Pharmacogenetics of tenofovir drug transporters in the context of HBV: Is there an impact?

BACKGROUND: Current treatments for chronic hepatitis B management include orally administered nucleos(t)ide analogues, such as tenofovir (TDF), which is an acyclic adenine nucleotide analogue used both in HBV and human immune deficiency virus (HIV). The course of HBV infection is mainly dependent on viral factors, such as HBV genotypes, immunological features and host genetic variables, but a few data are available in the context of HBV, in particular for polymorphisms of genes encoding proteins involved in drug metabolism and elimination. Consequently, the aim of this study was to evaluate the potential impact of genetic variants on TDF plasma and urine concentrations in patients with HBV, considering the role of HBV genotypes. METHODS: A retrospective cohort study at the Infectious Disease Unit of Amedeo di Savoia Hospital, Torino, Italy, was performed. Pharmacokinetic analyses were performed through liquidi chromatography, whereas pharmacogenetic analyses through real-time PCR. FINDINGS: Sixty - eight patients were analyzed: ABCC4 4976 C>T genetic variant showed an impact on urine TDF drug concentrations (p = 0.014). In addition, SLC22A6 453 AA was retained in the final regression multivariate model considering factors predicting plasma concentrations, while ABCC4 4976 TC/CC was the only predictor of urine concentrations in the univariate model. INTERPRETATION: In conclusion, this is the first study showing a potential impact of genetic variants on TDF plasma and urine concentrations in the HBV context, but further studies in different and larger cohorts of patients are required.

A novel estimate of biological aging by multiple fitness tests is associated with risk scores for age-related diseases.

Introduction: Recent research highlights the need for a correct instrument for monitoring the individual health status, especially in the elderly. Different definitions of biological aging have been proposed, with a consistent positive association of physical activity and physical fitness with decelerated aging trajectories. The six-minute walking test is considered the current gold standard for estimating the individual fitness status in the elderly. Methods: In this study, we investigated the possibility of overcoming the main limitations of assessing fitness status based on a single measure. As a result, we developed a novel measure of fitness status based on multiple fitness tests. In 176 Sardinian individuals aged 51-80 years we collected the results of eight fitness tests to measure participants' functional mobility, gait, aerobic condition, endurance, upper and lower limb strength, and static and dynamic balance. In addition, the participants' state of health was estimated through validated risk scores for cardiovascular diseases, diabetes, mortality, and a comorbidity index. Results: Six measures contributing to fitness age were extracted, with TUG showing the largest contribution (beta = 2.23 SDs), followed by handgrip strength (beta = -1.98 SDs) and 6MWT distance (beta = -1.11 SDs). Based on fitness age estimates, we developed a biological aging measure using an elastic net model regression as a linear combination of the results of the fitness tests described above. Our newly developed biomarker was significantly associated with risk scores for cardiovascular events (ACC-AHA: r = 0.61; p = 0.0006; MESA: r = 0.21; p = 0.002) and mortality (Levine mortality score: r = 0.90; p = 0.0002) and outperformed the previous definition of fitness status based on the six-minute walking test in predicting an individual health status. Discussion: Our results indicate that a composite measure of biological age based on multiple fitness tests may be helpful for screening and monitoring strategies in clinical practice. However, additional studies are needed to test standardisation and to calibrate and validate the present results.

Analysis of the oral microbiome during hormonal cycle and its alterations in menopausal women: the "AMICA" project.

The maintenance of human health is dependent on a symbiotic relationship between humans and associated bacteria. The diversity and abundance of each habitat's signature microbes vary widely among body areas and among them the oral microbiome plays a key role. Significant changes in the oral cavity, predominantly at salivary and periodontal level, have been associated with changes in estrogen levels. However, whether the oral microbiome is affected by hormonal level alterations is understudied. Hence the main objective pursued by AMICA project was to characterize the oral microbiome (saliva) in healthy women through: profiling studies using "omics" technologies (NMR-based metabolomics, targeted lipidomics by LC-MS, metagenomics by NGS); SinglePlex ELISA assays; glycosidase activity analyses and bioinformatic analysis. For this purpose, thirty-nine medically healthy women aged 26-77 years (19 with menstrual cycle and 20 in menopause) were recruited. Participants completed questionnaires assessing detailed medical and medication history and demographic characteristics. Plasmatic and salivary levels of sexual hormones were assessed (FSH, estradiol, LH and progesteron) at day 3 and 14 for women with menstrual cycle and only once for women in menopause. Salivary microbiome composition was assessed through meta-taxonomic 16S sequencing and overall, the salivary microbiome of most women remained relatively stable throughout the menstrual cycle and in menopause. Targeted lipidomics and untargeted metabolomics profiling were assessed through the use of LC-MS and NMR spectroscopy technologies, respectively and significant changes in terms of metabolites were identified in saliva of post-menopausal women in comparison to cycle. Moreover, glycosyl hydrolase activities were screened and showed that the ß-D-hexosaminidase activity was the most present among those analyzed. Although this study has not identified significant alterations in the composition of the oral microbiome, multiomics analysis have revealed a strong correlation between 2-AG and α-mannosidase. In conclusion, the use of a multidisciplinary approach to investigate the oral microbiome of healthy women provided some indication about microbiome-derived predictive biomarkers that could be used in the future for developing new strategies to help to re-establish the correct hormonal balance in post-menopausal women.

Contralateral Effects of Unilateral Strength and Skill Training: Modified Delphi Consensus to Establish Key Aspects of Cross-Education.

BACKGROUND: Cross-education refers to increased motor output (i.e., force generation, skill) of the opposite, untrained limb following a period of unilateral exercise training. Despite extensive research, several aspects of the transfer phenomenon remain controversial. METHODS: A modified two-round Delphi online survey was conducted among international experts to reach consensus on terminology, methodology, mechanisms of action, and translational potential of cross-education, and to provide a framework for future research. RESULTS: Through purposive sampling of the literature, we identified 56 noted experts in the field, of whom 32 completed the survey, and reached consensus (75% threshold) on 17 out of 27 items. CONCLUSION: Our consensus-based recommendations for future studies are that (1) the term 'cross-education' should be adopted to refer to the transfer phenomenon, also specifying if transfer of strength or skill is meant; (2) functional magnetic resonance imaging, short-interval intracortical inhibition and interhemispheric inhibition appear to be promising tools to study the mechanisms of transfer; (3) strategies which maximize cross-education, such as high-intensity training, eccentric contractions, and mirror illusion, seem worth being included in the intervention plan; (4) study protocols should be designed to include at least 13-18 sessions or 4-6 weeks to produce functionally meaningful transfer of strength, and (5) cross-education could be considered as an adjuvant treatment particularly for unilateral orthopedic conditions and sports injuries. Additionally, a clear gap in views emerged between the research field and the purely clinical field. The present consensus statement clarifies relevant aspects of cross-education including neurophysiological, neuroanatomical, and methodological characteristics of the transfer phenomenon, and provides guidance on how to improve the quality and usability of future cross-education studies.

Olfactory epithelium histopathological findings in long-term coronavirus disease 2019 related anosmia.

BACKGROUND: Olfactory dysfunction represents one of the most frequent symptoms of coronavirus disease 2019, affecting about 70 per cent of patients. However, the pathogenesis of the olfactory dysfunction in coronavirus disease 2019 has not yet been elucidated. CASE REPORT: This report presents the radiological and histopathological findings of a patient who presented with anosmia persisting for more than three months after infection with severe acute respiratory syndrome coronavirus-2. CONCLUSION: The biopsy demonstrated significant disruption of the olfactory epithelium. This shifts the focus away from invasion of the olfactory bulb and encourages further studies of treatments targeted at the surface epithelium.

Data on compounding lopinavir and ritonavir suspension for non-cooperative COVID-19 patients.

The COVID-19 outbreak is now one of the most critical crises to manage for most of national healthcare systems in the world. The situation is complicated by the absence of vaccines and authorized pharmacological treatments, except for remdesivir. In this context, many medicaments, including different Ebola and HIV antivirals, are used off-label in the hospital wards as life-treating medicines for COVID-19 patients. Authorized medicaments manipulation is sometimes necessary because they are not always formulated to be administered to non-cooperative patients or they are in shortage. It is this the case of the fixed combination of lopinavir/ritonavir, which was extensively used in the first phase of the outbreak inducing a shortage of the oral solution available in the EU market. This work provides data on size distribution, osmolarity other than drug chemical stability of a lopinavir/ritonavir extemporaneous preparation made by using the solid dosage form (i.e., tablet) available on the market as drug source. The reported data indicate that such preparation is suitable to be delivered through a nasogastric tube, and enough stable for two weeks from the preparation at room temperature.

Data on the stability of darunavir/cobicistat suspension after tablet manipulation.

The COVID-19 outbreak is now one of the most critical crises to manage for most of the national healthcare systems in the world. In the absence of authorised pharmacological treatments, many antiretrovirals, including darunavir/cobicistat fixed combination, are used off-label in the hospital wards as life-treating medicines for COVID-19 patients. Unfortunately, for most of them, the drug products available on the market are not designed to be administered by a nasogastric tube to inpatients of intensive care units. Therefore, their manipulation, even if it can strongly affect the product quality, is necessary for the preparation of suspension to meet patients' need. In this situation, it is urgent to provide data and guidance to support hospital pharmacists and clinicians in their activity. The data in this article indicate that darunavir/cobicistat suspensions compounded by pharmacists using as active ingredient a commercially available tablet can be stable at least for one week.

Antiretroviral concentrations in the presence and absence of valproic acid.

OBJECTIVES: An unexpected drug-drug interaction has been recently reported between dolutegravir, an HIV integrase inhibitor, and valproic acid. Despite there being several potential underlying mechanisms, plasma protein displacement has been suggested. The aim of this study was to assess plasma concentrations of several antiretrovirals when administered with or without valproic acid. METHODS: We performed a therapeutic drug monitoring registry analysis and identified patients concomitantly taking antiretrovirals and valproic acid and without clinical affecting conditions or interacting drugs. RESULTS: One hundred and thirty-four patients were identified. Median (IQR) age and BMI were 49.7 years (45-56) and 23.4 kg/m2 (20.8-26.3) and 78 were male (58.2%). Despite small groups, we observed no major effect on antiretroviral exposure, even when considering highly protein-bound compounds (such as etravirine), with the exception of dolutegravir trough concentrations [median (IQR) = 132 ng/mL (62-227) in individuals on valproic acid versus 760 ng/mL (333-1407) in those not receiving valproic acid]. CONCLUSIONS: Valproic acid does not have a major effect on antiretrovirals other than dolutegravir. The mechanism of this unexpected drug-drug interaction may be the combination of protein displacement, reduced absorption and CYP3A4 induction.

Gait changes following direct versus contralateral strength training: A randomized controlled pilot study in individuals with multiple sclerosis.

BACKGROUND: Contralateral strength training (CST) is increasingly investigated and employed as a non-conventional way to induce an indirect gain in strength in the weakened untrained limb. However, its effects on gait performance are more controversial. RESEARCH QUESTION: To assess and compare the effects of contralateral (CST) and direct (DST) strength training on spatio-temporal parameters, kinematic and kinetic descriptors of gait in persons with relapsing-remitting multiple sclerosis (PwMS). METHODS: Twenty-eight PwMS (EDSS 2.0-5.5) with inter-side difference in ankle dorsiflexors' strength ≥ 20 % and moderate gait impairment (walking speed 0.70-0.94 m/s), were randomly assigned to a CST (undergoing training of the less-affected dorsiflexors) or DST group (where the most-affected dorsiflexors were trained). Before and after a 6-week high-intensity resistance training (three 25-minute sessions/week), PwMS underwent bilateral measurements of dorsiflexors' maximal strength and assessment of gait spatio-temporal parameters, lower limb joint kinematics and kinetics. RESULTS AND SIGNIFICANCE: Following the training period, muscle strength increased significantly in both groups (on average, CST + 29.5 %, p < 0.0005; DST + 15.7 %, p = 0.001) with no difference between the two interventions. Significant changes in gait speed (+16.5 %; p < 0.0001) and stride length (+6.0 %; p = 0.04) were detected only after DST, while no difference was detected in the CST group. Ankle moment and ROM were unaffected by the training. In PwMS with mild to moderate disability and lower limb dorsiflexors' strength asymmetry, CST was not inferior to DST in inducing significant strength gains in the untrained most-affected limb. However, only DST significantly improved gait performance and, specifically, walking speed. Even though CST did not worsen asymmetry, data suggest that contralateral approaches should not be recommended straightaway if the training goal is to improve outcomes other than strength and, specifically, walking speed.

TREatment of ATopic eczema (TREAT) Registry Taskforce: protocol for a European safety study of dupilumab and other systemic therapies in patients with atopic eczema.

BACKGROUND: A long-term prospective observational safety study is essential to characterize fully the safety profile of systemic immunomodulating therapies for patients with atopic eczema. The TREatment of ATopic eczema (TREAT) Registry Taskforce offers a large platform to conduct such research using national registries that collect the same data using a predefined core dataset. OBJECTIVES: To present a protocol for a safety study comparing dupilumab with other systemic immunomodulating therapies in children and adults with moderate-to-severe atopic eczema, to assess the long-term safety risk of these therapies in a routine clinical care setting. METHODS: We describe a registry-embedded international observational prospective cohort study. Adult and paediatric patients who start treatment with dupilumab or another systemic immunomodulating agent for their atopic eczema will be included. The primary end point is the incidence of malignancies (excluding nonmelanoma skin cancer) compared between the treatment groups. Secondary end points include other serious adverse events and adverse events of special interest, such as eye disorders and eosinophilia. CONCLUSIONS: This protocol delineates a safety study for dupilumab in adult and paediatric patients with atopic eczema, using a standardized methodological approach across several national registries. The protocol could also be used for other novel systemic immunomodulating therapies, and could provide licensing and reimbursement authorities, pharmaceutical companies and clinicians with safety evidence from a routine clinical care setting. What's already known about this topic? There is a need for long-term data on the safety of systemic immunomodulating therapies in patients with atopic eczema. Regulatory bodies, such as the European Medicines Agency, increasingly stipulate the collection of such data as part of the licensing agreement for new treatments, to assess the new agent's long-term safety profile against established therapies. Large numbers of patients with a long duration of follow-up are necessary in order to detect rare events like malignancies. What does this study add? The TREAT Registry Taskforce offers a platform to conduct such research with a network of multiple national atopic eczema research registries. We present a protocol for an investigator-initiated multicentre safety study comparing dupilumab with other systemic immunomodulating therapies in adults and subsequently adolescents and children with moderate-to-severe atopic eczema. This protocol can be used as a framework for similar studies for other novel systemic immunomodulating therapies across both adult and paediatric populations.

Vestibulo masseteric reflex and acoustic masseteric Reflex. Normative data and effects of age and gender.

OBJECTIVE: To provide normative data for the Vestibulo-Masseteric Reflex (VMR) and Acoustic-Masseteric Reflex (AMR) in healthy subjects, stratified for age and gender. METHODS: A total of 82 healthy subjects (M:F 43:39, mean age 39.3 ±â€¯18.4 years, range 13-79 years) underwent recording of click-evoked VMR and AMR (0.1 ms duration, 5 Hz frequency) from active masseter muscles. Masseter responses to uni- and bilateral stimulation were recorded in a zygomatic and a mandibular configuration, according to the position of the reference electrode. Stimulation intensity curves were recorded for each reflex in ten subjects (mean age 20.7 ±â€¯8.1 years). Gender effect was investigated in 62 subjects and age effect was analyzed in six 10-subject groups aged from <25 to >65 years. Onset and peak latencies, interpeak intervals, raw and corrected amplitudes, latency and amplitude asymmetries were analyzed. RESULTS: VMR had a higher elicitation rate than AMR. For both reflexes, rates of elicitation, and corrected amplitudes were higher in the zygomatic configuration, and bilateral stimulation elicited larger responses. Best acoustic ranges of elicitation were 98-113 dB for AMR and 128-138 dB for VMR. Reflex latencies were shorter in females than males. Frequency and amplitude of VMR and AMR decreased substantially over 55 year olds. CONCLUSIONS: VMR and AMR can be easily performed in any clinical neurophysiology laboratory. SIGNIFICANCE: These reflexes can find application in the investigation of brainstem function in central neurological disorders.

TREatment of ATopic eczema (TREAT) Registry Taskforce: consensus on how and when to measure the core dataset for atopic eczema treatment research registries.

BACKGROUND: Comparative, real-life and long-term evidence on the effectiveness and safety of phototherapy and systemic therapy in moderate-to-severe atopic eczema (AE) is limited. Such data must come from well-designed prospective patient registries. Standardization of data collection is needed for direct comparisons and data pooling. OBJECTIVES: To reach a consensus on how and when to measure the previously defined domain items of the TREatment of ATopic eczema (TREAT) Registry Taskforce core dataset for research registries for paediatric and adult patients with AE. METHODS: Proposals for the measurement instruments were based on recommendations of the Harmonising Outcome Measures for Eczema (HOME) initiative, the existing AE database of TREATgermany, systematic reviews of the literature and expert opinions. The proposals were discussed at three face-to-face consensus meetings, one teleconference and via e-mail. The frequency of follow-up visits was determined by an expert survey. RESULTS: A total of 16 experts from seven countries participated in the 'how to measure' consensus process and 12 external experts were consulted. A consensus was reached for all domain items on how they should be measured by assigning measurement instruments. A minimum follow-up frequency of initially 4 weeks after commencing treatment, then every 3 months while on treatment and every 6 months while off treatment was defined. CONCLUSIONS: This core dataset for national AE research registries will aid in the comparability and pooling of data across centres and country borders, and enables international collaboration to assess the long-term effectiveness and safety of phototherapy and systemic therapy used in patients with AE. What's already known about this topic? Comparable, real-life and long-term data on the effectiveness and safety of phototherapy and systemic therapy in patients with atopic eczema (AE) are needed. There is a high diversity of outcomes and instruments used in AE research, which require harmonization to enhance comparability and allow data pooling. What does this study add? Our taskforce has reached international consensus on how and when to measure core domain items for national AE research registries. This core dataset is now available for use by researchers worldwide and will aid in the collection of unified data. What are the clinical implications of this work? The data collected through this core dataset will help to gain better insights into the long-term effectiveness and safety of phototherapy and systemic therapy in AE and will provide important information for clinical practice. Standardization of such data collection at the national level will also allow direct data comparisons and pooling across country borders (e.g. in the analysis of treatment-related adverse events that require large patient numbers).

Cross-education of muscular strength following unilateral resistance training: a meta-analysis.

PURPOSE: Cross-education (CE) of strength is a well-known phenomenon whereby exercise of one limb can induce strength gains in the contralateral untrained limb. The only available meta-analyses on CE, which date back to a decade ago, estimated a modest 7.8% increase in contralateral strength following unilateral training. However, in recent years new evidences have outlined larger contralateral gains, which deserve to be systematically evaluated. Therefore, the aim of this meta-analysis was to appraise current data on CE and determine its overall magnitude of effect. METHODS: Five databases were searched from inception to December 2016. All randomized controlled trials focusing on unilateral resistance training were carefully checked by two reviewers who also assessed the eligibility of the identified trials and extracted data independently. The risk of bias was assessed using the Cochrane Risk-of-Bias tool. RESULTS: Thirty-one studies entered the meta-analysis. Data from 785 subjects were pooled and subgroup analyses by body region (upper/lower limb) and type of training (isometric/concentric/eccentric/isotonic-dynamic) were performed. The pooled estimate of CE was a significant 11.9% contralateral increase (95% CI 9.1-14.8; p < 0.00001; upper limb: + 9.4%, p < 0.00001; lower limb: + 16.4%, p < 0.00001). Significant CE effects were induced by isometric (8.2%; p = 0.0003), concentric (11.3%; p < 0.00001), eccentric (17.7%; p = 0.003) and isotonic-dynamic training (15.9%; p < 0.00001), although a high risk of bias was detected across the studies. CONCLUSIONS: Unilateral resistance training induces significant contraction type-dependent gains in the contralateral untrained limb. Methodological issues in the included studies are outlined to provide guidance for a reliable quantification of CE in future studies.

Time course of strength adaptations following high-intensity resistance training in individuals with multiple sclerosis.

PURPOSE: No evidence exists regarding the time course and clinical relevance of muscle strength improvements following resistance training in people with multiple sclerosis (PwMS). The purpose of this study was to investigate the temporal course and the clinical meaningfulness of the changes in strength induced by high-intensity resistance training and whether these changes impact on muscle endurance to fatigue and functional outcomes. METHODS: PwMS with predominantly unilateral hyposthenia of the ankle dorsiflexors underwent a 6-week isokinetic training of the more affected ankle dorsiflexion muscles. Maximal strength was measured at baseline, during the training on a weekly basis, at the end of the intervention (POST) and at the 12-week follow-up. Muscle endurance to fatigue, mobility and walking outcomes were assessed at baseline, POST and follow-up. Reproducibility and responsiveness analyses were performed. RESULTS: Significant gains in muscle strength were already detected after 3 weeks of training with no further improvements in the following weeks. These improvements exceeded the cutoff values for relevant changes and were also positively correlated to improved muscle endurance to fatigue and mobility measures. None of the observed changes in muscle performance and functional outcomes was retained at the follow-up. CONCLUSIONS: Preliminary evidence showed that 3 weeks of high-intensity resistance training induces consistent and meaningful improvements in muscle performance of the ankle dorsiflexors in PwMS. These findings may have practical dose-response and cost-effectiveness implications in the management of MS-induced muscle weakness, potentially enhancing the understanding of the response to training exhibited by PwMS. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT02010398; December 2013.

No evidence of neural adaptations following chronic unilateral isometric training of the intrinsic muscles of the hand: a randomized controlled study.

PURPOSE: To test whether long-term cortical adaptations occur bilaterally following chronic unilateral training with a simple motor task. METHODS: Participants (n = 34) were randomly allocated to a training or control groups. Only the former completed a 4-week maximal-intensity isometric training of the right first dorsal interosseus muscle through key pinching. Maximal strength was assessed bilaterally in four different movements progressively less similar to the training task: key, tip and tripod pinches, and handgrip. Transcranial magnetic stimulation was used to probe, in the left and right primary hand motor cortices, a number of standard tests of cortical excitability, including thresholds, intra-cortical inhibition and facilitation, transcallosal inhibition, and sensory-motor integration. RESULTS: Training increased strength in the trained hand, but only for the tasks specifically involving the trained muscle (key +8.5 %; p < 0.0005; tip +7.2 %; p = 0.02). However, the effect size was small and below the cutoff for meaningful change. Handgrip and tripod pinch were instead unaffected. There was a similar improvement in strength in the untrained hand, i.e., a cross-education effect (key +6.4 %; p = 0.02; tip +4.7 %; p = 0.007). Despite these changes in strength, no significant variation was observed in any of the neurophysiological parameters describing cortico-spinal and intra-cortical excitability, inter-hemispheric inhibition, and cortical sensory-motor integration. CONCLUSIONS: A 4-week maximal-intensity unilateral training induced bilaterally spatial- and task-specific strength gains, which were not associated to direct or crossed cortical adaptations. The observed long-term stability of neurophysiological parameters might result from homeostatic plasticity phenomena, aimed at restoring the physiological inter-hemispheric balance of neural activity levels perturbed by the exercise. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT02010398.

The role of "closed abdomen" hyperthermic intraperitoneal chemotherapy (HIPEC) in the palliative treatment of neoplastic ascites from peritoneal carcinomatosis: report of a single-center experience.

PURPOSE: The purpose of this study was to review the results of a single-center experience in the management of "closed abdomen" hyperthermic intraperitoneal chemotherapy (HIPEC) using a sophisticated technical device (EXIPER®) in the palliative setting of neoplastic ascites from peritoneal carcinomatosis in patients with advanced cancer of different primary sites. PATIENTS AND METHODS: The study was an open, prospective, single-center, non-randomized study conducted at the Department of Medical Oncology 1, University of Cagliari, Italy, from May 2006 to October 2012. Fifteen patients with peritoneal carcinomatosis were treated with HIPEC: 5 males and 10 females (age range 51-82, median 62 years), for a total of 30 procedures (5 patients were treated more than once). Malignant ascites were from ovarian, uterine cervical, colorectal, gastric, malignant pleural mesothelioma, and unknown primary cancer. Main endpoints were increase of free interval between two consecutive procedures, progressive reduction of ascites volumes and improvement of quality of life assessed with ECOG performance status and EORTC QLQ-C30 questionnaire, and improvement of immunologic function. RESULTS: Twelve patients were completely evaluable while three patients were "lost" to follow-up. The treatment was well tolerated. The mean free interval between two consecutive drainages increased from 11.2 to 39.5 days. The mean ascites volume drained decreased from 7.8 to 1.8 l. ECOG PS improved in the majority of patients and EORTC QLQ-C30 scores in all patients as well as immunologic function. In September 2015, only one patient was still alive. CONCLUSIONS: Our study shows that good results may be achieved in terms of symptom palliation and improvement of quality of life in very advanced cancer patients with MA from PC. The treatment was generally well tolerated considering the limited treatment options available for these patients.

Trigeminal nerve stimulation modulates brainstem more than cortical excitability in healthy humans.

Multiple sites in the central nervous system (CNS) have been hypothesized to explain the beneficial effects of transcutaneous trigeminal nerve stimulation (TNS) on several disorders. This work investigated the acute effects of TNS on the excitability of brainstem and intracortical circuits, as well as on sensorimotor integration processes at cortical level in physiological conditions. Brainstem excitability was evaluated in seventeen healthy subjects measuring the R1 and R2 areas of the blink reflex (BR) and its recovery cycle, with cortical excitability and sensorimotor integration assessed by probing short-interval (SICI) and long-interval (LICI) intracortical inhibition, with short-interval (SICF), intracortical facilitation (ICF), short-latency (SAI) and long-latency (LAI) inhibition measuring motor potentials evoked in the first dorsal interosseous muscle by TMS of the contralateral motor cortex. Neurophysiological parameters were assessed, in seventeen healthy subjects, before and after cyclic 20-min TNS delivered bilaterally to the infraorbital nerve. After TNS, the area of the R2 was significantly reduced (p = 0.018). By contrast, R1 area and R2 recovery cycle were unaffected. Similarly, SICI, ICF, LICI, SICF, SAI and LAI appeared unaltered after TNS. These data suggest that, in normal subjects, TNS mainly acts on brainstem polysynaptic circuits mediating the R2 component of the BR and plays a minor role in modifying the activity of higher-level structures involved in the R2 recovery cycle and in modulation of cortical excitability. A further investigation of a chronic TNS-induced effect may disclose a higher potential for TNS in producing measurable after effects on its CNS targets.

Characterization of ankle dorsiflexors performance in healthy subjects following maximal-intensity isokinetic resistance training.

The purpose of this randomized trial was to examine, in healthy subjects, the effect of unilateral isokinetic-concentric training of the dominant ankle dorsiflexors (DF) on the peak moment (PM), mean PM (MPM), maximal work and mean work (meanW). Thirty volunteers (26.7±4.6years old) underwent bilateral isokinetic testing of ankle DF at 45 and 90°/s. Participants were randomly assigned to a control or a training group. The training lasted 4weeks (4-day/week). All dynamometric parameters increased significantly only in the training group for the trained leg (p<0.05), with greater gains in work (32-47% at 45°/s and 31-41% at 90°/s) than moment variables (14-18% at 45°/s and 14-28% at 90°/s). Similar increases in strength were also noted at both angular velocities in the untrained leg (p<0.01) for both work and moment parameters, depicting a cross-training effect. Correlations between 'moments' and 'works' increased in both legs after training from 0.59-0.77 to 0.79-0.95. Principal component analysis indicated that, at baseline, PM showed the highest weight on DF performance; after training, meanW at 90°/s and MPM at 45°/s exhibited the highest loadings. High-intensity training of ankle DF increase the ability in generating energy throughout the entire range of motion rather than maximizing the PM.