Fathoming the kynurenine pathway in migraine: why understanding the enzymatic cascades is still critically important

Kynurenine pathway, the quantitatively main branch of tryptophan metabolism, has been long been considered a source of nicotinamide adenine dinucleotide, although several of its products, the so-called kynurenines, are endowed with the capacity to activate glutamate receptors, thus potentially influencing a large group of functions in the central nervous system (CNS). Migraine, a largely unknown pathology, is strictly related to the glutamate system in the CNS pathologic terms. Despite the large number of studies conducted on migraine etio-pathology, the kynurenine pathway has been only recently linked to this disease. Nonetheless, some evidence suggests an intriguing role for some kynurenines, and an exploratory study on the serum kynurenine level might be helpful to better understand possible alterations of the kynurenine pathway in patients suffering from migrain

Factors associated with costs of hospitalization of severely mentally Ill patients

Background: Efforts to contain costs associated with general medical care include particular efforts for psychiatric disorders. Hospitalization represents the largest component of costs for psychiatric care and there is growing interest in balancing clinical needs against limiting costs of inpatient psychiatric care of patients with severe mental illnesses. This study aimed to evaluate clinical factors associated with actual costs of inpatient psychiatric care. Method: We evaluated a cohort of 589 hospitalized psychiatric patients with severe mental illnesses at a nonprofit, university-affiliated psychiatric hospital for factors associated with annualized total costs of inpatient care over a three-year period, using bivariate and multivariate analyses. Results: As expected, days-hospitalized was the major determinant of total costs of hospital care. In addition, several clinical and treatment factors also were associated significantly and independently with costs in multivariate modeling. These included presence of psychosis, electroconvulsive treatment, specialist consultations, use of multiple antipsychotics or of clozapine, and being discharged to a supervised living arrangement, but not sex, age, marital status, employment, or substance abuse. Discussion: As expected, costs of psychiatric hospitalization were dominated by per-diem charges, but also influenced by other, potentially modifiable treatment factors generally associated with more severe psychotic illnesses. The study is based on actual costs rather than on insurer-reimbursements and a large study-sample, though at a single institution. Specific factors identified encourage focusing on patient characteristics associated with greater costs and redoubled efforts to apply and improve alternative, cost-effective interventions such as partialhospital and intensive outpatient treatment

A two years open-label prospective study of OnabotulinumtoxinA 195 U in medication overuse headache. a real-world experience

BACKGROUND: The efficacy and safety of OnabotulinumtoxinA (BOTOX®) in adults with chronic migraine (CM) were demonstrated in the PREEMPT program. However, the dosage used in this study was flexible from 155 U to 195 U at the physician's discretion. Therefore, the objective of this prospective study was to compare the efficacy and safety of OnabotulinumtoxinA 195 U vs. 155 U for the treatment of CM and medication overuse headache (MOH) during a 2-year period. METHODS: We prospectively evaluated the mean reduction in headache days, migraine days, acute pain medication intake days and Headache Impact Test (HIT)-6 score in 172 patients injected with OnabotulinumtoxinA 195 U. Successively, we compared the efficacy measures with data of 155 patients injected with OnabotulinumtoxinA 155 U and followed up for 2 years. All patients were affected by CM and MOH, and failed one or more previous detoxification and preventative therapies. RESULTS: Both OnabotulinumtoxinA 195 U and 155 U reduced significantly the number of headache and migraine days, acute pain medication intake days and HIT-6 score, when compared with the baseline measures. Nevertheless, OnabotulinumtoxinA 195 U proved to be superior of 155 U in all efficacy measures since the first injection and for all the 2 years of treatment, with the exception of the reduction in pain medication intake days that resulted significantly larger with 195 U only after the 4th injection. The safety and tolerability of the two doses were similar and treatment related adverse events were transient and mild-moderate. CONCLUSIONS: This study represents the largest and longest post-marketing studies of doses comparison with OnabotulinumtoxinA in a real-life clinical setting. Here, we demonstrate the superior efficacy of OnabotulinumtoxinA 195 U compared to 155 U in CM patients with MOH during a 2-year treatment period with similar safety and tolerability profile

Eletriptan in the management of acute migraine. An update on the evidence for efficacy, safety, and consistent response

Migraine is a multifactorial, neurological and disabling disorder, also characterized by several autonomic symptoms. Triptans, selective serotonin 5-HT1B/1D agonists, are the first-line treatment option for moderate-to-severe headache attacks. In this paper, we review the recent data on eletriptan clinical efficacy, safety, and tolerability, and potential clinically relevant interactions with other drugs. Among triptans, eletriptan shows a consistent and significant clinical efficacy and a good tolerability profile in the treatment of migraine, especially for patients with cardiovascular risk factors without coronary artery disease. It shows the most favorable clinical response, together with sumatriptan injections, zolmitriptan and rizatriptan. Additionally, eletriptan shows the most complex pharmacokinetic/dynamic profile compared with the other triptans. It is metabolized primarily by the CYP3A4 hepatic enzyme and therefore the concomitant administration of CYP3A4-potent inhibitors should be carefully evaluated. A relatively low risk of serotonin syndrome is given by the co-administration with serotoninergic drugs. No clinically relevant interaction has been found with drugs used for migraine prophylactic treatment or other acute drugs, with the exception of ergot derivatives that should not be co-administered with eletriptan

Impact of migraine on fibromyalgia symptoms

Background: Fibromyalgia (FMS) and high frequency episodic/chronic migraine (M) very frequently co-occur, suggesting common pathophysiological mechanisms; both conditions display generalized somatic hyperalgesia. In FMS-M comorbidity we assessed if: a different level of hyperalgesia is present compared to one condition only; hyperalgesia is a function of migraine frequency; migraine attacks trigger FMS symptoms. Methods: Female patients with fibromyalgia (FMS)(n.40), high frequency episodic migraine (M1)(n.41), chronic migraine (M2)(n.40), FMS + M1 (n.42) and FMS + M2 (n.40) underwent recording of: −electrical pain thresholds in skin, subcutis and muscle and pressure pain thresholds in control sites, −pressure pain thresholds in tender points (TePs), −number of monthly migraine attacks and fibromyalgia flares (3-month diary). Migraine and FMS parameters were evaluated before and after migraine prophylaxis, or no prophylaxis, for 3 months with calcium-channel blockers, in two further FMS + H1 groups (n.49, n.39). 1-way ANOVA was applied to test trends among groups, Student’s t-test for paired samples was used to compare pre and post-treatment values. Results: The lowest electrical and pressure thresholds at all sites and tissues were found in FMS + M2, followed by FMS + H1, FMS, M2 and M1 (trend: p < 0.0001). FMS monthly flares were progressively higher in FMS, FMS + M1 and FMS + M2 (p < 0.0001); most flares (86–87 %) occurred within 12 h from a migraine attack in co-morbid patients (p < 0.0001). Effective migraine prophylaxis vs no prophylaxis also produced a significant improvement of FMS symptoms (decreased monthly flares, increased pain thresholds)(0.0001 < p < 0.003). Conclusions: Co-morbidity between fibromyalgia and migraine involves heightened somatic hyperalgesia compared to one condition only. Increased migraine frequency – with shift towards chronicity – enhances both hyperalgesia and spontaneous FMS pain, which is reversed by effective migraine prophylaxis. These results suggest different levels of central sensitization in patients with migraine, fibromyalgia or both conditions and a role for migraine as a triggering factor for FMS

A Combined Raman Spectroscopy and Atomic Force Microscopy System for In Situ and Real-Time Measures in Electrochemical Cells

: An innovative and versatile set-up for in situ and real time measures in an electrochemical cell is described. An original coupling between micro-Raman spectroscopy and atomic force microscopy enables one to collect data on opaque electrodes. This system allows for the correlation of topographic images with chemical maps during the charge exchange occurring in oxidation/reduction processes. The proposed set-up plays a crucial role when reactions, both reversible and non-reversible, are studied step by step during electrochemical reactions and/or when local chemical analysis is required

DEPRESSIVE SYMPTOMS, TEMPERAMENT/CHARACTER, AND ATTENTION DEFICIT/HYPERACTIVITY DISORDER TRAITS IN MEDICAL STUDENTS SEEKING COUNSELIN

Background: To investigate depressive symptoms, temperament, and attention deficit/hyperactivity disorder traits in medical students, comparing those who sought psychological counseling with those who did not seek it. Subjects and methods: We assessed 49 students seeking counseling (mean age=24.4 years, SD=4.07) and 49 noncounseling controls (mean age=21.7 years, SD=2.6). Participants were assessed for depressive symptoms with the Beck Depression Inventory- II, for temperament/character dimensions using the Temperament and Character Inventory-Revised, and for attention deficit/hyperactivity symptoms using the Adult ADHD Self-Report Scale. Results: Counseling-seeking students were more likely to have attention deficit/hyperactivity symptoms, scored higher on the Beck Depression Inventory-II and on the Temperament and Character Inventory-Revised Harm avoidance, and lower on the Temperament and Character Inventory-Revised Self-Directedness, compared to controls. Conclusions: Medical students applying for counseling should be carefully assessed for depressive symptoms, attention deficit/hyperactivity symptoms, and temperament characteristics; depressive and attention deficit/hyperactivity symptoms could be the focus of counseling interventions

Transcranial Doppler as a screening test to exclude intracranial hypertension in brain-injured patients: the IMPRESSIT-2 prospective multicenter international study

Background: Alternative noninvasive methods capable of excluding intracranial hypertension through use of transcranial Doppler (ICPtcd) in situations where invasive methods cannot be used or are not available would be useful during the management of acutely brain-injured patients. The objective of this study was to determine whether ICPtcd can be considered a reliable screening test compared to the reference standard method, invasive ICP monitoring (ICPi), in excluding the presence of intracranial hypertension. Methods: This was a prospective, international, multicenter, unblinded, diagnostic accuracy study comparing the index test (ICPtcd) with a reference standard (ICPi), defined as the best available method for establishing the presence or absence of the condition of interest (i.e., intracranial hypertension). Acute brain-injured patients pertaining to one of four categories: traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH) or ischemic stroke (IS) requiring ICPi monitoring, were enrolled in 16 international intensive care units. ICPi measurements (reference test) were compared to simultaneous ICPtcd measurements (index test) at three different timepoints: before, immediately after and 2 to 3 h following ICPi catheter insertion. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) were calculated at three different ICPi thresholds (> 20, > 22 and > 25 mmHg) to assess ICPtcd as a bedside real-practice screening method. A receiver operating characteristic (ROC) curve analysis with the area under the curve (AUC) was used to evaluate the discriminative accuracy and predictive capability of ICPtcd. Results: Two hundred and sixty-two patients were recruited for final analysis. Intracranial hypertension (> 22 mmHg) occurred in 87 patients (33.2%). The total number of paired comparisons between ICPtcd and ICPi was 687. The NPV was elevated (ICP > 20 mmHg = 91.3%, > 22 mmHg = 95.6%, > 25 mmHg = 98.6%), indicating high discriminant accuracy of ICPtcd in excluding intracranial hypertension. Concordance correlation between ICPtcd and ICPi was 33.3% (95% CI 25.6-40.5%), and Bland-Altman showed a mean bias of -3.3 mmHg. The optimal ICPtcd threshold for ruling out intracranial hypertension was 20.5 mmHg, corresponding to a sensitivity of 70% (95% CI 40.7-92.6%) and a specificity of 72% (95% CI 51.9-94.0%) with an AUC of 76% (95% CI 65.6-85.5%). Conclusions and relevance: ICPtcd has a high NPV in ruling out intracranial hypertension and may be useful to clinicians in situations where invasive methods cannot be used or not available. Trial registration: NCT02322970

PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis

Background & Aims: Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (ADNo ACLF), or with ACLF (AD-ACLF), defined by organ failure(s). Herein, we aimed to analyze and characterize the precipitants leading to both of these AD phenotypes. Methods: The multicenter, prospective, observational PREDICT study (NCT03056612) included 1,273 non-electively hospitalized patients with AD (No ACLF = 1,071; ACLF = 202). Medical history, clinical data and laboratory data were collected at enrolment and during 90-day follow-up, with particular attention given to the following characteristics of precipitants: induction of organ dysfunction or failure, systemic inflammation, chronology, intensity, and relationship to outcome. Results: Among various clinical events, 4 distinct events were precipitants consistently related to AD: proven bacterial infections, severe alcoholic hepatitis, gastrointestinal bleeding with shock and toxic encephalopathy. Among patients with precipitants in the AD-No ACLF cohort and the AD-ACLF cohort (38% and 71%, respectively), almost all (96% and 97%, respectively) showed proven bacterial infection and severe alcoholic hepatitis, either alone or in combination with other events. Survival was similar in patients with proven bacterial infections or severe alcoholic hepatitis in both AD phenotypes. The number of precipitants was associated with significantly increased 90day mortality and was paralleled by increasing levels of surrogates for systemic inflammation. Importantly, adequate first-line antibiotic treatment of proven bacterial infections was associated with a lower ACLF development rate and lower 90-day mortality. Conclusions: This study identified precipitants that are significantly associated with a distinct clinical course and prognosis in patients with AD. Specific preventive and therapeutic strategies targeting these events may improve outcomes in patients with decompensated cirrhosis. Lay summary: Acute decompensation (AD) of cirrhosis is characterized by a rapid deterioration in patient health. Herein, we aimed to analyze the precipitating events that cause AD in patients with cirrhosis. Proven bacterial infections and severe alcoholic hepatitis, either alone or in combination, accounted for almost all (96-97%) cases of AD and acute-on-chronic liver failure. Whilst the type of precipitant was not associated with mortality, the number of precipitant(s) was. This study identified precipitants that are significantly associated with a distinct clinical course and prognosis of patients with AD. Specific preventive and therapeutic strategies targeting these events may improve patient outcomes. (c) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology

Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF. A total of 1,071 patients with AD were enrolled. We collected detailed pre-specified information on the 3-month period prior to enrollment, and clinical and laboratory data at enrollment. Patients were then closely followed up for 3 months. Outcomes (liver transplantation and death) at 1 year were also recorded. Three groups of patients were identified. Pre-ACLF patients (n = 218) developed ACLF and had 3-month and 1-year mortality rates of 53.7% and 67.4%, respectively. Unstable decompensated cirrhosis (UDC) patients (n = 233) required ≥1 readmission but did not develop ACLF and had mortality rates of 21.0% and 35.6%, respectively. Stable decompensated cirrhosis (SDC) patients (n = 620) were not readmitted, did not develop ACLF and had a 1-year mortality rate of only 9.5%. The 3 groups differed significantly regarding the grade and course of systemic inflammation (high-grade at enrollment with aggravation during follow-up in pre-ACLF; low-grade at enrollment with subsequent steady-course in UDC; and low-grade at enrollment with subsequent improvement in SDC) and the prevalence of surrogates of severe portal hypertension throughout the study (high in UDC vs. low in pre-ACLF and SDC). Acute decompensation without ACLF is a heterogeneous condition with 3 different clinical courses and 2 major pathophysiological mechanisms: systemic inflammation and portal hypertension. Predicting the development of ACLF remains a major future challenge. ClinicalTrials.gov number: NCT03056612. Lay summary: Herein, we describe, for the first time, 3 different clinical courses of acute decompensation (AD) of cirrhosis after hospital admission. The first clinical course includes patients who develop acute-on-chronic liver failure (ACLF) and have a high short-term risk of death - termed pre-ACLF. The second clinical course (unstable decompensated cirrhosis) includes patients requiring frequent hospitalizations unrelated to ACLF and is associated with a lower mortality risk than pre-ACLF. Finally, the third clinical course (stable decompensated cirrhosis), includes two-thirds of all patients admitted to hospital with AD - patients in this group rarely require hospital admission and have a much lower 1-year mortality risk