Autoantibodies to insulin do appear in non-diabetic patients with autoimmune disorders: comparison with anti-immunoglobulin antibodies and other autoimmune phenomena

Insulin- and anti-immunoglobulin-antibodies have been recently reported in pre-diabetic subjects: the former has been proposed as a predictive marker of Type I diabetes in non-diabetic-subjects. To evaluate the diabetes-related specificity of these antibodies, the presence of insulin autoantibodies, using a recently developed and highly sensitive competitive radioimmune assay, and of anti-immunoglobulin antibodies together with that of immune complexes and of other autoantibodies has been investigated in patients with organ- or non-organ-specific autoimmune diseases. One hundred and eleven serum samples were assayed from patients with Graves' disease, primary hypothyroidism, chronic autoimmune thyroiditis, Addison's disease, chronic autoimmune hepatitis, pernicious anemia, lupus erythematosus, and rheumatoid arthritis, together with 45 serum samples from normal subjects. From patients with autoimmune diseases, 32.4% of all sera revealed values of insulin autoantibodies above the limit of positivity (p less than 0.001); anti-immunoglobulin antibodies were present in 4.1% of patients (NS); immune complexes were found in 19.5% (NS) of all patients, but in 38% of patients with Graves' disease and chronic hepatitis (p less than 0.02). There was a trend for multiple autoantibody positivity to be associated with high levels of insulin autoantibodies (p less than 0.05). Thus, whereas contrary to expectation anti-immunoglobulin antibodies are not associated with non-diabetes-related autoimmune diseases, increased humoral immunoresponsiveness to endogenous insulin appears to be related to autoimmunity in general rather than restricted to Type I diabetes.     

The evolution of methicillin resistance in Staphylococcus aureus: similarity of genetic backgrounds in historically early methicillin-susceptible and -resistant isolates and contemporary epidemic clones

The key genetic component of methicillin resistance, the mecA determinant, is not native to Staphylococcus aureus. Thus, the evolution of methicillin-resistant S. aureus (MRSA) must have begun with the acquisition of the mecA determinant from an unknown heterologous source some time before the first reported appearance of MRSA isolates in clinical specimens in the U.K. and Denmark (in the early 1960s). We compared the genetic backgrounds and phenotypes of a group of methicillin-susceptible S. aureus (MSSA) isolates to the properties of MRSA strains isolated in Denmark and the U.K. during the same time period, and also to the genetic profiles of contemporary epidemic clones of MRSA. All early MRSA isolates resembled a large group of the early MSSA blood isolates in phenotypic and genetic properties, including phage group, antibiotype (resistance to penicillin, streptomycin, and tetracycline), pulsed-field gel electrophoresis pattern, and spaA type and multilocus sequence type, strongly suggesting that the early MSSA examined here represented the progeny of a strain that served as one of the first S. aureus recipients of the methicillin-resistance determinant in Europe. The genetic background of this group of early MSSA isolates was also very similar to that of the widely disseminated contemporary "Iberian clone" of MRSA, suggesting that genetic determinants present in early MSSA and essential for some aspects of the epidemicity and/or virulence of these strains may have been retained by this highly successful contemporary MRSA lineage.     

Gender and racial differences in lipoprotein subclass distributions: the STRRIDE study

Recent research has focused on the potential atherogenicity of various lipoprotein subclasses and their link to coronary heart disease (CHD) risk. This investigation seeks to identify differences in lipoprotein subclass distributions among a biracial, middle-aged population, while controlling for a number of confounding risk factors. Fasting plasma samples were analyzed in 285 sedentary, mildly dyslipidemic, overweight individuals between 40 and 65 years with no known history of CHD or diabetes. Women had lower levels of small and medium LDL, medium VLDL, large VLDL, and small HDL with a much higher concentration of large HDL than men. Whites had significantly more IDL, small LDL, medium VLDL, and large VLDL with lower levels of large LDL than blacks. HDL and LDL size were larger among blacks and women; VLDL size was greater among whites and men. There was also a trend for men to have more LDL particles than women and whites to have a higher LDL particle concentration than blacks. Within this homogenous population, there were distinct differences between gender and racial groups. Blacks and women had less atherogenic profiles than whites and men, which was not evident from the standard lipid panel.     

DAB389IL-2 recombinant fusion toxin effect on lymphocyte- and macrophage-producing cytokine subpopulation cells in experimentally induced demyelinating disease in mice

Context: We have reported previously that DAB₃₈₉IL-2 recombinant fusion toxin targets IL-2R bearing CD4⁺ cells, and suppresses demyelinating disease in acute (A) - and chronic (C) - experimental autoimmune encephalomyelitis (EAE) animal models of multiple sclerosis.

Objectives: The present study was undertaken to investigate the effect of DAB₃₈₉IL-2 treatment on various cytokine-secreting cell populations in A-EAE and C-EAE mice.

Materials and methods: The effects of DAB₃₈₉IL-2 at doses of 200-, 800-, or 1600 kU administered i.v. on days 11–13 and 15 post disease induction on the clinical score and cytokine-secreting cell populations were examined using flow cytometry.

Results: C-EAE mice treated with 1600 kU DAB₃₈₉IL-2, but not A-EAE mice treated with 800 kU had significantly reduced disease. The CD3⁺CD25⁺ sub-population in spleens and spinal cords of A-EAE mice treated with 800 kU DAB₃₈₉IL-2 was increased, whereas in C-EAE mice treated with 1600 kU this population was decreased. DAB₃₈₉IL-2 treatment reduced CD3⁺CD4⁺, CD3⁺CD8⁺, CD4⁺CD8⁺, CD3⁺IL-2⁺, CD3⁺IFN-γ⁺ and CD3⁺TNF-α⁺ T cell subpopulations in the spinal cord in A-EAE, and C-EAE mice on day 16. CD11b⁺ macrophages that were IL-2-, IFN-γ-, and TNF-α- positive were reduced in A-EAE mice. DAB₃₈₉IL-2 treatment reduced CD19⁺ B-cells positive for IL-2 or CD11b⁺ in the spinal cord in acute and chronic disease. DAB₃₈₉IL-2 treatment also reduced lymph node CD3⁺CD8⁺, CD4⁺CD8⁺, CD3⁺CD25⁺ populations on day 16, and lymph node CD3⁺IL-10⁺ and peripheral blood CD3⁺CD25⁺ populations on day 24.

Discussion and conclusion: Our study demonstrates that DAB₃₈₉IL-2 fusion toxin suppresses EAE in a dose-dependent manner, and alters inflammatory cell sub-populations during disease development.     

Development and characterization of 17 polymorphic microsatellite loci in the faucet snail, Bithynia tentaculata (Gastropoda: Caenogastropoda: Bithyniidae)

Bithynia tentaculata (Linnaeus, 1758), a snail native to Europe, was introduced into the US Great Lakes in the 1870’s and has spread to rivers throughout the Northeastern US and Upper Mississippi River (UMR). Trematode parasites, for which B. tentaculata is a host, have also been introduced and are causing widespread waterfowl mortality in the UMR. Waterfowl mortality is caused by ingestion of trematode-infected B. tentaculata or insects infected with parasites released from the snails. We isolated and characterized 17 microsatellite loci from the invasive faucet snail, B. tentaculata (Gastropoda: Caenogastropoda: Bithyniidae). Loci were screened in 24 individuals of B. tentaculata. The number of alleles per locus ranged from 2 to 6, observed heterozygosity ranged from 0.050 to 0.783, and the probability of identity values ranged from 0.10 to 0.91. These new loci provide tools for examining the origin and spread of invasive populations in the US and management activities to prevent waterfowl mortality.     

Development and characterization of 16 microsatellite markers for the Louisiana pine snake, Pituophis ruthveni, and two congeners of conservation concern

We isolated and characterized 16 microsatellite loci from the Louisiana pine snake, Pituophis ruthveni. Loci were screened in 24 individuals from locations throughout its distribution in Louisiana and Texas. The number of alleles per locus ranged from 4 to 12, observed heterozygosity ranged from 0.200 to 0.875, and the probability of identity ranged from 0.043 to 0.298. We examined cross-species amplification at these loci in P. catenifer (bullsnakes and gopher snakes) and P. melanoleucus (pine snakes). These new markers provide tools for examining the conservation genetics of this species complex. Louisiana pine snakes face numerous threats: population densities are extremely low and their natural habitat has been severely altered and fragmented. In southern Canada, P. catenifer is at the northern extreme of its range and limited by the availability of suitable over-wintering sites. Hence, for these two species reduction of heterozygosity, potential for inbreeding, and increased effects of genetic drift are all of considerable conservation concern.     

Excellent therapeutic results achieved in chronic myeloid leukemia patients with front‐line imatinib and early treatment modifications in suboptimal responders: A retrospective study on 91 unselected patients

Second generation tyrosine kinase‐inhibitors (TKI) have been claimed to represent now the first‐choice therapy for chronic myeloid leukemia (CML). Indeed, they generally induce faster and deeper molecular responses compared to imatinib that, however, is equally effective in at least 50% of patients. Moreover, some recent reports have questioned the long term safety of dasatinib and nilotinib. Therefore, upfront imatinib with early shift to second generation TKI for patients with slow/incomplete response might be as effective as front‐line second generation TKI, with a possibly better safety profile. We retrospectively evaluated 91 chronic phase CML patients (median follow‐up 57 months, median age 61 years), treated front‐line with standard‐dose imatinib and early therapy modifications (at 3–12 months) in case of unsatisfactory response or intolerance. Thirty‐three patients (24 with unsatisfactory response, 9 intolerant) changed therapy, either by increasing imatinib dose (11/91) or by switching to second generation TKI (22 directly, 4 after high‐dose imatinib). Globally, our strategy led to complete cytogenetic response (CCyR) in 98% of the patients, major molecular response (MMR) in 88% and molecular response 4 logs (MR^4.0) in 62%. Three patients in CCyR (3%), 2 of them in MMR too, suddenly progressed to blastic phase. At the last follow‐up nine patients had died, seven of CML‐unrelated causes and two only of CML progression. These results suggest that our strategy could be as effective as front line second generation TKI, with most of patients still receiving imatinib, a drug of better known long‐term side effects and lower cost. Am. J. Hematol. 88:838–842, 2013. © 2013 Wiley Periodicals, Inc.     

A presenilin 1 mutation (Arg278Ser) associated with early onset Alzheimer's disease and spastic paraparesis

Early onset familial Alzheimer’s disease (EOFAD) has been associated with mutations in three genes, of which presenilin 1 (PSEN1) mutations are the most frequent. Several families with an association of progressive dementia and spastic paraplegia caused by PSEN1 mutations have been described. Here we described a novel PSEN1 mutation that was associated with dementia and spastic paraplegia in a family with 5 affected individuals in three generations. The proband was a 44-year-old woman who presented with 5 years history of progressive difficulties in walking, cognition and visuospatial impairment. Her maternal grandmother, mother and two maternal aunts also had similar neurological presentation. Molecular genetic analysis showed a missense mutation predicted to substitute an arginine residue for a serine residue at position 278 in the PSEN1 polypeptide (Arg278Ser). The novel PSEN1 mutation identified in this patient adds to the diverse list of existing mutations causing EOFAD associated with spastic paraparesis.     

Impairment in writing, but not reading, morphologically complex words

We report a patient, FP, with phonological dyslexia who is impaired in writing affixed words to dictation, but demonstrates no such deficit when reading affixed words. Moreover, she was much more impaired in the writing of regularly inflected words (e.g., "walked") as compared to irregularly inflected words (e.g., "ran") and derived words (e.g., "walker"). These findings indicate that FP's deficit was morphologically based and are consistent with accounts that assume that morphologically complex words are decomposed during lexical processing. The data also suggest that the lexical representations mediating reading and writing are, at least in part, dissociable.