Dynamic complexity of the microglial activation response in transgenic models of amyloid deposition: implications for Alzheimer therapeutics

The presence of activated microglia in postmortem Alzheimer disease specimens is used to support the argument that inflammation contributes to Alzheimer pathogenesis. Transgenic mice overexpressing the amyloid precursor protein (APP) gene form amyloid plaques that are accompanied by local activation of microglia/macrophages in a manner similar to the human disease. Many markers of microglial activation and inflammation increase in an age-dependent manner in these mice. However, manipulation of these inflammatory reactions can lead to unexpected outcomes with several instances of reduced pathology when microglia/macrophages are activated further. In particular, anti-Abeta immunotherapy in amyloid-depositing transgenic mice causes a complex series of changes in microglial markers, negating the implicit belief that such activation is monotonic and represented equally well by any of several "activation" markers. A survey of the peripheral macrophage literature identifies at least 2 distinct activation states of macrophages with different consequences for the surrounding tissue. These different activation states can often be distinguished by the markers that are expressed. Several markers are identified from studies outside the brain that neuroscientists might consider evaluating when attempting to more definitively describe the activation state of the monocyte-derived cells in the brain.     

'Importance sampling' in MS: use of diffusion tensor tractography to quantify pathology related to specific impairment

Specific neurological impairments in multiple sclerosis (MS) are dependent on the pathology in clinically eloquent areas of the central nervous system. We aimed to use diffusion tensor fiber tracking to identify the pyramidal tracts and corpus callosum in MS patients, measure the apparent diffusivity within the tracts, and evaluate whether this would correlate with relevant disability scores. Dual-echo and diffusion tensor magnetic resonance imaging (DT-MRI) brain scans were obtained from 29 patients with relapsing remitting MS, and 13 age and gender matched normal controls. Voxels from pyramidal tracts and corpus callosum were automatically identified using a tractography based algorithm. Mean apparent diffusion coefficient (ADC(av)) was measured for these tracts. Scores of Expanded Disability Status Scale (EDSS) and Paced Auditory Serial Addition Test (PASAT) were obtained. The median EDSS score was 2.5 (inter-quartile range 2-3.25). The ADC(av) in the pyramidal tracts (p=0.02) and corpus callosum (p=0.0004) in patients was significantly higher than in controls. Pyramidal tracts ADC(av) was correlated with pyramidal FSS (r=0.5, p=0.008). Corpus callosum ADC(av) was correlated with PASAT (r=-0.58, p=0.001). Global T2 lesion volume did not correlate with the EDSS, but correlated with ADC(av) of the pyramidal tracts (r=0.6, p=0.0007) and corpus callosum (r=0.8, p<0.0001). T2 lesion volume within the pyramidal tracts and corpus callosum correlated with ADC(av) in the pyramidal tracts (r=0.6, p=0.0009) and corpus callosum (r=0.65, p=0.0002) respectively, but not with pyramidal FSS or PASAT score. DT-MRI quantifies pathology in specific white matter tracts and may increase the specificity of MRI in monitoring progression of motor and cognitive deficits in MS.     

An open label study of the effects of rituximab in neuromyelitis optica

Eight patients with worsening neuromyelitis optica were treated with rituximab to achieve B cell depletion. Treatment was well tolerated. Six of eight patients were relapse free and median attack rate declined from 2.6 attacks/patient/year to 0 attacks/patient/year (p = 0.0078). Seven of eight patients experienced substantial recovery of neurologic function over 1 year of average follow-up. The pretreatment median Expanded Disability Status Scale score was 7.5, and at follow-up examination was 5.5 (p = 0.013).     

Condom use by male, enlisted, deployed navy personnel with multiple partners

STUDY QUESTION: Condom use by male enlisted personnel deployed on an aircraft carrier in spring 2002 who reported having casual sex partners in foreign ports and (1) only a steady partner, (2) only casual sex partners, or (3) both steady and casual sex partners in the home port. STUDY DESIGN: Cross-sectional survey, with analysis of the subsample reporting multiple partners (n = 378). RESULTS: Sexual behavior was less frequent and condom use was higher in foreign ports (p < 0.0001). Men involved with both steady and casual partners used condoms less consistently than did those involved with only casual partners (p < 0.05). Sexual behavior also varied with the type of partner (p < 0.0001). CONCLUSIONS: Navy strategies promoting condom use in foreign ports appear effective. New strategies are needed for home ports and for men involved with both steady and casual partners.     

Botulinum toxin: helpful adjunct to early resolution of laryngeal granulomas

Treating laryngopharyngeal reflux is the most accepted treatment for laryngeal granulomas. However, response to this treatment is prolonged and in some cases persistent. The authors hypothesize that this is due to the continuous trauma to the mucoperichondrium from adduction of the vocal folds thus preventing regeneration of healthy mucosa. A prospective study was performed on six patients with laryngeal granulomas failing prolonged laryngopharyngeal reflux treatment, speech therapy, and surgical excisions. Botulinum toxin A was injected into the affected thyroarytenoid to reduce adduction trauma. Video-stroboscopy was used to assess response. A 50 per cent reduction in the size of the granulomas was noted within two weeks with a complete and permanent response within two to eight weeks in five out of six patients. One patient had an obstructing pyogenic granuloma that required excision and recurred after excision but responded to a repeated injection. The addition of a single injection of botulinum toxin A to the standard treatment expeditiously eliminated persistent and recurrent laryngeal granulomas.     

Imidazoleacetic acid-ribotide: an endogenous ligand that stimulates imidazol(in)e receptors

We identified the previously unknown structures of ribosylated imidazoleacetic acids in rat, bovine, and human tissues to be imidazole-4-acetic acid-ribotide (IAA-RP) and its metabolite, imidazole-4-acetic acid-riboside. We also found that IAA-RP has physicochemical properties similar to those of an unidentified substance(s) extracted from mammalian tissues that interacts with imidazol(in)e receptors (I-Rs). ["Imidazoline," by consensus (International Union of Pharmacology), includes imidazole, imidazoline, and related compounds. We demonstrate that the imidazole IAA-RP acts at I-Rs, and because few (if any) imidazolines exist in vivo, we have adopted the term "imidazol(in)e-Rs."] The latter regulate multiple functions in the CNS and periphery. We now show that IAA-RP (i) is present in brain and tissue extracts that exhibit I-R activity; (ii) is present in neurons of brainstem areas, including the rostroventrolateral medulla, a region where drugs active at I-Rs are known to modulate blood pressure; (iii) is present within synaptosome-enriched fractions of brain where its release is Ca(2+)-dependent, consistent with transmitter function; (iv) produces I-R-linked effects in vitro (e.g., arachidonic acid and insulin release) that are blocked by relevant antagonists; and (v) produces hypertension when microinjected into the rostroventrolateral medulla. Our data also suggest that IAA-RP may interact with a novel imidazol(in)e-like receptor at this site. We propose that IAA-RP is a neuroregulator acting via I-Rs.     

Preclinical pharmacology of GW280430A (AV430A) in the rhesus monkey and in the cat: a comparison with mivacurium

BACKGROUND: No replacement for succinylcholine is yet available. GW280430A (AV430A) is a representative of a new class of nondepolarizing neuromuscular blocking drugs called asymmetric mixed-onium chlorofumarates. It undergoes rapid degradation in plasma by chemical hydrolysis and inactivation by cysteine adduction, resulting in a very short duration of effect. The neuromuscular, cardiovascular, and autonomic pharmacology of GW280430A is compared herein with that of mivacurium. METHODS: Adult male rhesus monkeys and adult male cats were anesthetized with nitrous oxide-oxygen-halothane and chloralose-pentobarbital, respectively. The neuromuscular blocking properties of GW280430A and mivacurium were compared at a stimulation rate of 0.15 Hz in the extensor digitorum of the foot (monkey) and the tibialis anterior (cat). Sympathetic responses were assayed in the cat in the nictitating membrane preparation, and vagal effects were evaluated in the cat via observation of bradycardic responses after stimulation of the cervical right vagus nerve. RESULTS: GW280430A and mivacurium were equipotent in the monkey (ED95 was 0.06 mg/kg in each case). GW280430A was half as potent as mivacurium in the cat. The total duration of action of GW280430A was less than half that of mivacurium in the monkey; recovery slopes were more than twice as rapid. The 25-75% recovery index of GW280430A did not vary significantly after various bolus doses or infusions, averaging 1.4-1.8 min in the monkey, significantly shorter than the same time interval (4.8-5.7 min) for mivacurium. Dose ratios for autonomic versus neuromuscular blocking properties in the cat were greater than 25 for both GW280430A and mivacurium. The ratio ED Hist:ED95 Neuromuscular Block in the monkey was significantly greater (approximately 53 vs. 13) for GW280430A, indicating approximately four times less relative prominence of the side effects of skin flushing and decrease of blood pressure, which are associated with release of histamine. CONCLUSIONS: These experiments show a much shorter neuromuscular blocking effect and much-reduced side effects in the case of GW280430A vis-à-vis mivacurium. These results, together with the novel chemical degradation of GW280430A, suggest further evaluation in human subjects.     

Algorithms for calculation of kinetic parameters from T1-weighted dynamic contrast-enhanced magnetic resonance imaging

PURPOSE: To quantify the errors involved in calculating dynamic parameters (K(trans) and ve) from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scans, and to develop alternative analyses to improve accuracy or increase processing speed. MATERIALS AND METHODS: This paper presents three different ways of handling the discrete samples of the arterial input and tissue response data with increasing fidelity, with which this continuous arterial input function (AIF) is represented. Also, a new noniterative approach to parameter estimation was developed from one used previously for analysis of radioactive tracer concentrations in radioangiography. The analysis methods were tested using simulated data. RESULTS: The more sophisticated schemes for data processing give more accurate parameter estimates when data are sparsely sampled, at least for the AIF that we modeled. The noniterative algorithm is very rapid in execution, but was more susceptible to measurement errors. CONCLUSION: The improved algorithms presented should be useful when the AIF and tissue response are sparsely sampled. The noniterative approach may be suitable for semiquantitative visualization, or where the AIF and tissue response are sampled accurately and with a small time interval between samples.     

A realistic 3-D gated cardiac phantom for quality control of gated myocardial perfusion SPET: the Amsterdam gated (AGATE) cardiac phantom

A realistic 3-D gated cardiac phantom with known left ventricular (LV) volumes and ejection fractions (EFs) was produced to evaluate quantitative measurements obtained from gated myocardial single-photon emission tomography (SPET). The 3-D gated cardiac phantom was designed and constructed to fit into the Data Spectrum anthropomorphic torso phantom. Flexible silicone membranes form the inner and outer walls of the simulated left ventricle. Simulated LV volumes can be varied within the range 45–200 ml. The LV volume curve has a smooth and realistic clinical shape that is produced by a specially shaped cam connected to a piston. A fixed 70-ml stroke volume is applied for EF measurements. An ECG signal is produced at maximum LV filling by a controller unit connected to the pump. This gated cardiac phantom will be referred to as the Amsterdam 3-D gated cardiac phantom, or, in short, the AGATE cardiac phantom. SPET data were acquired with a triple-head SPET system. Data were reconstructed using filtered back-projection following pre-filtering and further processed with the Quantitative Gated SPECT (QGS) software to determine LV volume and EF values. Ungated studies were performed to measure LV volumes ranging from 45 ml to 200 ml. The QGS-determined LV volumes were systematically underestimated. For different LV combinations, the stroke volumes measured were consistent at 60–61 ml for 8-frame studies and 63–65 ml for 16-frame studies. QGS-determined EF values were slightly overestimated between 1.25% EF units for 8-frame studies and 3.25% EF units for 16-frame studies. In conclusion, the AGATE cardiac phantom offers possibilities for quality control, testing and validation of the whole gated cardiac SPET sequence, and testing of different acquisition and processing parameters and software.An erratum to this article can be found at