Neurodevelopmental Outcome and Treatment Efficacy of Benzoate and Dextromethorphan in Siblings with Attenuated Nonketotic Hyperglycinemia.

OBJECTIVE: To evaluate the impact of sodium benzoate and dextromethorphan treatment on patients with the attenuated form of nonketotic hyperglycinemia. STUDY DESIGN: Families were recruited with 2 siblings both affected with attenuated nonketotic hyperglycinemia. Genetic mutations were expressed to identify residual activity. The outcome on developmental progress and seizures was compared between the first child diagnosed and treated late with the second child diagnosed at birth and treated aggressively from the newborn period using dextromethorphan and benzoate at dosing sufficient to normalize plasma glycine levels. Both siblings were evaluated with similar standardized neurodevelopmental measures. RESULTS: In each sibling set, the second sibling treated from the neonatal period achieved earlier and more developmental milestones, and had a higher developmental quotient. In 3 of the 4 sibling pairs, the younger sibling had no seizures whereas the first child had a seizure disorder. The adaptive behavior subdomains of socialization and daily living skills improved more than motor skills and communication. CONCLUSIONS: Early treatment with dextromethorphan and sodium benzoate sufficient to normalize plasma glycine levels is effective at improving outcome if used in children with attenuated disease with mutations providing residual activity and when started from the neonatal period.

Risk factors for hospital and long-term mortality of critically ill elderly patients admitted to an intensive care unit.

BACKGROUND: Data on long-term outcomes of elderly (≥65 years) patients in ICU are sparse. MATERIALS AND METHODS: Adult patients (n = 1563, 45.4% elderly) admitted over 28 months were analyzed by competing risks regression model to determine independent factors related to in-hospital and long-term mortality. RESULTS: 414 (26.5%) and 337 (21.6%) patients died in-hospital and during the 52 months following discharge, respectively; the elderly group had higher mortality during both periods. After discharge, elderly patients had 2.3 times higher mortality compared to the general population of the same age-group. In-hospital mortality was independently associated with mechanical ventilation (subdistribution hazard ratio (SHR) 2.74), vasopressors (SHR 2.56), neurological disease (SHR 1.77), and Mortality Prediction Model II score (SHR 1.01) regardless of age and with malignancy (SHR, hematological 3.65, nonhematological 3.4) and prior renal replacement therapy (RRT, SHR 2.21) only in the elderly. Long-term mortality was associated with low hemoglobin concentration (SHR 0.94), airway disease (SHR 2.23), and malignancy (SHR hematological 1.11, nonhematological 2.31) regardless of age and with comorbidities especially among the nonelderly. CONCLUSIONS: Following discharge, elderly ICU patients have higher mortality compared to the nonelderly and general population. In the elderly group, prior RRT and malignancy contribute additionally to in-hospital mortality risk. In the long-term, comorbidities (age-related), anemia, airway disease, and malignancy were significantly associated with mortality.

Increased expression of acyl-coenzyme A: cholesterol acyltransferase-1 and elevated cholesteryl esters in the hippocampus after excitotoxic injury.

Significant increases in levels of cholesterol and cholesterol oxidation products are detected in the hippocampus undergoing degeneration after excitotoxicity induced by the potent glutamate analog, kainate (KA), but until now, it is unclear whether the cholesterol is in the free or esterified form. The present study was carried out to examine the expression of the enzyme involved in cholesteryl ester biosynthesis, acyl-coenzyme A: cholesterol acyltransferase (ACAT) and cholesteryl esters after KA excitotoxicity. A 1000-fold greater basal mRNA level of ACAT1 than ACAT2 was detected in the normal brain. ACAT1 mRNA and protein were upregulated in the hippocampus at 1 and 2 weeks after KA injections, at a time of glial reaction. Immunohistochemistry showed ACAT1 labeling of oligodendrocytes in the white matter and axon terminals in hippocampal CA fields of normal rats, and loss of staining in neurons but increased immunoreactivity of oligodendrocytes, in areas affected by KA. Gas chromatography-mass spectrometry analyses confirmed previous observations of a marked increase in level of total cholesterol and cholesterol oxidation products, whilst nuclear magnetic resonance spectroscopy showed significant increases in cholesteryl ester species in the degenerating hippocampus. Upregulation of ACAT1 expression was detected in OLN93 oligodendrocytes after KA treatment, and increased expression was prevented by an antioxidant or free radical scavenger in vitro. This suggests that ACAT1 expression may be induced by oxidative stress. Together, our results show elevated ACAT1 expression and increased cholesteryl esters after KA excitotoxicity. Further studies are necessary to determine a possible role of ACAT1 in acute and chronic neurodegenerative diseases.

Low cerebrospinal fluid transthyretin levels in depression: correlations with suicidal ideation and low serotonin function.

BACKGROUND: Transthyretin (TTR) is a thyroid hormone binding protein synthesized by choroid plexus and secreted into cerebrospinal fluid (CSF). We sought to replicate and extend our previous findings of lower CSF TTR in depression. METHODS: Cerebrospinal fluid TTR concentrations of 17 medication-free patients with major depressive disorder (MDD) and 15 healthy individuals were determined by a sensitive, specific radioimmunoassay newly developed in our laboratory (ESL, TBC). RESULTS: Cerebrospinal fluid TTR was lower in the MDD patients compared with healthy volunteers (mean +/- SD, 19.7 +/- 1.6 vs. 21.8 +/- 2.2 mg/L, p = .005). Age correlated positively with CSF TTR (r = .38, p < .05). The group difference remained significant (p < .005) after covariance for age. Within the MDD group, Scale for Suicide Ideation total score correlated inversely with CSF TTR (beta = -.58, p < .05). In the entire sample of depressed and healthy individuals, CSF 5-hydroxyindoleacetic acid (5-HIAA) correlated positively (beta = .34, p < .05) with CSF TTR. CONCLUSIONS: We replicated our finding of low CSF TTR levels in depression and newly identified two relationships that may explain reports linking thyroid axis dysfunction and suicidal behaviors. Serotonergic hypofunction in depression, reflected by low CSF 5-HIAA, may result in decreased choroid plexus TTR production, alterations in central thyroid hormone kinetics, and increased vulnerability to suicidal ideation and perhaps suicide.