Gene expression correlates of neurofibrillary tangles in Alzheimer's disease

Neurofibrillary tangles (NFT) constitute one of the cardinal histopathological features of Alzheimer's disease (AD). To explore in vivo molecular processes involved in the development of NFTs, we compared gene expression profiles of NFT-bearing entorhinal cortex neurons from 19 AD patients, adjacent non-NFT-bearing entorhinal cortex neurons from the same patients, and non-NFT-bearing entorhinal cortex neurons from 14 non-demented, histopathologically normal controls (ND). Of the differentially expressed genes, 225 showed progressively increased expression (AD NFT neurons > AD non-NFT neurons > ND non-NFT neurons) or progressively decreased expression (AD NFT neurons < AD non-NFT neurons < ND non-NFT neurons), raising the possibility that they may be related to the early stages of NFT formation. Immunohistochemical studies confirmed that many of the implicated proteins are dysregulated and preferentially localized to NFTs, including apolipoprotein J, interleukin-1 receptor-associated kinase 1, tissue inhibitor of metalloproteinase 3, and casein kinase 2, beta. Functional validation studies are underway to determine which candidate genes may be causally related to NFT neuropathology, thus providing therapeutic targets for the treatment of AD.     

Morphological characterization of the breast in Proteus syndrome complicated by ductal carcinoma in situ

Proteus syndrome (PS) is a severe, variable, and rare disorder with asymmetric and disproportionate overgrowth of body parts, cerebriform connective tissue nevi, epidermal nevi, dysregulated adipose tissue, and vascular malformations. It is associated with benign and occasionally malignant tumors. We report the first case of ductal carcinoma in situ (DCIS) in a 28-yr-old woman with PS who underwent a mastectomy for asymmetric overgrowth. The cut surface of the tissue showed a discrete, white, lobulated, solid mass with multiple cysts with occasional small polypoid nodules. Microscopically, the tissue was characterized by neoplastic and non-neoplastic changes. The former consisted of multiple intraductal papillomas and low-grade intraductal papillary, solid, and cribriform carcinoma. The non-neoplastic changes were characterized by cysts of various sizes, lined by cuboidal or apocrine cells, focally with epithelial papillary proliferation; the lumens contained eosinophilic, mucicarmine-positive, and PAS-positive material. Variable ductal proliferation and periductal, peri- and intra-lobular fibrosis with loose fibrous connective tissue was present. The carcinoma was positive for ER, PR, CK7, and MIB-1 (40%), and negative for p53 and CK20 staining. We conclude that DCIS may be one of the tumors associated with PS and that the proliferative phenotype serves as an initiator for carcinogenesis. This case highlights the difficulty of recognizing small foci of carcinoma in an asymmetrical overgrowth of the breast in a young woman with PS.     

Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple deletions or depletion of mitochondrial DNA by a dHPLC-based assay

ANT1, TWINKLE and POLG genes affect mtDNA stability and are involved in autosomal dominant PEO, while mutations in POLG are responsible for numerous clinical presentations, including autosomal recessive PEO, sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO), spino-cerebellar ataxia and epilepsy (SCAE) or Alpers syndrome. In this study, we report on the mutational analysis of ANT1, TWINKLE and POLG genes in 15 unrelated patients, using a dHPLC-based protocol. This series of patients illustrates the large array of clinical presentations associated with mtDNA stability defects, ranging from isolated benign PEO to fatal Alpers syndrome. A total of seven different mutations were identified in six of 15 patients (40%). Six different recessive mutations were found in POLG, one in TWINKLE while no mutation was identified in ANT1. Among the POLG mutations, three are novel and include two missense and one frameshift changes. Seventeen neutral changes and polymorphisms were also identified, including four novel neutral polymorphisms. Overall, this study illustrates the variability of phenotypes associated with mtDNA stability defects, increases the mutational spectrum of POLG variants and provides an efficient and reliable detection protocol for ANT1, TWINKLE and POLG mutational screening.     

MD-2

Toll-like receptors (TLRs) are a small family of type-I glycoproteins that bind to and are activated by conserved non-self molecular signatures carried by microorganisms. Toll-like receptor 4 is triggered by most lipopolysaccharides (LPS). LPS is a complex amphipathic saccharolipidic glycan derived from Gram-negative bacteria. Unique among TLRs, TLR4 activity and interaction with its natural ligand(s) strictly depends on the presence of the extracellular adaptor MD-2. MD-2 is a small secreted glycoprotein that binds with cytokine-like affinities to both the hydrophobic portion of LPS and to the extracellular domain of TLR4. The interaction between MD-2 and LPS induces a triggering event on TLR4, which involves the molecular rearrangement of the receptor complex and its homotypic aggregation. In silico analysis suggests that MD-2 and MD-1 are paralogs derived from a common predecessor at the level of early vertebrates. In this review, we summarize the current state of knowledge concerning MD-2.     

Effect of rat kidney fraction 3 (rKF3) antigen and specific IgM antibody against rKF3 on the progression of slowly progressive Heymann nephritis

The aim of the present study was to find out if specific IgM (M) antibody (directed against rat kidney fraction 3 (rKF3)) or rKF3 antigen were able to influence disease progression in an experimental autoimmune kidney disease called slowly progressive Heymann nephritis (SPHN). The level of circulating autoantibodies (aabs) and the morphological and functional changes to the kidney were studied in six groups of rats. All of the treatment components (except post-treatment with M) used in the SPHN pre- and post-treated rats and post-treated-only rats had measurable beneficial effects (even during restimulation with the chemically modified renal antigen, 22 weeks after the induction of the disease) as demonstrated by diminished pathogenic IgG aab production, less severe kidney lesions, and proteinuria reductions. The injected rKF3 minimized progression best in this experiment, especially when administered in a pre- and post-treatment regimen. It is thought that the effect of rKF3 in the reduced progression of SPHN was due to increased production of specific IgM aabs, which in turn limited pathogenic aab production and continuous buildup of immune complexes in the glomeruli by facilitating removal or blockage of nephritogenic autoantigens from the circulation.     

Neutralizing the neurotoxic effects of exogenous and endogenous tPA

The clinical use of tissue-type plasminogen activator (tPA) in the treatment of stroke is profoundly constrained by its serious side effects. We report that the deleterious effects of tPA on cerebral edema and intracranial bleeding are separable from its fibrinolytic activity and can be neutralized. A hexapeptide (EEIIMD) corresponding to amino acids 350-355 of plasminogen activator inhibitor type 1 (PAI-1) abolished the tPA-induced increase in infarct size and intracranial bleeding in both mechanical and embolic models of stroke in rats, and reduced brain edema and neuronal loss after traumatic brain injury in pigs. These experiments suggest mechanisms to reduce the neurotoxic effects of tPA without compromising its fibrinolytic activity, through the use of selective antagonists and new tPA formulations.     

Incidence of delirium and associated mortality in hematopoietic stem cell transplantation patients.

Delirium has been associated with a high risk of mortality in medical patients. Despite the high incidence of delirium in patients who undergo hemapoietic stem cell transplantation (HSCT), delirium as a risk factor for death has not been examined in this population. Thirty adult patients undergoing HSCT who were admitted to the University of Iowa Blood and Marrow Transplantation Program inpatient unit were assessed prospectively from 1 to 2 weeks before transplantation, throughout their inpatient stay, and at 100 days after transplantation. The Delirium Rating Scale and Memorial Delirium Assessment Scale were used twice weekly during the inpatient period to assess delirium severity and occurence. Patients' self-reports of medical history, computerized medical records, and neuropsychological and psychiatric assessments were used to identify pretransplantation risk factors. The incidence of delirium (Delirium Rating Scale score >12 or Memorial Delirium Assessment Scale score >or=8) was 43% and occurred with highest frequency in the first 2 weeks after transplantion. The presence of delirium at any point during hospitalization after transplantation and transplant type (allogeneic) were highly predictive of mortality (p < .0005; odds ratios, 14.0 and 14.4). In conclusion, this study highlights the importance of monitoring for delirium during the acute recovery period after transplantation and suggests that early or even prophylactic treatment for delirium should be studied. Studies to determine the factors that connect delerium soon after transplantation to mortality are highly warranted.     

Beta-amyloid-dependent expression of NOS2 in neurons: prevention by an alpha2-adrenergic antagonist

The neurotransmitter noradrenaline (NA) exerts important antiinflammatory effects on glial cells including suppression of the inducible form of nitric oxide synthase (NOS2). The authors examined the consequences of manipulating NA in vivo by treating adult rats with the neurotoxin DSP4, which selectively lesions noradrenergic neurons of the locus ceruleus (LC), and reduces cortical NA levels. Following LC lesion, intracortical injection of aggregated amyloid beta 1-42 (Abeta1-42) caused appearance of NOS2 within neurons, and increased neuronal damage assessed by staining for nonphosphorylated neurofilament proteins with antibody SMI-32. Co-treatment with a selective alpha2-adrenergic antagonist reduced neuronal NOS2 staining as well as SMI-32 staining. Neuronal damage was dependent on NOS2 expression since injection of Abeta1-42 into DSP4-treated NOS2-deficient mice did not result in neuronal damage. These results demonstrate that decrease of NA levels in vivo can exacerbate inflammatory responses and neuronal damage due to inflammatory stimuli such as Abeta. These findings suggest that alpha2-adrenergic antagonists could provide therapeutic benefit in neurological diseases such as AD or PD where LC loss is known to occur.