Blastic plasmacytoid dendritic cell neoplasm and cerebral toxoplasmosis: a case report.

BACKGROUND: The present case contributes to the limited literature on central nervous system involvement of blastic plasmacytoid dendritic cell neoplasm (BPDCN).  CASE PRESENTATION : A 63-year-old male presented to the department of neurology with a three-day history of rapidly progressing headache, fatigue, and confusion. Physical examination revealed multiple bruise-like skin lesions. Initial laboratory workup raised suspicion of acute leukemia, and a brain computer tomography identified several hyperdense processes. A bone marrow biopsy gave the diagnosis BPDCN, a rare and aggressive hematologic malignancy derived from plasmacytoid dendritic cells with a poor prognosis. Lumbar puncture showed not only signs of BPDCN, but also cerebral toxoplasmosis, thus providing a differential diagnosis. Despite intensive systemic and intrathecal chemotherapy, the patient died 25 days later due to multi-organ failure. DISCUSSION: The exact incidence of BPDCN is unknown and perhaps underestimated but may account for 0.5 - 1% of all hematological malignancies. The median age at onset is 60 to 70 years, and most patients are men. Cutaneous lesions are the most frequent clinical manifestation at diagnosis. Other symptoms present at time of diagnosis or during disease progression include lymphadenopathy, splenomegaly and cytopenia caused by bone marrow involvement. Although the majority of BPDCN patients have no symptoms or signs of central nervous system involvement, plasmacytoid dendritic cells have been detected in the cerebrospinal fluid in more than 50%. CONCLUSIONS: This case highlights the importance of considering hematological malignancies as a differential diagnosis in patients developing acute neurological symptoms and raises suspicion of a possible association between toxoplasmosis and hematological malignancies.

Centrosome isolation and analysis by mass spectrometry-based proteomics.

Centrioles are microtubule-based scaffolds that are essential for the formation of centrosomes, cilia, and flagella with important functions throughout the cell cycle, in physiology and during development. The ability to purify centriole-containing organelles on a large scale, combined with advances in protein identification using mass spectrometry-based proteomics, have revealed multiple centriole-associated proteins that are conserved during evolution in eukaryotes. Despite these advances, the molecular basis for the plethora of processes coordinated by cilia and centrosomes is not fully understood. Considering the complexity and dynamics of centriole-related proteomes and the first-pass analyses reported so far, it is likely that further insight might come from more thorough proteome analyses under various cellular and physiological conditions. To this end, we here describe methods to isolate centrosomes from human cells and strategies to selectively identify and study the properties of the associated proteins using quantitative mass spectrometry-based proteomics.

The human core exosome interacts with differentially localized processive RNases: hDIS3 and hDIS3L.

The eukaryotic RNA exosome is a ribonucleolytic complex involved in RNA processing and turnover. It consists of a nine-subunit catalytically inert core that serves a structural function and participates in substrate recognition. Best defined in Saccharomyces cerevisiae, enzymatic activity comes from the associated subunits Dis3p (Rrp44p) and Rrp6p. The former is a nuclear and cytoplasmic RNase II/R-like enzyme, which possesses both processive exo- and endonuclease activities, whereas the latter is a distributive RNase D-like nuclear exonuclease. Although the exosome core is highly conserved, identity and arrangements of its catalytic subunits in different vertebrates remain elusive. Here, we demonstrate the association of two different Dis3p homologs--hDIS3 and hDIS3L--with the human exosome core. Interestingly, these factors display markedly different intracellular localizations: hDIS3 is mainly nuclear, whereas hDIS3L is strictly cytoplasmic. This compartmental distribution reflects the substrate preferences of the complex in vivo. Both hDIS3 and hDIS3L are active exonucleases; however, only hDIS3 has retained endonucleolytic activity. Our data suggest that three different ribonucleases can serve as catalytic subunits for the exosome in human cells.

[Valproate treatment during pregnancy: description of four cases with foetal valproate syndrome]. / Behandling med valproat under graviditet: beskrivelse af fire cases med føtalt valproatsyndrom.

INTRODUCTION: Treatment with valproate is associated with an increased risk of teratogenicity compared to other antiepileptic drugs and can cause a complex of serious symptoms usually referred to as "foetal valproate symdrome" which is characterised by major and minor malformations in association with developmental delay. This paper aims to give attention to the syndrome through four case descriptions. Furthermore, possible risk factors and the use of the mutation 677C-T as a risk marker are discussed. MATERIAL AND METHODS: Nine developmentally retarded children from a parent group, born of mothers who were treated with valproate during pregnancy, were neuropediatrically and neuropsychologically examined in a non-acute setting. The mothers were screened for the 677C-T mutation. RESULTS: Four of seven examined children fulfilled the criteria for foetal valproate syndrome. Only one of the four mothers was heterozygote for the 677C-T mutation (CT, n = 1/4) and none of the mothers were homozygote (TT, n = 0/4) CONCLUSION: The foetal valproate syndrome is a complex of symptoms which is probably underdiagnosed and should be considered in the diagnostic evaluation program for children with developmental delay who are born of mothers with epilepsy. The 677C-T mutation does not seem to be a useful genetic marker of this syndrome.

The ubiquitin-proteasome system is a key component of the SUMO-2/3 cycle.

Many proteins are regulated by a variety of post-translational modifications, and orchestration of these modifications is frequently required for full control of activity. Currently little is known about the combinatorial activity of different post-translational modifications. Here we show that extensive cross-talk exists between sumoylation and ubiquitination. We found that a subset of SUMO-2-conjugated proteins is subsequently ubiquitinated and degraded by the proteasome. In a screen for preferential SUMO-1 or SUMO-2 target proteins, we found that ubiquitin accumulated in purified SUMO-2 conjugates but not in SUMO-1 conjugates. Upon inhibition of the proteasome, the amount of ubiquitin in purified SUMO-2 conjugates increased. In addition, we found that endogenous SUMO-2/3 conjugates, but not endogenous SUMO-1 conjugates, accumulated in response to proteasome inhibitors. Quantitative proteomics experiments enabled the identification of 73 SUMO-2-conjugated proteins that accumulated in cells treated with proteasome inhibitors. Cross-talk between SUMO-2/3 and the ubiquitin-proteasome system controls many target proteins that regulate all aspects of nucleic acid metabolism. Surprisingly the relative abundance of 40 SUMO-2-conjugated proteins was reduced by proteasome inhibitors possibly because of a lack of recycled SUMO-2. We conclude that SUMO-2/3 conjugation and the ubiquitin-proteasome system are tightly integrated and act in a cooperative manner.

["Jaw drop" as an atypical manifestation of Kennedy's disease]. / "Tab af kaeben" som atypisk debutsymptom ved Kennedys syndrom.

Kennedy's disease, or spinal and bulbar muscular atrophy (SBMA), is an inherited X-linked degenerative disorder characterised by slowly progressive proximal limb weakness, bulbar weakness, fasciculations, signs of androgen insensitivity and characteristic EMG findings. The disease is caused by a trinucleotide (CAG) repeat in the androgen receptor gene. We describe a patient with atypical symptoms who was initially misdiagnosed after presenting with weakness of mm. masseter and mm. temporales that caused his jaw to hang open. The initial diagnosis was suspicion of myasthenia gravis or ALS. Genetic testing later confirmed the diagnosis of Kennedy's disease.