidence supporting the superiority of a dual-HER2 inhibition for the treatment of HER2-positive breast cancer.

Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial.

OBJECTIVES: This phase 2 randomized study compared the toxicity and assessed the efficacy of gemcitabine-cisplatin (GP) and gemcitabine-carboplatin (GC) in patients with advanced transitional cell carcinoma of the urothelium (TCC), with the main objective to demonstrate a reduction in toxicity of at least 25% in the GC arm. METHODS: A total of 110 chemonaive patients (55 per arm) with locally advanced or metastatic TCC received gemcitabine 1250 mg/m(2) on days 1 and 8 plus cisplatin 70 mg/m(2) on day 2 (GP) every 3 wk or gemcitabine 1250 mg/m(2) on days 1 and 8 plus carboplatin AUC 5 on day 2 (GC) every 3 wk for a maximum of six cycles. RESULTS: No differences between arms were noted in the overall toxicity profiles and any parameter of toxicity. The most frequent grade 3-4 hematologic toxicity was neutropenia in 34.6% of patients for GP and 45.4% for GC. The most frequent grade 3-4 nonhematologic toxicity was nausea and vomiting (GP: 9.1%; GC: 3.6%). Grade 1-2 nephrotoxicity occurred in 14 GP-treated patients (26.0%) and 9 GC-treated patients (16.3%). Per an intent-to-treat analysis, overall response, evaluated on 80 patients, was 49.1% for GP (CR: 14.5%; PR: 34.5%) and 40.0% for GC (CR: 1.8%; PR: 38.2%). Median time to progression was 8.3 mo for GP and 7.7 mo for GC. Median survival was 12.8 mo and 9.8 mo for GP and GC, respectively. CONCLUSIONS: GC has a comparably acceptable toxicity profile compared with that of GP and seems active in patients with TCC.

Cellular and pharmacogenetics foundation of synergistic interaction of pemetrexed and gemcitabine in human non-small-cell lung cancer cells.

Gemcitabine and pemetrexed are effective agents in the treatment of non-small-cell lung cancer (NSCLC), and the present study investigates cellular and genetic aspects of their interaction against A549, Calu-1, and Calu-6 cells. Cells were treated with pemetrexed and gemcitabine, and their interaction was assessed using the combination index. The role of drug metabolism in gemcitabine cytotoxicity was examined with inhibitors of deoxycytidine kinase (dCK), 5'-nucleotidase, and cytidine deaminase, whereas the role of pemetrexed targets, thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT) in drug chemosensitivity was analyzed in cytotoxicity rescue studies. The effect of gemcitabine and pemetrexed on Akt phosphorylation was investigated with enzyme-linked immunosorbent assay, whereas quantitative polymerase chain reaction (PCR) was used to study target gene-expression profiles and its modulation by each drug. Synergistic cytotoxicity was demonstrated, and pemetrexed significantly decreased the amount of phosphorylated Akt, enhanced apoptosis, and increased the expression of dCK in A549 and Calu-6 cells, as well as the expression of the human nucleoside equilibrative transporter 1 (hENT1) in all cell lines. PCR demonstrated a correlation between dCK expression and gemcitabine sensitivity, whereas expression of TS, DHFR, and GARFT was predictive of pemetrexed chemosensitivity. These data demonstrated that 1) gemcitabine and pemetrexed synergistically interact against NSCLC cells through the suppression of Akt phosphorylation and induction of apoptosis; 2) the gene expression profile of critical genes may predict for drug chemosensitivity; and 3) pemetrexed enhances dCK and hENT1 expression, thus suggesting the role of gene-expression modulation for rational development of chemotherapy combinations.