F. Guerriero

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.

A Systematic Review on the Effects of Botanicals on Skeletal Muscle Health in Order to Prevent Sarcopenia

We performed a systematic review to evaluate the evidence-based medicine regarding the main botanical extracts and their nutraceutical compounds correlated to skeletal muscle health in order to identify novel strategies that effectively attenuate skeletal muscle loss and enhance muscle function and to improve the quality of life of older subjects. This review contains all eligible studies from 2010 to 2015 and included 57 publications. We focused our attention on effects of botanical extracts on growth and health of muscle and divided these effects into five categories: anti-inflammation, muscle damage prevention, antifatigue, muscle atrophy prevention, and muscle regeneration and differentiation.

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.

Performance of Edmonton Frail Scale on frailty assessment: its association with multi-dimensional geriatric conditions assessed with specific screening tools

BackgroundThe aim of this study was to evaluate the performance of Edmonton Frail Scale (EFS) on frailty assessment in association with multi-dimensional conditions assessed with specific screening tools and to explore the prevalence of frailty by gender.MethodsWe enrolled 366 hospitalised patients (women\men: 251\115), mean age 81.5 years. The EFS was given to the patients to evaluate their frailty. Then we collected data concerning cognitive status through Mini-Mental State Examination (MMSE), health status (evaluated with the number of diseases), functional independence (Barthel Index and Activities Daily Living; BI, ADL, IADL), use of drugs (counting of drugs taken every day), Mini Nutritional Assessment (MNA), Geriatric Depression Scale (GDS), Skeletal Muscle Index of sarcopenia (SMI), osteoporosis and functionality (Handgrip strength).ResultsAccording with the EFS, the 19.7% of subjects were classified as non frail, 66.4% as apparently vulnerable and 13.9% with severe frailty.The EFS scores were associated with cognition (MMSE: β = 0.980; p < 0.01), functional independence (ADL: β = −0.512; p < 0.00); (IADL: β = −0.338; p < 0.01); use of medications (β = 0.110; p < 0.01); nutrition (MNA: β = −0.413; p < 0.01); mood (GDS: β = −0.324; p < 0.01); functional performance (Handgrip: β = −0.114, p < 0.01) (BI: β = −0.037; p < 0.01), but not with number of comorbidities (β = 0.108; p = 0.052). In osteoporotic patients versus not-osteoporotic patients the mean EFS score did not differ between groups (women: p = 0.365; men: p = 0.088), whereas in Sarcopenic versus not-Sarcopenic patients, there was a significant differences in women: p < 0.05.ConclusionsThis study suggests that measuring frailty with EFS is helpful and performance tool for stratifying the state of fragility in a group of institutionalized elderly. As matter of facts the EFS has been shown to be associated with several geriatric conditions such independence, drugs assumption, mood, mental, functional and nutritional status.

Extremely low frequency electromagnetic fields stimulation modulates autoimmunity and immune responses: a possible immuno-modulatory therapeutic effect in neurodegenerative diseases

Increasing evidence shows that extremely low frequency electromagnetic fields (ELF-EMFs) stimulation is able to exert a certain action on autoimmunity and immune cells. In the past, the efficacy of pulsed ELF-EMFs in alleviating the symptoms and the progression of multiple sclerosis has been supported through their action on neurotransmission and on the autoimmune mechanisms responsible for demyelination. Regarding the immune system, ELF-EMF exposure contributes to a general activation of macrophages, resulting in changes of autoimmunity and several immunological reactions, such as increased reactive oxygen species-formation, enhanced phagocytic activity and increased production of chemokines. Transcranial electromagnetic brain stimulation is a non-invasive novel technique used recently to treat different neurodegenerative disorders, in particular Alzheimers disease. Despite its proven value, the mechanisms through which EMF brain-stimulation exerts its beneficial action on neuronal function remains unclear. Recent studies have shown that its beneficial effects may be due to a neuroprotective effect on oxidative cell damage. On the basis of in vitro and clinical studies on brain activity, modulation by ELF-EMFs could possibly counteract the aberrant pro-inflammatory responses present in neurodegenerative disorders reducing their severity and their onset. The objective of this review is to provide a systematic overview of the published literature on EMFs and outline the most promising effects of ELF-EMFs in developing treatments of neurodegenerative disorders. In this regard, we review data supporting the role of ELF-EMF in generating immune-modulatory responses, neuromodulation, and potential neuroprotective benefits. Nonetheless, we reckon that the underlying mechanisms of interaction between EMF and the immune system are still to be completely understood and need further studies at a molecular level.

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.

New opioid prescribing guidelines released in the US: what impact will they have in the care of older patients with persistent pain?

A focus on older adults and the use of opioid treatment for persistent pain is warranted given the high prevalence of pain and its impact in later life, as well as the substantial prevalence of opioid treatment in older adults. Almost half of all adults over age 65 daily experience persistent and debilitating pain due to multiple causes, including degenerative arthritis, spinal stenosis, and nerve damage (e.g. post-herpetic and diabetes). Persistent pain is associated with substantial disability in this age group, characterized by reducd mobility, activity avoidance, increased risk of falls, and psychosocial morbidity, including depression, anxiety, and social isolation. Pain relief constitutes one of the most commonly endorsed goals of older adults and a large body of evidence now demonstrates that advanced age is a risk factor for under-treatment of pain. Possibly in response to this finding, US providers are prescribing opioids to older adults in record numbers. One large study examined prescribing patterns from 1999 to 2010 in the US and found that almost one in ten older patients received an opioid prescription. In 2015, as many as 30% of Medicare Part D enrollees received an opioid prescription suggesting that opioid prescribing continues to increase in this age group. Parallel to the dramatic increase in medical prescriptions of opioids (POs), which has occurred over the past two decades in the US, non-medical and misuse of POs has also strongly increased. Although an increase in prescribing strong opioids has also taken place in most EU countries over the past 15 years, the total number of prescriptions and PO-related mortality rates remain far lower than in the US. The public health consequences of the opioid epidemic in the US have been profound to include record numbers of unintentional overdoses as well as overdose-related deaths (more than 165,000 over a 16 year period). In an effort to address the opioid epidemic, the Centers for Disease Control and Prevention (CDC) recently released a guideline for prescribing opioids for chronic pain. The recommendations focus on the treatment of patients with chronic non-cancer pain (hereafter referred to as persistent pain) as opposed to those receiving active cancer treatment or palliative/end-of-life care. The guideline presents recommendations to help providers: (1) determine when to initiate opioids and guidance regarding the selection and dosing of opioids; (2) establish whether treatment benefits are occurring and decide whether to continue opioid therapy; and (3) conduct risk assessments and address harm that occurs as a consequence of opioid use. In this editorial, we review elements of the CDC guidelines that we believe could have positive or negative consequences when providing care to older adults with persistent pain. We also speculate about the implications of implementing the guidelines from a geriatric medicine perspective. In the sections below, we examine several of the CDC guidelines, highlighting their positive and problematic elements. We also raise questions about what impact implementing the guidelines could have on the care of older adults with persistent pain (Table 1). Readers are strongly encouraged to review all 12 recommendations that are part of the guideline.

Nutritional management in an elderly man with esophageal and gastric necrosis after caustic soda ingestion: a case report

The ingestion of corrosive industrial chemical agents, such as caustic soda, that are mostly used for household cleaning, usually occurs accidentally or for suicidal purposes. Multiple protocols are based on documented success in preventing impending complications. In this study, we present a case of a 70-year-old man who swallowed caustic soda in a suicide attempt, causing a development of strong esophageal and gastric necrosis with subsequent gastrectomy and digiunostomy. Initially, the recommended nutritional approach was via percutaneous endoscopic jejunostomy by a polymer and high-caloric formula, with an elevated content of soluble fiber. After 5 months, the medical team removed the percutaneous endoscopic jejunostomy and the patient switched from enteral to oral nutrition. In this step, it was decided to introduce two oral, high-caloric supplements: an energy supplement in powder, based on maltodextrin, immediately soluble in foods or in hot/cold drinks and a high-energy and protein drink, enriched with arginine, vitamin C, zinc, and antioxidants. Oral administration (per os) was well tolerated by consuming homogenized food mixed in water. After 1 month, the patient was discharged from the hospital and was able to eat a regular meal.