Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations

We describe 3 new families affected by Alzheimer's disease with spastic paraparesis. In affected individuals, including the earliest known patient with this clinical syndrome, neuropathological examination revealed large "cotton wool" plaques similar to those we have previously described in a Finnish family. In the families in which DNA was available, presenilin-1 mutations were observed. Transfection of cells with these mutant genes caused exceptionally large increases in secreted Abeta42 levels. Furthermore, brain tissue from individuals with this syndrome had very high amyloid-beta concentrations. These findings define the molecular pathogenesis of an important subgroup of Alzheimer's disease and have implications for the pathogenesis of the disease in general.     

Chromosome 13 dementia syndromes as models of neurodegeneration.

Two hereditary conditions, familial British dementia (FBD) and familial Danish dementia (FDD), are associated with amyloid deposition in the central nervous system and neurodegeneration. The two amyloid proteins, ABri and ADan, are degradation products of the same precursor molecule BriPP bearing different genetic defects, namely a Stop-to-Arg mutation in FBD and a ten-nucleotide duplication-insertion immediately before the stop codon in FDD. Both de novo created amyloid peptides have the same length (34 amino acids) and the same post-translational modification (pyroglutamate) at their N-terminus. Neurofibrillary tangles containing the classical paired helical filaments as well as neuritic components in many instances co-localize with the amyloid deposits. In both disorders, the pattern of hyperphosphorylated tau immunoreactivity is almost indistinguishable from that seen in Alzheimer's disease. These issues argue for the primary importance of the amyloid deposits in the mechanism(s) of neuronal cell loss. We propose FBD and FDD, the chromosome 13 dementia syndromes, as models to study the molecular basis of neurofibrillary degeneration, cell death and amyloid formation in the brain.     

UVB-induced leucocyte trafficking in the epidermis of photosensitive lupus erythematosus patients: normal depletion of Langerhans cells

BACKGROUND: The pathogenic mechanisms of UV-induced skin lesions of lupus erythematosus (LE) are unknown. In a recent study of pathogenic mechanisms of polymorphic light eruption (PLE), significantly more Langerhans cells (LCs) persisted in the epidermis after UVB overexposure than in healthy individuals. Interestingly, the same phenomenon was observed in one subacute cutaneous lupus erythematosus (SCLE) patient. It could therefore be hypothesized that both photodermatoses share a common pathogenic mechanism of photosensitivity. In the present study, we tested this hypothesis by investigating leucocyte trafficking in the initial phase of cutaneous LE after intense UVB exposure. METHODS: In 22 photosensitive LE patients (12 chronic discoid lupus erythematosus, seven systemic lupus erythematosus and three SCLE) and nine age/sex-matched controls, uninvolved buttock skin was exposed to six minimal erythemal dose (MED) UVB radiation. Subsequently, biopsies were taken after 24, 48 and 72 h, and one control biopsy was taken from unirradiated skin. Skin sections were stained for the presence of LCs, neutrophils and macrophages. Areal percentages of positively stained cells within the epidermis were quantified and compared between the patients and controls. RESULTS: A gradual decrease of epidermal LCs and a gradual increase of epidermal neutrophils and macrophages at several timepoints after six MED irradiation was observed equally in both LE patients and controls. CONCLUSION: Immunohistopathology of irradiated uninvolved skin of photosensitive LE patients did not reveal the same pathologic trafficking of LCs and neutrophils as described for PLE patients. We conclude that different mechanisms are operative in the pathogenesis of PLE and photosensitive LE.     

Review: An update on clinical,genetic and pathological aspects of frontotemporal lobar degenerations

The development of our understanding of frontotemporal dementia (FTD) has gathered pace over the last 10 years. After taking a back seat to Alzheimer's disease for many years FTD has emerged as a significant group of heterogeneous diseases often affecting people under the age of 65. FTD has also been brought into the spotlight as the major disease entities of the group have clinical, genetic and pathological links to motor neuron disease/amyotrophic lateral sclerosis, indicating that they form a disease spectrum. In this review, we overview how the pathological concept of frontotemporal lobar degeneration (FTLD) and the clinical concept of FTD evolved and show that FTLD, once thought of as a single disorder, represents a heterogeneous group of diseases with overlapping clinical symptoms, multiple causative genes and varying underlying pathology. We also provide a brief summary of the clinical manifestations, summarize the major genetic aspects and describe the main pathological features seen in the different subtypes of FTLD. We also summarize the correlations that exist between clinical presentations and pathological variants. An overview of the main pathogenic mechanisms is also provided.     

Genetics and molecular pathogenesis of sporadic and hereditary cerebral amyloid angiopathies

In cerebral amyloid angiopathy (CAA), amyloid fibrils deposit in walls of arteries, arterioles and less frequently in veins and capillaries of the central nervous system, often resulting in secondary degenerative vascular changes. Although the amyloid-β peptide is by far the commonest amyloid subunit implicated in sporadic and rarely in hereditary forms of CAA, a number of other proteins may also be involved in rare familial diseases in which CAA is also a characteristic morphological feature. These latter proteins include the ABri and ADan subunits in familial British dementia and familial Danish dementia, respectively, which are also known under the umbrella term BRI2 gene-related dementias, variant cystatin C in hereditary cerebral haemorrhage with amyloidosis of Icelandic-type, variant transthyretins in meningo-vascular amyloidosis, disease-associated prion protein (PrP^Sc) in hereditary prion disease with premature stop codon mutations and mutated gelsolin (AGel) in familial amyloidosis of Finnish type. In this review, the characteristic morphological features of the different CAAs is described and the implication of the biochemical, genetic and transgenic animal data for the pathogenesis of CAA is discussed. T. Revesz and J. L. Holton have contributed equally to this work. An erratum to this article can be found at     

Preferential association of serum amyloid P component with fibrillar deposits in familial British and Danish dementias: similarities with Alzheimer's disease

Two hereditary forms of cerebrovascular amyloidosis, familial British and Danish dementias (FBD and FDD), share striking similarities with Alzheimer's disease (AD) despite structural differences among their amyloid subunits (ABri in FBD, ADan in FDD, and Abeta in AD). Neuropathological lesions in these disorders include neurofibrillary tangles, parenchymal amyloid and pre-amyloid deposits and overwhelming cerebral amyloid angiopathy co-localizing with reactive microglia and multiple amyloid associated proteins including activation products of the complement cascade. Immunohistochemical analysis of FBD and FDD brain lesions unveiled the presence of serum amyloid P-component (SAP) primarily associated with thioflavin positive amyloid deposits in spite of the significant pre-amyloid burden existing in both disorders. Using affinity chromatography and ELISA binding assays we demonstrated specific, calcium-dependent, saturable, high affinity binding interactions between SAP and ABri/ADan peptides, with dissociation constant values in the sub-nanomolar range and within the same order of magnitude as those resulting from the interaction of SAP with Alzheimer's Abeta1-40 and Abeta1-42. The preferential association of SAP with fibrillar amyloid lesions and not with non-fibrillar pre-amyloid deposits is puzzling, suggesting that SAP modulates the assembly and stability of the final fibril rather than participating in the early steps of protein misfolding and oligomerization.     

Microbial health risk posed by table eggs in Trinidad

A survey of the microbial quality of table eggs sold in Trinidad was conducted. For 23 poultry layer farms each visited twice approximately 1 month apart, 25 pooled eggs constituted a composite sample, for 14 shopping malls each visited twice approximately 1 month apart, six pooled eggs made a composite sample and for a total of 102 other retailers across the country each visited once over a 4-month period, six pooled eggs constituted a composite sample. Swabs of egg shells and egg content were tested for selected bacteria. Twenty-four (13.0%), 68 (37.0%), and two (1.1%) of a total of 184 composite eggs (shells, egg content or both) sampled were positive for Salmonella, Escherichia coli, and Campylobacter respectively. All 184 samples tested were negative for Listeria spp. Salmonella was recovered from seven (3.8%) egg shell samples only compared with 14 (7.6%) egg content samples only positive for the pathogen. Fifty-two (28.3%) egg shell samples and seven (3.8%) egg content samples were positive for E. coli. Both isolates of Campylobacter coli originated from egg contents. Of a total of 24 composite egg samples positive for Salmonella, eight different serotypes of Salmonella were isolated from a total of 24 Salmonella-positive composite eggs of which S. Enteritidis was the most prevalent, 58.3% (14/24). Salmonella Georgia was isolated for the first time in Trinidad. Failure to properly handle or heat table eggs sold in Trinidad poses a potential health hazard to consumers because of their poor microbial quality.     

Unenhanced computerized axial tomography to detect retained calculi after percutaneous ultrasonic lithotripsy.

PURPOSE: We report our experience with unenhanced computerized axial tomography (CT) after percutaneous ultrasonic lithotripsy in patients thought to be at high risk for retained calculi. MATERIALS AND METHODS: CT was obtained in 121 patients (124 kidneys) within 12 to 36 hours of percutaneous ultrasonic lithotripsy for staghorn or large nonstaghorn renal calculi. Cases were grouped according to the CT findings as no retained calculi, insignificant retained calculi (fragments 1 to 3 mm.), retained calculi amenable to shock wave lithotripsy and retained fragments requiring second look percutaneous ultrasonic lithotripsy or flexible nephroscopy. RESULTS: No calculi were seen in 73 kidneys (59%) and retained calculi were identified in 51 (41%). Shock wave lithotripsy was used to treat 8 patients and another percutaneous ultrasonic lithotripsy or flexible nephroscopy was performed in 23 to remove retained stones. Insignificant calculi were noted in the remaining 21 patients. CONCLUSIONS: We believe that postoperative unenhanced CT is superior to plain renal tomography and is the best method to determine if a patient is stone-free after percutaneous ultrasonic lithotripsy. It helps to locate precisely those stones requiring a second percutaneous ultrasonic lithotripsy or nephroscopic extraction. An unenhanced renal CT devoid of calculi obviates routine postoperative second look flexible nephroscopy. We encourage others to consider this technique to define more accurately kidney stone status after percutaneous ultrasonic lithotripsy for large staghorn calculi or in any patient at high risk for retained calculi after percutaneous ultrasonic lithotripsy.