Normal cognitive behavior in two distinct congenic lines of transgenic mice hyperexpressing mutant APP SWE

Amyloid deposition appears to be an early and crucial event in Alzheimer's disease (AD). To generate animal models of AD, mice expressing full-length amyloid precursor protein (APP), with mutations linked to FAD, have been created. These animals exhibit abnormalities characteristic of AD, including deposits of beta-amyloid (Abeta), neuritic plaques, and glial responses. In studies of cognition in these animals, there have been several reports of memory disturbances well before the appearance of amyloid deposits. We have developed two distinct lines of transgenic mice (C3-3 and E1-2) that express the "Swedish" variant of APP (APP(SWE)) at levels that are approximately three-fold higher than endogenous mouse APP. Both lines have been backcrossed to C57BL/6J mice for 10 generations. Here, we use longitudinal and cross-sectional studies to evaluate the cognitive performance of our animals, where the concentration of Abeta1-42 in brain increases with aging from low levels (2-10 pmol/g) at 6-14 months of age to relatively high levels (60-100 pmol/g) at 24-26 months, when deposits of Abeta were beginning to form. When 12-month-old mice were tested in tasks that assess reference and working memory, transgenic mice from both lines could not be distinguished from nontransgenic littermates. Further study of 24- to 26-month-old transgenic mice (C3-3 line) found no evidence of memory impairment despite the presence of high levels of human Abeta (60-100 pmol/g). Thus, the expression of APP(SWE) at approximately three-fold over endogenous levels, which is sufficient to induce amyloid deposition at advanced ages, does not significantly erode cognitive performance in aged mice.     

Separate neurons in the paraventricular nucleus project to the median eminence and to the medulla or spinal cord

Double labeling experiments with the retrogradely transported fluorescent tracers bisbenzimide and True blue indicate that separate populations of cells in the paraventricular nucleus of the hypothalamus project to the median eminence and to the dorsomedial medulla or spinal cord in the rat. The cell populations giving rise to each projection are, however, at least partially intermixed in different parts of the nucleus.     

Managing conflict in the care of older people

This article offers a case study skill analysis of conflict management as it applies to the care of older people and assists the reader to conduct a similar review of their own.     

Inter-subject variability in the use of two different neuronal networks for reading aloud familiar words

Cognitive models of reading predict that high frequency regular words can be read in more than one way. We investigated this hypothesis using functional MRI and covariance analysis in 43 healthy skilled readers. Our results dissociated two sets of regions that were differentially engaged across subjects who were reading the same familiar words. Some subjects showed more activation in left inferior frontal and anterior occipito-temporal regions while other subjects showed more activation in right inferior parietal and left posterior occipito-temporal regions. To explore the behavioural correlates of these systems, we measured the difference between reading speed for irregularly spelled words relative to pseudowords outside the scanner in fifteen of our subjects and correlated this measure with fMRI activation for reading familiar words. The faster the lexical reading the greater the activation in left posterior occipito-temporal and right inferior parietal regions. Conversely, the slower the lexical reading the greater the activation in left anterior occipito-temporal and left ventral inferior frontal regions. Thus, the double dissociation in irregular and pseudoword reading behaviour predicted the double dissociation in neuronal activation for reading familiar words. We discuss the implications of these results which may be important for understanding how reading is learnt in childhood or re-learnt following brain damage in adulthood.     

Reversal of visceral and somatic hypersensitivity in a subset of hypersensitive rats by intracolonic lidocaine

Chronic abdominal pain is a common gastrointestinal symptom experienced by patients. We have previously shown that IBS patients with visceral hypersensitivity also have evidence of thermal hypersensitivity of the hand and foot that is reversed by rectal lidocaine jelly. We have also recently developed an animal model of chronic visceral and somatic hypersensitivity in rats treated with intracolonic trinitrobenzene sulfonic acid (TNBS). The objective of the current study was to determine the effects of intracolonic lidocaine on visceral/somatic hypersensitivity in TNBS-treated rats. A total of 20 hypersensitive rats received either 20mg intracolonic lidocaine (n=10) or saline jelly (n=10). In comparison to saline jelly, intracolonic lidocaine jelly reduced responses to nociceptive visceral/somatic stimuli in hypersensitive rats. The effects were present within 5-30 min after administration of lidocaine and lasted for 6h. Lidocaine had no effects on recovered rats or control rats that had originally been treated with intracolonic saline instead of TNBS. Local anesthetic blockade of peripheral impulse input from the colon reduces both visceral and somatic hypersensitivity in TNBS-treated rats, similar to results in IBS patients. The results provide further evidence that visceral and secondary somatic hypersensitivity in a subset of TNBS-treated rats reflect central sensitization mechanisms maintained by tonic impulse input from the colon. This study evaluates the reversal of visceral/somatic hypersensitivity in a subset of TNBS-treated rats with intracolonic lidocaine. This animal model may be used in the future to study the mechanisms of local anesthetic agents applied to the gut to reduce visceral pain.     

Cutaneous C-fiber pain abnormalities of fibromyalgia patients are specifically related to temporal summation

Temporal summation of "second pain" (TSSP) is considered to be the result of C-fiber-evoked responses of dorsal horn neurons, termed 'windup'. TSSP is dependent on stimulus frequency (> or=0.33Hz) and is relevant for central sensitization and chronic pain. We have previously shown that compared to normal controls (NC), fibromyalgia (FM) subjects show abnormal TSSP, requiring lower stimulus intensities/frequencies to achieve similar TSSP. However, it is unknown whether abnormal TSSP in FM is influenced by peripheral sensitization of C-fiber nociceptors and/or bias in pain ratings. Thus, we evaluated 14 FM subjects and 19 NC with pain threshold tests to selective C-fiber stimulation, 30s heat stimuli, and repetitive brief (1.5s) heat pulses at 0.33Hz using a contact heat stimulator (CHEPS). The intensity of heat pulses was varied to achieve maximal TSSP ratings of 45+/-10 (numerical pain scale 0-100) in both FM and NC groups. We found that NC and FM subjects had similar pain thresholds to C-fiber stimulation and yet FM subjects required lower heat pulse temperatures to generate the same magnitudes of TSSP (p<.05). This combination of findings does not support peripheral sensitization and suggests central TSSP abnormalities in FM subjects. In a second experiment, all aspects of individually adjusted TSSP heat pulses were kept the same except that the baseline temperature (BT) between heat pulses was surreptitiously alternated between 35 degrees C and 40 degrees C. These changes of BT resulted in significantly greater TSSP ratings of FM subjects compared to NC subjects, both at 35 degrees C and at 40 degrees C, but did not change their response to the first heat pulse of a stimulus train. These findings provide strong support for alterations of central pain sensitivity and not peripheral sensitization or rating bias as responsible for TSSP differences between NC and FM subjects.     

Hedgehog signalling in androgen independent prostate cancer

Objectives

Androgen-deprivation therapy effectively shrinks hormone-naïve prostate cancer, both in the prostate and at sites of distant metastasis. However prolonged androgen deprivation generally results in relapse and androgen-independent tumour growth, which is inevitably fatal. The molecular events that enable prostate cancer cells to proliferate in reduced androgen conditions are poorly understood. Here we investigate the role of Hedgehog signalling in androgen-independent prostate cancer (AIPC).

Methods

Activity of the Hedgehog signalling pathway was analysed in cultured prostate cancer cells, and circulating prostate tumour cells were isolated from blood samples of patients with AIPC.

Results

AIPC cells were derived through prolonged culture in reduced androgen conditions, modelling hormone therapy in patients, and expressed increased levels of Hedgehog signalling proteins. Exposure of cultured AIPC cells to cyclopamine, which inhibits Hedgehog signalling, resulted in inhibition of cancer cell growth. The expression of the Hedgehog receptor PTCH and the highly prostate cancer–specific gene DD3^PCA3 was significantly higher in circulating prostate cancer cells isolated from patients with AIPC compared with samples prepared from normal individuals. There was an association between PTCH and DD3^PCA3 expression and the length of androgen-ablation therapy.

Conclusions

Our data are consistent with reports implicating overactivity of Hedgehog signalling in prostate cancer and suggest that Hedgehog signalling contributes to the androgen-independent growth of prostate cancer cells. As systemic anti-Hedgehog medicines are developed, the Hedgehog pathway will become a potential new therapeutic target in advanced prostate cancer.     

Cytotoxic T lymphocytes, chemokines and antiviral immunity.

Evidence that CD8+ CTLs produce chemokines following engagement of viral antigens, and that MIP-1alpha is required for an inflammatory response to virus challenge, suggests that these molecules are key elements in the generation of effective antiviral immunity. Here, David Price and colleagues argue that the antigen-dependent release of chemokines by CTLs provides an elegant mechanism linking localization, amplification and coordination of the antiviral immune response to specific recognition of infected host cells beyond the confines of the lymphoid system.