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Novel pyrazolyl-derived diazonium tetrafluoroborate salts were used in the palladium-catalyzed Heck–Matsuda reaction for the diastereoselective synthesis of highly substituted cyclopenten-ols/-amines.

Prophylactic administration of somatostatin analogues (SA) to reduce the incidence of post-operative pancreatic fistula (POPF) remains contentious. This meta-analysis evaluated its impact on outcomes following pancreaticoduodenectomy (PD). The EMBASE, MEDLINE and Cochrane databases were searched for randomised controlled trials (RCTs) investigating prophylactic SA following PD. Comparative effects were summarised as odds ratio and weighted mean difference based on an intention to treat. Quantitative pooling of the effect sizes was derived using the random-effects model. Twelve RCTs were included involving 1615 patients [SA-treated group (n = 820) and control group (n = 795)]. The SA used included somatostatin-14, pasireotide, vapreotide and octreotide. Pooling of the data showed no significant benefit of its use for the primary outcome measure of all grades of POPF, odds ratio (OR) 0.73 [95% confidence interval (CI), 0.51–1.05, p = 0.09] and clinically relevant POPF, OR 0.48 [95% CI, 0.22–1.06, p = 0.07]. There were no benefits in the secondary outcome measures of delayed gastric emptying, OR 0.98 [95% CI, 0.57–1.69, p = 0.94]; infected abdominal collections, OR 0.80 [95% CI, 0.44–1.43, p = 0.80]; reoperation rates, OR 1.24 [95% CI, 0.73–2.13, p = 0.42]; duration of hospital stay, − 0.23 [95% CI − .59 to 1.13, p = 0.74]; and mortality, 1.78 [95% CI, 0.94–3.39, p = 0.08]. SA did not improve the post-operative outcomes following PD, including reducing the incidence of POPF. The routine administration of SA cannot be recommended following PD.

BackgroundAVT02 is an investigational biosimilar to adalimumab. It is approved in Europe, Canada, and the UK. It is not approved by the US Food and Drug Administration (FDA).ObjectivesTo evaluate the pharmacokinetic similarity of 100 mg/mL AVT02, an investigational biosimilar of adalimumab, when administered either via a pre-filled syringe, or with a newly developed autoinjector in healthy adult subjects.MethodsThis was a Phase 1, randomized, open-label, parallel-group study in which 207 healthy adult subjects were randomized in a 1:1 ratio to receive 100 mg/mL AVT02 either via a pre-filled syringe, or with an autoinjector, stratified by body weight. Subjects received a single subcutaneous 40 mg dose on Day 1. Pharmacokinetics, immunogenicity, local injection site reactions, and adverse events were assessed prior to, and up to 64 days after, study drug administration.ResultsThe results observed supported the assessment of pharmacokinetic similarity of investigational AVT02 administered by pre-filled syringe or with an autoinjector. The 90% CIs for the ratios of geometric least square means for the primary pharmacokinetic parameters Cmax, AUC0-t, and AUC0-∞ were contained within prespecified margins 80% and 125%, based on an analysis of variance model with treatment as a fixed effect. The mean serum concentration-time profile of adalimumab by treatment group is shown in Figure 1.Figure 1.Mean Serum Concentration-Time Profile of Adalimumab by Treatment Group on Semilogarithmic Scale (Pharmacokinetic Population)Binding anti-drug antibodies were detectable at the end of study visit on Day 64 in 100% and 97.0% of subjects in the pre-filled syringe administration and the autoinjector groups, respectively. Of those subjects positive for anti-drug antibodies, 85.7% and 86.5% further tested positive for neutralizing antibodies in the pre-filled syringe administration and autoinjector groups, respectively. The frequency of local administration site reactions was 11.8% overall and similar between treatment groups. The most frequently reported treatment-emergent adverse events in both treatment groups were under the SOC: Infections and infestations (56.0% in the AVT02-pre-filled syringe group and 45.2% in the AVT02-autoinjector group). The safety profiles were generally similar between treatment groups.ConclusionThe results observed supported the assessment of pharmacokinetic similarity between the pre-filled syringe and autoinjector delivery systems after a single subcutaneous 40 mg dose. The autoinjector delivery system was generally well tolerated in healthy subjects, with a safety and immunogenicity profile similar to that observed with 100 mg/mL AVT02 administered using a pre-filled syringe.ClinicalTrials.gov Identifier: NCT03983876Disclosure of InterestsChristopher Wynne: None declared, Heimo Stroissnig Employee of: Alvotech, Roshan Dias Employee of: Alvotech, Joanna Sobierska Employee of: Alvotech, Eric Guenzi Employee of: Alvotech, Hendrik Otto Employee of: Alvotech, Abid Sattar Employee of: Alvotech, Halimu N. Haliduola Employee of: Alvotech, Elin Edwald Employee of: Alvotech, Fausto Berti Employee of: Alvotech

BackgroundAVT02 is an investigational biosimilar to adalimumab. It is approved in Europe, Canada, and the UK. It is not approved by the US Food and Drug Administration (FDA).ObjectivesTo assess the real-life patient handling of an autoinjector (AI) in adult patients with moderate-to-severe active rheumatoid arthritis (RA) who self-inject AVT02 subcutaneously (s.c.).MethodsThis open-label study enrolled 107 adalimumab-naïve subjects with moderate-to-severe active RA to self-inject AVT02 with the proposed AI 40 mg s.c. in Week 1, and every other week thereafter through Week 8. In an optional extension phase through Week 56, subjects were switched from AVT02 AI to pre-filled syringe and followed for safety and efficacy. The primary endpoint was the percentage of successful self-injections as reported by both the trial site and by subjects using standardized questionnaires at Week 8. Additional endpoints included ease of use and robustness of the AI at Week 8, and efficacy in RA, assessment of serum trough levels of AVT02, and detection of antidrug antibodies (ADA) throughout the study.ResultsThe AI success rate was 100% as reported by both the trial site and by subjects. No handling events were noted through Week 8. Approximately 80% (78.1–84.9%) of subjects found the AI ‘very easy’ to use and, in general, less difficulty was reported as the study progressed. The first 110 AIs used were inspected for robustness and none showed any sign of damage or malfunction.All subjects who completed Week 8 (n = 106) took part in and completed the optional extension phase through Week 56.At Week 8, 49.1%, 5.7% and 0.9% subjects achieved ACR20, -50 and -70 responses, respectively. Improvement was also reported for the SDAI, DAS28 CRP and HAQ, with scores consistently decreasing through Week 8. In the extension phase, 70.8%, 47.2% and 13.2% subjects achieved ACR20, -50 and -70 responses at Week 56. Improvement was also reported for the SDAI, DAS28 CRP and HAQ, with scores consistently decreasing through Week 56.From Baseline through Week 8 the mean serum concentrations of investigational AVT02 increased consistently at each visit, reaching a peak at Week 24. There was no significant difference in serum concentrations of AVT02 based on injection subsite (abdomen or thigh).ADAs were detected in 65.1% of subjects through Week 8, reducing to 49.1% by Week 56. Of ADA-positive subjects, most were also positive for neutralizing antibodies through Week 8 (62.3%) increasing through Week 56 (90.4%). Subjects who were ADA-positive had lower serum concentrations of study drug compared with the overall population at Week 8 and Week 56 as expected.There were no clinically relevant safety or tolerability issues. Overall, treatment-emergent adverse events reported in at least 5% of subjects at the PT level were anaemia and influenza (6 subjects [5.6%)] reported 6 events each), and no local ISRs were reported.ConclusionThe fully successful self-injection with the AI in this study supported the use of the device while administering AVT02. Furthermore, subjects typically found the AI easy to use, with ease of use increasing as time progressed.The ACR20, -50, and -70, SDAI, DAS28 CRP and HAQ results supported the use of AVT02 to treat adult patients with moderate-to-severe RA, with the treatment effect persisting beyond Week 8 and through Week 56.The safety and immunogenicity profiles were as expected for adalimumab.ClinicalTrials.gov Identifier: NCT04224194Disclosure of InterestsNemanja Damjanov: None declared, Heimo Stroissnig Employee of: Alvotech, Matjaz Steiger Employee of: Alvotech, Joanna Sobierska Employee of: Alvotech, Eric Guenzi Employee of: Alvotech, Hendrik Otto Employee of: Alvotech, Abid Sattar Employee of: Alvotech, Halimu N. Haliduola Employee of: Alvotech, Elin Edwald Employee of: Alvotech, Fausto Berti Employee of: Alvotech

A total of 48 internal medicine or geriatric wards among the 93 adhering to the register REPOSI answered an online questionnaire aimed to investigate the characteristics and activities of converted and non-converted wards in the crucial period of the first wave of the epidemic, 22 February-4 May 2020

Made available in DSpace on 2020-12-10T17:35:31Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-07-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) The study evaluated the effect of gain rates during the growing phase and the possible interaction with finishing phase forage allowance in beef cattle. In Exp. 1, eighty Nellore cattle (386 +/- 7.90 kg; divided into 16 paddocks) were used in a randomized block design in a 2 x 2 factorial arrangement of treatments: (1) gain rate during the growing phase (low and high); (2) forage allowance during the finishing phase (low and high). In Exp. 2, twelve cannulated animals were used to evaluate ruminal parameters at the finishing phase. The animals were supplemented (2% of body weight [BW]) during 112 days. The average forage mass was 6507 and 2712 kg DM/ha, resulting in a forage allowance of 2.91 and 1.31 kg DM/kg BW, respectively, for high and low supply. In Exp. 1, there was interaction among factors (P = 0.01) for average daily gain (ADG): low gain rate animals that were finished on high forage allowance had an ADG 0.203 kg/day greater than average of other treatments (0.917 kg/day). Animals with a high gain rate in the growing phase started the finishing phase 51.5 kg heavier than low gain rate animals; this difference dropped to 35.5 kg in final BW (P < 0.01). In terms of the carcass, this difference was 27 kg at the beginning and dropped to 25 kg at the final carcass weight (P < 0.01). In Exp. 2, the acetate concentration at the end was higher for animals fed high forage allowance compared to low. However, propionate concentration was higher for animals fed low forage allowance compared to high (P = 0.01). Our results showed that the growing phase influences performance during the finishing phase; however, forage allowance with high supplementation at the finishing phase had negligible effects under these experimental conditions. Univ Estadual Paulista, Fac Ciencias Agr & Vet, Via Acesso, BR-14884900 Jaboticabal, SP, Brazil Agencia Paulista Tecnol Agronegocios APTA, Ave Rui Barbosa,Caixa Postal 35, BR-14770000 Colina, SP, Brazil Ctr Univ Fundacao Educ Barretos, Prof Roberto Frade Monte 389, BR-14783226 Barretos, SP, Brazil Univ Estadual Paulista, Fac Ciencias Agr & Vet, Via Acesso, BR-14884900 Jaboticabal, SP, Brazil FAPESP: 2017/50339-5 FAPESP: 2018/20176-0 FAPESP: 2014/05510-0

Anaplastic Astrocytoma(AA) is a malignant, diffusely infiltrating, primary brain tumor. According to the WHO 2016 classification of central-nervous-system tumors, AA has been described as a glial tumor with no co-deletion of 1p/19q, and is divided into IDH mutated tumor, characterized by better prognosis, and IDH wild-type form, with worse prognosis. The standard of care is maximal safe resection followed by radiotherapy and chemotherapy with temozolomide. Several efforts have been made to evaluate, according to molecular selection, which is the best post-surgical treatment. At recurrence, the treatment remains challenging and some trials are ongoing to evaluate new potential drugs, alone or in combination with chemotherapy. We performed a description of the status of the art on diagnosis, molecular characteristics and treatment of AA. In particular, we focused our details on new drugs; indeed, a deeper knowledge of the molecular characteristics of gliomas could lead to to development of active personalized treatments according with precision medicine.

BACKGROUND: GC is defined as a rare pattern of growth of gliomas, involving three or more cerebral lobes. Considering its rarity, it’s still difficult to define prognostic factors and standard of treatment. Retrospectively, we analyzed patients (PT) with GC from two neuro-oncology centers to identify main prognostic factors and the optimal management. MATERIAL AND METHODS: Medical records of patients ≥ 18years, with histological and/or radiological diagnosis of GC occurred between 2006 and 2017 were reviewed. Median progression free survival (PFS) and overall survival (OS) were calculated by Kaplan-Meier method. RESULTS: We analyzed 33PT, 22males and 11female; ECOG performance status (PS) was 0–1 in 21PT and ≥ 2 in 12PT. 22PT underwent biopsy: 16 were astrocytomas, 6oligodendrogliomas. MGMT was detected in 14PT: it was metilated in 8cases. IDH1 was analyzed in 16PT: it was mutated in 10PT. 15 of 33PT showed localized enhancing lesions at diagnosis. 9PT(27%) were treated with radiation therapy (RT) plus concurrent temozolomide (TMZ), 22PT(67%) received only TMZ, and 2PT(6%) underwent RT alone. Best response was complete response (CR) in 3PT(3%), partial response (PR) in 9PT(27%) and stable desease (SD) for 15PT(45%); only 8PT(25%) had a progression desease (PD). For all PT, PFS and OS were 19.1 and 30.7 months (ms) respectively. For PS 0–1 and ≥2, PFS was 34.6 vs 3.4ms (p

The aim of this trial was to evaluate the effect of encapsulated calcium ammonium nitrate as a partial substitute for soybean meals in the concentrate dry matter intake, average daily gain and feed efficiency of Nellore young bulls under grazing conditions, during the dry season. Sixty-four weaned Nellore (initial BW = 177.46±3.77 kg and 9 mo old) were used in a completely randomized assay. The study lasted 84 days on the dry season. Animals were allotted into 16 paddocks of 1.0 ha each of Urochloa brizantha, randomly assigned into one of two treatments: (CTL) supplement with 25% CP, without nitrate inclusion and; (ENP): supplement with 25% CP, with a inclusion of 50 g of encapsulated calcium ammonium nitrate to each 100 kg of body weight. Animals were fed with concentrate at 1.0% of body weight. Concentrate offered was monitored daily as well as his refusals were collected and weighed to determine daily concentrate dry matter intake (DMI) and feed efficiency (F:G). Animals were weighed every 28 d for calculating average daily gain (ADG). Data were analyzed as a completely randomized design, using ANOVA (α = 0.05). No effects of treatments (P > 0.3487) were observed for final BW (246.69 kg). The same for concentrate dry matter intake (P > 0.0550). Animals consumed 2.34 kg of supplement per day. The average daily gain (0.832 kg, P > 0.2649) and feed efficiency (0.356 kg, P > 0.7315) were not affected by the inclusion of nitrate. The inclusion of encapsulated calcium ammonium nitrate in supplement to Nellore young bulls under grazing conditions during the growing phase did not affect the performance.

Glioblastoma is the most common and aggressive primitive brain tumor in adults. Temozolomide (TMZ) administered daily with radiation therapy, followed by adjuvant TMZ has become the standard treatment. Although TMZ treatment has been considered to have a low toxicity profile, studies have noted the development of a severe myelosuppression, especially during the concomitant treatment; this toxicity may in some cases be prolonged and consequently treatment must be definitively discontinued. We analyzed two cases treated at our oncological center who developed severe and prolonged hematological toxicity during concomitant chemoradiotherapy treatment with TMZ. Hypothesizing that radiation therapy and daily TMZ could be the major causes of severe hematological toxicity during the concomitant phase, we decided to treat both patients with maintenance TMZ at the time of recovery of hematological values. Patients showed good tolerability without important myelosuppression. In conclusion, we suggest that glioblastoma patients with severe myelotoxicity during daily TMZ and radiation therapy be treated with maintenance TMZ at the time of blood value recovery.

Glycoconjugate vaccines play an enormous role in preventing infectious diseases. The main carrier proteins used in commercial conjugate vaccines are the non-toxic mutant of diphtheria toxin (CRM197), diphtheria toxoid (DT) and tetanus toxoid (TT). Modern childhood routine vaccination schedules include the administration of several vaccines simultaneously or in close sequence, increasing the concern that the repeated exposure to conjugates based on these carrier proteins might interfere with the anti-polysaccharide response. Extending previous observations we show here that priming mice with CRM197 or DT does not suppress the response to the carbohydrate moiety of CRM197 meningococcal serogroup A (MenA) conjugates, while priming with DT can suppress the response to DT-MenA conjugates. To explain these findings we made use of biophysical and immunochemical techniques applied mainly to MenA conjugates. Differential scanning calorimetry and circular dichroism data revealed that the CRM197 structure was altered by the chemical conjugation, while DT and the formaldehyde-treated form of CRM197 were less impacted, depending on the degree of glycosylation. Investigating the binding and avidity properties of IgGs induced in mice by non-conjugated carriers, we found that CRM197 induced low levels of anti-carrier antibodies, with decreased avidity for its MenA conjugates and poor binding to DT and respective MenA conjugates. In contrast, DT induced high antibody titers able to bind with comparable avidity both the protein and its conjugates but showing very low avidity for CRM197 and related conjugates. The low intrinsic immunogenicity of CRM197 as compared to DT, the structural modifications induced by glycoconjugation and detoxification processes, resulting in conformational changes in CRM197 and DT epitopes with consequent alteration of the antibody recognition and avidity, might explain the different behavior of CRM197 and DT in a carrier priming context.

The objective was to evaluate the effects of Bacillus toyonensis on performance, carcass traits and its influence on ruminal and intestinal mucosa development of Nellore bulls fed tropical grass pasture on dry season supplemented with concentrate at 2.0% BW for 133 d. Four animals were slaughtered at the beginning of the experiment so that the initial carcass yield could be estimated. Eighty Nellore bulls (initial BW 354.02 ± 3.38 kg) were blocked according to body weight and assigned to one of two treatments: concentrate with Bacillus toyonensis (animals fed 1.6 x 109 UFC/day) or without (control group). Then, the remaining animals were allocated in 16 paddocks of Urochloa brizantha with 1.0 ha each (eight paddocks/treatment and five animals/paddock). At the end of the trial, bulls were slaughtered and carcass traits such as HCW, dressing percentage, 12th-rib fat thickness, carcass gain and carcass ADG were obtained. Tissue from the ventral sac and jejunum were collected and fixed in buffered formalin for evaluation of rumen papillae and intestine villi morphology. Data were analyzed using the GLM procedure of SAS. Paddock was the experimental unit for all analyses. Results indicated there were no significant difference (P > 0.05) between treatments for final BW (528.2 kg), ADG (1.333 kg) and G:F (0.165). No significant differences were detected between treatments for HCW (299.8 kg), dressing percentage (56.82%), and carcass ADG (0.885 kg). Conversely, control group showed a significant (P < 0.025) higher 12th-rib fat thickness (4.06 vs 2.97 mm). No significant effect on the development of the ruminal and intestinal epithelium was observed with the use of probiotic. Probiotic based on Bacillus toyonensis did not improve growth performance and carcass characteristics on finishing Nellore bulls fed tropical grass pasture on dry season.

Purpose To evaluate the effects of kinesiophobia on both phases immediately after surgery and the final results after total knee arthroplasty (TKA). Methods This study evaluated prospectively 101 patients (mean age 66 ± 8.0 years, 70 women and 31 men), 5 days after surgery, at 1, 6, 12 months, and at a mean final follow-up of 3.2 ± 0.7 years (2.0–4.2 years). Kinesiophobia was assessed with the Tampa Scale for Kinesiophobia (TSK: Activity Avoidance—TSK1 and Harm—TSK2 subscales), and results were evaluated with range of motion, pain and function on 0–10 numeric rating scales, WOMAC and SF-12 (Physical and Mental subscales) scores. Results TSK1 was correlated with the acute postoperative pain measured at 5 days (p = 0.031), pain measured at 12 months (p = 0.018), patient perceived function at 12 months (p = 0.025), SF-12P at 6 months (p < 0.001), SF-12P and SF-12M at 12 months (p = 0.001 and p = 0.005, respectively), and WOMAC at both 6 and 12 months of follow-up (p = 0.005 and p = 0.001). The effect of TSK 1 on the final WOMAC score was significant when corrected by age and sex (p = 0.049, η 2 = 0.041): the youngest female patients were affected even by moderate kinesiophobia levels. Conclusions Fear of pain and even more avoidance of movement are strongly correlated both with the acute postoperative pain perception and recovery after surgery up to 1 year, thus presenting a relevant clinical impact on the outcome after TKA. Moreover, this study showed that even though at longer follow-up its impact decreases, patients with higher levels of kinesiophobia may present a poorer final outcome, especially women. Level of evidence IV.

Brain metastases are a serious relatively common complication of breast cancer. We evaluated prognostic factors for survival after diagnosis of brain metastases from breast cancer in a contemporary cohort of patients. Patients diagnosed with breast cancer brain metastases at our institution between 1999 and March 2016 were evaluated. Overall survival was defined as time from brain metastasis diagnosis to death or last follow-up. Patients were classified according to the Breast cancer-specific Graded Prognostic Assessment (BS-GPA), based on age, Karnofsky performance score and breast cancer phenotype. 181 patients were identified. Tumor phenotype distribution was as follows: triple negative (TN, 18.8%), hormone receptor (HR)−HER2+ (16.6%), HR+HER2+ (23.2%) and HR+HER2− (30.9%), not available (10.5%). Median overall survival from brain metastasis diagnosis was 7.7 mos (95% CI 5.4–10.0 mos). Although TN patients experienced the worse outcome, no significant difference was observed across tumor phenotypes (median 5.1, 7.7, 11.0 and 8.6 months in TN, HR−HER2+, HR+HER2+, HR+HER2−, p = 0.081). The BS-GPA index was significantly associated with overall survival (median 18.8, 8.8, 6.2 and 3.6 months, respectively, for BS-GPA categories 3.5–4, 2.5–3, 1.5–2 and 0–1, p = 0.014). Increased number of local treatments for brain metastasis (radiotherapy or neurosurgery) or the administration of systemic therapy after brain metastasis diagnosis were also significant predictors of better overall survival (p

The purpose of the study was to evaluate the clinical outcome of the association of BCNU wafers implantation and 5-aminolevulinic acid (5-ALA) fluorescence in the treatment of patients with newly diagnosed glioblastoma (ndGBM). Clinical and surgical data from patients who underwent 5-ALA surgery followed by BCNU wafers implantation were retrospectively evaluated (20 patients, Group I) and compared with data of patients undergoing surgery with BCNU wafers alone (42 patients, Group II) and 5-ALA alone (59 patients, Group III). Patients undergoing 5-ALA assisted resection followed by BCNU wafers implantation (Group I) resulted long survivors (>3 years) in 15 % of cases and showed a median PFS and MS of 11 and 22 months, respectively. Patients treated with BCNU wafers presented a significantly higher survival when tumor was removed with the assistance of 5-ALA (22 months with vs 18 months without 5-ALA, p

Patient engagement in a patient–physician decision-making process has been correlated with satisfaction and clinical outcomes. Aim of this study is to evaluate if patient control preference may also influence TKA results. One hundred and seventy-six patients (120w–56m, age 66 ± 9 years, BMI 28 ± 4) underwent TKA and were prospectively evaluated, before surgery and at 6 and 12 months. The preoperative assessment included the Control Preference Scale (CPS) and other scales measuring psychological aspects (STAI, BDI, TSK), as well as SF12 (physical and mental subscales) and the assessment of pain and function. Pain, function, and SF12 subscales were then used to evaluate the improvement at 6- and 12-month follow-up. Pain, function, and SF12 scores improved at 6 and 12 months. CPS correlated with the outcome: pain and functional improvement at 6 months (p = 0.014; p = 0.003, respectively), patient function at 6 months (p = 0.022), improvement of SF12 physical subscale at 6 and 12 months (p = 0.027; p = 0.037, respectively), and satisfaction at 6 months (p = 0.033). Moreover, the multivariate analysis confirmed the importance of CPS regardless of other demographic, physical or psychological characteristics. In contrast with previous literature findings, this study shows that patients with more propensity for control presented lower improvements of pain and function than those more prone to rely on the physician making the decision. Physicians should be aware that the patient control preference may influence the treatment outcome and undertake measurements to optimize patient participation in the shared process to optimize the chances of TKA success. IV.

A 72-year-old woman who developed a left temporal protrusion was referred to our center. An MRI showed a heterogeneous mass in the left temple with T2 signal hyperintensity within the intradiploic space of the greater wing of the sphenoid bone, measuring 2.4 x 2.1 cm. The patient underwent a surgical removal of the mass through the pterional approach. Pathology showed an epidermoid cyst. Intradiploic epidermoid cysts of the skull are rare benign tumors of the skull. These lesions grow slowly and are composed of epidermoid cells debris rich in cholesterol. The prophylactic removal of these tumors with the goal of preventing recurrences is recommended.

Medulloblastoma in adulthood is uncommon but not rare; annual incidence is 2-20/1,000,000. Some peculiarities characterize medulloblastoma in adult patients compared with the child type: lateral cerebellar location, heterogeneous signal intensity on magnetic resonance imaging, desmoplastic histological variant, and more favourable prognosis. Preoperative diagnosis is crucial for correct management of these patients. However, because of the low incidence of medulloblastoma in the adult population, preoperative diagnosis remains challenging and prognostic factors and best treatment options are still controversial. In this setting, some unusual findings, for example multifocal presentation and extra-axial location, can confound diagnosis and make treatment difficult. We present a short case-illustrated review on these remarkable issues.

Prevalence of symptomatic central nervous system (CNS) metastases among patients with breast cancer ranges from 5% to 16%, although autoptic studies have reported prevalence rates of up to 30%. Solid brain tumours are the most common presentation in the CNS (85-95%), and they tend to arise at the grey-white matter junction with a distribution that is proportional to the regional cerebral blood flow. Descriptions of solitary intra-ventricular metastasis are very rare; to date no cases from breast cancer have been reported in the literature. We present the unusual case of a breast cancer patient who developed a solitary choroid plexus metastasis in the left lateral ventricle.

PURPOSE A morphofunctional approach to the management of brain tumours has been claimed to increase diagnostic accuracy. Among the proposed single-photon emission tomography (SPET) tracers, (99m)Tc-sestamibi is able to distinguish recurrent tumour from radio-necrosis and to identify early response or resistance to chemotherapy. Major drawbacks of sestamibi, that is, poor morphological resolution and the sites of physiological uptake, could be overcome by dual-modality, integrated systems. The purpose of this study was to investigate the real usefulness of (99m)Tc-sestamibi SPET/computed tomography (CT) and to establish a semiquantitative index. METHODS Charts from 33 consecutive patients selected for surgery, who underwent preoperative SPET/CT and magnetic resonance imaging (MRI), were reviewed. Tumours were confirmed histologically after the surgery in all patients and classified according to WHO recommendations. Semiquantitative indexes were obtained on images (maximum likelihood expectation maximization reconstructed) with and without attenuation correction and visual analysis of SPET versus SPET/CT was performed. RESULTS A significant statistical difference was shown between SPET and SPET/CT in terms of the delineation of medial shift, oedema and the ability to distinguish tumour from the skull-meninges complex and plexus. With regard to semiquantitative indexes, a ratio obtained comparing counts/pixel derived from a region of interest in the tumour area with mirrored region of interest in the contralateral site revealed a sensitivity of 90.9% and specificity of 71.45% in discriminating WHO grade 4 gliomas from a lower grade. CONCLUSION SPET/CT can distinguish tumour from the skull and other sites of physiological uptake better than SPET alone (as confirmed by MRI in all cases) and affords a morphological map. The proposed semiquantitative index also seems promising in identifying higher-grade disease. SPET/CT thus seems a useful additional tool in brain tumour management, especially when MRI is not feasible or PET/CT is not available.

The increase in soybean productivity has contributed to a greater use of agrochemicals, which cause major problems, such as soil and water pollution and reduction of biodiversity, and have a negative impact on non-target species. The development of microbial biocontrol agents for soybean diseases can help to reduce pesticide abuse. Bacillus amyloliquefaciens BNM122 is a potential microbial biocontrol agent able to control the damping-off caused by Rhizoctonia solani when inoculated in soybean seeds, both in a plant growth chamber and in a greenhouse. In this study, we report the effect of soybean seed treatments with strain BNM122 or with two fungicides (thiram and carbendazim) on the structure and function of the bacterial community that colonizes the soybean rhizosphere. Also, soybean root nodulation by Bradyrhizobium japonicum , mycorrhization by arbuscular mycorrhizal fungi and plant growth were evaluated. We used the r - and K -strategist concept to evaluate the ecophysiological structure of the culturable bacterial community, community-level physiological profiles (CLPP) in Biolog™ EcoPlates to study bacterial functionality, and the patterns of 16S RNA genes amplified by PCR and separated by denaturing gradient gel electrophoresis (PCR–DGGE) to assess the genetic structure of the bacterial community. Neither the ecophysiological structure nor the physiological profiles of the soybean rhizosphere bacterial community showed important changes after seed inoculation with strain BNM122. On the contrary, seed treatment with fungicides increased the proportions of r -strategists and altered the metabolic profiles of the rhizosphere culturable bacterial community. The genetic structure of the rhizosphere bacterial community did not show perceptible changes between treated and non-treated seeds. Regarding the bacterial and fungal symbioses, seed treatments did not affect soybean nodulation, whereas soybean mycorrhization significantly decreased ( P It can be concluded that soybean seed treatment with B. amyloliquefaciens BNM122 had a lesser effect on soil microbial community than that with the fungicides, and that these differences may be attributed to the less environmental persistence and toxic effects of the strain, which deserve further studies in order to develop commercial formulations.

We present the case of a 57 year-old-right handed man with a history of alopecia presented with a visual loss, and an acute stroke of the left anterior cerebral artery and middle cerebral after scalp injection of platelet rich plasma (PRP) and stem cells for hair restoration.

The efficacy of temozolomide (TMZ) plus radiation therapy (RT) in elderly patients with glioblastoma is unclear. We performed a large multicenter retrospective study to analyze prognostic factors and clinical outcome in these patients. Inclusion criteria were age ≥65 years, newly histologically confirmed glioblastoma, ECOG PS 0-2, adjuvant treatment with RT plus TMZ. We enrolled 237 patients; the average age was 71 and ECOG PS was 0-1 in 196 patients; gross total resection was performed in 174 cases. MGMT was analyzed in 151 persons and was methylated in 56 %. IDH1 was assessed in 100 patients and was mutated in 6 %. Seventy-one patients were treated with RT 40 Gy and 166 with RT 60 Gy. Progression-free survival and overall survival (OS) were 11.3 and 17.3 months, respectively. Overall survival was 19.4 vs 13.8 months for patients treated with RT 60 Gy and 40 Gy (p = 0.02); OS was 17.7 versus 16.1 months for patients treated with gross total resection vs partial surgery (p = 0.02); OS was 21.2 versus 13.6 months for methylated and unmethylated MGMT (p < 0.001). On multivariate analysis, gross total resection, RT 60 Gy, methylated MGMT and ECOG PS 0-1 were independent predictors of longer survival. Twenty-five patients (10 %) had grade 3-4 haematological toxicity during the concomitant treatment. We showed that, in elderly patients in good clinical condition treated with concomitant treatment, standard-course irradiation might be more effective than short-course irradiation. Methylated MGMT remains the most important prognostic factor.

Background Temozolomide (TMZ) administered daily with radiation therapy (RT) for 6 weeks, followed by adjuvant TMZ for 6 cycles, is the standard therapy for newly diagnosed glioblastoma (GBM) patients. Although TMZ is considered to be a safe drug, it has been demonstrated to cause severe myelotoxicity; in particular, some case reports and small series studies have reported severe myelotoxicity developing during TMZ and concomitant RT. We performed a prospective study to analyze the incidence of early severe myelotoxicity and its possible clinical and genetic factors. Patients and methods From November 2010 to July 2012, newly diagnosed GBM patients were enrolled. They were eligible for the study if they met the following criteria: pathologically proven GBM, age 18 years and older, an Eastern Cooperative Oncology Group performance status of 0 to 2, adequate renal and hepatic function, and adequate blood cell counts before starting TMZ plus RT. Grading of hematologic toxicity developing during radiation and TMZ was based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Clinical factors from all patients were recorded. The methylation status and polymorphic variants of O-methylguanine-DNAmethyl-transferase gene in peripheral blood mononuclear cells, and polymorphic genetic variants of genes involved in the pharmacokinetics and pharmacodynamics of TMZ, were analyzed. For genetic analyses, patients with toxicity were matched (1:2) for age, performance status, anticonvulsants, and proton pump inhibitors with patients without myelotoxicity. Results We enrolled 87 consecutive GBM patients: 32 women and 55 men; the average age was 60 years. During TMZ and RT, 4 patients (5%) showed grade 3-4 myelotoxicity, and its median duration was 255 days. Predictor factors of severe myelotoxicity were female sex, pretreatment platelet count of ≤3,00,000/mm, methylated O-methylguanine-DNA methyltransferase promoter in the hematopoietic cell system, and specific polymorphic variants of the cytochrome P450 oxidoreductase and methionine adenosyltransferase 1A genes. Conclusions Although we studied a small population, we suggest that both clinical and genetic factors might simultaneously be associated with severe myelosuppression developed during TMZ plus RT. However, our results deserve validation in larger prospective studies and, if the factors associated with severe myelotoxicity are validated, dose adjustments of TMZ for those patients may reduce the risk of severe myelotoxicity during the concomitant treatment.

Background: various prospective clinical trials on high-grade gliomas were performed in the last years but patient (PTS) characteristics and outcome may be different in real clinical practice. We performed a retrospective analysis to evaluate the real-life experience in Padua Neuro-Oncology center. Matherials and Methods: retrospectively, we reviewed the medical records of PTS admitted to our observation from June 2010 to June 2015 with a diagnosis of AA or GBM. We analyzed clinical outcome with prognostic factors. Results: we analyzed 592 PTS with a diagnosis of CNS primary tumor. Among these, we enrolled 395 PTS: 33 (8.4%) with a histological diagnosis of AA, 293 (74%) with a histological diagnosis of GBM and 69 (17.4%) with a radiological diagnosis of GBM. At diagnosis, median age was 63.2 (range 24-88), 61.8% were male; 80% of PTS had an ECOG PS 0-2. Among PTS who underwent surgery, 48% had a radical surgery; 279 PTS (70.6%) performed RT in association to chemotherapy. 17% of PTS performed a second surgery at relapse and 45% a second-line treatment. MGMT was analyzed in all PTS who underwent surgery: it was methylated in 38.7% of PTS, IDH1 was mutated in 6%. GBM PTS with ECOG PS 0-2 and >2 had a median OS of 21.1 and 7.2 ms, respectively. GBM PTS with met and unmet MGMT had a mOS of 22.7 and 13.7 ms (p=0.005). AA PTS with met and unmet MGMT had a mOS of 29.5 and 16.6 ms (p=0.03). Considering all high-grade gliomas, PTS with met MGMT + mutIDH1 reported a mOS of 23.1ms, PTS with metMGMT + wtIDH1 had a mOS of 20.9 ms and PTS with unmetMGMT + wtIDH1 showed a mOS of 12.6ms (p

Background: MGMT gene promoter methylation status is acknowledged as a prognostic factor and predictive marker for temozolomide (TMZ) treatment. Although MGMT status determined by pyrosequencing was showed to correlate with progression free survival (PFS) and overall survival (OS), it is still unclear a cut-off value that discriminates between methylated and unmethylated patient (pts) and its correlation with the patient clinical outcome. Matherials and Methods: We analyzed the tissue samples from 128 PTS diagnosed with GBM from November 2009 to December 2015. All PTS underwent treatment with RT + TMZ and had an ECOG-PS 0-2. Methylation percentage for each sample was obtained by calculating the average methylation of all 10CpG sites (75-84) of MGMT promoter by pyrosequencing analysis. PTS with 0-6% of methylation were classified as unmethylated (UM), PTS with 7-24% as low methylated (LM) and PTS with ≥ 25% as high methylated (HM). 25% was the median value of methylation of our PTS having >6% of methylation. Results: Median age was 60 yrs (range 25-84), 60.9% were male, 74.2% had an ECOG PS 0-1, 50.8% underwent radical surgery, 85 PTS were dead at the time of analysis. 75 PTS were UM, 26 PTS were LM and 27 PTS were HM. On univariate analysis HM, LM and UM showed a PFS of 15.8, 10 and 9.1 ms, respectively (p=0.1). OS was 38.7, 21 and 18.8ms (p= 0.06). On multivariate analysis UM and LM PTS had a statistically lower PFS vs HM PTS (HR=2.57; p=0.001; HR= 2.5; p=0.007, respectively) and statistically lower OS (HR=3.47; p

Summary Background To investigate the efficacy of temozolomide in relation to response rate, toxicity, time to progression, and median survival time, a phase II study was conducted in patients with recurrent high-grade glioma following surgery plus radiotherapy and first-line chemotherapy based on nitrosourea, procarbazine and vincristine. Patients and methods Forty-one patients with high-grade glioma, at second recurrence or progression, of which twenty-two (54%) had glioblastoma multiforme, ten (24%) anaplastic astrocytoma, and nine (22%) anaplastic oligodendroglioma were administered temozolomide, 150 mg/m2/daily for five days every four weeks. Results Response was assessed in 40 patients. The overall response rate (complete + partial response) was 22.5% (95% confidence interval (CI): 9.5%–35%). The median time to progression for all 41 patients was 22.3 weeks; progression-free survival at 6 and 12 months was 48.5% and 34.7%, respectively. Median survival time was 37.1 weeks with 80.2% at 6 and 34.9% survival at 12 months. Conclusions On multivariate analysis, response to previous treatment was significant (P = 0.03) for time to progression and Karnofsky performance score for overall survivall (P = 0.002). Temozolomide gave a moderate response rate with acceptable toxicity as second-line chemotherapy in patients with recurrent high-grade glioma.

OBJECTIVE: IGF-I possesses specific myocardial receptors and is able to promote cardiac remodelling and even inotropic effects in both humans and other animals. In fact, reduced cardiac mass and performance are present in GH deficiency and these alterations are counteracted by recombinant human (rh) GH replacement, restoring IGF-I levels. Recently, the acute administration of 60 microg/kg rhIGF-I has also been reported to be able to improve cardiac performance evaluated by echocardiography or impedance cardiography in normal subjects. The aim of our study was to verify the effects of a subcutaneous low dose of rhIGF-I (20 microg/kg) on cardiac performance in humans. METHODS: In six healthy male adults (mean+/-S. e.m.: 35.7+/-4.3 years of age), the effects of rhIGF-I on left ventricular function evaluated by radionuclide angiocardiography and on circulating IGF-I, GH, insulin, glucose and catecholamines levels were studied. RESULTS: Administration of rhIGF-I increased circulating IGF-I (peak at +150 min vs baseline: 330.2+/- 9.6 vs 199. 7+/-8.7 microg/l, P

The anthocyanin cyanidin 3-O--glucopyranoside (Cy-g) is reported to be one of the most effective antioxidants, but little is currently known regarding its potential chemopreventive properties. In this study, we evaluated the ability of Cy-g to protect cultured human lymphocytes from micronucleus (MN) induction by four different mutagens: ethyl methanesulfonate (EMS), colchicine (COL), H2O2, and mitomycin C (MMC). To gain insight into the mechanisms of action of Cy-g, the cultures were treated with the compound before, during, and after treatment with the mutagens; in addition, the cultures were evaluated for the induction of apoptosis. When used by itself, up to 100 g/ml of Cy-g was nongenotoxic, while 100 g/ml Cy-g reduced the replicative index of the cells by nearly 50%. In addition, Cy-g was able to reduce the frequency of micronuclei induced by EMS, COL, and H2O2 using all three treatment protocols, but it had no significant effect on MN induction by MMC in any of the protocols. Apoptosis was produced in the cultures treated with Cy-g alone and was increased under conditions in which Cy-g produced anti-genotoxic effects, suggesting that Cy-g mediated-apoptosis may remove highly damaged cells. However, increases in apoptosis were found under conditions in which Cy-g was not significantly anti-genotoxic, indicating that the increases in apoptosis were not sufficient to account for the anti-genotoxicity of Cy-g. Taken together, our findings indicate that Cy-g possesses anti-genotoxic activity in vitro, which suggests its potential use as a chemopreventive agent.

Natural fibers have attracted much attention due to their applications as reinforcements in thermoplastic and biodegradable polymers, and improvements in the mechanical and barrier properties of the biofilms. In literature it is reported that the addition of cellulose fibers considerably increased the tensile strength and Young modulus of the films, and reduced their elongation capacity. Nanofibers may have properties similar to traditional fibers. In this context, the objective of this study was to incorporate bacterial cellulose nanofibers in starch acetate films and characterize those films by mechanical and barrier properties. The films were obtained from suspensions prepared with 3 g of starch acetate (produced in laboratory), 100 g distilled water, glycerol (0.30 g.g-1 starch acetate), guar gum (0.06 g.g-1 starch acetate) and bacterial cellulose fibers (0.025, 0.075 e 0.125 g.g-1 starch acetate), dispersed in a mechanical shaker, heated to 85°C and stirred for 30 min to dissolve the starch acetate. While still heated, the suspensions were spread on acrylic plates and dried at 35 °C for 7 h in a forced air circulation oven until the moisture equilibrium was reached (11. 5 ± 0.8 %) ("casting" method). After drying, samples were cut from the films and conditioned at 58 %, for 4 d, before testing. Starch acetate films were used as control. The results of tensile trials showed that the acetylated films with addition of bacterial cellulose increased 2, 3 and 7 times the values of stress at break and 2, 3 and 11 times, approximately, the values of Young modulus when comparing to the results of the control films. These results indicated that the addition of nanofibers is an alternative to improve the mechanical resistance of the films. The reductions in the values of hygroscopicity were small.

Vitiligo represents a selective destruction of the melanocytes. It is a relatively common, probably autoimmune disorder that affects people of all backgrounds and both genders. No particular group seems to be preferentially affected. Half of vitiligo patients have an onset before the age of 18 years. In regions where leprosy is endemic, individuals with vitiligo are often stigmatized due to similarities in appearance between the two diseases. We will review this important subject, emphasizing the latest therapeutic advances.

High-grade gliomas (HGG) are aggressive and highly vascularized brain tumours. Despite multimodality therapy including surgery, radiation therapy and in many cases temozolomide chemotherapy, the prognosis is dismal. Salvage therapies following progression after radiation therapy and chemotherapy have historically yielded disappointing results. Bevacizumab is an interesting antiangiogenic drug used as a second-line treatment but although most patients benefit, essentially all patients ultimately progress. Moreover, some clinical studies have documented low activity of a second attempt at vascular endothelial growth factor pathway inhibition after failure of a first. The use of another drug with a different angiogenic pathway inhibition may probably result in a higher activity. Here, we describe, to our knowledge for the first time, the activity and safety of cilengitide, an agent with a different antiangiogenic and anti-invasive activity, administered in two bevacizumab-refractory patients with HGG. In addition, we present a rapid review of the activity of cilengitide in HGG.

Intestinal-type adenocarcinoma of the nasal cavities and paranasal sinuses is a relatively rare tumor. Standard therapeutic modalities include surgery followed by radiotherapy, sometimes with chemotherapy treatment. Despite these treatments, the outcome is poor due to frequent local recurrences constituting the main cause of death among patients; leptomeningeal carcinomatosis is not a frequent event, and its presence indicates short expected survival. The therapy of neoplastic meningitis includes cranial irradiation, intrathecal chemotherapy and high-dose systemic chemotherapy. However, these approaches report important side effects with only modest efficacy. Thus, it is important to discover better treatment for this cancer complication. We present, for the first time, a case of leptomeningeal carcinomatosis from invasive intestinal-type adenocarcinoma treated with temozolomide and cisplatin chemotherapy obtaining a prolonged reduction and stabilization of the lesion improving the clinical condition of the patient.

Summary The present work reports the synthesis of a series of compounds structurally related to the antiinflammatory and antihistaminic agent nimesulide (I), in which the p-nitrophenyl moiety has been replaced by pyridine (1a-c) and pyridine N-oxide (2a-c). In addition, two compounds (3a, 4a) have been synthesized in which the p-nitro group of I was substituted by a cyano and a iH-tetrazol-5-yl group, respectively. Representative 1a and 2a were also modified by replacing the methanesulfonamido group with an acetamido group (5a, 6a). The pharmacological evaluation of compounds 1-6 in comparison to I, indicates that such modifications are detrimental to the activity. Moreover 3a and 4a caused bronchoconstriction and hypotension, thus behaving as histaminic-like rather then antihistaminic agents.

OBJECTIVE: To investigate the pattern of care and outcomes for newly diagnosed glioblastoma in Italy and compare our results with the previous Italian Patterns of Care study to determine whether significant changes occurred in clinical practice during the past 10 years. METHODS: Clinical, pathological, therapeutic, and survival data regarding 1059 patients treated in 18 radiotherapy centers between 2002 and 2007 were collected and retrospectively reviewed. RESULTS:Most patients underwent both computed tomography and magnetic resonance imaging either preoperatively (62.7%) or postoperatively (35.5%). Only 123 patients (11.6%) underwent a biopsy. Radiochemotherapy with temozolomide was the most frequent adjuvant treatment (70.7%). Most patients (88.2%) received 3-dimensional conformal radiotherapy. Median survival was 9.5 months. Two- and 5-year survival rates were 24.8% and 3.9%, respectively. Multivariate analysis showed the statistical significance of age, postoperative Karnofsky Performance Status scale score, surgical extent, use of 3-dimensional conformal radiotherapy, and use of chemotherapy. Use of a more aggressive approach was associated with longer survival in elderly patients. Comparing our results with those of the subgroup of patients included in our previous study who were treated between 1997 and 2001, relevant differences were found: more frequent use of magnetic resonance imaging, surgical removal more common than biopsy, and widespread use of 3-dimensional conformal radiotherapy + temozolomide. Furthermore, a significant improvement in terms of survival was noted (P < .001). CONCLUSION: Changes in the care of glioblastoma over the past few years are documented. Prognosis of glioblastoma patients has slightly but significantly improved with a small but noteworthy number of relatively long-term survivors.

Psoas abscess following spine surgery is a rare condition that can be overlooked or delayed as a result of its vague clinical manifestations. Gone unchecked, it can lead to severe morbidity and even death. We present a 71-year-old female patient who developed bilateral psoas abscess immediately following L2 through S1 posterior instrumented fusion. The patient underwent CT-guided percutaneous drainage of the bilateral psoas abscess and blood cultures revealed methicillin-resistant Staphylococcus aureus (MRSA) sensitive to vancomycin. Following surgical re-exploration, debridement and removal of part of the instrumentation, the patient received antibiotic treatment for 12 weeks and at 1-year follow-up the patient continues asymptomatic.

In three general medical settings (general practice, hospital medical wards and emergency rooms) about 20% of the adult attenders had a DSM-III mental disorder, mainly in the area of affective and anxious disorders. Some of these disorders were quite severe. Of those cases reassessed 1 year and 2 years after the first interview, less than a quarter reached a "no-diagnosis status". The chronicity of most cases dependent on the interplay not only of either relapse or duration of the main disorder but also of comorbidity and incidence of new disorders. A high incidence of more transient disorders in subjects who were well at first assessment was also found.

Hydrogen sulphide (H(2)S) is an endogenous gaseous mediator active in the multilevel regulation of pathophysiological functions in mammalian cardiovascular tissues.This study investigated the pharmacological activity of a new H(2)S-releasing derivative of diclofenac, S-diclofenac (2-[(2,6-dichlorophenyl)amino]benzeneacetic acid 4-(3H-1,2-dithiole-3-thione-5-yl)-phenyl ester) in the isolated rabbit heart submitted to low-flow ischaemia-reperfusion damage.S-diclofenac (3, 10 and 30 microM), despite inhibiting prostacyclin generation by cardiac tissues, achieved dose-dependent normalization of coronary perfusion pressure, reducing left ventricular contracture during ischaemia and improving left ventricular developed pressure and +/-dP/dt(max) at reperfusion. Creatine kinase and lactate dehydrogenase activities in heart perfusates were significantly reduced during reperfusion. These effects were accompanied by substantial release of reduced glutathione (GSH), indicating that the H(2)S moiety may have up-regulated cysteine transport. The anti-ischaemic activities of S-diclofenac and the H(2)S-donor sodium hydro sulphide (NaHS) were partially prevented by the K(ATP) channel antagonist glibenclamide, suggesting a mechanism similar to H(2)S-induced cardioprotection in metabolic ischaemic preconditioning. Perfusion with the nitric oxide (NO) synthase inhibitor N(G)-monomethyl-L-arginine worsened the myocardial ischaemia-reperfusion damage, but this was dose-dependently prevented by S-diclofenac and NaHS, suggesting that the released H(2)S may have overcome NO deficiency.These data show that S-diclofenac had marked anti-ischaemic activity in ischaemic-reperfused rabbit hearts despite inhibition of prostaglandin generation. Increased GSH formation leading to activation of K(ATP) channels may have contributed to this beneficial effect. The pharmacological profile of S-diclofenac and its anti-inflammatory activity, with diminished gastrointestinal side effects, offer therapeutic applications in cardiovascular disease.

Phosphodiesterase-5 inhibitors are beneficial in pulmonary hypertension and congestive heart failure, the two conditions associated with coronary heart disease and ischaemia. We investigated whether sildenafil counteracts the cardiovascular alterations induced by N -nitro-L-arginine methyl ester (L-NAME) in the rat.Sildenafil was given orally to rats at doses of 0.37, 0.75 or 1.5 mg kg-1day-1 for four weeks, either alone or with L-NAME (35-40 mg kg-1 day-1 in the drinking water). Systolic blood pressure and urinary parameters (6-keto-prostaglandin F1alpha, thromboxane B2, 8-isoprostane-prostaglandin F2 and nitrite/nitrate) were measured in conscious rats. Isolated hearts were subjected to low flow ischaemia-reperfusion, and myocardial levels of guanosine 3', 5'cyclic monophosphate (cGMP) were determined. Endothelial vascular dysfunction was examined in aortic rings.Sildenafil dose-dependently prevented the rise in systolic blood pressure in L-NAME-treated rats. This activity was associated with a normalization of urinary 8-isoprostane-prostaglandin F2alpha and other biochemical parameters. In perfused hearts, the post-ischaemic ventricular dysfunction was worse in preparations from L-NAME-treated rats than in controls. Sildenafil dose-dependently reduced this effect, and creatine kinase and lactate dehydrogenase release were lower too. cGMP levels, which were low in myocardial tissue from L-NAME-treated rats, were restored by sildenafil. In noradrenaline-precontracted aortic rings from L-NAME-treated rats acetylcholine lost its vasorelaxant effect, and sildenafil restored it.In a rat model of chronic nitric oxide deprivation, where hypertension and aggravation of post-ischaemic ventricular dysfunction are associated with loss of vascular endothelium-relaxant function, sildenafil provided significant cardiovascular protection, primarily by maintaining tissue cGMP levels.