Tumoral non-amyloidotic monoclonal immunoglobulin light chain deposits ('aggregoma'): presenting feature of B-cell dyscrasia in three cases with immunohistochemical and biochemical analyses

Tumoral monoclonal immunoglobulin (Ig) light chain non-fibrillar deposits ('aggregomas'), which can be considered analogous to solitary light chain amyloidomas, are a rare presenting feature of B-cell dyscrasias. It is not certain if they are truly localized or if in reality they represent an initial expression of a silent systemic non-amyloid light chain deposition disease (LCDD). This report describes three patients, two of whom presented with cervical masses and the third with a solitary lung nodule, each comprising granular aggregates of monoclonal kappa light chain. Extracted deposits from the lymph node of one patient were shown by N-terminal amino acid sequence analysis to belong to the variable-region kappa I (Vkappa I) light chain subgroup, the first reported kappa-LCDD protein encoded by the L9 gene and the first report of an expressed protein related to this gene. Extracted deposits from the lung nodule of the second patient belonged to the Vkappa IV light chain subgroup encoded by the B3 germ line gene. The N-terminal amino acid sequences of the light chains from the aggregomas were compared with the related germ line sequences and to the N-terminal amino acid sequences of the nine other known kappa-LCDD light chains reported thus far from patients with systemic LCDD.     

Comparison of stent versus balloon angioplasty for pulmonary vein stenosis complicating pulmonary vein isolation

Introduction: Pulmonary vein stenosis (PVS) is a rare but significant complication of pulmonary vein isolation (PVI). Dilation and stent angioplasty have been described but not compared.
Methods and Results: All percutaneous interventions for PVS complicating PVI between December 2000 and March 2007 were reviewed. Acute success, defined as post-intervention stenosis ≤30%, and long-term outcome of dilation versus stent angioplasty were compared. Freedom from restenosis was defined as freedom from repeat intervention. Overall outcome for all interventions was examined. We studied 34 patients with 55 stenotic veins followed for a mean of 25 months. Dilation was performed in 39 veins and stenting in 40 veins (16 primarily, 24 after dilation restenosis). Acute success and restenosis rates were 42% and 72% for dilation versus 95% (P < 0.001) and 33% for stenting. Time to restenosis was greater for stent angioplasty (P = 0.003). Stents ≥10 mm in diameter had lower restenosis than smaller stents. Risk factors for restenosis included small reference vessel diameter and longer time from PVI to intervention for PVS. All but two patients experienced improvement (n = 10) or resolution of symptoms (n = 22). The mean percent stenosis decreased from 82% to 21% for the entire cohort and mean flow to the lung quadrant increased from 10% to 17%.
Conclusion: Stent angioplasty results in less restenosis than dilation, particularly for stents ≥10 mm. Early referral may improve long-term patency by minimizing reference vessel atrophy. Most patients with PVS post-PVI can be improved symptomatically with catheter intervention.     

Inhibitory Effects of Incomplete Freund's Adjuvant on Experimental Autoimmune Encephalomyelitis

Freund's incomplete adjuvant (IFA), an aqueous/oil emulsion that is widely used in combination with antigenic proteins and peptides to induce tolerance, is considered to be immunologically inert. However, sporadic reports indicate that IFA may itself have inhibitory properties on induction of adjuvant induced arthritis and spontaneous diabetes. In the current study, the effects of IFA/saline were evaluated on the induction of experimental autoimmune encephalomyelitis (EAE) in three different strains of mice. IFA/saline given i.p. in two doses of >100 &#117 &#119 l 10 &#117 days apart were found to inhibit EAE induction to varying degrees in all three strains of mice in a dose dependent fashion. The IFA/saline injections inhibited both mitogen and antigen-induced T cell proliferation, induced elevated secretion of IFN- &#110 and IL-10 by neuroantigen specific T cells, and reduced expression of cytokines, chemokines, and chemokine receptors of CNS-infiltrating mononuclear cells. These data demonstrate for the first time a direct inhibitory effect of IFA/saline on EAE, and re-emphasize the need to properly control experiments using IFA to induce antigen-specific tolerance.     

The tumor suppressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation

The establishment of the epigenetic mark H4K20me1 (monomethylation of H4K20) by PR-Set7 during G₂/M directly impacts S-phase progression and genome stability. However, the mechanisms involved in the regulation of this event are not well understood. Here we show that SirT2 regulates H4K20me1 deposition through the deacetylation of H4K16Ac (acetylation of H4K16) and determines the levels of H4K20me2/3 throughout the cell cycle. SirT2 binds and deacetylates PR-Set7 at K90, modulating its chromatin localization. Consistently, SirT2 depletion significantly reduces PR-Set7 chromatin levels, alters the size and number of PR-Set7 foci, and decreases the overall mitotic deposition of H4K20me1. Upon stress, the interaction between SirT2 and PR-Set7 increases along with the H4K20me1 levels, suggesting a novel mitotic checkpoint mechanism. SirT2 loss in mice induces significant defects associated with defective H4K20me1–3 levels. Accordingly, SirT2-deficient animals exhibit genomic instability and chromosomal aberrations and are prone to tumorigenesis. Our studies suggest that the dynamic cross-talk between the environment and the genome during mitosis determines the fate of the subsequent cell cycle.     

A Novel Regulatory Defect in the Branched‐Chain α‐Keto Acid Dehydrogenase Complex Due to a Mutation in the PPM1K Gene Causes a Mild Variant Phenotype of Maple Syrup Urine Disease

This article describes a hitherto unreported involvement of the phosphatase PP2Cm, a recently described member of the branched‐chain α‐keto acid dehydrogenase (BCKDH) complex, in maple syrup urine disease (MSUD). The disease‐causing mutation was identified in a patient with a mild variant phenotype, involving a gene not previously associated with MSUD. SNP array‐based genotyping showed a copy‐neutral homozygous pattern for chromosome 4 compatible with uniparental isodisomy. Mutation analysis of the candidate gene, PPM1K, revealed a homozygous c.417_418delTA change predicted to result in a truncated, unstable protein. No PP2Cm mutant protein was detected in immunocytochemical or Western blot expression analyses. The transient expression of wild‐type PPM1K in PP2Cm‐deficient fibroblasts recovered 35% of normal BCKDH activity. As PP2Cm has been described essential for cell survival, apoptosis and metabolism, the impact of its deficiency on specific metabolic stress variables was evaluated in PP2Cm‐deficient fibroblasts. Increases were seen in ROS levels along with the activation of specific stress‐signaling MAP kinases. Similar to that described for the pyruvate dehydrogenase complex, a defect in the regulation of BCKDH caused the aberrant metabolism of its substrate, contributing to the patient's MSUD phenotype—and perhaps others.     

A prospective randomized evaluation of three schedules of mesna administration in patients receiving an ifosfamide-containing chemotherapy regimen: sustained efficiency and simplified administration

Chemotherapy with oxazaphosphorines, such as ifosfamide, is often limited by unacceptable urotoxicity. Without uroprotection hemorrhagic cystitis becomes doselimiting. Mesna, a thiol compound, is a drug able to bind the toxic metabolites, forming nontoxic compounds in the urine. A total of 122 patients were enrolled in this study and 228 chemotherapy cycles with an ifosfamide-containing regimen were performed (225 evaluable). Mesna was given at the same total dose as the ifosfamide in all arms. On arm A, mesna was given i. v. in equal doses 15 min before and 4 h and 8 h following the ifosfamide dose. On arm B, mesna was given in three equivalent doses 15 min before (i.v.) and 4 h (i.v.) and 8 h (p.o., double dose) following ifosfamide. On arm C, mesna was given i.v. intwo equal doses given 15 min before and 4 h following. The incidence of urotoxicity was very low (lower than 15%) in the three arms, 0% in A, 1.36% in B and 2.70% in C. All three arms were equally efficient. Schedule C was considered superior to the others, since it was equally effective, simpler and more convenient.