Project description:The lack of biomarkers to identify target populations greatly limits the promise of precision medicine for major depressive disorder (MDD), a primary cause of ill health and disability. The endogenously produced molecule acetyl-l-carnitine (LAC) is critical for hippocampal function and several behavioral domains. In rodents with depressive-like traits, LAC levels are markedly decreased and signal abnormal hippocampal glutamatergic function and dendritic plasticity. LAC supplementation induces rapid and lasting antidepressant-like effects via epigenetic mechanisms of histone acetylation. This mechanistic model led us to evaluate LAC levels in humans. We found that LAC levels, and not those of free carnitine, were decreased in patients with MDD compared with age- and sex-matched healthy controls in two independent study centers. Secondary exploratory analyses showed that the degree of LAC deficiency reflected both the severity and age of onset of MDD. Moreover, these analyses showed that the decrease in LAC was larger in patients with a history of treatment-resistant depression (TRD), among whom childhood trauma and, specifically, a history of emotional neglect and being female, predicted the decreased LAC. These findings suggest that LAC may serve as a candidate biomarker to help diagnose a clinical endophenotype of MDD characterized by decreased LAC, greater severity, and earlier onset as well as a history of childhood trauma in patients with TRD. Together with studies in rodents, these translational findings support further exploration of LAC as a therapeutic target that may help to define individualized treatments in biologically based depression subtype consistent with the spirit of precision medicine.
Project description:At micromolar concentrations, acetyl-CoA inhibited hepatic carnitine acyltransferase activity and mitochondrial fatty acid oxidation. The inhibitory effects were not nearly as potent on a molar basis as those of malonyl-CoA; nevertheless, the cytosolic concentrations of acetyl-CoA, as yet unknown, may be sufficient (greater than 30 microM) to curtail appreciably the mitochondrial transfer of long-chain acyl-CoA units and fatty acid oxidation. Hence acetyl-CoA may also partially regulate hepatic ketogenesis.
Project description:OBJECTIVES:Hepatic encephalopathy (HE) is common in advanced cirrhosis and is characterized by marked neuropsychiatric abnormalities. However, despite its severity and effects on brain function, the impact of HE on psychological status of patients has not been adequately assessed. The aim of this study was to evaluate the effect of HE on psychological status of patients and their informal caregivers. METHODS:Fifteen patients with cirrhosis and episodic or persistent HE and their corresponding informal caregivers were included. Semistructured interviews were performed in patients and caregivers. Quality of life (QoL) was assessed by the short-form 36 in both patients and caregivers, and the Zarit burden score was measured in caregivers. The analysis of interviews was performed using qualitative methodology. RESULTS:HE causes a major psychological impact on patients with HE. The first episode of HE caused a very significant impact that was reported with deep feelings, mainly of fear, anger, misery, anxiety, and sorrow, which persisted with time. Symptoms causing more psychological impact on patients were impaired ability to walk and speak. All effects were associated with a marked impairment in QoL. The psychological impact was also marked in caregivers who had a major burden, as assessed by the Zarit score. Moreover, QoL, particularly the mental component score, was markedly impaired in caregivers in intensity similar to that of patients. DISCUSSION:HE has a profound psychological impact on patients and their informal caregivers, associated with a marked negative influence on QoL. The psychological effects of HE on patients and caregivers should be evaluated and treated.
Project description:The sensory system constantly receives stimuli from the external world. To discriminate two stimuli correctly as two temporally distinct events, the temporal distance or stimulus onset asynchrony (SOA) between the two stimuli has to exceed a specific threshold. If the SOA between two stimuli is shorter than this specific threshold, the two stimuli will be perceptually fused and perceived as one single stimulus. Patients with hepatic encephalopathy (HE) are known to show manifold perceptual impairments, including slowed visual temporal discrimination abilities as measured by the critical flicker frequency (CFF). Here, we hypothesized that HE patients are also impaired in their tactile temporal discrimination abilities and, thus, require a longer SOA between two tactile stimuli to perceive the stimuli as two temporally distinct events. To test this hypothesis, patients with varying grades of HE and age-matched healthy individuals performed a tactile temporal discrimination task. All participants received two tactile stimuli with varying SOA applied to their left index finger and reported how many distinct stimuli they perceived ("1" vs. "2"). HE patients needed a significantly longer SOA (138.0 ± 11.3 ms) between two tactile stimuli to perceive the stimuli as two temporally distinct events than healthy controls (78.6 ± 13.1 ms; p < 0.01). In addition, we found that the temporal discrimination ability in the tactile modality correlated positively with the temporal discrimination ability in the visual domain across all participants (i.e., negative correlation between tactile SOA and visual CFF: r = -0.37, p = 0.033). Our findings provide evidence that temporal tactile perception is substantially impaired in HE patients. In addition, the results suggest that tactile and visual discrimination abilities are affected in HE in parallel. This finding might argue for a common underlying pathophysiological mechanism. We argue that the known global slowing of neuronal oscillations in HE might represent such a common mechanism.
Project description:Carnitine is an essential co-factor in fatty acid metabolism. Carnitine deficiency can impair fatty acid oxidation, rarely leading to hyperammonemia and encephalopathy. We present the case of a 35-year-old woman who developed acute mental status changes, asterixis, and diffuse muscle weakness. Her ammonia level was elevated at 276 microg/dL. Traditional ammonia-reducing therapies were initiated, but proved ineffective. Pharmacologic, microbial, and autoimmune causes for the hyperammonemia were excluded. The patient was severely malnourished and her carnitine level was found to be extremely low. After carnitine supplementation, ammonia levels normalized and the patient's mental status returned to baseline. In the setting of refractory hyperammonemia, this case illustrates how careful investigation may reveal a treatable condition.
Project description:ObjectiveCisplatin (CDDP) toxicity is a dose-limiting clinical problem in clinical practice, mainly because of nephrotoxicity or ototoxicity. However, the mechanism of CDDP-induced cardiotoxicity is poorly understood. Acetyl-l-carnitine (ALCAR) is an antioxidant agent with protective effects against the side effects of various chemotherapeutics. CDDP-induced cardiotoxicity and the protective role of ALCAR were evaluated in this study.MethodsMorphological changes were evaluated in hematoxylin and eosin-stained sections, and immunohistochemistry for caspase-3, superoxide dismutase-2 (SOD-2), inducible nitrite oxide synthase (iNOS), cyclooxygenase-2, and Bcl-2 was performed using the hearts of athymic nude mice carrying xenograft neuroblastoma tumors. Mice were randomized (six/group) to the control, CDDP (16 mg/kg), and ALCAR (200 mg/kg)+CDDP (16 mg/kg) groups. Results were analyzed using nonparametric tests.ResultsNo difference was observed in the rates of cardiac necrosis, dilated/congested blood vessels, hemorrhage, polymorphonuclear leukocyte infiltration, edema, and pyknotic nuclei among the groups. SOD-2 expression was increased in the CDDP group but not in the ALCAR+CDDP group. iNOS, Bcl-2, and caspase-3 levels were not significantly different among the groups.ConclusionsALCAR might be a candidate protective agent for CDDP-induced cardiotoxicity. SOD-2, as a member of the oxidant system, should be evaluated in further studies as a biomarker of cardiotoxicity.
Project description:Minimal hepatic encephalopathy (MHE) adversely affects the clinical outcomes of patients with liver cirrhosis. This prospective study aimed to evaluate the utility of the Stroop test in the diagnosis of MHE and prediction of overt hepatic encephalopathy (OHE) in Japanese patients with cirrhosis. We enrolled 152 patients who underwent the Stroop test between November 2018 and February 2020. MHE was diagnosed using a combination of neuropsychological tests as the gold standard. The enrolled patients were followed up prospectively until the occurrence of OHE or August 2020. The optimal cutoff value of the Stroop test measurements was determined by receiver operating characteristic (ROC) curve analysis, and its predictive ability was assessed using the area under the ROC curve (AUC). Among the 139 eligible patients, 50 (36%) were diagnosed with MHE. The OffTime+OnTime cutoff value of 218.3 seconds had the best discriminative ability for MHE diagnosis, with an AUC of 0.77, a sensitivity of 74%, and a specificity of 75%. During a median follow-up of 10.8 months, 6 (4%) patients developed OHE. The OffTime+OnTime cutoff value of 305.6 seconds had the highest predictive ability for OHE, with an AUC of 0.79, a sensitivity of 67%, and a specificity of 92%. This value predicted OHE occurrence independent of liver functional reserve and prior OHE (hazard ratio, 19.8; P = 0.003). These two cutoff values remained statistically significant even when patients with prior OHE were excluded from the analysis. Conclusion: The Stroop test was useful for diagnosing patients with MHE and predicting OHE in Japanese patients with cirrhosis.
Project description:BACKGROUND AND AIM:L-Acetyl-carnitine (LAC) exerts an energetic effect on nerves and muscles. Recently, preclinical experiments have demonstrated a central anti-nociceptive action. OBJECTIVE:Our objective was to assess the effects of LAC on neuroprotection, pain, and function in carpal tunnel syndrome (CTS), a very frequent chronic compressive neuropathy. METHODS:In a multicentre, examiner-blinded, clinical and neurophysiological 4-month study, we enrolled 82 patients and examined 120 hands with CTS of mild to moderate severity. Patients were assessed at baseline and 10, 60 and 120 days after treatment with LAC 500 mg twice daily (BID). All patients underwent a conduction study of the median nerve, the Boston Carpal Tunnel Questionnaire (BCTQ) and the Neuropathic Pain Symptom Inventory (NPSI). The primary endpoint was the sensory conduction velocity (SCV) of the median nerve. RESULTS:The primary endpoint was met, with significant improvement of the SCV (P < 0.0001). All sensory neurophysiological measures also significantly improved. BCTQ score changed significantly (P < 0.0001), with a greater improvement in the symptom component. Nine of the NPSI types of pain, particularly squeezing and pressure pain and pain evoked by pressure, showed a significant reduction (P < 0.0001). CONCLUSIONS:Our clinical and neurophysiological study indicated that 4 months of treatment with LAC exerted a neuroprotective effect. LAC reduced pain in patients with mild and moderate CTS, a result that is possibly due to both its neuroprotective action and its central anti-nociceptive properties. Clinical Trials Registration code: EudraCT 2014-002289-62.
Project description:AIM:To evaluate the reversibility of minimal hepatic encephalopathy (MHE) following liver transplantation (LT) in Egyptian cirrhotic patients. METHODS:This prospective study included twenty patients with biopsy-proven liver cirrhosis listed for LT and twenty age- and sex-matched healthy control subjects. All underwent neuro-psychiatric examination, laboratory investigations, radiological studies and psychometric tests including trail making test A (TMT A), TMT B, digit symbol test and serial dotting test. The psychometric hepatic encephalopathy score (PHES) was calculated for patients to diagnose MHE. Psychometric tests were repeated six months following LT in the cirrhotic patient group. RESULTS:Before LT, psychometric tests showed highly significant deficits in cirrhotic patients in comparison to controls (P < 0.001). There was a statistically significant improvement in test values in the patient group after LT; however, their values were still significantly worse than those of the controls (P < 0.001). The PHES detected MHE in 16 patients (80%) before LT with a median value of -7 ± 3.5. The median PHES value was significantly improved following LT, reaching -4.5 ± 5 (P < 0.001), and the number of patients with MHE decreased to 11 (55%). The pre-transplant model for end-stage liver disease (MELD) score ? 15 was significantly related to the presence of post-transplant MHE (P = 0.005). More patients in whom reversal of MHE was observed had a pre-transplant MELD score < 15. CONCLUSION:Reversal of MHE in cirrhotic patients could be achieved by LT, especially in those with a MELD score < 15.