Publications by authors named "Silvia Natoli"

39 Publications

Facemasks and face recognition: Potential impact on synaptic plasticity.

Neurobiol Dis 2021 06 26;153:105319. Epub 2021 Feb 26.

Department of Clinical Science and Translational Medicine, University of Rome Tor Vergata, Rome, Italy.

Visual recognition of facial expression modulates our social interactions. Compelling experimental evidence indicates that face conveys plenty of information that are fundamental for humans to interact. These are encoded at neural level in specific cortical and subcortical brain regions through activity- and experience-dependent synaptic plasticity processes. The current pandemic, due to the spread of SARS-CoV-2 infection, is causing relevant social and psychological detrimental effects. The institutional recommendations on physical distancing, namely social distancing and wearing of facemasks are effective in reducing the rate of viral spread. However, by impacting social interaction, facemasks might impair the neural responses to recognition of facial cues that are overall critical to our behaviors. In this survey, we briefly review the current knowledge on the neurobiological substrate of facial recognition and discuss how the lack of salient stimuli might impact the ability to retain and consolidate learning and memory phenomena underlying face recognition. Such an "abnormal" visual experience raises the intriguing possibility of a "reset" mechanism, a renewed ability of adult brain to undergo synaptic plasticity adaptations.
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http://dx.doi.org/10.1016/j.nbd.2021.105319DOI Listing
June 2021

Oxycodone/Acetaminophen: The Tailoring Combination Treatment for Specific Clinical Profile of Opioid Well-Responsive Cancer Pain.

Cancer Manag Res 2021 19;13:1747-1756. Epub 2021 Feb 19.

Primary Care Unit, ASL RM1, Rome, 00165, Italy.

Background: International guidelines recommend moderate-to-severe cancer pain to be treated with strong opioids. However, pain management remains an unsolved matter, at least in the demanding oncology and palliative care setting. Although cancer pain consists of multiple components, which interact in complex ways where combination therapy can better intercept multiple pain characteristics, few studies have used a non-opioid/opioid association to exploit possible synergistic actions. Even the efforts of a recent approach emphasizing appropriate pain assessment and accurate classification to obtain personalized pain management have not produced a satisfactory analgesic strategy.

Objective: This analysis was intended to evaluate the effectiveness of the immediate release fixed combination of oxycodone/acetaminophen (OxyIR/Par) for the treatment of moderate-to-severe intensity background pain used alone or in combination with other strong opioids in cancer patients with breakthrough cancer pain (BTcP). This is a secondary analysis of a wider observational, prospective, multicenter study [Italian Oncologic Pain multiSetting Multicentric Survey (IOPS-MS)] performed on 179 patients treated with opioids for cancer pain who received the fixed combination of oxycodone/acetaminophen (OxyIR/Par) for the treatment of background pain (BGP).

Results: Cancer patients with breakthrough cancer pain and controlled BGP (Background Pain) were classified according to the presence of analgesic therapy with tablets of fixed combination OxyIR/Par alone (group A, n=120) or tablets of fixed combination OxyIR/Par combined with other strong opioids (group B, n=59). Clinical features of group A were different to group B: higher mean Karnofsky Performance Status Index 70.3% (95% CI=67.2-73.5; median=70, CI=60-80) vs 58.3 (95% CI=53.4-63.2; median=50, CI=45-70) (<0.001), and mainly group A patients were treated in an ambulatory setting (55.0% group A vs 33.9% group B) (p<0.001). Both groups had managed BGP with similar mean dosages (group A: 12.0, CI=10.5-13.4; group B: 13.1, CI=11.0-15.1) and frequencies of OxyIR/Par alone for group A and in association to other opioids for group B, but Breakthrough cancer Pain (BTcP) exhibited different characteristics in the two groups, showing a lower mean intensity numerical rating scale (NRS) of 7.5 (95% CI=7.2-7.7; median=7, CI=7-8 group A) vs 7.9 (95% CI=7.6, 8.2; median= 8, CI=7-9 group B) (=0.04) and a higher percentage of patients had a faster onset, defined as the maximum intensity reached in less than 10 minutes, 81.7% (N=98) in group A vs 59.3% (n=35) in group B (=0.002).

Conclusion: This is the first analysis about the efficacy of an immediate-release fixed combination of OxyIR/Par in the real world for moderate-to-severe background cancer pain and breakthrough cancer pain. The oral fixed combination OxyIR/Par provided an adequate level of analgesia for moderate-severe background cancer pain, in a different cohort of cancer patients with different performance status, both in ambulatory and palliative settings. The low dosage of fixed combination OxyIR/Par was effective alone or in association with other opioids.
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http://dx.doi.org/10.2147/CMAR.S290551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903954PMC
February 2021

Effect of Gabapentin in a Neuropathic Pain Model in Mice Overexpressing Human Wild-Type or Human Mutated Torsin A.

Life (Basel) 2021 Jan 12;11(1). Epub 2021 Jan 12.

School of Hospital Pharmacy, University "Magna Graecia" of Catanzaro and Department of Health Sciences, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy.

Background: DYT1 dystonia is the most common form of early-onset inherited dystonia, which is caused by mutation of torsin A (TA) belonging to the "ATPases associated with a variety of cellular activities" (AAA + ATPase). Dystonia is often accompanied by pain, and neuropathic pain can be associated to peripherally induced movement disorder and dystonia. However, no evidence exists on the effect of gabapentin in mice subjected to neuropathic pain model overexpressing human normal or mutated TA.

Methods: Mice subjected to L5 spinal nerve ligation (SNL) develop mechanical allodynia and upregulation of the α2δ-1 L-type calcium channel subunit, forming a validated experimental model of neuropathic pain. Under these experimental conditions, TA is expressed in dorsal horn neurons and astrocytes and colocalizes with α2δ-1. Similar to this subunit, TA is overexpressed in dorsal horn 7 days after SNL. This model has been used to investigate (1) basal mechanical sensitivity; (2) neuropathic pain phases; and (3) the effect of gabapentin, an α2δ-1 ligand used against neuropathic pain, in non-transgenic (NT) C57BL/6 mice and in mice overexpressing human wild-type (hWT) or mutant (hMT) TA.

Results: In comparison to non-transgenic mice, the threshold for mechanical sensitivity in hWT or hMT does not differ (Kruskal-Wallis test = 1.478; = 0.4777, although, in the latter animals, neuropathic pain recovery phase is delayed. Interestingly, gabapentin (100 mg/Kg) reduces allodynia at its peak (occurring between post-operative day 7 and day 10) but not in the phase of recovery.

Conclusions: These data lend support to the investigation on the role of TA in the molecular machinery engaged during neuropathic pain.
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http://dx.doi.org/10.3390/life11010041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826569PMC
January 2021

Breakthrough Cancer Pain Clinical Features and Differential Opioids Response: A Machine Learning Approach in Patients With Cancer From the IOPS-MS Study.

JCO Precis Oncol 2020 4;4. Epub 2020 Nov 4.

Medical Oncology Department, Campus Bio-Medico University of Rome, Rome, Italy.

Purpose: A large proportion of patients with cancer suffer from breakthrough cancer pain (BTcP). Several unmet clinical needs concerning BTcP treatment, such as optimal opioid dosages, are being investigated. In this analysis the hypothesis, we explore with an unsupervised learning algorithm whether distinct subtypes of BTcP exist and whether they can provide new insights into clinical practice.

Methods: Partitioning around a k-medoids algorithm on a large data set of patients with BTcP, previously collected by the Italian Oncologic Pain Survey group, was used to identify possible subgroups of BTcP. Resulting clusters were analyzed in terms of BTcP therapy satisfaction, clinical features, and use of basal pain and rapid-onset opioids. Opioid dosages were converted to a unique scale and the BTcP opioids-to-basal pain opioids ratio was calculated for each patient. We used polynomial logistic regression to catch nonlinear relationships between therapy satisfaction and opioid use.

Results: Our algorithm identified 12 distinct BTcP clusters. Optimal BTcP opioids-to-basal pain opioids ratios differed across the clusters, ranging from 15% to 50%. The majority of clusters were linked to a peculiar association of certain drugs with therapy satisfaction or dissatisfaction. A free online tool was created for new patients' cluster computation to validate these clusters in future studies and provide handy indications for personalized BTcP therapy.

Conclusion: This work proposes a classification for BTcP and identifies subgroups of patients with unique efficacy of different pain medications. This work supports the theory that the optimal dose of BTcP opioids depends on the dose of basal opioids and identifies novel values that are possibly useful for future trials. These results will allow us to target BTcP therapy on the basis of patient characteristics and to define a precision medicine strategy also for supportive care.
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http://dx.doi.org/10.1200/PO.20.00158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713587PMC
November 2020

Quality of life and functional outcomes with tapentadol prolonged release in chronic musculoskeletal pain: analysis.

Pain Manag 2021 Mar 26;11(2):173-187. Epub 2020 Nov 26.

Global Medical Affairs, Grünenthal GmbH, Aachen, 52099, Germany.

To investigate quality of life (QOL) and functionality changes in chronic pain during tapentadol prolonged release (PR) treatment. analysis of data from three Phase III trials in patients with osteoarthritis knee pain or low back pain. QOL and functionality changes were assessed by SF-36 scores. All SF-36 subdomain scores improved progressively to week 3 of tapentadol titration and were sustained during 12-week maintenance treatment. Improvements in SF-36 scores were similar between tapentadol dose groups (e.g., 200 to <300 mg vs ≥500 mg), with no greater effect from higher doses. QOL and functionality improvements were consistently greater with tapentadol PR than oxycodone controlled release. Tapentadol PR provides consistent, clinically relevant improvements in QOL and functionality in chronic pain.
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http://dx.doi.org/10.2217/pmt-2020-0084DOI Listing
March 2021

A Dual Centre Study of Pain in Parkinson's Disease and Its Relationship with Other Non-Motor Symptoms.

J Parkinsons Dis 2020 ;10(4):1817-1825

Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.

Background: Pain is a disabling and often underestimated non-motor symptom (NMS) detrimentally affecting the quality of life of patients with Parkinson's disease (PD).

Objective: Here, we conducted a cross-sectional, observational international study on 167 patients with idiopathic PD in order to analyze the potential relationship between pain and other NMS.

Methods: Subjects were assessed with the Unified Parkinson's Disease Rating Scale (UPDRS) part III, Hoehn and Yahr (H&Y) stage, King's Parkinson's Disease Pain Scale (KPPS), Brief Pain Inventory (BPI), Non-Motor Symptoms Scale (NMSS), and Beck Depression Inventory (BDI). Spearman's rank correlation coefficient, multiple regression and multiple index-based clustering algorithms were used for data analysis.

Results: The prevalence of pain was 88.6%, was not correlated with age, motor severity (UPDRS part III) or disease duration, whereas a weak correlation with female gender and H&Y stage >2.5 was found. Multiple NMS correlated significantly with pain. Specifically, sleep disturbance had the strongest correlation with pain, followed by depression, gastrointestinal and cardiovascular disturbances. Further analyses showed that sleep and cardiovascular disturbance were independently associated with pain, and that these symptoms clustered together in a subset of PD patients. The relationship between pain, sleep and dysautonomia persisted independently from dopamine replacement therapy.

Conclusion: Our study suggests that sleep disruption and cardiovascular disturbance are associated with pain in PD, and possibly identifies a specific subtype within PD patients with pain. Our data also indicate that sleep disruption, pain and dysautonomia may have a common pathophysiology, possibly involving non-dopaminergic pathways.
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http://dx.doi.org/10.3233/JPD-202088DOI Listing
January 2020

Is transcranial direct current stimulation (tDCS) effective for chronic low back pain? A systematic review and meta-analysis.

J Neural Transm (Vienna) 2020 09 9;127(9):1257-1270. Epub 2020 Jul 9.

Unit of Pain Therapy, Policlinic of Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy.

Transcranial direct current stimulation (tDCS) has been used to reduce pain in range of chronic pain states. The aim of this review is to evaluate the effectiveness of tDCS on pain reduction and related disability in patients with non-specific chronic low back pain (CLBP). A computer-based systematic literature search was performed in five databases according to PRISMA guidelines. Randomized controlled trials (RCTs) that assessed the effects of tDCS on pain and related disability in patients with non-specific CLBP were included. Modified Jadad scale and Cochrane's risk of bias assessment were used to determine the studies' quality and risk of bias. Meta-analyses were performed by calculating the standardized mean difference (SMD) at 95% confidence interval (CI). Nine RCTs (411 participants) were included in the systematic review according to inclusion criteria, while only five studies could be included in the meta-analysis. The primary motor cortex (M1) was the main stimulated target. The meta-analysis showed non-significant effect of multiple sessions of tDCS over M1 on pain reduction and disability post-treatment respectively, (SMD = 0.378; 95% CI = - 0.264-1.020; P = 0.249), (SMD = 0.143; 95% CI = - 0.214-0.499; P = 0.434). No significant adverse events were reported. The current results do not support the clinical use of tDCS for the reduction of pain and related disability in non-specific CLBP. However, the limited number of available evidence limits our conclusions on the effectiveness of these approaches.
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http://dx.doi.org/10.1007/s00702-020-02223-wDOI Listing
September 2020

Mesotherapy: From Historical Notes to Scientific Evidence and Future Prospects.

ScientificWorldJournal 2020 1;2020:3542848. Epub 2020 May 1.

Department of Clinical Science and Translational Medicine, Tor Vergata University, Rome, Italy.

Intradermal therapy, known as mesotherapy, is a technique used to inject a drug into the surface layer of the skin. In particular, it involves the use of a short needle to deposit the drug in the dermis. The intradermal microdeposit modulates the drug's kinetics, slowing absorption and prolonging the local mechanism of action. It is successfully applied in the treatment of some forms of localized pain syndromes and other local clinical conditions. It could be suggested when a systemic drug-sparing effect is useful, when other therapies have failed (or cannot be used), and when it can synergize with other pharmacological or nonpharmacological therapies. Despite the lack of randomized clinical trials in some fields of application, a general consensus is also reached in nonpharmacological mechanism of action, the technique execution modalities, the scientific rationale to apply it in some indications, and the usefulness of the informed consent. The Italian Mesotherapy Society proposes this position paper to apply intradermal therapy based on scientific evidence and no longer on personal bias.
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http://dx.doi.org/10.1155/2020/3542848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305548PMC
May 2020

Careful Breakthrough Cancer Pain Treatment through Rapid-Onset Transmucosal Fentanyl Improves the Quality of Life in Cancer Patients: Results from the BEST Multicenter Study.

J Clin Med 2020 Apr 2;9(4). Epub 2020 Apr 2.

Epidemiology and Biostatistics Unit, Istituto Nazionale Tumori, IRCCS. Fondazione G. Pascale, 80131 Napoli, Italy.

Objectives: To explore the effect of breakthrough cancer pain (BTcP) treatment on quality of sleep and other aspects of the health-related quality of life (HRQoL) in patients with cancer pain.

Methods: In an observational, multicenter, cohort study, cancer patients from palliative care units, oncology departments, and pain clinics and affected by BTcP were included. Enrolled patients were assessed at the four visits: T0 (baseline), T7, T14, and T28. Stable chronic background pain (numeric rating scale, NRS ≤ 4) during the whole study period was mandatory. BTcP was treated through transmucosal fentanyl. Three questionnaires were used to measure the HRQoL: EORTC QLQ-C15-PAL, Pittsburgh Sleep Quality Index (PSQI), and the Edmonton Symptom Assessment System (ESAS).

Results: In 154 patients, the HRQoL showed a significant improvement for all physical and emotional characteristics in the EORTC QLQ-C15-PAL, except for nausea and vomiting (linear -value = 0.1) and dyspnea (Linear -value = 0.05). The ESAS and PSQI questionnaires confirmed these positive results ( < 0.0001 and = 0.002, respectively).

Conclusions: This prospective investigation by an Italian expert group, has confirmed that careful management of BTcP induces a paramount improvement on the HRQoL. Because in cancer patients there is a high prevalence of BTcP and this severe acute pain has deleterious consequences, this information can have an important clinical significance.
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http://dx.doi.org/10.3390/jcm9041003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230287PMC
April 2020

Toward more focused multimodal and multidisciplinary approaches for pain management in Parkinson's disease.

J Pain Res 2019 22;12:2201-2209. Epub 2019 Jul 22.

Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Naples, Italy.

In Parkinson's disease (PD), pain represents a significant issue in terms of prevalence, clinical features, and treatment. Painful manifestations not strictly related to the disease are often amplified by the motor dysfunction. On the other hand, typical pain problems may specifically concern this vulnerable population. In turn, pain may have a deep impact on patients' health-related quality of life. However, pain treatment in PD remains an unmet need as only about half of patients with pain use analgesics and pain is often managed by simply increasing doses of PD medications. In this complex scenario, pain treatments should follow multimodal approaches through a careful combination of pharmacological agents with non-pharmacological strategies, depending on the type of pain and the clinical context. A multidisciplinary approach involving medical specialists from different disciplines could be a winning strategy to address the issue. This work is aimed to provide practical suggestions useful for different types of clinicians and care professionals for pain management in this vulnerable population.
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http://dx.doi.org/10.2147/JPR.S209616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660097PMC
July 2019

Opioid use in addiction: swinging between pain under-treatment and opioids harms.

Authors:
Silvia Natoli

Minerva Anestesiol 2019 08;85(8):819-821

Department of Clinical Science and Translational Medicine, Tor Vergata University, Rome, Italy -

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http://dx.doi.org/10.23736/S0375-9393.19.13767-4DOI Listing
August 2019

Factors Influencing the Clinical Presentation of Breakthrough Pain in Cancer Patients.

Cancers (Basel) 2018 Jun 1;10(6). Epub 2018 Jun 1.

Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy.

The aim of this study was to identify potential variables influencing the clinical presentation of breakthrough cancer pain (BTP). Cancer patients with a diagnosis of BTP were enrolled. Demographic and clinical characteristics, as well as background pain and BTP characteristics were collected. Multivariate analyses were conducted to assess the correlation between BTP characteristics and the variables examined. Data of 4016 patients were analysed. Average daily number of BTP episodes was 2.4, mean intensity was 7.5, and a mean duration was 43.3 min. A short onset BTP was observed in 68.9% of patients. In 30.5% of patients BTP was predictable. There were 86.0% of participants who reported a marked interference of BTP with their daily activities. Furthermore, 86.8% of patients were receiving opioids for the management of BTP. The average time to meaningful pain relief was 16.5 min and 70.9% of patients were satisfied with their BTP medications. Age, head and neck cancer, Karnofsky, background pain intensity, predictable and fast onset BTP were independently associated with the number of BTP episodes. BTP pain intensity was independently associated with background pain intensity, fast onset BTP, and Karnofsky. Neuropathic pain mechanism was independently associated with unpredictable BTP. Variables independently associated with a longer duration of BTP were age, place of visit, cancer diagnosis, disease-oriented therapy, background pain intensity and mechanism, and unpredictable BTP. Age, Karnofsky, background pain intensity, fast onset, and long duration of BTP were independently associated with interference with daily activity. BTP has a variable presentation depending on interdependent relationships among its different characteristics.
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http://dx.doi.org/10.3390/cancers10060175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025469PMC
June 2018

The challenge of perioperative pain management in opioid-tolerant patients.

Ther Clin Risk Manag 2017 5;13:1163-1173. Epub 2017 Sep 5.

Unit of Anaesthesia and Intensive Care, Dei Colli Hospital, V. Monaldi, Naples, Italy.

The increasing number of opioid users among chronic pain patients, and opioid abusers among the general population, makes perioperative pain management challenging for health care professionals. Anesthesiologists, surgeons, and nurses should be familiar with some pharmacological phenomena which are typical of opioid users and abusers, such as tolerance, physical dependence, hyperalgesia, and addiction. Inadequate pain management is very common in these patients, due to common prejudices and fears. The target of preoperative evaluation is to identify comorbidities and risk factors and recognize signs and symptoms of opioid abuse and opioid withdrawal. Clinicians are encouraged to plan perioperative pain medications and to refer these patients to psychiatrists and addiction specialists for their evaluation. The aim of this review was to give practical suggestions for perioperative management of surgical opioid-tolerant patients, together with schemes of opioid conversion for chronic pain patients assuming oral or transdermal opioids, and patients under maintenance programs with methadone, buprenorphine, or naltrexone.
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http://dx.doi.org/10.2147/TCRM.S141332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5592950PMC
September 2017

Breakthrough Cancer Pain: Preliminary Data of The Italian Oncologic Pain Multisetting Multicentric Survey (IOPS-MS).

Adv Ther 2017 01 21;34(1):120-135. Epub 2016 Nov 21.

Palliative Care, FARO Foundation, Turin, Italy.

Introduction: An ongoing national multicenter survey [Italian Oncologic Pain multiSetting Multicentric Survey (IOPS-MS)] is evaluating the characteristics of breakthrough cancer pain (BTP) in different clinical settings. Preliminary data from the first 1500 cancer patients with BTP enrolled in this study are presented here.

Methods: Thirty-two clinical centers are involved in the survey. A diagnosis of BTP was performed by a standard algorithm. Epidemiological data, Karnofsky index, stage of disease, presence and sites of metastases, ongoing oncologic treatment, and characteristics of background pain and BTP and their treatments were recorded. Background pain and BTP intensity were measured. Patients were also questioned about BTP predictability, BTP onset (≤10 or >10 min), BTP duration, background and BTP medications and their doses, time to meaningful pain relief after BTP medication, and satisfaction with BTP medication. The occurrence of adverse reactions was also assessed, as well as mucosal toxicity.

Results: Background pain was well controlled with opioid treatment (numerical rating scale 3.0 ± 1.1). Patients reported 2.5 ± 1.6 BTP episodes/day with a mean intensity of 7.5 ± 1.4 and duration of 43 ± 40 min; 977 patients (65.1%) reported non-predictable BTP, and 1076 patients (71.7%) reported a rapid onset of BTP (≤10 min). Higher patient satisfaction was reported by patients treated with fast onset opioids.

Conclusions: These preliminary data underline that the standard algorithm used is a valid tool for a proper diagnosis of BTP in cancer patients. Moreover, rapid relief of pain is crucial for patients' satisfaction. The final IOPS-MS data are necessary to understand relationships between BTP characteristics and other clinical variables in oncologic patients.

Funding: Molteni Farmaceutici, Italy.
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http://dx.doi.org/10.1007/s12325-016-0440-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216057PMC
January 2017

Non-convulsive status epilepticus in a patient with carbon-monoxide poisoning treated with hyperbaric oxygen therapy.

Neuroradiol J 2016 Dec 22;29(6):431-435. Epub 2016 Aug 22.

Neuroradiology COU, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Italy.

The presentation of carbon monoxide poisoning is non-specific and highly variable. Hyperbaric oxygen therapy is used for the treatment of this condition. Various reports show the occurrence of self-limiting seizures after carbon monoxide poisoning and as a consequence of hyperbaric oxygen therapy. Contrary to the seizures, status epilepticus has been rarely observed in these conditions. The exact pathophysiology underlying seizures and status epilepticus associated with carbon monoxide poisoning and hyperbaric oxygen therapy is not really clear, and some elements appear to be common to both conditions. We describe a case of non-convulsive status epilepticus in a patient with carbon monoxide poisoning treated with hyperbaric oxygen therapy. The mechanism, MRI findings and implications are discussed.
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http://dx.doi.org/10.1177/1971400916665379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131761PMC
December 2016

Switching to low-dose oral prolonged-release oxycodone/naloxone from WHO-Step I drugs in elderly patients with chronic pain at high risk of early opioid discontinuation.

Clin Interv Aging 2016 13;11:641-9. Epub 2016 May 13.

Department of Emergency and Critical Care Medicine, Pain Medicine and Anaesthesiology, Tor Vergata Polyclinic, University of Rome, Rome, Italy.

Purpose: Chronic pain has a high prevalence in the aging population. Strong opioids also should be considered in older people for the treatment of moderate to severe pain or for pain that impairs functioning and the quality of life. This study aimed to assess the efficacy and safety of the direct switch to low-dose strong opioids (World Health Organization-Step III drugs) in elderly, opioid-naive patients.

Patients And Methods: This was a single-center, retrospective, observational study in opioid-naive patients aged ≥75 years, with moderate to severe chronic pain (>6-month duration) and constipation, who initiated treatment with prolonged-release oxycodone/naloxone (OXN-PR). Patients were re-evaluated after 15, 30, and 60 days (T60, final observation). Response to treatment was defined as an improvement in pain of ≥30% after 30 days of therapy without worsening of constipation.

Results: One-hundred and eighty-six patients (mean ± SD age 80.7±4.7 years; 64.5% women) with severe chronic pain (mean average pain intensity 7.1±1.0 on the 11-point numerical rating scale) and constipation (mean Bowel Function Index 64.1±24.4; 89.2% of patients on laxatives) were initiated treatment with OXN-PR (mean daily dose 11.3±3.5 mg). OXN-PR reduced pain intensity rapidly and was well tolerated; 63.4% of patients responded to treatment with OXN-PR. At T60 (mean daily OXN-PR dose, 21.5±9.7 mg), the pain intensity was reduced by 66.7%. In addition, bowel function improved (mean decrease of Bowel Function Index from baseline to T60, -28.2, P<0.0001) and the use of laxatives decreased. Already after 15 days and throughout treatment, ~70% of patients perceived their status as much/extremely improved. Only 1.6% of patients discontinued treatment due to adverse events.

Conclusion: Low-dose OXN-PR in elderly patients naive to opioids proved to be an effective option for the treatment of moderate to severe chronic pain. Large-scale trials are needed to improve clinical guidance in the assessment and treatment of pain in older people.
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http://dx.doi.org/10.2147/CIA.S105821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874636PMC
February 2017

Should the General Practitioner Consider Mesotherapy (Intradermal Therapy) to Manage Localized Pain?

Pain Ther 2016 Jun 26;5(1):123-6. Epub 2016 May 26.

Department of Clinical Science and Translational Medicine, Policlinico di Tor Vergata, University of Rome Tor Vergata, Rome, Italy.

Wide variations in the types of pain and response to analgesic pharmacotherapy mean that a variety of treatment strategies are needed. One approach is mesotherapy (intradermal therapy). This consists of microinjections into the skin and is ideally suited to the management of localized pain. Advantages include increasing the duration of drug activity, reduced risk of adverse events and interactions, and possible synergy with other therapies. Mesotherapy provides general practitioners with another tool for the treatment of local pain. However, it is important to provide patients with full details of the pros and cons of this approach and obtain informed patient consent.
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http://dx.doi.org/10.1007/s40122-016-0052-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912973PMC
June 2016

Retrospective Evaluation of a Fixed-Dose Combination of Oxycodone and Acetaminophen to Manage Moderate Pain: The Lower the Better.

Adv Ther 2016 06 3;33(6):1025-32. Epub 2016 May 3.

Department of Clinical Science and Translational Medicine, University of Rome Tor Vergata, Rome, Italy.

Introduction: Oxycodone is one of the most commonly used opioid analgesics in the clinical management of pain. The present retrospective analysis aimed to determine the dose of oxycodone that could achieve effective control of moderate pain when combined with a fixed dose of acetaminophen, and the time required to reach a clinically relevant reduction in intensity of pain.

Methods: Data of patients treated with a combination of oxycodone (5, 10, and 20 mg) and acetaminophen (325 mg) were evaluated for gender, current disease condition, basal pain intensity, total daily dose, days of controlled pain at the initial low dose, and pain intensity after treatment using a numeric pain rating scale.

Results: Data from a total of 491 patients were assessed; of these 93.5% of patients experienced persistent non-cancer pain and had an average baseline pain score of 5.68 ± 1.35. For the overall population, the pain score was reduced to 2.49 ± 1.71 with a mean dose of 8.68 ± 4.96 mg oxycodone after 21.60 ± 6.12 days of treatment with the combination. Almost 97% of the patients who reported relief of pain received 1.61 ± 0.67 doses of oxycodone 5 mg combined with 325 mg of acetaminophen.

Conclusion: A low-dose combination of oxycodone with acetaminophen can be effective in the management of moderate pain and may help in reducing the treatment-associated adverse reactions and drug dependence.

Funding: Sponsorship for article processing charges was provided by Molteni Farmaceutici, Florence, Italy.
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http://dx.doi.org/10.1007/s12325-016-0339-0DOI Listing
June 2016

Microbiologic characteristics and predictors of mortality in bloodstream infections in intensive care unit patients: A 1-year, large, prospective surveillance study in 5 Italian hospitals.

Am J Infect Control 2015 Nov 4;43(11):1178-83. Epub 2015 Aug 4.

Clinical Infectious Diseases, Tor Vergata Hospital, Rome, Italy.

Background: Bloodstream infections (BSIs) from multidrug-resistant (MDR) bacteria cause morbidity and mortality in intensive care unit (ICU) patients worldwide. This study investigated the incidence of BSIs in 5 adult general ICUs in Rome, Italy, and evaluated the mortality rate and risk factors associated with these infections.

Methods: Over a 12-month period, 1,318 patients were enrolled. Demographic characteristics, Simplified Acute Physiology Score II (SAPS II), comorbidities, and BSI isolate data were collected. After stratification for the outcome, statistical analysis was performed to assess the impact of patient risk factors on in-hospital mortality.

Results: There were 324 BSIs in 175 patients recorded, with an in-hospital mortality rate of 46%. Univariate analysis revealed that SAPS II, cardiac comorbidity, and Klebsiella pneumoniae BSI were significantly associated with a higher risk of death. Having a K pneumoniae BSI and cardiac illness at admission were both confirmed to be associated with death by multivariate analysis (P = .0162 and P = .0158, respectively). Most of the K pneumoniae isolates showed high resistance rates to carbapenems.

Conclusion: BSIs caused by K pneumoniae and cardiovascular comorbidity in ICU patients are associated with a higher risk of death. Thorough surveillance for MDR pathogens and stratification of the patients' risk on admission into the ICU are key to improving the outcomes of these infections.
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http://dx.doi.org/10.1016/j.ajic.2015.06.023DOI Listing
November 2015

Efficacy and safety profile of prolonged release oxycodone in combination with naloxone (OXN PR) in Parkinson's disease patients with chronic pain.

J Neurol 2015 Sep 2;262(9):2164-70. Epub 2015 Jul 2.

Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.

Pain is a relevant and often underestimated non-motor symptom affecting the quality of life of patients with Parkinson's disease (PD). Although some pain symptoms can be effectively treated by dopaminergic medication, a correct diagnosis of the different types and distribution of pain in PD is challenging, and accordingly, its treatment remains troublesome. We evaluated the efficacy and the safety of a prolonged release oral formulation of oxycodone hydrochloride combined with naloxone hydrochloride dehydrate, in a fixed ratio of 2:1 (OXN PR). A total of 16 PD patients with history of pain with a minimum intensity of four on numerical rating scale (NRS) received low-dose OXN PR (5/2.5 mg twice daily) and were observed for a period of 8 weeks. The primary efficacy measure was the pain severity measured with NRS and Brief Pain Inventory (BPI). Secondary efficacy measured the safety profile by recording the occurrence of side effects, clinical global impression of change (CGI-C), Parkinson's disease sleep scale 2 (PDSS-2), Bowel function index (BFI). Data were collected and analyzed using descriptive statistics. Patients who completed the study (14 out of 16) reported a significant pain relief as observed by the reduction of NRS and BPI scores. No adjustment of dopaminergic therapy was required. No significant changes were observed in bowel function and constipation symptoms as measured by the BFI during the 8-week period. Similarly, no changes were observed in PDSS-2 score, whereas an improvement was recorded by CGI-C compared to baseline. Low-dose oral OXN PR was efficacious for the management of pain symptoms of patients with PD. More importantly, patients did not experience significant side effects, such as constipation or sedation. Our study provides evidence that opioids can be used to treat pain symptoms in PD patients.
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http://dx.doi.org/10.1007/s00415-015-7823-3DOI Listing
September 2015

Italian Oncological Pain Survey (IOPS): a multicentre Italian study of breakthrough pain performed in different settings.

Clin J Pain 2015 Mar;31(3):214-21

*Anesthesia and Intensive Care & Pain Relief and Supportive Care, La Maddalena Cancer Center, Palermo †Emergency Care, Critical Care Medicine, Pain Medicine and Anesthesiology Department, Tor Vergata University of Rome ‡Anesthesiology, Resuscitation, and Pain Therapy Department, Umberto I Hospital ¶Molecular and Clinical Medicine Medical Oncology, La Sapienza University of Rome #IDI-IRCCS ‡‡‡‡Primary Care, ASL RM F, Rome §Anesthesiology, Resuscitation, and Pain Therapy Department ¶Abdominal Medical Oncology, National Cancer Institute, IRCCS Foundation Pascale ††Medical Oncology, A.O.R.N "A. Cardarelli" Hospital †††Pain Relief, A.O. Dei Colli, Monaldi Hospital, Naples ∥Palliative Care ASL3, Genoa ##Palliative Care, Gerontology and Physical Education Department, E.O. Galliera Hospitals, Genoa **Pain Relief, Palliative Care, Oncology Department, Careggi Hospital, Florence ‡‡Hematology Oncology Center Subalpine (COES), A.O. City Health and Science, Molinette §§§Palliative Care, FARO Foundation, Turin §§IRCCS Foundation National Cancer Institute of Milan, Milan ***Palliative Care, Pain Relief, ASL 13 Mirano Veneto Region ‡‡‡Palliative Care, Pain Relief, Infermi Hospital, Rimini ∥∥∥Medical Oncology, Humanitas Oncology Center of Catania, Catania ¶¶¶Medical Oncology 1, Careggi Hospital, Florence ###Pain Relief, IRCCS Veneto Oncological Institute, Padua ****Pain Relief, Palliative Care, AV3 Macerata Hospital, Macerata ††††Medical Oncology A.O. Treviglio, Bergamo, Italy ∥∥European Palliative Care Research Center, Norwegian University of Science and Technology, Trondheim, Norway.

Objective: A survey of breakthrough pain (BTP) was performed in five palliative care units (PCU), seven oncology departments (ONC), and nine pain clinics (OPC).

Methods: A standard algorithm was used to confirm the diagnosis of BTP of patients refereed to different settings.

Results: 1,412 evaluable cancer patients were enrolled. 53.9% were males and the mean age was 63.7±13.1 years. The mean intensity of background pain was 2.8±0.73. Patients reported 2.4±1.1 BTP episodes/day with a mean intensity of 7.37±1.28. 80.6% patients reported that the BTP had a significant negative impact in everyday life. The majority of patients reported a fast onset of BTP, which was predictable in 50.7% of cases, while BTP with a gradual onset (>10 min) was less predictable (29%) (P=0.001). PCU patients were older, had lower Karnofsky levels, a lower number of BTP episodes/day, a slow onset of BTP onset, and a less predictable BTP. Cancer diagnosis was performed a mean of 23.5 months (SD±32.8) before the assessment. The mean duration of background pain was 3.5 months (SD±3.5), and the mean duration of any analgesic treatment was 2.5 months (SD±3). BTP started a mean of 2.2 months (SD±1.9) before the assessment. Characteristics of BTP were influenced by the course of disease, as well as the duration of background pain and initiation of BTP. Most patients took rapid onset opioids and were satisfied with the treatment. BTP diagnosis was prevalently made by ONC and OPC physicians, and rarely by GPs.

Conclusion: This survey performed by an Italian observatory expert review group, has confirmed that the BTP represents a clinically relevant condition with a negative impact on the patient's quality of life. BTP was detected in all settings involved. A number of factors are associated with the BTP. Also factors regarding the course of disease and setting of care have been assessed. This information may help in stratifying patients or predicting the risk of development of BTP with specific characteristics.
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http://dx.doi.org/10.1097/AJP.0000000000000161DOI Listing
March 2015

Open questions in the treatment of cancer pain: time for a strong evidence-based approach?

Expert Opin Pharmacother 2015 Jan 12;16(1):1-4. Epub 2014 Nov 12.

University of Rome Tor Vergata, Department of Clinical Science and Translational Medicine Policlinico di Tor Vergata, Viale Oxford 81,00133 , Rome , Italy.

Pain affects patients with cancer at any stage of their disease. Yet, it is not adequately treated in a significant percentage of cases. In 1986, the WHO proposed a three-step approach for the treatment of pain in cancer patients (from nonopioids to weak opioids to strong opioids, according to pain intensity) following the recommendations of an international group of experts. The application of the WHO strategy demonstrated that a clear and simple approach is of educational value and ensured worldwide dissemination. However, there is little evidence that the WHO approach is the best, and there are still several points to debate on the treatment of cancer pain.
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http://dx.doi.org/10.1517/14656566.2015.980724DOI Listing
January 2015

Upregulation of the inhibitory receptor ILT4 in monocytes from septic patients.

Hum Immunol 2013 Oct 2;74(10):1244-50. Epub 2013 Aug 2.

Dept. of Internal Medicine, University of Rome "Tor Vergata", Rome, Italy.

Sepsis-induced immune dysfunction is a complex phenomenon that involves both innate and adaptive responses. Upregulation of the inhibitor receptor named immunoglobulin like transcript 4 (ILT4) is crucial to the tolerogenic function of monocytes. Here, ILT4 expression, endotoxin-induced IL-12 and IL-10 production and CD86 expression were investigated in circulating monocytes from 16 patients with severe sepsis and 16 age and sex matched controls. We found that monocytes from patients with severe sepsis express significantly higher levels of ILT4 than monocytes from controls. Upregulation of ILT4 expression appeared to be induced by soluble factors present in the serum of septic patients and directly correlated with the degree of organ dysfunction. ILT4(+) monocytes from septic patients also displayed an alteration in the cytokine response to endotoxin stimulation characterized by reduced IL-12 production and increased IL-10 production, and a reduced expression of the costimulatory molecule CD86. In conclusion, the increased ILT4 expression and IL-10 production and the decreased CD86 expression and IL-12 production indicate that during sepsis monocytes undergo substantial modulation of the surface and cytokine phenotype. These phenotypic changes may interfere with the antigen presenting cell activity of monocytes, which may contribute to the impairment of adaptive immune responses that takes place during sepsis.
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http://dx.doi.org/10.1016/j.humimm.2013.07.012DOI Listing
October 2013

Increased blood-cerebrospinal fluid transfer of albumin in advanced Parkinson's disease.

J Neuroinflammation 2012 Aug 8;9:188. Epub 2012 Aug 8.

Department of Neuroscience, University of Rome Tor Vergata, Rome, Italy.

Background: Alterations in blood-brain barrier permeability have been proposed to represent a relevant factor contributing to Parkinson's disease progression. However, few studies have addressed this issue in patients at different stages of disease.

Methods: Albumin was measured in cerebrospinal fluid and serum samples obtained from 73 non-demented subjects with idiopathic Parkinson's disease and 47 age-matched control subjects. The albumin ratio (AR) was calculated to assess blood-cerebrospinal fluid and blood-brain barrier function. The group of patients with Parkinson's disease included 46 subjects with Hoehn-Yahr staging between 1 and 2 and 27, with a score ranging from 2.5 to 4.

Results: Statistically significant differences in albumin ratio were found between patients with advanced disease, and both early-stage and unaffected groups. Conversely, early-phase patients did not differ from healthy subjects. Additionally, dopaminergic treatment seems to exert a possible effect on AR values.

Conclusions: Our study demonstrates that possible dysfunction of the blood-cerebrospinal fluid barrier, blood-brain barrier, or both, characterize Parkinson's disease progression. The associations between clinical scores, treatments and biochemical findings suggest a progressive impairment of barrier integrity during the course of the disease.
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http://dx.doi.org/10.1186/1742-2094-9-188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3441323PMC
August 2012

Emergence of KPC-producing Klebsiella pneumoniae in Italy.

BMC Res Notes 2010 Feb 23;3:40. Epub 2010 Feb 23.

Department of Experimental Medicine and Biochemical Sciences, "Tor Vergata" University of Rome - Via Montpellier 1, Rome, 00133, Italy.

Background: The emergence of KPC-producing K. pneumoniae has now become a global concern. KPC beta-lactamases are plasmid-borne and, like extended spectrum beta lactamases (ESBLs), can accumulate and transfer resistance determinants to other classes of antibiotics. Therefore, infection control guidelines on early identification and control of the spread of organisms carrying these resistant determinants are needed.

Findings: Klebsiella pneumoniae carbapenemase (KPC) was detected in two isolates of carbapenem-resistant K. pneumoniae obtained from patients at an Italian teaching hospital. The first strain was isolated from a culture drawn from a central venous device (CVC) in a patient with Crohn's disease who was admitted to a gastroenterology ward. The second was isolated from a urine sample collected from an indwelling urinary catheter in an intensive care unit (ICU) patient with a subdural haematoma. The patients had not travelled abroad. Both isolates were resistant to all beta-lactams and were susceptible to imipenem and meropenem but resistant to ertapenem. Isolates also showed resistance to other classes of non-beta-lactam antibiotics, such as quinolones, aminoglycosides (with the exception for amikacin), trimethoprim-sulfamethoxazole (TMP-SMX) and nitrofurantoin. They were determined to contain the plasmid encoding the carbapenemase gene bla-KPC and were also positive in the Hodge test.

Conclusions: This is the second report of KPC-producing isolates in Italy, but the first concerning KPC type 2 gene, and it may have important implications for controlling the transmission of microorganisms resistant to antibiotics.
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http://dx.doi.org/10.1186/1756-0500-3-40DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2844393PMC
February 2010

Characterization of coagulase-negative staphylococcal isolates from blood with reduced susceptibility to glycopeptides and therapeutic options.

BMC Infect Dis 2009 Jun 4;9:83. Epub 2009 Jun 4.

Intensive Care Unit, Department of Surgery, Tor Vergata University of Rome, Rome, Italy.

Background: Coagulase-negative staphylococci (CoNS) are a major cause of nosocomial blood stream infection, especially in critically ill and haematology patients. CoNS are usually multidrug-resistant and glycopeptide antibiotics have been to date considered the drugs of choice for treatment. The aim of this study was to characterize CoNS with reduced susceptibility to glycopeptides causing blood stream infection (BSI) in critically ill and haematology patients at the University Hospital Tor Vergata, Rome, Italy, in 2007.

Methods: Hospital microbiology records for transplant haematology and ICU were reviewed to identify CoNS with elevated MICs for glycopeptides, and isolates were matched to clinical records to determine whether the isolates caused a BSI. The isolates were tested for susceptibility to new drugs daptomicin and tigecycline and the genetic relationship was assessed using f-AFLP.

Results: Of a total of 17,418 blood cultures, 1,609 were positive for CoNS and of these, 87 (5.4%) displayed reduced susceptibility to glycopeptides. Clinical review revealed that in 13 cases (7 in haematology and 6 in ICU), CoNS with reduced susceptibility to glycopeptides were responsible for a BSI. Staphylococcus epidermidis was the causative organism in 11 instances and Staphylococcus haemolyticus in 2. The incidence of oxacillin resistance was high (77%), although all isolates remained susceptible to linezolid, daptomycin and tigecycline. Fingerprinting of CoNS identified one clonal relationship between two isolates.

Conclusion: Multi-resistant CoNS with reduced susceptibility to glycopeptides, although still relatively infrequent in our hospital, are emerging pathogens of clinical concern. Surveillance by antibiotyping with attention to multi-resistant profile, and warning to clinicians, is necessary.
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http://dx.doi.org/10.1186/1471-2334-9-83DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2701436PMC
June 2009

Downregulation of CD40 ligand response in monocytes from sepsis patients.

Clin Vaccine Immunol 2008 Dec 22;15(12):1851-8. Epub 2008 Oct 22.

Department of Public Health and Cellular Biology, Intensive Care Unit, University of Rome Tor Vergata, Rome, Italy.

It has been suggested that a defective adaptive immune response contributes to septic immunosuppression. Here, the response of monocytes to CD40 ligand (CD40L) for patients with sepsis due to infection with gram-negative organisms has been analyzed. Compared to cells from controls, monocytes from septic patients showed significantly reduced production of tumor necrosis factor alpha, interleukin-1beta (IL-1beta), and IL-12 and were unable to acquire high levels of CD80 and CD86 molecules. These alterations were observed at the onset of sepsis and persisted at day 7. However, the ability of monocytes to respond to CD40L stimulation was partially but significantly restored in cells from patients who recovered from sepsis. In addition, costimulation of autologous CD4+ T lymphocytes by CD40L-activated monocytes from septic patients failed to induce cell proliferation and gamma interferon production. Finally, the ability of CD40L to rescue monocytes from apoptosis was severely impaired. We conclude that downregulation of the CD40L response may be an appropriate model for the monocyte alteration observed during septic immunosuppression and may help in the development of novel therapeutic strategies.
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http://dx.doi.org/10.1128/CVI.00184-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2593171PMC
December 2008

Acinetobacter baumannii in intensive care unit: a novel system to study clonal relationship among the isolates.

BMC Infect Dis 2008 Jun 8;8:79. Epub 2008 Jun 8.

Department of Experimental Medicine and Biochemical Sciences, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy.

Background: The nosocomial infections surveillance system must be strongly effective especially in highly critic areas, such as Intensive Care Units (ICU). These areas are frequently an epidemiological epicentre for transmission of multi-resistant pathogens, like Acinetobacter baumannii. As an epidemic outbreak occurs it is very important to confirm or exclude the genetic relationship among the isolates in a short time. There are several molecular typing systems used with this aim. The Repetitive sequence-based PCR (REP-PCR) has been recognized as an effective method and it was recently adapted to an automated format known as the DiversiLab system.

Methods: In the present study we have evaluated the combination of a newly introduced software package for the control of hospital infection (VIGI@ct) with the DiversiLab system. In order to evaluate the reliability of the DiversiLab its results were also compared with those obtained using f-AFLP.

Results: The combination of VIGI@ct and DiversiLab enabled an earlier identification of an A. baumannii epidemic cluster, through the confirmation of the genetic relationship among the isolates. This cluster regards 56 multi-drug-resistant A. baumannii isolates from several specimens collected from 13 different patients admitted to the ICU in a ten month period. The A. baumannii isolates were clonally related being their similarity included between 97 and 100%. The results of the DiversiLab were confirmed by f-AFLP analysis.

Conclusion: The early identification of the outbreak has led to the prompt application of operative procedures and precautions to avoid the spread of pathogen. To date, 6 months after the last A. baumannii isolate, no other related case has been identified.
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http://dx.doi.org/10.1186/1471-2334-8-79DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2443154PMC
June 2008

Lipopolysaccharide desensitizes monocytes-macrophages to CD40 ligand stimulation.

Immunology 2007 Nov 29;122(3):362-70. Epub 2007 Jun 29.

Department of Public Health and Cellular Biology, Chair of Infectious Diseases, University of Rome 'Tor Vergata', Rome, Italy.

Polymicrobial sepsis induces the suppression of macrophage function as determined by a reduction of pro-inflammatory cytokine production upon re-exposure to lipopolysaccharide (LPS) in vitro. Here, we examined whether macrophages were refractory to only LPS or if they were unable to respond to other stimuli such as CD40 ligand (CD40L). Monocytic cells exposed in vitro to LPS showed a dose-dependent reduction of their ability to produce interleukin-12 and tumour necrosis factor-alpha upon subsequent CD40L stimulation, as compared to cells stimulated with CD40L alone. Similarly, LPS interfered with the up-regulation of CD40, CD80 and CD86 induced by CD40L in monocytic cells. The effect of LPS on the response of monocytes to CD40L was similar whether these cells were directly exposed to LPS or cocultured with LPS-pretreated cells, indicating that soluble factors released by LPS stimulation could mediate tolerance to CD40L. We also show that the functional alterations induced by LPS in monocytes can be reversed by indomethacin, thus suggesting a role for inducible cyclooxygenase in mediating the LPS-induced hyporesponsive state of monocytes to CD40L. In conclusion, we propose that in vitro CD40L tolerance may be an appropriate model of monocyte alteration observed during septic immunosuppression and may help in the development of novel therapeutic strategies.
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http://dx.doi.org/10.1111/j.1365-2567.2007.02648.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2266011PMC
November 2007

Electrophysiologic changes in ventral midbrain dopaminergic neurons resulting from (+/-) -3,4-methylenedioxymethamphetamine (MDMA-"Ecstasy").

Biol Psychiatry 2007 Sep 23;62(6):680-6. Epub 2007 May 23.

Laboratory of Experimental Neurology, Fondazione Santa Lucia-IRCCS and Neurological Clinic, University of Rome Tor Vergata, Rome, Italy.

Background: Although dopamine (DA) has been implicated in the psychostimulant properties of 3,4-methylenedioxymethamphetamine (MDMA), there is no detailed information on its modalities of action on single ventral midbrain dopaminergic neurons.

Methods: We examined the actions of MDMA on intracellularly recorded dopaminergic neurons maintained in slices.

Results: At 1 micromol/L, MDMA depolarized and excited the cells; at 3 micromol/L, either excited or inhibited the neurons. Interestingly, higher concentrations (10-30 micromol/L) inhibited firing through membrane hyperpolarization or caused an outward current. Whereas MDMA's excitatory effects were antagonized by pindolol, indicating involvement of 5-HT 1B receptors, the inhibitory effects were counteracted by sulpiride indicating involvement D2 receptors. Treatment of the cells with carbidopa eliminated MDMA-induced firing inhibition and membrane hyperpolarization. MDMA enhanced DA-induced cellular responses but reduced those of amphetamine. Cocaine-induced outward currents were not affected by MDMA. These actions are consistent with inhibition of the DA transporter. Moreover, MDMA depressed the GABA(B) IPSP by activating 5-HT 1B receptors.

Conclusions: Our data demonstrate that 3-30 micromol/L MDMA preferentially inhibits the dopaminergic cells via indirect activation of D2 autoreceptors due to increased extracellular concentration of DA. In contrast, reduction of the GABA(B) IPSP could partially account for excitation caused by 1-3 micromol/L drug.
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http://dx.doi.org/10.1016/j.biopsych.2006.11.019DOI Listing
September 2007