Causes of Death among Commercially Insured Multiple Sclerosis Patients in the United States

Background

Information on causes of death (CODs) for patients with multiple sclerosis (MS) in the United States is sparse and limited by standard categorizations of underlying and immediate CODs on death certificates. Prior research indicated that excess mortality among MS patients was largely due to greater mortality from infectious, cardiovascular, or pulmonary causes.

Objective

To analyze disease categories in order to gain insight to pathways, which lead directly to death in MS patients.

Methods

Commercially insured MS patients enrolled in the OptumInsight Research database between 1996 and 2009 were matched to non-MS comparators on age/residence at index year and sex. The cause most-directly leading to death from the death certificate, referred to as the “principal” COD, was determined using an algorithm to minimize the selection of either MS or cardiac/pulmonary arrest as the COD. Principal CODs were categorized into MS, cancer, cardiovascular, infectious, suicide, accidental, pulmonary, other, or unknown. Infectious, cardiovascular, and pulmonary CODs were further subcategorized.

Results

30,402 MS patients were matched to 89,818 controls, with mortality rates of 899 and 446 deaths/100,000 person-years, respectively. Excluding MS, differences in mortality rate between MS patients and non-MS comparators were largely attributable to infections, cardiovascular causes, and pulmonary problems. Of the 95 excessive deaths (per 100,000 person-years) related to infectious causes, 41 (43.2%) were due to pulmonary infections and 45 (47.4%) were attributed to sepsis. Of the 46 excessive deaths (per 100,000 person-years) related to pulmonary causes, 27 (58.7%) were due to aspiration. No single diagnostic entity predominated for the 60 excessive deaths (per 100,000 person-years) attributable to cardiac CODs.

Conclusions

The principal COD algorithm improved on other methods of determining COD in MS patients from death certificates. A greater awareness of the common CODs in MS patients will allow physicians to anticipate potential problems and, thereby, improve the care that they provide.     

The Antarctic Psychrobacter sp. TAD1 has two cold-active glutamate dehydrogenases with different cofactor specificities. Characterisation of the NAD+-dependent enzyme

Psychrobacter sp. TAD1 is a psychrotolerant bacterium from Antarctic frozen continental water that grows from 2 to 25 degrees C with optimal growth rate at 20 degrees C. The new isolate contains two glutamate dehydrogenases (GDH), differing in their cofactor specificities, subunit sizes and arrangements, and thermal properties. NADP+-dependent GDH is a hexamer of 47 kDa subunits and it is comparable to other hexameric GDHs of family-I from bacteria and lower eukaria. The NAD+-dependent enzyme, described in this communication, has a subunit weight of 160 kDa and belongs to the novel class of GDHs with large size subunits. The enzyme is a dimer; this oligomeric arrangement has not been reported previously for GDH. Both enzymes have an apparent optimum temperature for activity of approximately 20 degrees C, but their cold activities and thermal labilities are different. The NAD+-dependent enzyme is more cold active: at 10 C it retains 50% of its maximal activity, compared with 10% for the NADP+-dependent enzyme. The NADP+-dependent enzyme is more heat stable, losing only 10% activity after heating for 30 min, compared with 95% for the NAD+-dependent enzyme. It is concluded that in Psychrobacter sp. TAD1 not only does NAD+-dependent GDH have a novel subunit molecular weight and arrangement, but that its polypeptide chains are folded differently from those of NADP+-dependent GDH, providing different cold-active properties to the two enzymes.     

DJ-1 Modulates α-Synuclein Aggregation State in a Cellular Model of Oxidative Stress: Relevance for Parkinson's Disease and Involvement of HSP70

Background

Parkinson''s disease (PD) is a neurodegenerative pathology whose molecular etiopathogenesis is not known. Novel contributions have come from familial forms of PD caused by alterations in genes with apparently unrelated physiological functions. The gene coding for alpha-synuclein (α-syn) (PARK1) has been investigated as α-syn is located in Lewy bodies (LB), intraneuronal inclusions in the substantia nigra (SN) of PD patients. A-syn has neuroprotective chaperone-like and antioxidant functions and is involved in dopamine storage and release. DJ-1 (PARK7), another family-PD-linked gene causing an autosomal recessive form of the pathology, shows antioxidant and chaperone-like activities too.

Methodology/Principal Findings

The present study addressed the question whether α-syn and DJ-1 interact functionally, with a view to finding some mechanism linking DJ-1 inactivation and α-syn aggregation and toxicity. We developed an in vitro model of α-syn toxicity in the human neuroblastoma cell line SK-N-BE, influencing DJ-1 and α-syn intracellular concentrations by exogenous addition of the fusion proteins TAT-α-syn and TAT-DJ-1; DJ-1 was inactivated by the siRNA method. On a micromolar scale TAT-α-syn aggregated and triggered neurotoxicity, while on the nanomolar scale it was neuroprotective against oxidative stress (induced by H₂O₂ or 6-hydroxydopamine). TAT-DJ-1 increased the expression of HSP70, while DJ-1 silencing made SK-N-BE cells more susceptible to oxidative challenge, rendering TAT-α-syn neurotoxic at nanomolar scale, with the appearance of TAT-α-syn aggregates.

Conclusion/Significance

DJ-1 inactivation may thus promote α-syn aggregation and the related toxicity, and in this model HSP70 is involved in the antioxidant response and in the regulation of α-syn fibril formation.     

Group I metabotropic glutamate receptors mediate the inhibition of phosphatidylserine synthesis in rat cerebellar slices: a possible role in physiology and pathology

In cerebellar slices, the lowering of oxygen availability, obtained by bubbling N(2) in the medium, reduced the incorporation of radioactive serine into phosphatidylserine (PtdSer). CPCCOEt, an antagonist of metabotropic glutamate receptors type 1 (mGluR1) counteracted the effect, whereas antagonists of NMDA or AMPA receptors were ineffective. In oxygenated slices, agonists of Group I mGluRs, which include mGluR1, inhibited PtdSer synthesis. This effect was also counteracted by CPCCOEt. These findings indicate that glutamate inhibits PtdSer synthesis by acting on mGluR1. This could be important in relation to the known release of glutamate in hypoxia-ischaemia conditions. In cerebellar Purkinje cells, mGluR1 are involved in the generation of mGluR-EPSP evoked by parallel fibre stimulation. The administration of l-serine to cerebellar slices reduced in a dose-dependent manner the mGluR-EPSP evoked by parallel fibre stimulation. The effect was mostly due to the increased synthesis of PtdSer. Thus inhibition of PtdSer synthesis, mediated by mGluR1, may participate in the generation of mGluR-EPSP.     

Metabolic engineering of potato tuber carotenoids through tuber-specific silencing of lycopene epsilon cyclase

Background  

Potato is a major staple food, and modification of its provitamin content is a possible means for alleviating nutritional deficiencies. beta-carotene is the main dietary precursor of vitamin A. Potato tubers contain low levels of carotenoids, composed mainly of the xanthophylls lutein, antheraxanthin, violaxanthin, and of xanthophyll esters. None of these carotenoids have provitamin A activity.     

Epigenetic Switch at Atp2a2 and Myh7 Gene Promoters in Pressure Overload-Induced Heart Failure

Re-induction of fetal genes and/or re-expression of postnatal genes represent hallmarks of pathological cardiac remodeling, and are considered important in the progression of the normal heart towards heart failure (HF). Whether epigenetic modifications are involved in these processes is currently under investigation. Here we hypothesized that histone chromatin modifications may underlie changes in the gene expression program during pressure overload-induced HF. We evaluated chromatin marks at the promoter regions of the sarcoplasmic reticulum Ca²⁺ATPase (SERCA-2A) and β-myosin-heavy chain (β-MHC) genes (Atp2a2 and Myh7, respectively) in murine hearts after one or eight weeks of pressure overload induced by transverse aortic constriction (TAC). As expected, all TAC hearts displayed a significant reduction in SERCA-2A and a significant induction of β-MHC mRNA levels. Interestingly, opposite histone H3 modifications were identified in the promoter regions of these genes after TAC, including H3 dimethylation (me2) at lysine (K) 4 (H3K4me2) and K9 (H3K9me2), H3 trimethylation (me3) at K27 (H3K27me3) and dimethylation (me2) at K36 (H3K36me2). Consistently, a significant reduction of lysine-specific demethylase KDM2A could be found after eight weeks of TAC at the Atp2a2 promoter. Moreover, opposite changes in the recruitment of DNA methylation machinery components (DNA methyltransferases DNMT1 and DNMT3b, and methyl CpG binding protein 2 MeCp2) were found at the Atp2a2 or Myh7 promoters after TAC. Taken together, these results suggest that epigenetic modifications may underlie gene expression reprogramming in the adult murine heart under conditions of pressure overload, and might be involved in the progression of the normal heart towards HF.     

Synergy of molecular and serological methods in minimally invasive diagnosis of enteroviral cardiac infection

Treatment of myocarditis and pericarditis can differ on the basis of aetiology: systemic or auto-immune disease can be positively influenced by corticoid therapy, whereas this kind of treatment can worsen the course of virus-induced disease. Therefore, the aetiological diagnosis is extremely important. The synergistic use of minimally invasive serological, IgG, IgM, IgA, and neutralizing titres, and RNA detection was evaluated on representative patients out of 238 suffering from cardiopathies. The results obtained for each case can yield reliable guidelines that rapidly highlight the presence of a viral aetiology so that an endomyocardial biopsy can be performed thus eliminating incorrect therapies. Thus, not only is this technique rapid, minimally invasive providing the clinician with decisive data, but it is cost effective for the health system.