C. Sgarlata

Neuroinflammation, immune system and Alzheimer disease: searching for the missing link

Due to an increasingly aging population, Alzheimer disease (AD) represents a crucial issue for the healthcare system because of its widespread prevalence and the burden of its care needs. Several hypotheses on AD pathogenesis have been proposed and current therapeutical strategies have shown limited effectiveness. In the last decade, more evidence has supported a role for neuroinflammation and immune system dysregulation in AD. It remains unclear whether astrocytes, microglia and immune cells influence disease onset, progression or both. Amyloid-β peptides that aggregate extracellularly in the typical neuritic plaques generate a constant inflammatory environment. This causes a prolonged activation of microglial and astroglial cells that potentiate neuronal damage and provoke the alteration of the blood brain barrier (BBB), damaging the permeability of blood vessels. Recent data support the role of the BBB as a link between neuroinflammation, the immune system and AD. Hence, a thorough investigation of the neuroinflammatory and immune system pathways that impact neurodegeneration and novel exciting findings such as microglia-derived microvesicles, inflammasomes and signalosomes will ultimately enhance our understanding of the pathological process. Eventually, we should proceed with caution in defining a causal or consequential role of neuroinflammation in AD, but rather focus on identifying its exact pathological contribution.

Efficacy and tolerability of low-dose oral prolonged-release oxycodone/naloxone for chronic nononcological pain in older patients.

Purpose Chronic pain is highly prevalent in older adults. Increasing evidence indicates strong opioids as a valid option for chronic pain management in geriatrics. The aim of this study was to evaluate efficacy and safety of low-dose oral prolonged-release oxycodone–naloxone (OXN-PR) in patients aged ≥70 years. Methods This open-label prospective study assessed older patients naïve to strong opioids presenting with moderate-to-severe chronic pain. Patients were prescribed OXN-PR at an initial dose of 10/5 mg/day for 28 days. In case of insufficient analgesia, the initial daily dose could be increased gradually. The primary efficacy measure was change in pain intensity from baseline, assessed by a ten-point Numeric Rating Scale (NRS) at day 28 (T28). Changes in cognitive state, daily functioning, quality of life, constipation, and other adverse events were assessed. Results Of 53 patients enrolled (mean 81.7±6.2 years [range 70–92 years]), 52 (98.1%) completed the 28-day observation. At T28, the primary end point (≥30% reduction in mean pain from baseline in the absence of bowel function deterioration) was achieved in 38 patients (71.7%). OXN-PR significantly relieved pain (NRS score –3.26; P<0.0001), as well as daily need for rescue paracetamol (from 86.8% at baseline to 40.4% at T28; P<0.001), and reduced impact of pain on daily activities (Brief Pain Inventory Short Form from 6.2±1.5 to 3.4±2.1; P<0.0001). OXN-PR was also associated with significant improvement in daily functioning (Barthel Index from 53.3±14.1 to 61.3±14.3; P<0.01). No changes were observed in cognitive status and bowel function. OXN-PR was well tolerated; only one patient (1.9%) prematurely withdrew from treatment, due to drowsiness. Conclusion Findings from this open-label prospective study suggest that low-dose OXN-PR may be effective and well tolerated for treatment of moderate-to-severe chronic pain in older patients. Besides its effectiveness, these data indicate that low-dose OXN-PR may be considered a safe analgesic option in this fragile population and warrants further investigation in randomized controlled studies.

Long-term efficacy and safety of oxycodone–naloxone prolonged release in geriatric patients with moderate-to-severe chronic noncancer pain: a 52-week open-label extension phase study

Background Two-thirds of older people suffer from chronic pain and finding valid treatment options is essential. In this 1-yearlong investigation, we evaluated the efficacy and safety of prolonged-release oxycodone–naloxone (OXN-PR) in patients aged ≥70 (mean 81.7) years. Methods In this open-label prospective study, patients with moderate-to-severe noncancer chronic pain were prescribed OXN-PR for 1 year. The primary endpoint was the proportion of patients who achieved ≥30% reduction in pain intensity after 52 weeks of treatment, without worsening bowel function. The scheduled visits were at baseline (T0), after 4 weeks (T4), and after 52 weeks (T52). Results Fifty patients completed the study. The primary endpoint was achieved in 78% of patients at T4 and 96% at T52 (P<0.0001). Pain intensity, measured on a 0–10 numerical rating scale, decreased from 6.0 at T0 to 2.8 at T4 and to 1.7 at T52 (P<0.0001). Mean daily dose of oxycodone increased from 10 to 14.4 mg (T4) and finally to 17.4 mg (T52). Bowel Function Index from 35.1 to 28.7 at T52. No changes were observed in cognitive functions (Mini-Mental State Examination evaluation), while daily functioning improved (Barthel Index from 53.1 to 61.0, P<0.0001). The Screener and Opioid Assessment for Patients with Pain-Revised score at 52 weeks was 2.6 (standard deviation 1.6), indicating a low risk of aberrant medication-related behavior. In general, OXN-PR was well tolerated. Conclusion This study of the long-term treatment of chronic pain in a geriatric population with OXN-PR shows satisfying analgesic effects achieved with a stable low daily dose, coupled with a good safety profile and, in particular, with a reduction of constipation, often present during opioid therapy. Our findings support the indications of the American Geriatrics Society, suggesting the use of opioids to treat pain in older people not responsive to acetaminophen or nonsteroidal anti-inflammatory drugs.

an innovative intervention for the treatment of cognitive impairment-emisymmetric bilateral stimulation improves cognitive functions in alzheimer's disease and mild cognitive impairment: an open-label study

Background and aims In the last decade, the development of different methods of brain stimulation by electromagnetic fields (EMF) provides a promising therapeutic tool for subjects with impaired cognitive functions. Emisymmetric bilateral stimulation (EBS) is a novel and innovative EMF brain stimulation, whose working principle is to introduce very weak noise-like stimuli through EMF to trigger self-arrangements in the cortex of treated subjects, thereby improving cognitive faculties. The aim of this pilot study was to investigate in patients with cognitive impairment the effectiveness of EBS treatment with respect to global cognitive function, episodic memory, and executive functions. Methods Fourteen patients with cognitive decline (six with mild cognitive impairment and eight with Alzheimer’s disease) underwent three EBS applications per week to both the cerebral cortex and auricular-specific sites for a total of 5 weeks. At baseline, after 2 weeks and 5 weeks, a neuropsychological assessment was performed through mini–mental state examination, free and cued selective reminding tests, and trail making test. As secondary outcomes, changes in behavior, functionality, and quality of life were also evaluated. Results After 5 weeks of standardized EBS therapy, significant improvements were observed in all neurocognitive assessments. Mini–mental state examination score significantly increased from baseline to end treatment (+3.19, P=0.002). Assessment of episodic memory showed an improvement both in immediate and delayed recalls (immediate recall =+7.57, P=0.003; delayed recall =+4.78, P<0.001). Executive functions significantly improved from baseline to end stimulation (trail making test A −53.35 seconds; P=0.001). Of note, behavioral disorders assessed through neuropsychiatric inventory significantly decreased (−28.78, P<0.001). The analysis concerning the Alzheimer’s disease and mild cognitive impairment group confirmed a significant improvement of cognitive functions and behavior after EBS treatment. Conclusion This pilot study has shown EBS to be a promising, effective, and safe tool to treat cognitive impairment, in addition to the drugs presently available. Further investigations and controlled clinical trials are warranted.

Effectiveness of an Innovative Pulsed Electromagnetic Fields Stimulation in Healing of Untreatable Skin Ulcers in the Frail Elderly: Two Case Reports

Introduction. Recalcitrant skin ulcers are a major burden in elderly patients. Specifically, chronic wounds result in significant morbidity and mortality and have a profound economic impact. Pulsed electromagnetic fields (PEMFs) have proved to be a promising therapy for wound healing. Here we describe the first reported case of an innovative PEMF therapy, Emysimmetric Bilateral Stimulation (EBS), used to successfully treat refractory skin ulcers in two elderly and fragile patients. Case Presentation. Two elderly patients developed multiple chronic skin ulcerations. Despite appropriate treatment, the ulcers showed little improvement and the risk of amputation was high. Both patients underwent daily EBS therapy and standard dressing. After few weeks of treatment, major improvements were observed and all ulcers had healed. Conclusion. In patients with refractory ulceration, EBS therapy may be of real benefit in terms of faster healing. This case supports the supportive role for PEMFs in the treatment of skin ulceration in diabetes and is suggestive of a potential benefit of EBS in this clinical condition.

Is oxycodone/naloxone effective and safe in managing chronic pain of a fragile elderly patient with multiple skin ulcers of the lower limbs? A case report.

Skin ulcers are a common issue in the elderly, as physiological loss of skin elasticity, alterations in microcirculation, and concomitant chronic diseases typically occur in advanced age, thereby predisposing to these painful lesions. Wound-related pain is often associated with skin ulcers and negatively impacts both the patient’s quality of life and, indirectly, wound healing. Pain management is an ongoing issue in the elderly, and remains underestimated and under-treated in this fragile population. Recent guidelines suggest the use of opioids as the frontline treatment of moderate and severe pain in nononcological pain in the elderly. However, due to the concerns of adverse reactions, drug interactions, and addiction, clinicians frequently hesitate to prescribe opioids. This case report describes an elderly diabetic patient with multiple ulcers of the lower limbs suffering wound-related pain. In our report, oxycodone/naloxone has proved to be an effective and safe drug, providing pain relief as well as increased compliance when redressing wounds and faster healing compared to that in similar patients. Our case provides anecdotal evidence, supported by other studies, to justify future, larger studies on chronic pain using this therapy.

Munch's Scream Sign: An Unusual Case of Dysphagia in Advanced Dementia

for the heart in elderly patients with Alzheimer’s disease? Am J Alzheimers Dis Other Demen 2012;27:171–174. 3. Knudtzen FC, Christophersen TB. Third degree atrioventricular block associated with treatment with rivastigmine transdermal patch. J Geriatr Cardiol 2013;10:113–115. 4. Naranjo CA, Busto U, Sellers EM et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239–245. 5. Paulison B, L eos CL. Potential cardiotoxic reaction involving rivastigmine and betablockers: A case report and review of the literature. Cardiovasc Toxicol 2010;10:306–310.

P458: Safety and tolerability of combined prolonged-release oxycodone and naloxone in the management of chronic pain in the elderly

with an estimated glomular filtration rate (eGFR) of ≤50ml/min and with active renally eliminated medications were selected daily by using the hospital information system (CSC). The selected patients were screened by the pharmacists. When a dose adjustment was required or if a drugs were prescribed that are unwanted in renal failure, the prescribing physician was notified. Results: In 2013 there were 295 notifications for dose adjustments according to the clinical rule in our hospital with 450 beds. More data will be presented in the poster presentation. Conclusions: Implementation of the clinical rule for dose adjustment according to renal function has lead to abundant interventions by prescribing physicians.

Pain treatment in the elderly: A new pharmacological approach

ing Scale) in order to determine fall risk in elderly people. One hundred and fifty subjects with mild fall risk met inclusion criteria (mean age 64,85 ys) were randomized into two groups: 75 for group treated with Human Body Posturizer (HBP) and 75 for placebo group. Results.– HBP group showed a significant difference in Short Physical Performance Battery, Tinetti Scale and Pain Numeric Rating Scale (P<0.05). A significant reduction in fall risk was shown in HBP group. Conclusion.– The use of exoskeleton Human Body Posturizer seems to be a new significant device for prevention of fall in elder patients. Further studies will be performed in order to demonstrate the efficacy of this device on elder patients.

Meccanobiologia della riparazione tissutale: dalla fisiopatologia alle implicazioni terapeutiche

Molte delle funzioni cellulari sono controllate o mediate da forze meccaniche. Le cellule sono in grado di rispondere a variazioni delle proprieta meccaniche della matrice trasducendo tali informazioni in risposte molecolari mirate: i segnali meccanici sono in grado di determinare lo sviluppo di una cellula staminale, o di modulare il funzionamento di un intero tessuto, e giocano un ruolo centrale in numerose patologie. Inoltre, sulla base delle proprieta meccaniche dell’ambiente circostante le cellule sono in grado di modificare la loro motilita e la loro attivita metabolica, agendo non come passivi recettori degli stimoli meccanici, ma anche manipolando attivamente la matrice nella quale si trovano sia producendone le principali componenti, che modificandone attivamente la tensione meccanica. Di conseguenza, la meccanotrasduzione svolge un ruolo fondamentale nella riparazione e nel rimodella mento tissutale, suggerendo importanti implicazioni terapeutiche, e permettendo di valutare sotto una nuova luce vecchie terapie empiriche spesso sottovalutate.