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Background and aims Multiple direct-acting antiviral (DAA) regimens are available to treat HCV genotype 1 infection. However, comparative effectiveness from randomized controlled trials of DAA regimens is unavailable. Approach and results We conducted a pragmatic randomized controlled trial (NCT02786537) to compare the effectiveness of DAAs for HCV genotype 1a or 1b on viral response, safety, tolerability, and medication nonadherence. Adults with compensated liver disease, HCV genotype 1, not pregnant or breastfeeding, and with health insurance likely to cover ledipasvir/sofosbuvir (LDV/SOF) were recruited from 34 US viral hepatitis clinics. Participants were randomized (± ribavirin) to LDV/SOF, elbasvir/grazoprevir (EBR/GZR), and paritaprevir/ritonavir/ombitasvir+dasabuvir (PrOD; treatment arm stopped early). Primary outcomes included sustained viral response at 12 weeks (SVR12), clinician-recorded adverse events, patient-reported symptoms, and medication nonadherence. Between June 2016 and March 2018, 1,609 participants were randomized. Among 1,128 participants who received ≥1 dose of EBR/GZR or LDV/SOF (± ribavirin), SVR12 was 95.2% (95% CI, 92.8%-97.6%) and 97.4% (95% CI, 95.5%-99.2%), respectively, with a difference estimate of 2.2% (-0.5% to 4.7%), falling within the "equivalence" interval (-5% to 5%). While most (56%) participants experienced adverse events, few were serious (4.2%) or severe (1.8%). In the absence of ribavirin, discontinuations due to adverse events were rare. Patient-reported symptoms and medication nonadherence were similar. Study limitations were dropout due to insurance denial and loss to follow-up after treatment, limiting the ability to measure SVR12. Conclusions This pragmatic trial demonstrated high SVR12 for participants treated with EBR/GZR and LDV/SOF with few adverse effects. Overall, the two regimens were equivalent in effectiveness. The results support current HCV guidelines that do not distinguish between ribavirin-free EBR/GZR and LDV/SOF.

Introduction Although registries can rapidly identify clinical study participants, it is unknown which follow up methods for recruiting are most effective. We examined the efficacy of three communication strategies for recruiting and enrolling patients who were identified via a contact registry (i.e., registry linked to a consent to re-contact program) into a clinical study. Methods Patients who met the study criteria were identified via the contact registry and targeted for recruitment. In condition 1, patients established in the university hepatology specialty clinics were contacted one time via phone call by the study coordinator and asked to participate (C1). In condition 2, non-established specialty clinic patients were mailed an IRB-approved letter with study information and instructions for calling the study coordinator to participate (C2). Condition 2A included patients who called within two weeks of receiving the letter (C2A); condition 2B included patients who did not call after receiving the letter but were subsequently contacted via phone call. Results A registry identified 1060 patients, of which 661 were eligible and targeted for recruiting. All 37 patients were reached in C1 and 17 (45.9%) were recruited. Nineteen of the 624 patients in C2A were reached and 10 were recruited whereas 120 of the 605 patients in C2B were reached and 53 (8.7%) were recruited. Seventy patients enrolled with C2B being the most effective (total, cost) recruitment strategy (n = 50) (p Conclusion The efficacy of enrolling patients identified via a contact registry into clinical trials varies based on the communication strategies used for recruiting.

Sorafenib is currently the only approved systemic therapy shown to have efficacy in the treatment of advanced hepatocellular carcinoma (HCC). Recent studies suggest that hepatitis C (HCV)-related HCC patients derive more clinical benefit from sorafenib than other subgroups, but the mechanism for this effect is unknown. In vitro data suggest that sorafenib may exert anti-viral properties, and thus our aim in this study was to evaluate potential anti-viral activity of sorafenib in patients with HCV-related HCC.To evaluate potential anti-viral activity of sorafenib in patients with HCV-related HCC.We prospectively enrolled patients with HCV-related HCC treated with sorafenib for up to 6 months. Baseline clinical, viral and oncologic data were collected. Patients' HCV viral loads were obtained at various time points, and compared with their baseline viral levels. No patients received any known anti-viral therapy during this time.Thirty-three patients were identified with baseline and subsequent HCV levels available for analysis. Six patients completed 6 months of full dose sorafenib, and comparisons of their HCV viral loads showed no significant change at week 24 (difference of means = 0.3500, CI: -0.1799-0.8799, P = 0.150), or the interim time points. Similarly, the HCV viral loads of all patients who received sorafenib and the viral loads of those patients who had tumour response to sorafenib showed no significant changes at any time point.Despite preclinical data and previous subgroup analyses suggesting that sorafenib has an anti-viral effect against HCV, this study suggests that sorafenib lacks significant anti-viral activity in HCV patients with HCC.

Objective: In familial amyotrophic lateral sclerosis (fALS) harboring superoxide dismutase (SOD1) mutations (fALS1), SOD1 toxicity has been linked to its propensity to misfold and aggregate. It has recently been proposed that misfolded SOD1 may be causative of all types of ALS, including sporadic cases (sALS). In the present study, we have used a specific antibody to test for the presence of monomer/misfolded SOD1 in sALS. Methods: Sections from lumbar spinal cords of 5 fALS1 cases, 13 sALS cases, and 1 non-SOD1 fALS case were labeled immunocytochemically using SOD1-exposed-dimer-interface (SEDI) antibody, which we have previously validated as being specific for pathological monomer/misfolded forms of SOD1. Results: Monomer/misfolded SOD1 was detected with SEDI antibody in all 5 of the fALS1 cases, localizing predominantly to hyaline conglomerate inclusions, a specific pathological feature of fALS1. In contrast, monomer/misfolded SOD1 was not detected in any of the 13 sALS cases or in the non-SOD1 fALS cases. These results were confirmed by immunoprecipitation. Interpretation: Although SEDI antibody does not necessarily label all misfolded forms of SOD1, these findings show a distinct difference between fALS1 and sALS, and do not support that monomer/misfolded SOD1 is a common disease entity linking all types of ALS. This is important to our understanding of ALS disease pathogenesis and to considerations of the applicability of using therapeutics that target misfolded SOD1 to non-SOD1-related cases.

The neuronal intermediate filament protein peripherin is a component of ubiquitinated inclusions and of axonal spheroids in amyotrophic lateral sclerosis (ALS). Overexpression of peripherin causes motor neuron degeneration in transgenic mice and variations within the peripherin gene have been identified in ALS cases. We have shown previously the abnormal expression of a neurotoxic peripherin splice variant in transgenic mice expressing mutant superoxide dismutase-1. These findings indicated that abnormalities of peripherin splicing may occur in ALS. In the current study, peripherin splice variants were identified by reverse transcription-PCR of human neuronal RNA and comparisons in expression made between control and ALS spinal cord using Western blot analysis and immunocytochemistry. Using this approach we have identified a novel peripherin transcript retaining introns 3 and 4 that results in a 28 kDa splice isoform, designated Per 28. Using an antibody specific to Per 28, we show that this isoform is expressed at low stoichiometric levels from the peripherin gene, however causes peripherin aggregation when its expression is upregulated. Importantly we show an upregulation of Per 28 expression in ALS compared with controls, at both the mRNA and protein levels, and that Per 28 is associated with disease pathology, specifically round inclusions. These findings are the first to establish that peripherin splicing abnormalities occur in ALS, generating aggregation-prone splice isoforms.

Despite intense research efforts, the physiological function and molecular environment of the amyloid precursor protein has remained enigmatic. Here we describe the application of time-controlled transcardiac perfusion cross-linking, a method for the in vivo mapping of protein interactions in intact tissue, to study the interactome of the amyloid precursor protein (APP). To gain insights into the specificity of reported protein interactions the study was extended to the mammalian amyloid precursor-like proteins (APLP1 and APLP2). To rule out sampling bias as an explanation for differences in the individual datasets, a small scale quantitative iTRAQ (isobaric tags for relative and absolute quantitation)-based comparison of APP, APLP1, and APLP2 interactomes was carried out. An interactome map was derived that confirmed eight previously reported interactions of APP and revealed the identity of more than 30 additional proteins that reside in spatial proximity to APP in the brain. Subsequent validation studies confirmed a physiological interaction between APP and leucine-rich repeat and Ig domain-containing protein 1, demonstrated a strong influence of Ig domain-containing protein 1 on the proteolytic processing of APP, and consolidated similarities in the biology of APP and p75.

The cellular prion protein, PrP(C), is neuroprotective in a number of settings and in particular prevents cerebellar degeneration mediated by CNS-expressed Doppel or internally deleted PrP ('DeltaPrP'). This paradigm has facilitated mapping of activity determinants in PrP(C) and implicated a cryptic PrP(C)-like protein, 'pi'. Shadoo (Sho) is a hypothetical GPI-anchored protein encoded by the Sprn gene, exhibiting homology and domain organization similar to the N-terminus of PrP. Here we demonstrate Sprn expression and Sho protein in the adult CNS. Sho expression overlaps PrP(C), but is low in cerebellar granular neurons (CGNs) containing PrP(C) and high in PrP(C)-deficient dendritic processes. In Prnp(0/0) CGNs, Sho transgenes were PrP(C)-like in their ability to counteract neurotoxic effects of either Doppel or DeltaPrP. Additionally, prion-infected mice exhibit a dramatic reduction in endogenous Sho protein. Sho is a candidate for pi, and since it engenders a PrP(C)-like neuroprotective activity, compromised neuroprotective activity resulting from reduced levels may exacerbate damage in prion infections. Sho may prove useful in deciphering several unresolved facets of prion biology.

Recapitulation of tau pathologies in an animal model has been a long-standing goal in neurodegenerative disease research. We generated transgenic (TgTau P301L ) mice expressing a frontotemporal dementia with parkinsonism linked to chromosome 17 (FTPD-17) mutation within the longest form of tau (2N, 4R). TgTau P301L mice developed florid pathology including neuronal pretangles, numerous Gallyas-Braak-positive neurofibrillary tangles, and glial fibrillary tangles in the frontotemporal areas of the cerebrum, in the brainstem, and to a lesser extent in the spinal cord. These features were accompanied by gliosis, neuronal loss, and cerebral atrophy. Accumulated tau was hyperphosphorylated, conformationally changed, ubiquitinated, and sarkosyl-insoluble, with electron microscopy demonstrating wavy filaments. Aged TgTau P301L mice exhibited impairment in hippocampally dependent and independent behavioral paradigms, with impairments closely related to the presence of tau pathologies and levels of insoluble tau protein. We conclude that TgTau P301L mice recreate the substantial phenotypic variation and spectrum of pathologies seen in FTDP-17 patients. Identification of genetic and/or environmental factors modifying the tau phenotype in these mice may shed light on factors modulating human tauopathies. These transgenic mice may aid therapeutic development for FTDP-17 and other diseases featuring accumulations of four-repeat tau, such as Alzheimer's disease, corticobasal degeneration, and progressive supranuclear palsy.

γ-secretase depends on presence of presenilins (PS), Nct, Aph-1, and PEN-2 within a core complex. This endoproteolytic activity cleaves within transmembrane domains of amyloid-β precursor protein (APP) and Notch, and familial Alzheimer's disease (FAD) mutations in PS1 or PS2 genes shift APP cleavage from production of amyloid-β (Aβ) 40 peptide to greater production of Aβ42. Although studies in PS1/PS2-deficient embryonic cells define overlapping activities for these proteins, in vivo complementation of PS1-deficient animals described here reveals an unexpected spectrum of activities dictated by PS1 and PS2 alleles. Unlike PS1 transgenes, wild-type PS2 transgenes expressed in the mouse CNS support little Aβ40 or Aβ42 production, and FAD PS2 alleles support robust production of only Aβ42. Although wild-type PS2 transgenes failed to rescue Notch-associated skeletal defects in PS1 hypomorphs, a “gained” competence in this regard was apparent for FAD alleles of PS2. The range of discrete and divergent processing activities in mice reconstituted with different PS genes and alleles argues against γ-secretase being a single enzyme with intrinsically relaxed substrate and cleavage site specificities. Instead, our studies define functionally distinct γ-secretase variants. We speculate that extrinsic components, in combination with core complexes, may tailor functional variants of this enzyme to their preferred substrates.

Alzheimer's disease (AD) is characterized by memory impairment leading to dementia, deposition of amyloid plaques and neurofibrillary tangles (NFTs), and neuronal loss. The major component of plaques is the amyloid beta peptide, A beta, whereas NFTs contain hyperphosphorylated forms of the microtubule-associated protein tau (tau). Familial AD (FAD) mutations either elevate A beta synthesis by favoring 'secretase' of the Alzheimer beta-amyloid precursor protein (APP) or enhance the fibrillogenic properties of this peptide. Mutations in the tau gene cause a different disease denoted FTPD-17, but suggest that the aberrant forms of tau seen in AD are unlikely to be benign. These findings imply a complex pathogenic cascade in AD and important goals of transgenic modeling are to capture and stratify this pathogenic process. Several laboratories have created APP transgenic (Tg) mice that exhibit AD-like amyloid pathology and A beta burdens. These Tg lines also exhibit deficits in spatial reference and/or working memory, with immunization against A beta attenuating both AD-associated phenotypes. Tangle-like pathologies are observed in mice expressing FTPD-17 mutant forms of tau, but florid tau pathologies based upon the wild type (wt) tau isoforms present in AD have proven more elusive. Creation of animal models with robust amyloid and tau pathologies, yet free of irrelevant confounding pathologies, remains a major objective in this field.

Alzheimer's disease (AD), the pathological hallmarks of which are amyloid plaques, neurofibrillary tangles and neuronal loss, is the most common dementia in elderly persons. To date, much evidence supports the hypothesis that the excess extracellular deposition of amyloid β-peptide (Aβ) is the most likely initiator of the pathogenesis of the disease. Recently, immunization of Aβ in PDAPP transgenic mouse model of AD was reported to reduce the burden of amyloid in the central nervous system. We show here that immunization results in an ∼50% reduction in dense-core amyloid plaques and an improvement in cognitive impairment in both the young and old TgCRND8 murine model of AD, without changing the total amount of Aβ in the brain. The induced sera had strong immunoreactivity with dense-cored Aβ plaques, not with the amyloid precursor protein, and reduced Aβ fibril formation and cytotoxicity of Aβ in vitro. These findings suggest that immunization may be a potential therapy, although undesirable immune reactions must be avoided.

Immunization of transgenic mouse models of Alzheimer disease using amyloid-beta peptide (Abeta) reduces both the Alzheimer disease-like neuropathology and the spatial memory impairments of these mice. However, a therapeutic trial of immunization with Abeta42 in humans was discontinued because a few patients developed significant meningo-encephalitic cellular inflammatory reactions. Here we show that beneficial effects in mice arise from antibodies selectively directed against residues 4-10 of Abeta42, and that these antibodies inhibit both Abeta fibrillogenesis and cytotoxicity without eliciting an inflammatory response. These findings provide the basis for improved immunization antigens as well as attempts to design small-molecule mimics as alternative therapies.

Much evidence indicates that abnormal processing and extracellular deposition of amyloid-β peptide (Aβ), a proteolytic derivative of the β-amyloid precursor protein (βAPP), is central to the pathogenesis of Alzheimer's disease (reviewed in ref. 1). In the PDAPP transgenic mouse model of Alzheimer's disease, immunization with Aβ causes a marked reduction in burden of the brain amyloid2,3. Evidence that Aβ immunization also reduces cognitive dysfunction in murine models of Alzheimer's disease would support the hypothesis that abnormal Aβ processing is essential to the pathogenesis of Alzheimer's disease, and would encourage the development of other strategies directed at the ‘amyloid cascade’. Here we show that Aβ immunization reduces both deposition of cerebral fibrillar Aβ and cognitive dysfunction in the TgCRND8 murine model of Alzheimer's disease without, however, altering total levels of Aβ in the brain. This implies that either a ∼50% reduction in dense-cored Aβ plaques is sufficient to affect cognition, or that vaccination may modulate the activity/abundance of a small subpopulation of especially toxic Aβ species.

The relationship between amyloid beta and cognitive dysfunction in mouse models of Alzheimer's disease has been evaluated predominantly with the spatial reference memory version of the water maze task. However, as Alzheimer's disease encompasses decline in multiple memory systems, it is important to also utilize non-spatial tasks to fully characterize the role of amyloid on behaviour in animal models. We used the TgCRND8 mouse model of Alzheimer's disease to evaluate the effect of amyloid on spatial reference memory, as well as on the non-spatial task of acquisition of conditioned taste aversion, and on the procedural task of swimming to a visible platform. We demonstrate that 8- to 12-month-old TgCRND8 mice are significantly impaired in all three tasks, and that the levels of soluble amyloid beta are significantly correlated with impairment in spatial reference memory, but not with impairment in conditioned taste aversion or swimming to a visible platform. Insoluble fractions of amyloid, which correspond closely to amyloid plaque burden in the brain, are not associated with any behavioural measure. Our study extends the characterization of the model to stages of advanced amyloid pathology and demonstrates that older TgCRND8 mice are impaired in multiple memory systems, including procedural tasks, which are spared at younger ages. The lack of association between amyloid plaques and memory decline supports clinical findings in Alzheimer's patients.

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the presence of various types of ubiquitinated inclusions in the cytoplasm of affected motor neurons. The identification of the ubiquitinated targets within these inclusions has represented a major challenge, as this may provide new gene candidates and/or clues to understanding the neurodegenerative mechanism(s) underlying the disease. As such, the nuclear factor TAR DNA-binding protein (TDP-43) was recently identified as a component of ubiquitinated skein-like inclusions and round inclusions in ALS. This identification combined with biochemical evidence led to the suggestion that TDP-43 is the key ubiquitinated target and major disease protein in ALS. Here, using 3-dimensional deconvolution imaging, we have obtained remarkable resolution of skein-like inclusions and round inclusions in ALS. Surprisingly we have found that in contrast to current thinking, TDP-43 is not the major ubiquitinated target within these types of inclusions. These findings raise the possibility that TDP-43 may not necessarily be the key disease protein in ALS and indicate that the major target(s) of ubiquitination remain to be identified.

Mislocalization of the TAR-DNA binding protein (TDP-43) from the nucleus to the cytoplasm of diseased motor neurons and association with intraneuronal ubiquitinated inclusions has recently been reported in amyotrophic lateral sclerosis (ALS). Here, we have investigated TDP-43 immunoreactivity in three lines of mutant SOD1 transgenic mice, G93A, G37R and G85R and compared with labeling in one sporadic ALS case and two familial ALS cases carrying mutations in SOD1, A4T and I113T. Our findings show that there is no mislocalization of TDP-43 to the cytoplasm in motor neurons of mutant SOD1 transgenic mice, nor association of TDP-43 with ubiquitinated inclusions. In contrast, mislocalization of TDP-43 to the cytoplasm and association with ubiquitinated inclusions was found in the ALS cases, including those carrying mutations in SOD1. Interestingly, there was no association of TDP-43 with ubiquitinated hyaline conglomerate inclusions, pathology closely associated with ALS cases carrying mutations in SOD1. Our findings indicate that the process of motor neuron degeneration in mutant SOD1 transgenic mice is unlikely to involve the abnormalities of TDP-43 described in the human disease.

Recapitulation of tau pathologies in an animal model has been a long-standing goal in neurodegenerative disease research. We generated transgenic (TgTauP301L) mice expressing a frontotemporal dementia with parkinsonism linked to chromosome 17 (FTPD-17) mutation within the longest form of tau (2N, 4R). TgTauP301L mice developed florid pathology including neuronal pretangles, numerous Gallyas-Braak-positive neurofibrillary tangles, and glial fibrillary tangles in the frontotemporal areas of the cerebrum, in the brainstem, and to a lesser extent in the spinal cord. These features were accompanied by gliosis, neuronal loss, and cerebral atrophy. Accumulated tau was hyperphosphorylated, conformationally changed, ubiquitinated, and sarkosyl-insoluble, with electron microscopy demonstrating wavy filaments. Aged TgTauP301L mice exhibited impairment in hippocampally dependent and independent behavioral paradigms, with impairments closely related to the presence of tau pathologies and levels of insoluble tau protein. We conclude that TgTauP301L mice recreate the substantial phenotypic variation and spectrum of pathologies seen in FTDP-17 patients. Identification of genetic and/or environmental factors modifying the tau phenotype in these mice may shed light on factors modulating human tauopathies. These transgenic mice may aid therapeutic development for FTDP-17 and other diseases featuring accumulations of four-repeat tau, such as Alzheimer’s disease, corticobasal degeneration, and progressive supranuclear palsy.

Misfolding of Cu/Zn-superoxide dismutase (SOD1) is emerging as a mechanism underlying motor neuron degeneration in individuals with amyotrophic lateral sclerosis (ALS) who carry a mutant SOD1 gene (SOD1 ALS). Here we describe a structure-guided approach to developing an antibody that specifically recognizes monomer-misfolded forms of SOD1. We raised this antibody to an epitope that is normally buried in the SOD1 native homodimer interface. The SOD1 exposed dimer interface (SEDI) antibody recognizes only those SOD1 conformations in which the native dimer is disrupted or misfolded and thereby exposes the hydrophobic dimer interface. Using the SEDI antibody, we established the presence of monomer-misfolded SOD1 in three ALS mouse models, with G37R, G85R and G93A SOD1 mutations, and in a human individual with an A4V SOD1 mutation. Despite ubiquitous expression, misfolded SOD1 was found primarily within degenerating motor neurons. Misfolded SOD1 appeared before the onset of symptoms and decreased at the end stage of the disease, concomitant with motor neuron loss.

Mutations of the DJ-1 (PARK7) gene are linked to familial Parkinson's disease. We used gene targeting to generate DJ-1-deficient mice that were viable, fertile, and showed no gross anatomical or neuronal abnormalities. Dopaminergic neuron numbers in the substantia nigra and fiber densities and dopamine levels in the striatum were normal. However, DJ-1–/– mice showed hypolocomotion when subjected to amphetamine challenge and increased striatal denervation and dopaminergic neuron loss induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine. DJ-1–/–embryonic cortical neurons showed increased sensitivity to oxidative, but not nonoxidative, insults. Restoration of DJ-1 expression to DJ-1–/– mice or cells via adenoviral vector delivery mitigated all phenotypes. WT mice that received adenoviral delivery of DJ-1 resisted 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine-induced striatal damage, and neurons overexpressing DJ-1 were protected from oxidative stress in vitro . Thus, DJ-1 protects against neuronal oxidative stress, and loss of DJ-1 may lead to Parkinson's disease by conferring hypersensitivity to dopaminergic insults.

Cu ions have been suggested to enhance the assembly and pathogenic potential of the Alzheimer's disease amyloid-β (Aβ) peptide. To explore this relationship in vivo , toxic-milk ( tx J ) mice with a mutant ATPase7b transporter favoring elevated Cu levels were analyzed in combination with the transgenic (Tg) CRND8 amyloid precursor protein mice exhibiting robust Aβ deposition. Unexpectedly, TgCRND8 mice homozygous for the recessive tx J mutation examined at 6 months of age exhibited a reduced number of amyloid plaques and diminished plasma Aβ levels. In addition, homozygosity for tx J increased survival of young TgCRND8 mice and lowered endogenous CNS Aβ at times before detectable increases in Cu in the CNS. These data suggest that the beneficial effect of the tx J mutation on CNS Aβ burden may proceed by a previously undescribed mechanism, likely involving increased clearance of peripheral pools of Aβ peptide.

up CT imaging and the microscopic examination showed intraarterial degradation of gelfoam and microsphere. The blood tests demonstrated insignificant changes of liver and renal functions. Conclusion: Our microspheres, with the characteristics of calibrated, radiopaque, and biodegradable, can be used for TAE with effects equivalent to or better than gelfoam and embosphere in pigs. Currently used drug-eluting beads can only be bound by positive charged drugs. As our microsphere was made of pharmaceutical excipients, it will not be limited to the electric charge of drugs and has a potential to combinewith different chemotoxic agents for TACE. Hemodynamic Changes of Liver Before and After Embolization

We have created early-onset transgenic (Tg) models by exploiting the synergistic effects of familial Alzheimer's disease mutations on amyloid beta-peptide (Abeta) biogenesis. TgCRND8 mice encode a double mutant form of amyloid precursor protein 695 (KM670/671NL+V717F) under the control of the PrP gene promoter. Thioflavine S-positive Abeta amyloid deposits are present at 3 months, with dense-cored plaques and neuritic pathology evident from 5 months of age. TgCRND8 mice exhibit 3,200-4,600 pmol of Abeta42 per g brain at age 6 months, with an excess of Abeta42 over Abeta40. High level production of the pathogenic Abeta42 form of Abeta peptide was associated with an early impairment in TgCRND8 mice in acquisition and learning reversal in the reference memory version of the Morris water maze, present by 3 months of age. Notably, learning impairment in young mice was offset by immunization against Abeta42 (Janus, C., Pearson, J., McLaurin, J., Mathews, P. M., Jiang, Y., Schmidt, S. D., Chishti, M. A., Horne, P., Heslin, D., French, J., Mount, H. T. J., Nixon, R. A., Mercken, M., Bergeron, C., Fraser, P. E., St. George-Hyslop, P., and Westaway, D. (2000) Nature 408, 979-982). Amyloid deposition in TgCRND8 mice was enhanced by the expression of presenilin 1 transgenes including familial Alzheimer's disease mutations; for mice also expressing a M146L+L286V presenilin 1 transgene, amyloid deposits were apparent by 1 month of age. The Tg mice described here suggest a potential to investigate aspects of Alzheimer's disease pathogenesis, prophylaxis, and therapy within short time frames.

The moss Neckera intermedia Brid. was discovered in the abdominal cavity of North America's only Guanche mummy (RED-i), which is housed in the Redpath Museum, McGill University, Montreal. The mummy, from the Canary Islands, was '4C-dated to 1,380 B.P. ? 80. This appears to be the first report of a moss being.used in mummifying a human. Humans, throughout history, have found a variety of ways to utilize mosses, most of which are familiar to bryologists. The most common and best known of these are the horticultural uses of mosses, especially of the genus Sphagnum. Among the rare and poorly known uses are the manufacture of peatcrete (a light-weight concrete) and peatwood in Canada and Finland (Ando & Matsuo 1984) and the stuffing of pillows by Fijians (Thieret 1956). Certainly one of the more bizarre uses of a moss has recently been discovered. The senior author, on a visit to the Redpath Museum, McGill University, Montreal, discovered several plants of the moss Neckera intermedia Brid. inside the abdominal cavity of North America's only Guanche mummy during a noninvasive examination. The mummy, now designated RED-1, came from the Canary Islands and was donated to the Redpath in 1892. Wrapped in several layers of goat skin, the remains are-for the most part-skeletal with skin and associated tissues covering the arms and legs. Full-body Xrays showed no osseous lesions except for some mild vertebral arthritis. Appropriate long-bone measurements showed that in life RED-1 stood at 1.62 m. Further studies showed the individual to be male and of middle age with a mean of 36.8 years. A sample of goat skin was submitted to Geochron Laboratories, Cambridge, MA, for 14C-dating, which showed the remains date to 1,380 B.P. ? 80 (where B.P. = 1950). During the examination process approximately 100 cc of dust and debris were removed from the abdominal area. Examination of this material showed it to be rich in pollen and moss fragments. Although much of the moss had disintegrated into tiny fragments there was still a large quantity of whole plants, including several stems of the moss Neckera intermedia Brid. Some of the stems were 4.5 cm in length, with entire leaves and antheridial buds containing antheridia still attached. All of the plants used in packing the mummy were yellowed but otherwise in a remarkable state of preservation considering their age. A sample of the plants is in the herbarium of the Canadian Museum of Nature (CANM). We feel confident the moss was put inside the mummy while it was still on the Canary Islands since Neckera intermedia is endemic to that region. This moss grows on trees, especially Laurus azorica (Seub.) Franco, and is known only from the Canary Islands, the Azores, Madeira (Stormer 1959), and Spain (Corley et al. 1981). The Canary Islands, lying some 100 km off the northwest coast of Africa, were invaded in 1407 and shortly thereafter colonized by the Spanish. At the time of their conquest the islands were inhabited by a people known as the Guanche, long since extinct. Ethnohistorical documents reveal that these people spoke a mixture of Berber, Arabic, and other tongues. There has been much speculation as to their origins. Over many centuries various groups undoubtedly made the Canaries home, beginning with Africans from south of Morocco in the Neolithic period. These people, with no knowledge of horticulture and bringing with them sheep and goats, probably came from the Atlas region and settled in the southern Islands. About the same time a race of tall fair-skinned people arrived in the Canaries, probably Berber-speaking but of uncertain origin. Another invasion, termed the Mediterranean, occurred somewhat later, during the Bronze Age. Much of the little we know of the Guanche comes from the study of their remains. At the time of Spanish conquest, it was observed that while the common inhabitants were buried in sandy graves, members of the ari tocracy were mummified and stored in secluded mortuary caves. It is believed that one such cave held up to 1,000 mummies. Regrettably, with 0007-2745/91/407-408$0.35/0 This content downloaded from 157.55.39.8 on Wed, 30 Nov 2016 05:07:58 UTC All use subject to http://about.jstor.org/terms 408 THE BRYOLOGIST [VOL. 94 the passage of time, few of these mummies remain, and there are now less than 20 complete mummies in the Canaries with a few more scattered in museums around the world. We know from historical documents and the only other published account of a Guanche mummy examination (Brothwell et al. 1969) that as part of the mummification process packing was used in both major (abdominal-thoracic) cavities as well as subcutaneously. In that mummy, bark (probably of Pinus canariensis C. Sm.) was identified as part of the largely unidentifiable mud-like packing. Pine pollen, probably of the same origin, was a prominent component of the abdominal content of RED-1 submitted to palynological analysis (Jarzen, pers. comm.). Other instances of moss material being used for human burial purposes have been discussed by Ando and Matsuo (1984). In Alaska, for example, moss was used by early Eskimos as a bed upon which to lay bodies of the dead for burial. Also, mosses found inside a coffin (about 1,300 years old) in Japan were considered to have been bedding material for the buried body. One other example, not mentioned by Ando and Matsuo, is described by Rudenko (1970). The roofs of the tombs used for Iron Age burials in the permafrost of the Pazyryk Valley, western Siberia, were lined with stitched sheets of birch bark. "Where the edge of one sheet touched the edge of another there was a lining of moss. This moss consisted of the same species as now grow in the neighbourhood of the valley, among them Rhytidium rugosum (Hedw.) Lindb.; Pleurozium schreberi (Willd.) Mitt.; Ptilium crista-castrensis (Hedw.) De Not." The tombs are "about 2,500 years old, and even organic material was preserved by 'refrigeration' in virtually pristine condition." Perhaps it should be mentioned that there is a report (Zimmerman & Smith 1975) of a moss, Meesia triquetra (Richt.) Aongstr., in the lungs of a frozen cadaver of an Eskimo woman, dead for approximately 1,600 years, on St. Lawrence Island in the Bering Sea about 209 km from mainland Alaska. However, this was thought to be a probable case of accidental burial of an elderly woman who was believed to have aspirated the moss when she was buried alive. Our report is to our knowledge the first to document use of moss in the mummification process of a human. Whether Neckera intermedia was believed by th Guanche to possess preservative properties, as is widely known for Sphagnum (Richardson 1981) and hence the reason for its use in connection with burial, whether it was used for ritualistic purposes, or whether it was merely used as packing material to fill the body cavity is not known. It is of interest to note that both Bronze Age (ca. 800 B.C.) and Iron Age (ca. 200 B.C.) people used another Neckera, N. complanata (Hedw.) Hiib., as caulking material between the planks of boats (Dickson 1973). Although the reason for its selection is unknown, perhaps it too was thought to have preservative qualities.

A review of helminth eggs encountered in precontact, human coprolites and palaeofaecal material from mummified human remains of the New World is presented. Included is a brief description of parasites and their effects on the host from the three phyla represented, Nematoda (roundworms), Platyhelminthes (flatworms) and Acanthocephala (thorny-headed worms).

• We believe this is the first report of a mummy temporal bone successfully processed by decalcification and serial sectioning. The condition of the bone required modifications of standard processing technique. Examination of the sections revealed evidence of antemortem otitis media and mastoiditis. The technique described should prove useful in otopathological studies of other paleontological specimens. ( Arch Otolaryngol 102:713-715, 1976)