Effect of Teflon Transmittance on Sensitivity of Thermoluminescence Dosimeter Cards.

Thermoluminescence dosimeter cards purchased by the US Navy in recent years have different radiation sensitivities, e.g., they exhibit a different amount of light per dose unit. Presented tests indicate that the optical transparency of the Teflon encapsulation is partially responsible for the significant variation of the DT-702/PD radiation sensitivity. It was confirmed also that the Teflon transparency is in fact a primary cause of the radiation sensitivity increase in the most recently produced dosimetric cards. This conclusion is based on the correlation found between the calibrated radiation sensitivity of the dosimeter card element and the optical transparency of its Teflon encapsulation. The transparency measurements were performed at the wavelength of 400 nm within a 10 nm spectral interval effectively covering the spectral range of the thermoluminescence. It is anticipated that the experimentally determined correlation will help to approve the acceptance of new thermoluminescence dosimeter cards in the Naval Dosimetry Center inventory as well as improve the production process.

Perforated esophageal intervention focus (PERF) study: a multi-center examination of contemporary treatment.

The treatment of esophageal perforation (EP) remains a significant clinical challenge. While a number of investigators have previously documented efficient approaches, these were mostly single-center experiences reported prior to the introduction of newer technologies: specifically endoluminal stents. This study was designed to document contemporary practice in the diagnosis and management of EP at multiple institutions around the world and includes early clinical outcomes. A five-year (2009-2013) multicenter retrospective review of management and outcomes for patients with thoracic or abdominal esophageal perforation was conducted. Demographics, etiology, diagnostic modalities, treatments, subsequent early outcomes as well as morbidity and mortality were captured and analyzed. During the study period, 199 patients from 10 centers in the United States, Canada, and Europe were identified. Mechanisms of perforation included Boerhaave syndrome (60, 30.1%), iatrogenic injury (65, 32.6%), and penetrating trauma (25, 12.6%). Perforation was isolated to the thoracic segment alone in 124 (62.3%), with 62 (31.2%) involving the thoracoabdominal esophagus. Mean perforation length was 2.5 cm. Observation was selected as initial management in 65 (32.7%), with only two failures. Direct operative intervention was initial management in 65 patients (32.6%), while 29 (14.6%) underwent esophageal stent coverage. Compared to operative intervention, esophageal stent patients were significantly more likely to be older (61.3 vs. 48.3 years old, P < 0.001) and have sustained iatrogenic mechanisms of esophageal perforation (48.3% vs.15.4%). Secondary intervention requirement for patients with perforation was 33.7% overall (66). Complications included sepsis (56, 28.1%), pneumonia (34, 17.1%) and multi-organ failure (23, 11.6%). Overall mortality was 15.1% (30). In contemporary practice, diagnostic and management approaches to esophageal perforation vary widely. Despite the introduction of endoluminal strategies, it continues to carry a high risk of mortality, morbidity, and need for secondary intervention. A concerted multi-institutional, prospectively collected database is ideal for further investigation.

The development of a non-invasive behavioral model of thermal heat stress in laboratory mice (Mus musculus).

BACKGROUND: Many behavioral and physiological studies of laboratory mice employ invasive methods such as radio telemetry to measure key aspects of behavior and physiology. Radio telemetry requires surgical implants, which may impact mouse health and behavior, and thus reduce the reliability of the data collected. NEW METHOD: We developed a method to measure key aspects of thermoregulatory behavior without compromising animal welfare. We examined the thermoregulatory response to heat stress in a custom-built arena that permitted the use of simultaneous and continuous infrared thermography (IRT) and video capture. This allowed us to measure changes in surface body temperature and determine total distance traveled using EthoVision XT animal tracking software. RESULTS: Locomotor activity and surface body temperature differed between heat-stressed mice and mice kept within their thermal comfort zone. The former had an increase in surface body temperature and a decline in locomotor activity, whereas the latter had a stable surface body temperature and showed greater activity levels. METHODS: Surface body temperature and locomotor activity are conventionally quantified by measurements taken at regular intervals, which limit the use and accuracy of the data. We obtained data of high resolution (i.e., recorded continuously) and accuracy that allowed for the examination of key physiological measurements such as energy expenditure and peripheral vasomotor tone. CONCLUSIONS: This novel experimental method for studying thermoregulatory behavior in mice using non-invasive tools has advantages over radio-telemetry and represents an improvement in laboratory animal welfare.

Broadband Radiometric LED Measurements.

At present, broadband radiometric measurements of LEDs with uniform and low-uncertainty results are not available. Currently, either complicated and expensive spectral radiometric measurements or broadband photometric LED measurements are used. The broadband photometric measurements are based on the CIE standardized V(λ) function, which cannot be used in the UV range and leads to large errors when blue or red LEDs are measured in its wings, where the realization is always poor. Reference irradiance meters with spectrally constant response and high-intensity LED irradiance sources were developed here to implement the previously suggested broadband radiometric LED measurement procedure [1, 2]. Using a detector with spectrally constant response, the broadband radiometric quantities of any LEDs or LED groups can be simply measured with low uncertainty without using any source standard. The spectral flatness of filtered-Si detectors and low-noise pyroelectric radiometers are compared. Examples are given for integrated irradiance measurement of UV and blue LED sources using the here introduced reference (standard) pyroelectric irradiance meters. For validation, the broadband measured integrated irradiance of several LED-365 sources were compared with the spectrally determined integrated irradiance derived from an FEL spectral irradiance lamp-standard. Integrated responsivity transfer from the reference irradiance meter to transfer standard and field UV irradiance meters is discussed.

Aqueous-phase mechanism for secondary organic aerosol formation from isoprene: application to the Southeast United States and co-benefit of SO2 emission controls.

Isoprene emitted by vegetation is an important precursor of secondary organic aerosol (SOA), but the mechanism and yields are uncertain. Aerosol is prevailingly aqueous under the humid conditions typical of isoprene-emitting regions. Here we develop an aqueous-phase mechanism for isoprene SOA formation coupled to a detailed gas-phase isoprene oxidation scheme. The mechanism is based on aerosol reactive uptake coefficients (γ) for water-soluble isoprene oxidation products, including sensitivity to aerosol acidity and nucleophile concentrations. We apply this mechanism to simulation of aircraft (SEAC4RS) and ground-based (SOAS) observations over the Southeast US in summer 2013 using the GEOS-Chem chemical transport model. Emissions of nitrogen oxides (NOx ≡ NO + NO2) over the Southeast US are such that the peroxy radicals produced from isoprene oxidation (ISOPO2) react significantly with both NO (high-NOx pathway) and HO2 (low-NOx pathway), leading to different suites of isoprene SOA precursors. We find a mean SOA mass yield of 3.3 % from isoprene oxidation, consistent with the observed relationship of total fine organic aerosol (OA) and formaldehyde (a product of isoprene oxidation). Isoprene SOA production is mainly contributed by two immediate gas-phase precursors, isoprene epoxydiols (IEPOX, 58% of isoprene SOA) from the low-NOx pathway and glyoxal (28%) from both low- and high-NOx pathways. This speciation is consistent with observations of IEPOX SOA from SOAS and SEAC4RS. Observations show a strong relationship between IEPOX SOA and sulfate aerosol that we explain as due to the effect of sulfate on aerosol acidity and volume. Isoprene SOA concentrations increase as NOx emissions decrease (favoring the low-NOx pathway for isoprene oxidation), but decrease more strongly as SO2 emissions decrease (due to the effect of sulfate on aerosol acidity and volume). The US EPA projects 2013-2025 decreases in anthropogenic emissions of 34% for NOx (leading to 7% increase in isoprene SOA) and 48% for SO2 (35% decrease in isoprene SOA). Reducing SO2 emissions decreases sulfate and isoprene SOA by a similar magnitude, representing a factor of 2 co-benefit for PM2.5 from SO2 emission controls.

Safety, bioavailability and mechanism of action of nitric oxide to control Bovine Respiratory Disease Complex in calves entering a feedlot.

Bovine Respiratory Disease Complex (BRDc), a multi-factorial disease, negatively impacts the cattle industry. Nitric oxide (NO), a naturally occurring molecule, may have utility controlling incidence of BRDc. Safety, bioavailability, toxicology and tolerance/stress of administering NO to cattle is evaluated herein. Thirteen, crossbred, multiple-sourced, commingled commercial weaned beef calves were treated multiple times intranasally over a 4 week period with either a nitric oxide releasing solution (treatment) or saline (control). Exhaled NO, methemoglobin percent (MetHg) and serum nitrites demonstrated biological availability as a result of treatment. Cortisol levels, tissue nitrites, behavior and gross and macroscopic pathology of organs were all normal. Moreover, preliminary in vitro studies using Mannheimia haemolytica, Infectious Bovine Rhinotracheitis, Bovine Parainfluenza-3 and Bovine Respiratory Syncytial Virus, suggest a potential explanation for the previously demonstrated efficacy for BRDc. These data confirm the bioavailability, safety and lack of residual of NO treatment to cattle, along with the bactericidal and virucidal effects.

Influence of environmental factors on infrared eye temperature measurements in cattle.

Environmental factors were evaluated to determine potential limitations in using cattle eye temperatures obtained through infrared thermography (IRT) for early disease detection systems or in animal welfare research studies. The effects of the following factors on IRT eye temperatures in cattle and a fabricated surrogate "eye" were evaluated: camera to object distance, wind speed, camera settings (distance, emissivity, and humidity), and solar loading. Wind speed in both live animals and using a surrogate "eye" was found to decrease the IRT temperature. In the presence of ∼ 7 km/h wind, the mean IRT eye temperature decreased by 0.43 ± 0.13 °C and; at higher wind speeds (∼ 12 km/h), the temperature decreased by 0.78 ± 0.33 °C. Direct sunlight was found to increase the IRT eye temperature by 0.56 ± 0.36 °C. It was determined that environmental factors impact IRT temperature measurements significantly and therefore must be managed to ensure reproducible and accurate readings.

A nitric oxide-releasing solution as a potential treatment for fungi associated with tinea pedis.

AIMS: To test a nitric oxide-releasing solution (NORS) as a potential antifungal footbath therapy against Trichophyton mentagrophytes and Trichophyton rubrum during the mycelial and conidial phases. METHODS AND RESULTS: NORS (sodium nitrite citric acid) produces nitric oxide verified by gas chromatography and mass spectrometry (GC-MS). Antifungal activity of this solution was tested against mycelia and conidia of T. mentagrophytes and T. rubrum, using 1-20 mmol l(-1) nitrites and 10-30 min exposure times. The direct effect of the gas released from the solution on the viability of those fungi was tested. NORS demonstrated strong antifungal activity and was found to be dose and time dependent. NO and nitrogen dioxide (NO(2) ) were the only gases detected from this reaction and are likely responsible for the antifungal effect. CONCLUSIONS: This in vitro research suggests that a single 20-min exposure to NORS could potentially be used as an effective single-dose treatment against fungi that are associated with tinea pedis in both mycelia and spore phase. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides the background for developing a user-friendly footbath treatment for Athlete's Foot that will kill both vegetative fungi and its spores.

Performance of the NIST goniocolorimeter with a broad-band source and multichannel charged coupled device based spectrometer.

The authors describe the NIST high-efficiency instrument for measurements of bidirectional reflectance distribution function of colored materials, including gonioapparent materials such as metallic and pearlescent coatings. The five-axis goniospectrometer measures the spectral reflectance of samples over a wide range of illumination and viewing angles. The implementation of a broad-band source and a multichannel CCD spectrometer corrected for stray light significantly increased the efficiency of the goniometer. In the extended range of 380 nm to 1050 nm, a reduction of measurement time from a few hours to a few minutes was obtained. Shorter measurement time reduces the load on the precise mechanical assembly ensuring high angular accuracy over time. We describe the application of matrix-based correction of stray light and the extension of effective dynamic range of measured fluxes to the values of 10(6) to 10(7) needed for the absolute characterization of samples. The measurement uncertainty was determined to be 0.7% (k = 2), which is comparable with similar instruments operating in a single channel configuration. Several examples of reflectance data obtained with the improved instrument indicate a 0.3% agreement compared to data collected with the single channel configuration.

Lemur tyrosine kinase-2 signalling regulates kinesin-1 light chain-2 phosphorylation and binding of Smad2 cargo.

A recent genome-wide association study identified the gene encoding lemur tyrosine kinase-2 (LMTK2) as a susceptibility gene for prostate cancer. The identified genetic alteration is within intron 9, but the mechanisms by which LMTK2 may impact upon prostate cancer are not clear because the functions of LMTK2 are poorly understood. Here, we show that LMTK2 regulates a known pathway that controls phosphorylation of kinesin-1 light chain-2 (KLC2) by glycogen synthase kinase-3ß (GSK3ß). KLC2 phosphorylation by GSK3ß induces the release of cargo from KLC2. LMTK2 signals via protein phosphatase-1C (PP1C) to increase inhibitory phosphorylation of GSK3ß on serine-9 that reduces KLC2 phosphorylation and promotes binding of the known KLC2 cargo Smad2. Smad2 signals to the nucleus in response to transforming growth factor-ß (TGFß) receptor stimulation and transport of Smad2 by kinesin-1 is required for this signalling. We show that small interfering RNA loss of LMTK2 not only reduces binding of Smad2 to KLC2, but also inhibits TGFß-induced Smad2 signalling. Thus, LMTK2 may regulate the activity of kinesin-1 motor function and Smad2 signalling.

Amyotrophic lateral sclerosis mutant vesicle-associated membrane protein-associated protein-B transgenic mice develop TAR-DNA-binding protein-43 pathology.

Cytoplasmic ubiquitin-positive inclusions containing TAR-DNA-binding protein-43 (TDP-43) within motor neurons are the hallmark pathology of sporadic amyotrophic lateral sclerosis (ALS). TDP-43 is a nuclear protein and the mechanisms by which it becomes mislocalized and aggregated in ALS are not properly understood. A mutation in the vesicle-associated membrane protein-associated protein-B (VAPB) involving a proline to serine substitution at position 56 (VAPBP56S) is the cause of familial ALS type-8. To gain insight into the molecular mechanisms by which VAPBP56S induces disease, we created transgenic mice that express either wild-type VAPB (VAPBwt) or VAPBP56S in the nervous system. Analyses of both sets of mice revealed no overt motor phenotype nor alterations in survival. However, VAPBP56S but not VAPBwt transgenic mice develop cytoplasmic TDP-43 accumulations within spinal cord motor neurons that were first detected at 18 months of age. Our results suggest a link between abnormal VAPBP56S function and TDP-43 mislocalization.

Serum myoglobin and renal morbidity and mortality following thoracic and thoraco-abdominal aortic repair: does rhabdomyolysis play a role?

OBJECTIVES: The intractability of renal dysfunction following thoracic and thoraco-abdominal aortic repair leads us to believe that the accepted mechanisms of renal injury - ischaemia and embolism - are incompletely explanatory. We studied postoperative myoglobinaemia and renal dysfunction following aortic surgery. METHODS: Between September 2006 and February 2008, we studied serum myoglobin in 109 patients requiring thoracic/thoraco-abdominal repair for three postoperative days. Forty-two of the 109 (38%) patients were female. The median age was 67 years (range 23-84 years). As we have focussed more attention on renal function, our independent renal consultants have dialysed more aggressively. We divided dialysis into: (1) creatinine indication, (2) non-creatinine indication and (3) no dialysis. RESULTS: Thirteen of the 109 (12%) patients met creatinine indication for dialysis (>4 mg dl(-1)) and an additional 28 (26%) were dialysed for other reasons. Overall mortality was 12 out of 109 (11%) cases: 11 out of 41 (27%) in dialysed patients and one out of 68 (1.5%) in non-dialysed patients. Mortality did not differ between the indications for dialysis. Predictors of mortality were baseline glomerular filtration rate (GFR), postoperative myoglobin and dialysis. The only predictor of dialysis was postoperative myoglobin. CONCLUSION: A strong relationship between postoperative serum myoglobin and renal failure suggests a rhabdomyolysis-like contributing aetiology following thoraco-abdominal aortic repair. We postulate a novel mechanism of renal injury for which mitigation strategies should be developed.

Thoracic aortic aneurysms.

Remarkable progress has been made in the surgical treatment of thoracoabdominal aortic aneurysms. The decline in mortality and complication rates can be attributed to improvements in perioperative care and in surgical technique, particularly the adoption of adjunct distal aortic perfusion and cerebrospinal fluid drainage. Neurologic deficit is no longer a major threat to patients, as the use of adjuncts has brought the incidence down to 2.4% for all thoracoabdominal aortic aneurysms. However, we continue to pursue research to improve organ preservation, particularly for the most troublesome extent II thoracoabdominal aortic aneurysm.

Potential application of gaseous nitric oxide as a topical antimicrobial agent.

The presence of bacterial colonization in non-healing wounds and burn injuries interferes significantly with the normal process of healing. Recent evidence suggests that nitric oxide (NO) plays an important role in host defense against infection and regulates wound healing and angiogenesis. We investigated the potential application of a medical-grade gaseous form of NO (gNO) as a novel antibacterial agent in wound infection. Using a continuous horizontal-flow delivery system, the antibacterial activity of gNO was tested in vitro against a range of pathogens, including clinical isolates of Staphylococcus aureus, methicillin-resistant S. aureus, Escherichia coli, Group B Streptococcus, Pseudomonas aeruginosa, and Candida albicans. To probe the effect of topical application of gNO on the human skin, the proliferation and extracellular matrix gene expression of human dermal fibroblasts in culture were also analyzed by (3)H-thymidine incorporation assay and Northern blot techniques, respectively. Potent bacteriocidal activity was observed at 200 ppm gNO with an average of 4.1 +/- 1.1 h to completely stop bacterial growth. Interestingly, this dose of gNO did not show any cytotoxic effect in human dermal fibroblasts in culture exposed for up to 48 h. Analysis of gene transcription in fibroblasts revealed a significant increase in MMP-1 mRNA expression as early as 2 h post-exposure to gNO. Although to a lesser degree, a significant reduction in type I procollagen was also observed in the same fibroblasts. The results of this study suggest that exogenous gaseous NO has potent significant antibacterial properties that can be beneficial in reducing bacterial burden in infected wound in burn injuries or non-healing ulcers.

A direct nitric oxide gas delivery system for bacterial and mammalian cell cultures.

Nitric oxide (NO) is the smallest known gaseous signaling molecule released by mammalian and plant cells. To investigate the pathophysiologic role of exogenous NO gas (gNO) in bacterial and mammalian cell cultures, a validated in vitro delivery method is required. The system should be able to deliver gNO directly to bacterial and/or cell cultures in a continuous, predictable, and reproducible manner over a long period of time (days). To accomplish this, a gas delivery system was designed to provide optimal growth conditions for bacteria and/or mammalian cells. Parameters for cell exposure, such as concentration of gNO, nitrogen dioxide (NO(2)), oxygen (O(2)), temperature, and relative humidity (RH) were continuously monitored and evaluated. Uptake of gNO into various media was monitored by measuring the nitrite concentration using the Griess reagent technique. A selection of standard growth media [saline, tryptic soy broth (TSB), Middlebrook 7H9 (MB 7H9), and Dulbecco's modified Eagle's medium (DMEM)] exposed to various concentrations of gNO revealed a steady and consistent transfer of gNO into the aqueous phase over a 48-h period. Validation of optimal growth conditions within the device, as compared to a conventional incubator, were accomplished by growing and observing viability of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and human fibroblast cultures in the absence of gNO. These results indicate that an optimal growth environment for the above tested cells was accomplished inside the proposed delivery system. Dose-dependent toxicological data revealed a significant bacteriostatic effect on P. aeruginosa and S. aureus with continuous exposure to 80 ppm gNO. No toxic effects were observed on dermal fibroblast proliferation at concentrations up to 400 ppm gNO for 48 h. In conclusion, the designed gNO exposure system is capable of supporting cellular viability for a representative range of prokaryote and eukaryotic cells. The exposure system is also capable of obtaining toxicological data. Therefore, the proposed device can be utilized to continuously expose cells to various levels of gNO for up to 72 h to study the in vitro effects of gNO therapy.

Number needed to treat: analyzing of the effectiveness of thoracoabdominal aortic repair.

BACKGROUND: Number needed to treat (NNT) is a method used to calculate the number of patients who need to be treated to prevent one adverse outcome. To analyze the effectiveness of thoracoabdominal and descending thoracic aortic aneurysm repair, we computed the NNT required to prevent one death. METHODS: Between Jan 1991 and Feb 2003, we repaired 1004 aneurysms of the descending thoracic and thoracoabdominal aorta. We followed the patients from surgery until death. Five-year actuarial survival in our population was computed by the Kaplan-Meier method. Natural history data for comparison were taken from the population-based work of Bickerstaff et al., 1982. NNT was calculated as the reciprocal of the risk difference at 5 years. 95% confidence intervals were computed by the method of Daly. RESULTS: Five-year mortality in the population-based cohort was 87 vs. 39% in our treated population, for a risk difference of 48%. 1/0.48=2, indicating that two patients need to be treated to prevent one death at 5 years (95% CI 1.8-2.5, p<0.0001). CONCLUSION: An NNT of two demonstrates the effectiveness of surgical repair of descending thoracic and thoracoabdominal aortic aneurysms when compared to the natural history. By comparison, carotid endarterectomy for symptomatic lesions >70% has an NNT of 15 to prevent a single stroke or death. NNT can also be applied to aneurysm size criteria to estimate the effort required to prevent death or rupture for a given aneurysm size.

Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study.

Microglial activation is implicated in the pathogenesis of ALS and can be detected in animal models of the disease that demonstrate increased survival when treated with anti-inflammatory drugs. PK11195 is a ligand for the "peripheral benzodiazepine binding site" expressed by activated microglia. Ten ALS patients and 14 healthy controls underwent [(11)C](R)-PK11195 PET of the brain. Volumes of interest were defined to obtain [(11)C](R)-PK11195 regional binding potential values for motor and "extra-motor" regions. Significantly increased binding was found in motor cortex (P = 0.003), pons (P = 0.004), dorsolateral prefrontal cortex (P = 0.010) and thalamus (P = 0.005) in the ALS patients, with significant correlation between binding in the motor cortex and the burden of upper motor neuron signs clinically (r = 0.73, P = 0.009). These findings indicate that cerebral microglial activation can be detected in vivo during the evolution of ALS, and support the previous observations that cerebral pathology is widespread. They also argue for the development of therapeutic strategies aimed at inflammatory pathways.

Validation of a morphometric method for evaluating fibroblast numbers in normal and pathologic tissues.

The aim of this work was to validate an image analysis method, based on cell nuclei form factor determination, for counting fibroblasts within human dermis. We first used reconstructed dermal equivalents in which fibroblasts can also be counted directly after lysis of the collagen matrix. We found a good correlation between the results of direct counting and those of image analysis from day 10 to day 28 of culture. When applied to young normal donors' skin biopsies fixed in Bouin's solution and embedded in paraffin, the image analysis method yielded mid-dermis fibroblast counts of between 2100 and 4100 per mm3 of fresh tissue. A nuclear form factor (FF) comprised between 0.35 and 0.84 was found to be a biologic marker of fibroblasts. This was confirmed after fibroblast discrimination from other cell types, which had rounder nuclei (FF >/= 0.85) and were identified either by their location (e.g. endothelial cells) or by labeling with specific antibodies (e.g. lymphocytes and monocytes/macrophages). Similar results were obtained with seven healthy donors' skin biopsies that had been frozen in nitrogen liquid and cryostat-sectioned, showing that this counting method is independent of the histologic procedure. Finally, analysis of samples of hypertrophic scars from two patients revealed that fibroblast density in some parts of the dermis was more than twice the value found in other parts presenting a fibroblast density almost normal, showing that this cell counting method can also be used to assess fibroblast heterogeneity within a given tissue.

Expression of the Fe65 adapter protein in adult and developing mouse brain.

Fe65 is a multimodular adaptor protein expressed mainly in the nervous system. Fe65 binds to the Alzheimer's disease amyloid precursor protein (APP) and the interaction is mediated via a phosphotyrosine binding domain in Fe65 and the carboxy-terminal cytoplasmic domain of APP. Fe65 modulates trafficking and processing of APP, including production of the beta-amyloid peptide that is believed to be central to the pathogenesis of Alzheimer's disease. Fe65 also facilitates translocation of a carboxy-terminal fragment of APP to the nucleus and is required for APP-mediated transcription events. In addition, Fe65 functions in regulation of the actin cytoskeleton and cell movement. Here we report the distribution profile of Fe65 immunoreactivity in adult mouse brain. Fe65 expression was found to be widespread in neurones in adult brain. The areas of highest expression included regions of the hippocampus in which the earliest abnormalities of Alzheimer's disease are detectable. Fe65 was also highly expressed in the cerebellum, thalamus and selected brain stem nuclei. Fe65 was evident in a sub-set of astrocytes within the stratum oriens and radiatum in the hippocampus. Expression of Fe65 was found to be developmentally regulated with levels reducing after embryonic day 15 and increasing again progressively from post-partum day 10 up to adulthood, a developmental pattern that partially parallels that of APP. These data indicate a widespread distribution of Fe65 in neurones throughout mouse brain and also suggest that Fe65 may have functions independent of APP and any potential role in the pathogenesis of Alzheimer's disease.

Axonal transport of neurofilaments in normal and disease states.

Neurofilaments are among the most abundant organelles in neurones. They are synthesised in cell bodies and then transported into and through axons by a process termed 'slow axonal transport' at a rate that is distinct from that driven by conventional fast motors. Several recent studies have now demonstrated that this slow rate of transport is actually the consequence of conventional fast rates of movement that are interrupted by extended pausing. At any one time, most neurofilaments are thus stationary. Accumulations of neurofilaments are a pathological feature of several human neurodegenerative diseases suggesting that neurofilament transport is disrupted in disease states. Here, we review recent advances in our understanding of neurofilament transport in both normal and disease states. Increasing evidence suggests that phosphorylation of neurofilaments is a mechanism for regulating their transport properties, possibly by promoting their detachment from the motor(s). In some neurodegenerative diseases, signal transduction mechanisms involving neurofilament kinases and phosphatases may be perturbed leading to disruption of transport.