Pathophysiology of Nociception and Rare Genetic Disorders with Increased Pain Threshold or Pain Insensitivity.

Pain and nociception are different phenomena. Nociception is the result of complex activity in sensory pathways. On the other hand, pain is the effect of interactions between nociceptive processes, and cognition, emotions, as well as the social context of the individual. Alterations in the nociceptive route can have different genesis and affect the entire sensorial process. Genetic problems in nociception, clinically characterized by reduced or absent pain sensitivity, compose an important chapter within pain medicine. This chapter encompasses a wide range of very rare diseases. Several genes have been identified. These genes encode the Nav channels 1.7 and 1.9 (SCN9A, and SCN11A genes, respectively), NGFß and its receptor tyrosine receptor kinase A, as well as the transcription factor PRDM12, and autophagy controllers (TECPR2). Monogenic disorders provoke hereditary sensory and autonomic neuropathies. Their clinical pictures are extremely variable, and a precise classification has yet to be established. Additionally, pain insensitivity is described in diverse numerical and structural chromosomal abnormalities, such as Angelman syndrome, Prader Willy syndrome, Chromosome 15q duplication syndrome, and Chromosome 4 interstitial deletion. Studying these conditions could be a practical strategy to better understand the mechanisms of nociception and investigate potential therapeutic targets against pain.

The challenge of pain assessment in children with cognitive disabilities: Features and clinical applicability of different observational tools.

Children with cognitive disabilities are at greater risk of experiencing pain. It has been shown that this paediatric population often receive inadequate pain management. Pain may be very difficult to assess, especially in a defined subgroup with non-communicating intellectual disability or severe cognitive disability. Accordingly, several observational pain assessment tools have been proposed to overcome this issue. Due to the absence of an ideal measurement tool, accurate pain assessment requires, after a case-by-case analysis, selecting the more appropriate tool or a variety of combined instruments. The aim of this work is to provide a comprehensive review of the pain assessment tools commonly used in cognitively impaired children. Critical discussion on features and clinical applicability may suggest how to overcome this difficult challenge. Furthermore, this review will help further research aiming to design new instruments and to improve already-in-use tools.

Chemotherapy-related cognitive impairment: mechanisms, clinical features and research perspectives.

The term chemotherapy-related cognitive impairment (CRCI), or cognitive dysfunction, or chemo fog, or chemo brain, is referred to a decline in a variety of neuropsychological tasks after chemotherapy, or following other anticancer treatments such as radiation therapy or surgery, in patients with non-central nervous system cancers. Furthermore, several pieces of evidence suggest that clinical manifestations of cognitive impairment may occur in cancer patients, prior to chemotherapy or in those not treated with cancer therapies. In these circumstances, it should be more appropriate to use the term cancer-related cognitive dysfunction. Because there is no consensus about its definition and diagnostic criteria, no specific test for CRCI diagnose exists. Whatever the cause, this manifestation of central nervous system toxicity is of increasing concern as the survival rates for cancer have improved steadily and, in turn, cognitive dysfunction can negatively impact the patients and cancer survivors' quality of life. The aim of this work is to offer an overview of the topic and recommendations for future research.

Towards a better understanding of anesthesia emergence mechanisms: Research and clinical implications.

Emergence from anesthesia (AE) is the ending stage of anesthesia featuring the transition from unconsciousness to complete wakefulness and recovery of consciousness (RoC). A wide range of undesirable complications, including coughing, respiratory/cardiovascular events, and mental status changes such as emergence delirium, and delayed RoC, may occur during this critical phase. In general anesthesia processes, induction and AE represent a neurobiological example of "hysteresis". Indeed, AE mechanisms should not be simply considered as reverse events of those occurring in the induction phase. Anesthesia-induced loss of consciousness (LoC) and AE until RoC are quite distinct phenomena with, in part, a distinct neurobiology. Althoughanaesthetics produce LoC mostly by affecting cortical connectivity, arousal processes at the end of anesthesia are triggered by structures deep in the brain, rather than being induced within the neocortex. This work aimed to provide an overview on AE processes research, in terms of mechanisms, and EEG findings. Because most of the research in this field concerns preclinical investigations, translational suggestions and research perspectives are proposed. However, little is known about the relationship between AE neurobiology, and potential complications occurring during the emergence, and after the RoC. Thus, another scope of this review is to underline why a better understanding of AE mechanisms could have significant clinical implications, such as improving the patients' quality of recovery, and avoiding early and late postoperative complications.

Dissecting the Potential Roles of Nigella sativa and Its Constituent Thymoquinone on the Prevention and on the Progression of Alzheimer's Disease.

Several nutraceuticals have been investigated for preventing or retarding the progression of different neurodegenerative diseases, including Alzheimer's disease (AD). Because Nigella sativa (NS) and its isolated compound thymoquinone (TQ) have significant anti-oxidant and anti-inflammatory proprieties, they could represent effective neuroprotective agents. The purpose of this manuscript is to analyze and to recapitulate the results of in vitro and in vivo studies on the potential role of NS/TQ in AD's prevention and treatment. The level of evidence for each included animal study has been assessed by using a modified CAMARADES (Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies) 10-item checklist. We used MEDLINE and EMBASE databases to screen relevant articles published up to July 2017. A manual search was also performed. The database search yielded 38 studies, of which 18 were included in this manuscript. Results from these approaches suggest that NS or TQ could represent an effective strategy against AD due to the balancing of oxidative processes and the binding to specific intracellular targets. The overall effects mainly regard the prevention of hippocampal pyramidal cell loss and the increased cognitive functions.

Anesthetic dreaming, anesthesia awareness and patient satisfaction after deep sedation with propofol target controlled infusion: A prospective cohort study of patients undergoing day case breast surgery.

BACKGROUND: Anesthetic dreaming and anesthesia awareness are well distinct phenomena. Although the incidence of intraoperative awareness is more common among patients who reported a dream after surgery, the exact correlation between the two phenomena remains an unsolved rebus. The main purpose of this study was to investigate anesthetic dreaming, anesthesia awareness and psychological consequences eventually occurred under deep sedation. Intraoperative dreaming experiences were correlated with dream features in natural sleep. METHODS: Fifty-one patients, undergoing surgical excision of fibroadenomas under a Bispectral index-guided deep sedation anesthesia with propofol target controlled infusion, were enrolled into this prospective study. Psychological assessment was performed through the State Trait Anxiety Inventory. A questionnaire was adopted to register dreaming and anesthesia awareness. Data were collected after emergence (t0), 24 hours (t1), 1 month (t2), 6 months (t3). RESULTS: Six patients (12%) reported anesthetic dreaming at t0 confirming the response at each subsequent evaluation. One patient (2%) confirmed dreaming during anesthesia in all, but denied it at t0. There was a high correlation between the intraoperative dream contents and the features of dreams in natural sleep. No cases of anesthesia awareness were detected. A similar level of satisfaction was observed in dreaming and no-dreaming patients. CONCLUSIONS: Anesthetic dreaming does not seem to influence satisfaction of patients undergoing deep sedation with propofol target controlled infusion. A psychological assessment would seem to improve the evaluation of possible psychological consequences in dreamer patient.

Pain insensitivity in a child with a de novo interstitial deletion of the long arm of the chromosome 4: Case report.

Terminal and interstitial deletions of the distal segment of the long arm of chromosome 4 (Cr4q del) are not common genetic disorders. The severity of the phenotype is correlated with the size of the deletion because small deletions have little clinical impact, whereas large deletions are usually associated with multiple congenital anomalies, postnatal growth failure, and moderate to severe intellectual disability. Alteration in pain tolerance has not been included among these features, also in case of large deletions. The purpose of this report is to document a case of a child affected by interstitial Cr4q del, expressing pain insensitivity as clinical feature not previously described. We also offer a discussion on genetic disorders featuring pain insensitivity/indifference. CASE REPORT: A Caucasian girl aged 12 came to our observation for a developmental delay with multiple congenital abnormalities and moderate intellectual disability (IQ 47). A de novo interstitial Cr4 del between band q31.3 and q32.2 (Cr4 del q31.3 to q32.2) was found. The child also expresses no evidence of pain perception to injures which normally evoke pain. Consequently, she is affected by severe disability caused by painless injuries and self-injurious behaviours, such as excessive self-rubbing and scratching. The neurological examination manifested high pain threshold with preserved tactile sensitivity. CONCLUSIONS: This is the first report of pain insensitivity in a patient with a specific genetic deletion involving the interstitial region of the distal long arm of Cr4. Moreover, this report could serve as a useful model to better understand mechanisms of pain perception and its modulation.

The efficacy of Epigallocatechin-3-gallate (green tea) in the treatment of Alzheimer's disease: an overview of pre-clinical studies and translational perspectives in clinical practice.

Alzheimer's disease (AD) is a neurodegenerative disorder and the most common form of dementia characterized by cognitive and memory impairment. One of the mechanism involved in the pathogenesis of AD, is the oxidative stress being involved in AD's development and progression. In addition, several studies proved that chronic viral infections, mainly induced by Human herpesvirus 1 (HHV-1), Cytomegalovirus (CMV), Human herpesvirus 2 (HHV-2), and Hepatitis C virus (HCV) could be responsible for AD's neuropathology. Despite the large amount of data regarding the pathogenesis of Alzheimer's disease (AD), a very limited number of therapeutic drugs and/or pharmacological approaches, have been developed so far. It is important to underline that, in recent years, natural compounds, due their antioxidants and anti-inflammatory properties have been largely studied and identified as promising agents for the prevention and treatment of neurodegenerative diseases, including AD. The ester of epigallocatechin and gallic acid, (-)-Epigallocatechin-3-Gallate (EGCG), is the main and most significantly bioactive polyphenol found in solid green tea extract. Several studies showed that this compound has important anti-inflammatory and antiatherogenic properties as well as protective effects against neuronal damage and brain edema. To date, many studies regarding the potential effects of EGCG in AD's treatment have been reported in literature. The purpose of this review is to summarize the in vitro and in vivo pre-clinical studies on the use of EGCG in the prevention and the treatment of AD as well as to offer new insights for translational perspectives into clinical practice.

Role of Nigella sativa and Its Constituent Thymoquinone on Chemotherapy-Induced Nephrotoxicity: Evidences from Experimental Animal Studies.

BACKGROUND: Most chemotherapeutic drugs are known to cause nephrotoxicity. Therefore, new strategies have been considered to prevent chemotherapy-induced nephrotoxicity. It is of note that Nigella sativa (NS), or its isolated compound Thymoquinone (TQ), has a potential role in combating chemotherapy-induced nephrotoxicity. AIM: To analyze and report the outcome of experimental animal studies on the protective effects of NS/TQ on chemotherapy-associated kidney complications. DESIGN: Standard systematic review and narrative synthesis. DATA SOURCES: MEDLINE, EMBASE databases were searched for relevant articles published up to March 2017. Additionally, a manual search was performed. Criteria for a study's inclusion were: conducted in animals, systematic reviews and meta-analysis, containing data on nephroprotective effects of NS/TQ compared to a placebo or other substance. All strains and genders were included. RESULTS: The database search yielded 71 studies, of which 12 (cisplatin-induced nephrotoxicity 8; methotrexate-induced nephrotoxicity 1; doxorubicin-induced nephrotoxicity 2; ifosfamide-induced nephrotoxicity 1) were included in this review. CONCLUSIONS: Experimental animal studies showed the protective effect of NS, or TQ, on chemotherapy-induced nephrotoxicity. These effects are caused by decreasing lipid peroxidation and increasing activity of antioxidant enzymes in renal tissue of chemotherapy-treated animals.

Pain insensitivity in a child with a de novo interstitial deletion of the long arm of the chromosome 4: Case report / Insensibilidad al dolor en un niño con una deleción intersticial de novo del brazo largo del cromosoma 4

Terminal and interstitial deletions of the distal segment of the long arm of chromosome 4 (Cr4q del) are not common genetic disorders. The severity of the phenotype is correlated with the size of the deletion because small deletions have little clinical impact, whereas large deletions are usually associated with multiple congenital anomalies, postnatal growth failure, and moderate to severe intellectual disability. Alteration in pain tolerance has not been included among these features, also in case of large deletions. The purpose of this report is to document a case of a child affected by interstitial Cr4q del, expressing pain insensitivity as clinical feature not previously described. We also offer a discussion on genetic disorders featuring pain insensitivity/indifference. Case report. A Caucasian girl aged 12 came to our observation for a developmental delay with multiple congenital abnormalities and moderate intellectual disability (IQ 47). A de novo interstitial Cr4 del between band q31.3 and q32.2 (Cr4 del q31.3 to q32.2) was found. The child also expresses no evidence of pain perception to injures which normally evoke pain. Consequently, she is affected by severe disability caused by painless injuries and self-injurious behaviours, such as excessive self-rubbing and scratching. The neurological examination manifested high pain threshold with preserved tactile sensitivity. Conclusions. This is the first report of pain insensitivity in a patient with a specific genetic deletion involving the interstitial region of the distal long arm of Cr4. Moreover, this report could serve as a useful model to better understand mechanisms of pain perception and its modulation.

Potential application of the Kampo medicine goshajinkigan for prevention of chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common and severe adverse effects related to cancer treatment. Unfortunately, although several agents and protocols have been proposed, no prophylactic strategies have yet to be proven useful. Therefore, new alternative therapies have been considered for CIPN prevention. Herbal medicine in Japan, called Kampo medicine, is derived from traditional Chinese medicine. Goshajinkigan (GJG) is a Kampo medicine, that is comprised of ten herbs. The aim of this work is to analyse the results of pre-clinical and clinical studies on the potential applications of GJG in CIPN prevention.

Features and Role of Minimally Invasive Palliative Procedures for Pain Management in Malignant Pelvic Diseases: A Review.

Pain is a common and debilitating symptom in pelvic cancer diseases. Failure in controlling this pain through pharmacological approaches calls for employing multimodal management and invasive techniques. Various strategies are commonly used for this purpose, including palliative radiotherapy, epidural medications and intrathecal administration of analgesic and local anesthetic drugs with pumps, and neural or plexus blockade. This review focuses on the features of minimally invasive palliative procedures (MIPPs), such as radiofrequency ablation, laser-induced thermotherapy, cryoablation, irreversible electroporation, electrochemotherapy, microwave ablation, and cementoplasty as well as their role in palliation of cancer pelvic pain. Despite the evidence of effectiveness and safety of these interventions, there are still many barriers to accessing MIPPs, including the availability of trained staff, the lack of precise criteria of indication, and the high costs.

The underestimated role of psychological and rehabilitation approaches for management of cancer pain. A brief commentary.

Individually tailored pharmacological regimen is the standard approach for treating patients affected by cancer pain, allowing the control of symptoms in approximately 90% of cases. If this strategy is ineffective it is possible to use more complex invasive, or minimally invasive, techniques. Nevertheless, both patients and health care professionals often underestimate the impact of cancer pain on psychological distress, and do not consider the potential benefits of psychological treatments to help manage cancer pain. These non-pharmacological strategies should be part of the multidisciplinary pain therapy, supporting and strengthening drug therapy. The purpose of this brief commentary is to discuss the role of psychological and rehabilitation approaches for improving the quality of life and the psychosocial outcomes in patients with cancer pain.

Consciousness fluctuation during general anesthesia: a theoretical approach to anesthesia awareness and memory modulation.

With anesthesia awareness as a model of study we debate the both fascinating and dangerous phenomenon called consciousness fluctuation that takes place during surgical anesthesia. In accordance with current scientific knowledge this paradox is the consequence of our limits in both precise knowledge of anesthesia mechanisms and our inability to accurately assess the level of anesthesia with brain monitoring. We also focus on the relationships between memory and anesthesia, as well as the possibility of interfering with memory during general anesthesia.

A 7-Year Retrospective Multisource Analysis on the Incidence of Anesthesia Awareness With Recall in Cancer Patients: A Chance of Collaboration Between Anesthesiologists and Psycho-Oncologists for Awareness Detection.

Although randomized controlled studies reported an incidence of anesthesia awareness with recall ∼1 to 2 per 1000 (0.1-0.2%), recent data from the NAP5 study showed an incidence of only 1:19,600. Although in a prospective study many tools for anesthesia awareness detection can be used, a retrospective analysis requires a careful collection of information.The aim of the study was to evaluate the incidence of anesthesia awareness with recall in a cohort of cancer patients through a multisource retrospective analysis, and the clinical description, including the psychological outcome, of the cases detected. We also tested whether our retrospective analysis would be improved by a routinely psycho-oncological assessment. As secondary endpoints we evaluated the use of depth of anesthesia monitoring over a large cohort of patients, and the correlation between the brain monitoring and the incidence of awareness.We have carried out a 7-year retrospective analysis in a large cohort of cancer patients on the incidence of awareness with recall during general anesthesia. Of 35,595 patients assessed for eligibility, 21,099 were studied. We analyzed all data from the operative rooms' database, the anesthesia records, and from the database of the surgical divisions. In addition we examined reports from psychologists and spontaneous reports to the quality team of the hospital.Two certain cases of awareness were detected, with an incidence of 1:10,550 (0.0095%). They occurred during elective surgery, in female patients without other risk factors. One case came from the report of a psychologist. In both episodes, brain monitoring was not applied and no long-term psychological sequelae were reported.Despite the limitations, our investigation suggests that the incidence of anesthesia awareness is very low, also in a specific cohort of patients, such as the cancer patients, and even when the depth of anesthesia monitoring is rarely used. The limitations caused by both the retrospective analysis and the absence of specific tools for direct awareness detection, such as structured interviews, can be filled with an effective postoperative psychological assessment which is often of routine in a cancer center. This observation could suggest the usefulness of inserting specific questions within the psychological tools commonly used by psycho-oncologists.

Early onset intellectual disability in chromosome 22q11.2 deletion syndrome.

Chromosome 22q11.2 deletion syndrome, or DiGeorge syndrome, or velocardiofacial syndrome, is one of the most common multiple anomaly syndromes in humans. This syndrome is commonly caused by a microdelection from chromosome 22 at band q11.2. Although this genetic disorder may reflect several clinical abnormalities and different degrees of organ commitment, the clinical features that have driven the greatest amount of attention are behavioral and developmental features, because individuals with 22q11.2 deletion syndrome have a 30-fold risk of developing schizophrenia. There are differing opinions about the cognitive development, and commonly a cognitive decline rather than an early onset intellectual disability has been observed. We report a case of 22q11.2 deletion syndrome with both early assessment of mild intellectual disabilities and tetralogy of Fallot as the only physic manifestation.

Early onset intellectual disability in chromosome 22q11.2 deletion syndrome / Inicio temprano de discapacidad intelectual en el Síndrome de deleción del cromosoma 22q11.2

Chromosome 22q11.2 deletion syndrome, or DiGeorge syndrome, or velocardiofacial syndrome, is one of the most common multiple anomaly syndromes in humans. This syndrome is commonly caused by a microdelection from chromosome 22 at band q11.2. Although this genetic disorder may reflect several clinical abnormalities and different degrees of organ commitment, the clinical features that have driven the greatest amount of attention are behavioral and developmental features, because individuals with 22q11.2 deletion syndrome have a 30-fold risk of developing schizophrenia. There are differing opinions about the cognitive development, and commonly a cognitive decline rather than an early onset intellectual disability has been observed. We report a case of 22q11.2 deletion syndrome with both early assessment of mild intellectual disabilities and tetralogy of Fallot as the only physic manifestation.

El síndrome del cromosoma 22q11.2, también conocido como supresión o síndrome de DiGeorge o síndrome velocardiofacial, es uno de los síndromes más comunes de anomalías múltiples en los seres humanos. Este síndrome es comúnmente causado por una microdeleción del cromosoma 22 en q11.2 banda. Aunque este trastorno genético muestra varias anomalías clínicas y diferentes grados de compromiso orgánico, las características clínicas que han atraído la mayor atención son el comportamiento y el desarrollo, porque las personas con síndrome de deleción 22q11.2 tienen un riesgo 30 veces mayor de desarrollar esquizofrenia. Hay diferentes opiniones sobre el desarrollo cognitivo, y comúnmente se se ha observado un deterioro cognitivo en lugar de un inicio temprano de discapacidad intelectual. Presentamos un caso de síndrome de deleción 22q11.2 tanto con la evaluación temprana de discapacidades intelectuales leves como con la tetralogía de Fallot como única manifestación física.