Morphometric investigations of the mitochondrial damage in ceroid lipopigment accumulation due to vitamin E deficiency

Numeric (Nv) and volume (Vv) densities, as well as the average size (skeleton: Sk) of synaptic mitochondria from adult, normally fed and adult, vitamin E deficient animals (11 months of age) were semiautomatically measured by computer-assisted morphometry in the cerebellar granular layer. Nv, Vv and the average mitochondrial volume (V) were measured on perikaryal Purkinje cell organelles preferentially stained for succinic dehydrogenase (SDH) activity. Adult vitamin E deficient animals showed a significant decrease of Nv, a significant increase of Sk and an unchanged value of Vv. While in adult normally fed animals the mitochondria of increased size (Sk>5 microm) were 5.3%, in the adult vitamin E deficient rats this fraction accounted for 25.5%. In Purkinje cell perikarya, vitamin E deficiency resulted in a significant decrease of Vv, Nv and V, as well as a steeper reduction of the percentage of SDH-positive mitochondria of larger size. Taken together, these findings document that vitamin E deficiency is responsible of mitochondrial morphometric alterations in adult rats. Structurally deteriorated mitochondria are reported to play a role in producing increased amounts of free radicals, which can facilitate the accumulation of ceroid pigment.     

The role of macrophage colony-stimulating factor in patients with acute myocardial infarction: a pilot study

We assessed whether macrophage colony-stimulating factor (M-CSF) levels are associated with left ventricular systolic dysfunction (LVSD) in patients with acute myocardial infarction (AMI). We studied 56 patients with AMI (mean age: 67 ± 12 years) and identified those with clinical (Killip class >II) or echocardiographic signs (ejection fraction ≤45%) of LVSD. We evaluated the established cardiovascular risk factors and measured several cardiovascular biomarkers, including M-CSF. Serum M-CSF concentrations (pg/mL) were significantly increased in patients with both clinical and echocardiographic signs of LVSD (460 ± 265 vs 290 ± 210, P = .0103 and 493 ± 299 vs 287 ± 174, P = .0028, respectively). We found a significant inverse association between M-CSF and ejection fraction (r = -.351, P = .0079). Logistic regression analysis revealed that, among all evaluated clinical and biochemical parameters, the stronger predictor of LVSD was M-CSF (odds ratios 2.1, 95% confidence interval 1.1-2.9, P = .0168). This is the first study reporting plasma M-CSF levels as independent determinants of low LV ejection fraction and clinical LV dysfunction in patients with AMI.     

Long-term use of deferiprone significantly enhances left-ventricular ejection function in thalassemia major patients

A multicenter randomized open-label long-term sequential deferiprone–deferoxamine (DFP-DFO) versus DFP alone trial (sequential DFP-DFO) performed in patients with thalassemia major (TM) was retrospectively reanalyzed to assess the variation in the left ventricular ejection fraction (LVEF) [1].     

Successful long-term outcome after renal transplantation in a patient with atypical haemolytic uremic syndrome with combined membrane cofactor protein CD46 and complement factor I mutations

Background

Atypical haemolytic uremic syndrome (aHUS) is often associated with a high risk of disease recurrence and subsequent graft loss after isolated renal transplantation. Evidence-based recommendations for a mutation-based management after renal transplantation in aHUS caused by a combined mutation with complement factor I (CFI) and membrane cofactor protein CD46 (MCP) are limited.

Case-diagnosis/Treatment

We describe a 9-year-old boy with a first manifestation of aHUS at the age of 9 months carrying combined heterozygous mutations in the CFI and MCP genes. At the age of 5 years, he underwent isolated cadaveric renal transplantation. Fresh frozen plasma was administered during and after transplantation, tapered and finally stopped after 3 years.

Conclusions

During the 5-year follow-up after transplantation there have been no signs of aHUS recurrence and graft function has remained good. The combination of heterozygous MCP and CFI mutations with aHUS might have a positive impact on the post-transplant course, possibly predicting a lower risk of aHUS recurrence after an isolated cadaveric renal transplantation     

Proteomic and metabolomic profiling reveals time-dependent changes in hippocampal metabolism upon paroxetine treatment and biomarker candidates

Most of the commonly used antidepressants block monoamine reuptake transporters to enhance serotonergic or noradrenergic neurotransmission. Effects besides or downstream of monoamine reuptake inhibition are poorly understood and yet presumably important for the drugs' mode of action. In the present study we aimed at identifying hippocampal cellular pathway alterations in DBA/2 mice using paroxetine as a representative Selective Serotonin Reuptake Inhibitor (SSRI). Furthermore we identified biomarker candidates for the assessment of antidepressant treatment effects in plasma. Hippocampal protein levels were compared between chronic paroxetine- and vehicle-treated animals using in vivo¹⁵N metabolic labeling combined with mass spectrometry. We also studied the time course of metabolite level changes in hippocampus and plasma using a targeted polar metabolomics profiling platform. In silico pathway analyses revealed profound alterations related to hippocampal energy metabolism. Glycolytic metabolite levels acutely increased while Krebs cycle metabolite levels decreased upon chronic treatment. Changes in energy metabolism were influenced by altered glycogen metabolism rather than by altered glycolytic or Krebs cycle enzyme levels. Increased energy levels were reflected by an increased ATP/ADP ratio and by increased ratios of high-to-low energy purines and pyrimidines. In the course of our analyses we also identified myo-inositol as a biomarker candidate for the assessment of antidepressant treatment effects in the periphery. This study defines the cellular response to paroxetine treatment at the proteome and metabolome levels in the hippocampus of DBA/2 mice and suggests novel SSRI modes of action that warrant consideration in antidepressant development efforts.