Towards a Precision Medicine Approach Based on Machine Learning for Tailoring Medical Treatment in Alkaptonuria.

ApreciseKUre is a multi-purpose digital platform facilitating data collection, integration and analysis for patients affected by Alkaptonuria (AKU), an ultra-rare autosomal recessive genetic disease. It includes genetic, biochemical, histopathological, clinical, therapeutic resources and quality of life scores that can be shared among registered researchers and clinicians in order to create a Precision Medicine Ecosystem (PME). The combination of machine learning application to analyse and re-interpret data available in the ApreciseKUre shows the potential direct benefits to achieve patient stratification and the consequent tailoring of care and treatments to a specific subgroup of patients. In this study, we have developed a tool able to investigate the most suitable treatment for AKU patients in accordance with their Quality of Life scores, which indicates changes in health status before/after the assumption of a specific class of drugs. This fact highlights the necessity of development of patient databases for rare diseases, like ApreciseKUre. We believe this is not limited to the study of AKU, but it represents a proof of principle study that could be applied to other rare diseases, allowing data management, analysis, and interpretation.

Safety and Efficacy of Reperfusion Therapies for Acute Ischemic Stroke Patients with Active Malignancy.

BACKGROUND AND PURPOSE: Epidemiological correlations between active malignancy (AM) and acute ischemic stroke (AIS) are well-established. However, the effect of reperfusion strategies, particularly mechanical thrombectomy (MT), has been barely investigated in patients with AIS and AM. We aim to evaluate safety and efficacy of reperfusion strategies in such patients. MATERIALS AND METHODS: We performed a case-control analysis comparing patients with AM and AIS (AM group) to a group of cancer-free patients with AIS (control group). All enrolled patients underwent reperfusion therapies (i.e. intravenous thrombolysis, MT, intravenous thrombolysis plus MT). Main outcomes were 3-month functional independence, successful reperfusion, 3-month mortality, symptomatic intracranial hemorrhage. RESULTS: Total 24 patients with AM and AIS (mean age: 69 ± 10.1) were individually matched to 24 control patients (mean age: 70.7 ± 9.3). In both groups 50% were treated with MT, 46% with intravenous thrombolysis and 4% with intravenous thrombolysis plus MT. No difference were found in successful reperfusion, 3-month functional independence, symptomatic intracranial hemorrhage, and mortality. However an overall mortality of 33% in the AM group was reported. CONCLUSIONS: Reperfusion strategies for AIS patients with AM seem to be safe and effective. However an individualized approach to understand cancer stage and life-expectation is warranted.

Endovascular Stroke Treatment of Acute Tandem Occlusion: A Single-Center Experience.

PURPOSE: To evaluate outcomes and prognostic factors in patients with acute ischemic stroke caused by tandem internal carotid artery/middle cerebral artery occlusion undergoing endovascular treatment. MATERIALS AND METHODS: Characteristics of consecutive patients with tandem occlusion (TO) were extracted from a prospective registry. Collateral vessel quality on pretreatment computed tomographic (CT) angiography was evaluated on a 4-point grading scale, and patients were dichotomized as having poor or good collateral flow. Outcome measures included successful reperfusion according to Thrombolysis In Cerebral Infarction score, good outcome at 3 months defined as a modified Rankin scale score ≤ 2, symptomatic intracranial hemorrhage (ICH; sICH), and mortality. RESULTS: A total of 72 patients with TO (mean age, 65.6 y ± 12.8) were treated. Intravenous thrombolysis was performed in 54.1% of patients, and a carotid stent was inserted in 48.6%. Successful reperfusion was achieved in 64% of patients, and a good outcome was achieved in 32%. sICH occurred in 12.5% of patients, and the overall mortality rate was 32%. Univariate analysis demonstrated that good outcome was associated with good collateral flow (P = .0001), successful reperfusion (P = .001), and lower rate of any ICH (P = .02) and sICH (P = .04). On multivariate analysis, good collateral flow (odds ratio [OR], 0.18; 95% confidence interval [CI], 0.04-0.75; P = .01) and age (OR, 1.08; 95% CI, 1.01-1.15; P = .01) were the only predictors of good outcome. The use of more than one device for thrombectomy was the only predictor of sICH (OR, 10.74; 95% CI, 1.37-84.13; P = .02). CONCLUSIONS: Endovascular treatment for TO resulted in good outcomes. Collateral flow and age were independent predictors of good clinical outcomes at 3 months.

Evidence of hydrogen sulfide involvement in amyotrophic lateral sclerosis.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease whose pathophysiological deficits, causing impairment in motor function, are largely unknown. Here we propose that hydrogen sulfide (H2 S), as a glial-released inflammatory factor, contributes to ALS-mediated motor neuron death. METHODS: H2 S concentrations were analyzed in the cerebrospinal fluid of 37 sporadic ALS patients and 14 age- and gender-matched controls, in tissues of a familial ALS (fALS) mouse model, and in spinal cord culture media by means of a specific and innovative high-performance liquid chromatography method. The effects of H2 S on motor neurons cultures was analyzed immunohistochemically and by patch clamp recordings and microfluorometry. RESULTS: We found a significantly high level of H2 S in the spinal fluid of the ALS patients. Consistently, we found increased levels of H2 S in the tissues and in the media from mice spinal cord cultures bearing the fALS mutation SOD1G93A. In addition, NaHS, an H2 S donor, added to spinal culture, obtained from control C57BL/6J mice, is toxic for motor neurons, and induces an intracellular Ca(2+) increase, attenuated by the intracytoplasmatic application of adenosine triphosphate. We further show that H2 S is mainly released by astrocytes and microglia. INTERPRETATION: This study unravels H2 S as an astroglial mediator of motor neuron damage possibly involved in the cellular death characterizing ALS.

The Use of Virtual Reality Interventions to Promote Positive Mental Health: Systematic Literature Review.

BACKGROUND: A large body of research has documented the efficacy of psychological interventions integrated with virtual reality (VR) therapies in treating psychiatric disorders. However, the concept of positive mental health calls for a 2-fold approach in which both symptoms and positive functioning should be addressed by modern interventions. OBJECTIVE: This review aimed to summarize studies that applied VR therapies by embracing the positive mental health perspective. METHODS: A literature search was conducted by entering the following keywords-"virtual reality" AND "intervention" OR "treatment" OR "therapy" AND "mental health" NOT "systematic review or meta-analysis"-and limiting it to "journal article" and the English language. To be included in this review, articles had to present at least one quantitative measure of positive functioning and one quantitative measure of symptoms or distress and had to investigate adult populations, including populations with psychiatric disorders. RESULTS: A total of 20 articles were included. They described various VR protocols that were applied for the treatment of anxiety disorders (5/20, 25%), depression (2/20, 10%), posttraumatic stress disorder (3/20, 15%), psychosis (3/20, 15%), and stress (7/20, 35%). Most of the studies (13/20, 65%) showed the beneficial effects of VR therapies in improving stress and negative symptoms. However, 35% (7/20) of the studies showed no or a small effect on the various dimensions of positivity, particularly in clinical samples. CONCLUSIONS: VR interventions might be cost-effective and largely scalable, but further research is needed to develop existing VR software and treatments according to the modern positive mental health approach.

Venlafaxine-propafenone interaction resulting in hallucinations and psychomotor agitation.

OBJECTIVE: To report a case of visual hallucinations and psychomotor agitation probably induced by an interaction between venlafaxine and propafenone. CASE SUMMARY: An 85-year-old woman was admitted for evaluation of a mood disorder on March 20, 2006. Her general practitioner had prescribed sertraline for treatment, which had started about 6 months earlier. The patient's medical history included hypertension, supraventricular tachycardia, chronic bronchitis, and arthritis, for which she received ramipril, ticlopidine, torsemide, theophylline, acetaminophen, and triazolam. The patient had also received propafenone 150 mg every 12 hours for 3 years. Results of biochemical tests were normal; however, a computed tomography (CT) scan of the brain showed signs of cortical atrophy. Sertraline was discontinued after a few days because of its reduced effectiveness and was replaced with extended-release venlafaxine 75 mg/day. No other changes to the patient's drug therapy were made. Four weeks later, because of the persistence of psychiatric disturbance, the venlafaxine dosage was increased to 150 mg/day. Ten days later the patient returned to our observation due to the onset of visual hallucinations lasting about 2 hours, especially at night, and psychomotor agitation. Venlafaxine was discontinued, with a complete remission of hallucinations and psychomotor agitation in about 4 days. The Naranjo probability scale indicated a probable relationship between venlafaxine and the patient's symptoms. Citalopram was started one month later for the persistence of mood disorders, with no adverse effects. DISCUSSION: A CT scan documented signs of cortical atrophy in our patient's brain but excluded vascular brain injury, while clinical evaluation and anamnesis excluded a relationship between hallucinations and cortical atrophy. Genetic and pharmacologic factors may be involved in venlafaxine-induced adverse effects. Venlafaxine is metabolized primarily by CYP2D6 and is a substrate of P-glycoprotein. Propafenone, a known substrate and inhibitor of both CYP2D6 and P-glycoprotein, could therefore be involved in venlafaxine-induced hallucinations through the increase of venlafaxine plasma concentrations. CONCLUSIONS: To prevent the onset of clinical disturbances during venlafaxine treatment, we suggest careful evaluation of concomitant treatment with CYP2D6 or P-glycoprotein inhibitors (eg, propafenone) and, when possible, venlafaxine serum concentration monitoring.

Mechanical thrombectomy of acute ischemic stroke with a new intermediate aspiration catheter: preliminary results.

BACKGROUND AND PURPOSE: To report clinical and procedural outcomes of acute ischemic stroke patients after endovascular treatment with the new thromboaspiration catheter AXS Catalyst 6. METHODS: Patients with anterior and posterior circulation stroke were selected. Successful reperfusion defined as a Thrombolysis in Cerebral Infarction (TICI) score ≥2 b and 3-month functional independence defined as a modified Rankin Scale (mRS) ≤2 were the main efficacy outcomes. Symptomatic intracranial hemorrhage and mortality were the main safety outcomes. RESULTS: 107 patients were suitable for analysis. Mean age was 73.18±12.62 year and median baseline NIHSS was 17 (range: 3-32). The most frequent site of occlusion was the middle cerebral artery (MCA) (60.7%). 76.6% of patients were treated with AXS Catalyst 6 alone without the need for rescue devices or thromboaspiration catheters. Successful reperfusion was achieved in 84.1%, functional independence in 47.6%, symptomatic intracranial hemorrhage occurred in 3.7%, and mortality in 21.4%. CONCLUSIONS: Endovascular treatment with AXS Catalyst 6 proved to be safe, technically feasible, and effective. Comparison analyses with other devices for mechanical thrombectomy are needed.

Pretreatment predictors of malignant evolution in patients with ischemic stroke undergoing mechanical thrombectomy.

BACKGROUND: Few data exist on malignant middle cerebral artery infarction (MMI) among patients with acute ischemic stroke (AIS) after endovascular treatment (ET). Numerous predictors of MMI evolution have been proposed, but a comprehensive research of patients undergoing ET has never been performed. Our purpose was to find a practical model to determine robust predictors of MMI in patients undergoing ET. METHODS: Patients from a prospective single-center database with AIS secondary to large intracranial vessel occlusion of the anterior circulation, treated with ET, were retrospectively analyzed. We investigated demographic, clinical, and radiological data. Multivariate regression analysis was used to identify clinical and imaging predictors of MMI. RESULTS: 98 patients were included in the analysis, 35 of whom developed MMI (35.7%). No differences in the rate of successful reperfusion and time from stroke onset to reperfusion were found between the MMI and non-MMI groups. The following parameters were identified as independent predictors of MMI: systolic blood pressure (SBP) on admission (p=0.008), blood glucose (BG) on admission (p=0.024), and the CTangiography (CTA) Alberta Stroke Program Early CT Score (ASPECTS) (p=0.001). A scoreof ≤5 in CTA ASPECTS was the best cut-off to predict MMI evolution (sensitivity 46%; specificity 97%; positive predictive value 78%; negative predictive value 65%). CONCLUSIONS: in our study a clinical and radiological features-based model was strongly predictive of MMI evolution in AIS. High SBP and BG on admission and, especially, a CTA ASPECTS ≤5 may help to make decisions quickly, regardless of time to treatment and successful reperfusion.

Influence of levetiracetam on the anticonvulsant efficacy of conventional antiepileptic drugs against audiogenic seizures in DBA/2 mice.

Levetiracetam (LEV, [S]-alpha-ethyl-2-oxo-1-pyrrolidine acetamide) is a new antiepileptic that has been used as adjunctive therapy to treat patients with intractable epilepsy. Systemic administration of levetiracetam (2.5-30 mg/kg, intraperitoneally (i.p.)) was able to produce a dose-dependent decrease in DBA/2 audiogenic seizure severity score. In combination with conventional antiepileptic drugs, levetiracetam, 5mg/kg, i.p., which per se did not significantly affect the occurrence of audiogenic seizures in DBA/2 mice, potentiated the anticonvulsant activity of some antiepileptic drugs studied against sound-induced seizures in DBA/2 mice. The degree of potentiation induced by levetiracetam was greater, approximately twice, for carbamazepine, diazepam, felbamate, topiramate, gabapentin, and valproate, less for lamotrigine, phenobarbital and phenytoin. This increase was associated with a comparable impairment in motor activity; however, the therapeutic index of combined treatment of antiepileptic drugs with levetiracetam was more favourable than the combination with saline with the exception of lamotrigine, phenytoin and phenobarbital. Since levetiracetam did not significantly influence the total and free plasma and the brain levels of antiepileptics studied. In addition, levetiracetam did not significantly affect the hypothermic effects of the anticonvulsants tested. In conclusion, levetiracetam showed an additive anticonvulsant effect when administered in combination with some classical anticonvulsants, most notably carbamazepine, diazepam, felbamate, gabapentin, topiramate and valproate, implicating a possible therapeutic relevance of such drug combinations.

Efficacy and Safety of Mechanical Thrombectomy in Older Adults with Acute Ischemic Stoke.

OBJECTIVES: To evaluate the safety and efficacy of endovascular therapy in elderly adults treated for acute ischemic stroke. DESIGN: Retrospective cohort study. SETTING: Comprehensive Stroke Center, University of Tor Vergata, Rome, Italy. PARTICIPANTS: Elderly adults treated for acute ischemic stroke (N = 219). MEASUREMENTS: Participants were divided into two groups based on their age (n = 62, ≥80; n = 157, <80). Baseline and procedural characteristics, safety outcomes such as intracranial hemorrhage (ICH) and mortality and efficacy outcomes such as successful reperfusion and 3-month good clinical outcome of the two groups were compared. Mutivariable analysis was performed to identify predictors of clinical outcome. RESULTS: Intravenous thrombolysis was more frequent (67.7% vs 52.8%, P = .04), and onset to reperfusion time was shorter (318.7 ± 128.7 vs 282 ± 53.5, P = .02) in participants aged 80 and older, but no between-group differences were found in terms of successful reperfusion (69% vs 63%, P = .4), good clinical outcome (30.6% vs 34.3%, P = .6), any (37% vs 37.5%, P > .99) or symptomatic (11% vs 14%, P = .6) ICH, or mortality (40.3% vs 29.2%, P = .14). Multivariable analysis revealed that, in the older group, onset National Institute of Health Stroke Scale (NIHSS) score (odds ratio (OR) = 0.65, 95% confidence interval (CI) = 0.44-0.96, P = .03) and 24-hour clinical improvement (OR = 141.13, 95% CI = 2.96-6,720.7, P = .01) were independent predictors of 3-month functional independence. CONCLUSION: These findings suggest that endovascular treatment for stroke in selected elderly adults could be safe and effective. Major determinants of outcome in this subgroup of elderly patients are presentation NIHSS score and 24-hour clinical improvement.

Ameliorating effects of aripiprazole on cognitive functions and depressive-like behavior in a genetic rat model of absence epilepsy and mild-depression comorbidity.

Aripiprazole (APZ) is regarded as a first-line atypical antipsychotic used for the treatment of first and multiple episodes of schizophrenia to improve positive- and negative-symptoms. Its therapeutic indications were extended to acute manic and mixed episodes associated with bipolar disorder. In addition, APZ was approved as an adjunct therapy for major depressive disorder in 2007. Compared to other antipsychotic drugs, APZ has a unique pharmacological profile. It is a partial agonist at D2 dopamine receptors and serotonin 5-HT(1A) and 5-HT7 receptors, whereas it is an antagonist at serotonin 5-HT(2A) and 5-HT6 receptors. Since epilepsy is often accompanied with neurological comorbidities such as depression, anxiety and cognitive deficits caused by both the disease and/or drug treatment, we wished to examine the effects of a sub-chronic treatment (>14 consecutive days) with APZ (0.3, 1 and 3 mg/kg; i.p.) on both absence seizures and WAG/Rij rat's behavior using different standard paradigms: Open field (OF) test, elevated plus maze (EPM) test, forced swimming (FS) test, sucrose consumption (SC) test and Morris water maze (MWM). WAG/Rij rats represent a validated genetic animal model of absence epilepsy with mild-depression comorbidity, also including other behavioral alterations. APZ treatment showed some anti-absence properties and regarding the behavioral comorbidity in this rat strain, we observed that APZ possesses clear antidepressant effects in the FS and SC tests also increasing memory/learning function in the Morris water maze test. In the two anxiety models used, APZ showed only minor effects. In conclusion, our results indicate that APZ might actually have a potential in treating absence seizures or as add-on therapy but more interestingly, these effect might be accompanied by positive modulatory actions on depression, anxiety and memory which might be also beneficial in other epileptic syndromes. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Electrophysiological effects of trace amines on mesencephalic dopaminergic neurons.

Trace amines (TAs) are a class of endogenous compounds strictly related to classic monoamine neurotransmitters with regard to their structure, metabolism, and tissue distribution. Although the presence of TAs in mammalian brain has been recognized for decades, until recently they were considered to be by-products of amino acid metabolism or as "false" neurotransmitters. The discovery in 2001 of a new family of G-protein-coupled receptors (GPCRs), namely trace amines receptors, has re-ignited interest in TAs. In particular, two members of the family, trace amine receptor 1 (TA(1)) and trace amine receptor 2 (TA(2)), were shown to be highly sensitive to these endogenous compounds. Experimental evidence suggests that TAs modulate the activity of catecholaminergic neurons and that TA dysregulation may contribute to neuropsychiatric disorders, including schizophrenia, attention deficit hyperactivity disorder, depression and Parkinson's disease, all of which are characterized by altered monoaminergic networks. Here we review recent data concerning the electrophysiological effects of TAs on the activity of mesencephalic dopaminergic neurons. In the context of recent data obtained with TA(1) receptor knockout mice, we also discuss the mechanisms by which the activation of these receptors modulates the activity of these neurons. Three important new aspects of TAs action have recently emerged: (a) inhibition of firing due to increased release of dopamine; (b) reduction of D2 and GABA(B) receptor-mediated inhibitory responses (excitatory effects due to disinhibition); and (c) a direct TA(1) receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization. While the first two effects have been well documented in our laboratory, the direct activation of GIRK channels by TA(1) receptors has been reported by others, but has not been seen in our laboratory (Geracitano et al., 2004). Further research is needed to address this point, and to further characterize the mechanism of action of TAs on dopaminergic neurons.