Ovarian teratoma in a common marmoset (Callithrix jacchus).
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Animals↗
Biomedical subjects
R Haworth
Publications and source records attributed to R Haworth.
Ultrastructural and behavioural changes precede amyloid deposition in a transgenic model of Alzheimer's disease.
We describe the thorough characterisation of a new transgenic mouse line overexpressing the 695-amino acid isoform of human amyloid precursor protein harbouring the Swedish double familial Alzheimer's disease mutation. This line, referred to as TAS10, exhibits neuropathological features and cognitive deficits that are closely correlated to the accumulation of Abeta in their brain and that are reminiscent of those observed in AD. Data on the TAS10 line are presented at five time points: 2, 6, 12, 18 and 24 months in a longitudinal study. The TAS10 line is characterised by the following changes: i) significant age-related increases in the levels of total and individual species (1-40, 1-42) of beta-amyloid in the brains of transgenics compared with non-transgenic littermates; ii) transgenic mice showed pronounced spatial learning deficits in the Morris water maze at 6 months and working memory deficits by 12 months; iii) amyloid plaque and associated pathologies were observed by the 12-month time point and the burden increased substantially, particularly in the cortex, by 18 months; iv) electron microscopy of the hippocampus of transgenic mice showed evidence of abnormal ultrastructural features such as dystrophic neurites and lipid deposits that developed from 6 months and increased in number and severity with age. Morphometric studies demonstrate that the synapse to neuron ratio is higher in transgenics than in control mice at 12 months, but this ratio decreases as they age and synapse size increases. Thus, this mouse model exhibits a close correlation of amyloid burden with behavioural deficits and ultrastructural abnormalities and so represents an ideal system to study the mechanisms underlying the impact of amyloid pathology on CNS function.
Alzheimer Disease↗
The PCR assay in the preclinical safety evaluation of nucleic acid medicines.
The polymerase chain reaction (PCR) is a highly efficient gene amplification procedure which is increasingly being applied to the safety assessment of nucleic acid (NA) medicines such as gene therapies and DNA vaccines. Although clinical experience is limited, a number of potential safety issues exist with these new compounds including toxicity associated with the expression of encoded gene products, autoimmunity due to the induction of anti-DNA antibodies and insertional mutagenesis. PCR enables these questions to be addressed and provides data on mRNA expression, biodistribution and integration. In this review the use of PCR methodologies in the preclinical safety evaluation of NA medicines is discussed. Particular consideration is given to the issues surrounding the use of PCR in regulatory toxicology, including sensitivity requirements, cross-contamination problems, tissue sampling procedures and good laboratory practice (GLP) compliance. In addition, the use of a PCR-based assay to demonstrate the integration of DNA vector into host DNA is described. As the use of PCR in the development of NA medicines will undoubtedly increase over the next few years, it is important that pathologists and toxicologists familiarise themselves with the principles and applications of this technique.
Animals↗
Regulation and functional involvement of macrophage scavenger receptor MARCO in clearance of bacteria in vivo.
The scavenger receptors expressed by macrophages are thought to play an important role in the immune response against bacteria by mediating binding and phagocytosis. A novel member of the class A scavenger receptor family, macrophage receptor with collagenous structure (MARCO), has recently been identified. In this study we have generated a panel of mAbs with specificities for different domains of this receptor. Two of those reacting with the C-terminal cysteine-rich domain block ligand binding of MARCO. The in vivo expression of this murine receptor is normally restricted to distinct populations of macrophages in the spleen and lymph nodes. During bacillus Calmette-Guérin (BCG) infection, during bacterial sepsis, or after the injection of purified LPS, however, the expression of MARCO is rapidly induced on macrophages in other tissues, including Kupffer cells in the liver. Using the mouse macrophage cell line J774.2, it was shown that LPS stimulation up-regulates surface expression of MARCO in a dose- and time-dependent fashion. The proinflammatory cytokines IL-1, IL-6, TNF-alpha, and IFN-gamma had little or no effect. Using inhibitory mAbs, the relevance of MARCO for the clearance of circulating bacteria in vivo was determined. Although the overall elimination of live Escherichia coli and Staphylococcus aureus from the blood did not appear to be affected by treatment with these Abs, the capturing of heat-killed bacteria by macrophages in the marginal zone areas of the spleen was clearly inhibited. This study suggests a role for MARCO in the host antibacterial defense.
Animals↗
The macrophage scavenger receptor type A is expressed by activated macrophages and protects the host against lethal endotoxic shock.
During gram-negative bacterial infections, lipopolysaccharide (LPS) stimulates primed macrophages (Mphi) to release inflammatory mediators such as tumor necrosis factor (TNF)-alpha, which can cause hypotension, organ failure, and often death. Several different receptors on Mphi have been shown to bind LPS, including the type A scavenger receptor (SR-A). This receptor is able to bind a broad range of polyanionic ligands such as modified lipoproteins and lipoteichoic acid of gram-positive bacteria, which suggests that SR-A plays a role in host defense. In this study, we used mice lacking the SR-A (SRKO) to investigate the role of SR-A in acquired immunity using a viable bacillus Calmette Guérin (BCG) infection model. We show that activated Mphi express SR-A and that this molecule is functional in assays of adhesion and endocytic uptake. After BCG infection, SRKO mice are able to recruit Mphi to sites of granuloma formation where they become activated and restrict BCG replication. However, infected mice lacking the SR-A are more susceptible to endotoxic shock and produce more TNF-alpha and interleukin-6 in response to LPS. In addition, we show that an antibody which blocks TNF-alpha activity reduces LPS-induced mortality in these mice. Thus SR-A, expressed by activated Mphi, plays a protective role in host defense by scavenging LPS as well as by reducing the release by activated Mphi of proinflammatory cytokines. Modulation of SR-A may provide a novel therapeutic approach to control endotoxic shock.
Animals↗
Phosphorylation and regulation of the Na+/H+ exchanger through mitogen-activated protein kinase.
We examined mitogen-activated protein kinase-mediated phosphorylation and activation of the Na+/H+ exchanger isoform type 1. A rabbit skeletal muscle extract was fractionated by FPLC chromatography. Four main fractions had the ability to phosphorylate the carboxyl-terminal region of NHE1. Western blot analysis and immunoprecipitation showed that three of these were associated with MAP kinase-dependent phosphorylation. Phosphorylation studies using purified MAP kinase showed that the region involved was the carboxyl-terminal 178 amino acids of the protein and that the stoichiometry was 1 phosphate/mol of protein. In-gel kinase assays showed that cytosolic extracts from smooth muscle cells also phosphorylate the carboxyl-terminal of NHE1 and that the MAP kinase-dependent phosphorylation could be activated by PDGF and AngII. Mutant cell lines with an inducible dominant negative MAP kinase showed decreased serum activation of Na+/H+ exchange but normal hypertonic activation of the protein. The results show that MAP kinase is intimately involved in regulation of the Na+/H+ exchanger, possibly through phosphorylation of one amino acid of the carboxyl-terminal cytosolic domain.
Animals↗
Scalar timing in temporal generalization in humans with longer stimulus durations.
Three experiments investigated temporal generalization performance in humans by using stimulus durations similar to those previously used with rats. In most conditions, chronometric counting was prevented by concurrent shadowing of temporally irregular numbers. Experiment 1 examined performance with visual stimuli, when the standard was 4.0 s long and nonstandard stimuli were spaced either linearly or logarithmically around the standard. Generalization gradients were asymmetrical with linear spacing but symmetrical with logarithmic spacing, a result obtained previously with humans. Experiment 2 used auditory stimuli and varied the standard across values of 2.0, 4.0, 6.0, and 8.0 s. All gradients were asymmetrical, and good superposition was obtained, indicating conformity to scalar timing. Experiment 3 prevented or encouraged chronometric counting by changing instructions, and temporal generalization gradients differed when counting was and was not used.
Animals↗
Resolution of refractory pancreatic ascites after continuous infusion of octreotide acetate.
The treatment of pancreatic ascites remains a clinical challenge. Both medical and surgical management have high rates of mortality and recurrence. New methods in the treatment of pancreatic ascites are actively sought. We describe the successful use of a continuous infusion of octreotide acetate in the treatment of refractory alcoholic pancreatic ascites.
Alcoholism↗
Attitudes toward women and rape among male adolescents convicted of sexual versus nonsexual crimes.
Adolescence is an important period in the development of adult sexual offending against women, yet it has received little attention in research on attitudes toward women and rape. The present study used the Attitudes Toward Women Scale (AWS) and Burt's (1980) Rape Myth Acceptance Scale (BRMAS) to compare the attitudes of 31 male adolescents convicted of sexual assaults on women (rape, attempted rape, indecent assault) with the attitudes of 27 male adolescents convicted of nonsexual violent crimes. The results showed no significant difference between the two groups on either measure. Furthermore, a more traditional, conservative attitude toward women, as measured on the AWS, did not significantly correlate with the endorsement of rape myths as measured on the BRMAS. The findings are discussed with reference to the validity and reliability of these measures when used with adolescents.
Adolescent↗
Mobile arm supports: an evaluation.
The results of a follow-up survey of 124 patients fitted with mobile arm supports at Mary Marlborough Lodge between 1970 and 1976 are presented. Of the patients fitted with mobile arm supports 33% are known to have used them for over one year, and 47% of those who were contacted were still using them. The reasons for non-use and the implications of the necessity for readjustments are discussed.
Adolescent↗
The crystallization of beef heart mitochondrial adenosine triphosphatase.
Conditions are described under which crystals are formed with the ATPase enzyme from beef heart mitochondria. Enzyme activity is retained during the crystallization process. Some unit cell parameters have been determined by electron microscopy of negatively stained crystals; comparison with the unit cell crystalline matris inclusions indicates that such inclusions could be ATPase crystals.
Adenosine Triphosphatases↗