Cerebrospinal fluid levels of amitriptyline, nortriptyline, imipramine and desmethylimipramine. Relationship to plasma levels and treatment outcome

Fifty-five (55) depressed patients were treated with amitriptyline (AMI) or imipramine (IMI). Concentrations of AMI, IMI, and their metabolites, nortriptyline (NT) and desmethylimipramine (DMI), were measured in cerebrospinal fluid (CSF) and plasma at steady state by gas chromatography mass spectrometry (GC/MS). Highly significant correlations between CSF and plasma levels of AMI, NT, IMI, and DMI were found (r greater than 0.75; P less than 0.0001 in all cases). There were no significant sex, diagnostic subgroup, or geographic difference in any of the drug parameters measured. An evaluation of the relationship between CSF levels of drug variables and clinical response showed essentially no significant correlations between these various parameters. The results obtained do not support the concept of a 'therapeutic window' for levels of plasma NT in AMI-treated patients. Furthermore, the highly significant correlations between CSF and plasma compartments in terms of drug and metabolite levels would argue against the need to measure CSF levels of these parameters in clinical practice. Plasma level measurements should be equally informative, and simpler to obtain.     

Blood exosomes as a tool for monitoring treatment efficacy and progression of neurodegenerative diseases

<正>Alzheimer’s disease,Parkinson’s disease,Huntington’s disease,amyotrophic lateral sclerosis,and prion disease are representative neurodegenerative diseases that share common sub-cellular features,the most obvious of which is a strong association with the accumulation of misfolded,aggregated,and insoluble forms of proteins in the brain,as evidenced in post-mortem brain tissues of patients.Diagnosis of neurodegenerative diseases is often made     

Skeletal muscle-specific Cre recombinase expression,controlled by the human α-skeletal actin promoter,improves glucose tolerance in mice fed a high-fat diet

Aims/hypothesis

Cre-loxP systems are frequently used in mouse genetics as research tools for studying tissue-specific functions of numerous genes/proteins. However, the expression of Cre recombinase in a tissue-specific manner often produces undesirable changes in mouse biology that can confound data interpretation when using these tools to generate tissue-specific gene knockout mice. Our objective was to characterise the actions of Cre recombinase in skeletal muscle, and we anticipated that skeletal muscle-specific Cre recombinase expression driven by the human α-skeletal actin (HSA) promoter would influence glucose homeostasis.

Methods

Eight-week-old HSA-Cre expressing mice and their wild-type littermates were fed a low- or high-fat diet for 12 weeks. Glucose homeostasis (glucose/insulin tolerance testing) and whole-body energy metabolism (indirect calorimetry) were assessed. We also measured circulating insulin levels and the muscle expression of key regulators of energy metabolism.

Results

Whereas tamoxifen-treated HSA-Cre mice fed a low-fat diet exhibited no alterations in glucose homeostasis, we observed marked improvements in glucose tolerance in tamoxifen-treated, but not corn-oil-treated, HSA-Cre mice fed a high-fat diet vs their wild-type littermates. Moreover, Cre dissociation from heat shock protein 90 and translocation to the nucleus was only seen following tamoxifen treatment. These improvements in glucose tolerance were not due to improvements in insulin sensitivity/signalling or enhanced energy metabolism, but appeared to stem from increases in circulating insulin.

Conclusions/interpretation

The intrinsic glycaemia phenotype in the HSA-Cre mouse necessitates the use of HSA-Cre controls, treated with tamoxifen, when using Cre-loxP models to investigate skeletal muscle-specific gene/protein function and glucose homeostasis.

     

Pineal cyst apoplexy and memory loss: a novel complication

An 8-year-old boy presented to our hospital complaining of a bilateral headache associated with episodes of anterograde amnesia. He had a road traffic accident 3 years ago when a computed tomography (CT) scan revealed traumatic brain injury. In addition, a small pineal cyst (PC) was noted with minor intramural calcifications. A follow-up CT a day later demonstrated increased density in the pineal gland of 60 Hounsfield Units, suggestive of apoplectic changes in the PC. However, the patient was lost to follow-up and presented with memory loss a year and a half later, upon which CT and magnetic resonance imaging revealed enlargement of the PC. PC apoplexy is a very rare occurrence usually affecting young adult women; cases in children are rarely reported. Furthermore, PC apoplexy secondary to severe craniofacial trauma manifesting as memory loss has not yet been reported in the literature to the best of our knowledge.