bluuebunny/crossref_metadata_2025 huggingface dataset:
Pyroclastic flow and explosive activity at Soufrière Hills Volcano, Montserrat, during a period of virtually no magma extrusion (March 1998 to November 1999)
Authors: Norton G. E. , Watts R. B. , Voight B. , Mattioli G. S. , Herd R. A. , Young S. R. , Devine J. D. , Aspinnall W. P. , Bonadonna C. , Baptie B. J. , Edmonds M. , Harford C. L. , Jolly A. D. , Loughlin S. C. , Luckett R. , Sparks R. S. J.
Published: August 2007

Dome growth at Soufrière Hills Volcano halted in early March 1998. After dome growth ceased, seismicity reduced significantly, but activity related to dome disintegration and degassing of magma at depth continued. A sustained episode of pyroclastic flows on 3 July 1998 marked the single largest collapse from March 1998 to November 1999. This led to a remarkable episode of dome collapses, low-energy explosions and ash-venting that resulted in the regular production of ash plumes, commonly reaching 1.5-6 km above sea level (a.s.l), but sometimes up to 11 km a.s.l., and the development of a small block-and-ash cone around the explosion crater. During the period of this residual activity, higher levels of activity occurred approximately every five to six weeks. This periodicity was similar to the cycles observed during active dome growth during 1995 to 1998, and probably had a similar cause. The relatively high level of observed activity caused continued concern regarding volcanic hazards and their potential to impact upon the resident population. Vigorous magma extrusion resumed in November 1999. The activity of the intervening period is attributed to the continued cooling and degassing of the dome, conduit and deep magma body, the impact of rising volcanic gases in the volcanic edifice, and limited magma flow in the conduit.
Dynamics of volcanic and meteorological clouds produced on 26 December (Boxing Day) 1997 at Soufrière Hills Volcano, Montserrat
Authors: Mayberry G. C. , Rose W. I. , Bluth G. J. S.
Published: August 2007

The 26 December 1997 explosive activity of Soufrière Hills Volcano, Montserrat, provided an opportunity to study the evolution of a volcanic cloud by merging data from various satellites with wind-trajectory data. The activity involved a debris avalanche that descended SSW from the lava dome, to the coast, and a pyroclastic density current that traversed the coast and entered the sea. The slope failure and subsequent dome collapse occurred at
c
. 07:01 universal time (UT; 03:01 local time), lasted 15.2 minutes, and produced an upwardly convecting volcanic ash cloud that cloud temperatures suggest rose to
c
. 15 km. The volcanic ash cloud was unusual because the pyroclastic density current transported hot fine ash to the sea, where it rapidly transferred its heat to the sea water. The evaporation of large volumes of water produced a volcanogenic meteorological (VM) cloud that convected along with the volcanic ash cloud.

The evolution of the volcanic and VM clouds was studied using an isentropic wind trajectory model and data from three satellite sensors: Geostationary Observational Environmental Satellite 8 (GOES 8), Advanced Very High Resolution Radiometer (AVHRR), and Total Ozone Mapping Spectrometer (TOMS). The high temporal resolution of the GOES 8 images filled many of the time gaps the other satellites left, and allowed quantitative retrievals to be performed using a two-band infrared retrieval method. The three-dimensional morphology of the volcanic cloud was reconstructed using GOES 8 data and by determining the heights of air parcels from wind-trajectory data. The volcanic cloud was estimated to contain up to 4.5 x 10
7
kg of silicate ash. Between
c
. 07:39 UT and 13:39 UT the ash signal of the volcanic cloud was masked by the VM cloud, which had a mass of up to 1.5 x 10
8
kg of ice. Ice forms when moist air is convected upwards to temperatures of less than -40°C and becomes saturated.

Ice formation in volcanic clouds is especially likely when hot volcanic material is cooled by seawater rather than the atmosphere. The efficiency of evaporation of the seawater was calculated to be
c
. 5%, based on physical and GOES 8 data. TOMS data showed the SO
2
in the volcanic cloud rose higher than the ash in the volcanic cloud, as has occurred in several other eruptions.

A comparison between GOES 8 and AVHRR data showed that AVHRR data retrieved higher fine-ash silicate masses and higher cloud areas than GOES 8 due to the finer spatial resolution of AVHRR images. The effect on retrieval data of the high water vapour content in the lower troposphere of the tropical atmosphere was quantified; the high humidity in the Montserrat region caused the characteristic ash signal to the infrared sensors to be depressed by up to 80%. This signal depression caused a corresponding underestimation of the mass and area of the volcanic cloud when the infrared brightness temperature difference retrieval technique was used.
Monitoring of airborne particulate matter during the eruption of Soufrière Hills Volcano, Montserrat
Authors: Moore K. R. , Duffell H. , Nicholl A. , Searl A.
Published: August 2007

abstract

A programme of air quality monitoring was devised to investigate concentrations and behaviour of repirable ash in the air on Montserrat. Sampling strategies used were short environmental tests, occupational tests, and continuous environmental monitoring in periods of both high and low volcanic activity. The results obtained between September 1996 and July 1999 allow comparison of the contributions made to airborne particles by different eruptive styles. Vulcanian explosions and ash-venting increased average background concentrations (c.30 µg m
-3
) of airbrne particles (≤10 µm in diameter) by up to a factor of ten. Large dome collapses released large amounts of ash into the atmosphere in an extremely sort time and airborne particle concentrations reached more than 600 µg m
-3
. Aggregates of ash particles broke up on impact wth the gournd and ash re-suspension by wind caused airborne particle concentrations of approximately 250 µg m
-3
. which were sometimes significantly higher than those caused by tephra fallout. Airborne particle concentration decreased with distance from the ash source, and wind an drain effectively removed ash from the atmosphere. Generally, airborne particle concentrations in inhabited areas of Montserrat remained low, even during elevated volcanic activity, when volcanic products were carried away by winds
The relationship between degassing and rockfall signals at Soufrière Hills Volcano, Montserrat
Authors: Luckett R. , Baptie B. , Neuberg J.
Published: August 2007

One of the most common types of seismic event recorded during the eruption of Soufrière Hills Volcano from 1995 to 1999 is known as a rockfall signal because signals recorded when rockfalls were observed on the dome are of this type. Evidence is presented that two seismic sources contributed to these events. The action of falling debris on the dome generated seismicity between 2 Hz and 8 Hz, while many rockfall signals also have a marked spectral peak between 1 Hz and 2 Hz. Deployment of a pressure sensor near the volcano has shown that the 1-2 Hz energy was associated with degassing at the surface of the dome; however, the relative timing of gas escape and seismic signal showed that the first was not the direct source of the second. Resonance of the magma conduit linked to degassing at the surface is invoked as a probable source for the 1-2 Hz seismicity. The relative importance of the two seismic sources that contributed to rockfall signals is examined in the context of the behaviour of the volcano.
A model of the seismic wavefield in gas-charged magma: application to Soufrière Hills Volcano, Montserrat
Authors: Neuberg J. , O'Gorman C.
Published: August 2007

Abstract: A stationary two-phase magma model is used to derive the relationship between gas mass and volume fractions, gas and magma bulk densities, temperature and pressure as a function of depth. In turn, these parameters are used to obtain the vertical seismic velocity profile in the gas-charged magma. A two-dimensional finite-difference model of a magma-filled conduit embedded in an elastic medium is then employed to generate the seismic wavefield in and around the conduit. The high impedance contrast between gas-rich magma and surrounding rock results in the seismic energy being efficiently trapped in the conduit; this leads to the generation of a long-lived resonance of tens of seconds commonly observed as low-frequency earthquakes and harmonic tremor. During a single seismic event, a variety of different seismic radiation patterns along the conduit is observed, leading to the occurrence of several distinct seismic phases in the synthetic seismograms. Observations from several volcanoes show peaked amplitude spectra with integer harmonic overtones that exhibit a time-dependent gliding. These features are successfully modelled by varying the excess pressure and, consequently, the gas volume fraction and the seismic velocity, representing sudden degassing events, such as the reduction of pressure by ash-venting, a dome collapse or a Vulcanian explosion, or, in turn, the pressurization of the conduit prior to such events.
Variation in HCl/SO
2
gas ratios observed by Fourier transform spectroscopy at Soufrière Hills Volcano, Montserrat
Authors: Oppenheimer C. , Edmonds M. , Francis P. , Burton M.
Published: August 2007

We present here the results of open-path Fourier transform infrared (FTIR) spectroscopy of gases emitted from the lava dome of Soufrière Hills Volcano. Although measurement campaigns have been discontinuous, they do span a three-year period and provide strong evidence of secular change in the HCl/SO
2
molar ratio from ≥5 in 1996 to <0.5 in 1999. The post-1996 spectral data represent the only available measurements of gas ratios for the volcano's summit emissions, and complement SO
2
emission rate data obtained by ultraviolet correlation spectroscopy (COSPEC), enhancing the interpretation of degassing at the volcano. The long-term decreasing HCl/SO
2
ratio accompanied an increasing SO
2
emission rate, and suggests a transition from degassing of andesitic to basaltic magma, or progressive tapping of a sulphur-rich vapour phase that was introduced by mafic magma, or that was already resident within the andesite magma reservoir. On timescales of minutes to hours, we observed variations in HCl/SO
2
ratios associated with dome collapses. On 27 July 1998, for example, the HCl/SO
2
ratio dropped from about 0.7 to 0.4 within minutes of a minor dome collapse. A much larger collapse event on 26 October 1998 was followed by a decrease in HCl/SO
2
from 0.6 to 0.1, some 14 hours later. These changes are suggestive of transient degassing from a sulphur-rich source region - larger collapses resulted in tapping of deeper sources, with exsolved gases taking longer to reach the surface. The sustained degassing and response to dome collapse events suggest a permeable upper conduit system established by syneruptive vesiculation, and efficient transfer of volatiles out of the magma chamber by degassing-driven convection in the lower part of the central conduit. Open-path FTIR spectroscopy represents a means for remote geochemical surveillance when access to vent regions is restricted for safety reasons, yielding valuable insights into degassing mechanisms.
Modelling of conduit flow dynamics during explosive activity at Soufrière Hills Volcano, Montserrat
Authors: Melnik O. , Sparks R. S. J.
Published: August 2007

Magmatic explosive activity at Soufrière Hills Volcano involved a sub-Plinian eruption, on 17 September 1996 and two series of repetitive short-lived (c. 1 min) Vulcanian explosions in 1997. Explosive activity followed major collapses of the dome. We have modelled unsteady conduit flow in explosive eruptions after unloading. Two cases are investigated: (i) equilibrium between gas dissolved in the melt and bubbles for sustained sub-Plinian eruption; and (ii) no mass transfer between pre-existing gas bubbles and melt for Vulcanian explosions. The models for Vulcanian explosions agree with observations of erupted volumes, eruption durations (tens of seconds), typical drawdown depths (a few hundred metres to c. 2 km), exit velocities and discharge rates. Explosive mixtures are predicted to have high densities consistent with the occurrence of fountain collapse. The models for sub-Plinian eruption show good agreement with observed erupted volumes and drawdown depths (c. 4 km). Three fragmentation criteria were studied, namely fragmentation at fixed porosity, at a critical gas overpressure, and at a critical elongation strain rate. Results are similar for the three cases, but the critical overpressure and critical strain-rate criteria both predict strong pulsations, whereas the fixed-porosity criterion predicts continuous fragmentation. Pulsations are caused by feedback, with the threshold conditions for magma fragmentation being repeatedly crossed. Pulsations are indicated from seismic and video observations.
A Fortunate Life in Physical Chemistry
Authors: Rice Stuart A.
Published: August 2007

This article contains a very personal account of my evolution as a physical chemist/chemical physicist, with commentary on some of the influences on that evolution and summary accounts of research accomplishments in four of the subject areas that have engaged my attention, ranging from isolated molecules to condensed matter.
Metabolic and electrical oscillations: partners in controlling pulsatile insulin secretion
Authors: Bertram Richard , Sherman Arthur , Satin Leslie S.
Published: August 2007

Impairment of insulin secretion from the β-cells of the pancreatic islets of Langerhans is central to the development of type 2 diabetes mellitus and has therefore been the subject of much investigation. Great advances have been made in this area, but the mechanisms underlying the pulsatility of insulin secretion remain controversial. The period of these pulses is 4–6 min and reflects oscillations in islet membrane potential and intracellular free Ca2+. Pulsatile blood insulin levels appear to play an important physiological role in insulin action and are lost in patients with type 2 diabetes and their near relatives. We present evidence for a recently developed β-cell model, the “dual oscillator model,” in which oscillations in activity are due to both electrical and metabolic mechanisms. This model is capable of explaining much of the available data on islet activity and offers possible resolutions of a number of longstanding issues. The model, however, still lacks direct confirmation and raises new issues. In this article, we highlight both the successes of the model and the challenges that it poses for the field.
Luminal antigens access late endosomes of intestinal epithelial cells enriched in MHC I and MHC II molecules: in vivo study in Crohn's ileitis
Authors: Hundorfean Gheorghe , Zimmer Klaus-Peter , Strobel Stephan , Gebert Andreas , Ludwig Diether , Büning Jürgen
Published: August 2007

In contrast to healthy conditions, intestinal epithelial cells (IECs) stimulate proinflammatory CD4+and CD8+T cells during Crohn's disease (CD). The underlying regulatory mechanisms remain unknown. Here we investigated the epithelial expression of major histocompatibility complex (MHC) I and MHC II and its interference with endocytic pathways, in vivo. During ileoscopy, ovalbumin (OVA) was sprayed onto ileal mucosa of CD patients (ileitis and remission) and controls. The epithelial traffic of OVA and MHC I/II pathways were studied in biopsies using fluorescence and electron microscopy. We found MHC I and MHC II to accumulate within multivesicular late endosomes (MVLE) of IECs. Faint labeling for these molecules was seen in early endosomes and lysosomes. MVLE were entered by OVA 10 min after exposure. Exosomes carrying MHC I, MHC II, and OVA were detected in intercellular spaces of the epithelium. OVA trafficking and labeling patterns for MHC I and MHC II in IECs showed no differences between CD patients and controls. Independent of inflammatory stimuli, MHC I and MHC II pathways intersect MVLE in IECs, which were efficiently targeted by luminal antigens. Similar to MHC II-enriched compartments in professional antigen presenting cells, these MVLE might be critically involved in MHC I- and MHC II-related antigen processing in IECs and the source of epithelial-released exosomes. The access of luminal antigens to MHC I in MVLE might indicate that the presentation of exogenous antigens by IECs must not be restricted to MHC II but might also occur as “cross-presentation” via MHC I to CD8+T cells.
The protective effect of the vagus nerve in a murine model of chronic relapsing colitis
Authors: Ghia Jean-Eric , Blennerhassett Patricia , El-Sharkawy Rami T. , Collins Stephen M.
Published: August 2007

The vagus nerve inhibits the response to systemic administration of endotoxin, and we have recently extended this observation to show that the vagus attenuates acute experimental colitis in mice. The purpose of the present study was to determine whether there is a tonic counterinflammatory influence of the vagus on colitis maintained over several weeks. We assessed disease activity index, macroscopic and histological damage, myeloperoxidase (MPO) activity, and Th1 and Th2 cytokine profiles in chronic colitis induced by administration of dextran sodium sulfate (DSS) in drinking water for three cycles during 5 days with 11 days of rest between each cycle (DSS 3, 2, 2%) in healthy and vagotomized C57BL/6 mice and in mice deficient in macrophage-colony stimulating factor (M-CSF). A pyloroplasty was performed in vagotomized mice. Vagotomy accelerated the onset and the severity of inflammation during the first and second but not the third cycle. Although macroscopic scores were not significantly changed, histological scores as well as MPO activity and colonic tissue levels of IL-1α, TNF-α, IFN-γ, and IL-18 but not IL-4 were significantly increased in vagotomized mice compared with sham-operated mice that received DSS. In control mice (without colitis), vagotomy per se did not affect any inflammatory marker. Vagotomy had no effect on the colitis in M-CSF-derived macrophage-deficient mice. These results indicate that the vagus protects against acute relapses on a background of chronic inflammation. Identification of the molecular mechanisms underlying the protective role of parasympathetic nerves opens a new therapeutic avenue for the treatment of acute relapses of chronic inflammatory bowel disease.
IKKβ inhibition attenuates myocardial injury and dysfunction following acute ischemia-reperfusion injury
Authors: Moss Nancy C. , Stansfield William E. , Willis Monte S. , Tang Ru-Hang , Selzman Craig H.
Published: August 2007

Despite years of experimental and clinical research, myocardial ischemia-reperfusion (IR) remains an important cause of cardiac morbidity and mortality. The transcription factor nuclear factor-κB (NF-κB) has been implicated as a key mediator of reperfusion injury. Activation of NF-κB is dependent upon the phosphorylation of its inhibitor, IκBα, by the specific inhibitory κB kinase (IKK) subunit, IKKβ. We hypothesized that specific antagonism of the NF-κB inflammatory pathway through IKKβ inhibition reduces acute myocardial damage following IR injury. C57BL/6 mice underwent left anterior descending (LAD) artery ligation and release in an experimental model of acute IR. Bay 65-1942, an ATP-competitive inhibitor that selectively targets IKKβ kinase activity, was administered intraperitoneally either prior to ischemia, at reperfusion, or 2 h after reperfusion. Compared with untreated animals, mice treated with IKKβ inhibition had significant reduction in left ventricular infarct size. Cardiac function was also preserved following pretreatment with IKKβ inhibition. These findings were further associated with decreased expression of phosphorylated IκBα and phosphorylated p65 in myocardial tissue. In addition, IKKβ inhibition decreased serum levels of TNF-α and IL-6, two prototypical downstream effectors of NF-κB activity. These results demonstrate that specific IKKβ inhibition can provide both acute and delayed cardioprotection and offers a clinically accessible target for preventing cardiac injury following IR.
Influence of airway diameter and cell confluence on epithelial cell injury in an in vitro model of airway reopening
Authors: Yalcin H. C. , Perry S. F. , Ghadiali S. N.
Published: August 2007

Recent advances in the ventilation of patients with acute respiratory distress syndrome (ARDS), including ventilation at low lung volumes, have resulted in a decreased mortality rate. However, even low-lung volume ventilation may exacerbate lung injury due to the cyclic opening and closing of fluid-occluded airways. Specifically, the hydrodynamic stresses generated during airway reopening may result in epithelial cell (EpC) injury. We utilized an in vitro cell culture model of airway reopening to investigate the effect of reopening velocity, airway diameter, cell confluence, and cyclic closure/reopening on cellular injury. Reopening dynamics were simulated by propagating a constant-velocity air bubble in an adjustable-height parallel-plate flow chamber. This chamber was occluded with different types of fluids and contained either a confluent or a subconfluent monolayer of EpC. Fluorescence microscopy was used to quantify morphological properties and percentage of dead cells under different experimental conditions. Decreasing channel height and reopening velocity resulted in a larger percentage of dead cells due to an increase in the spatial pressure gradient applied to the EpC. These results indicate that distal regions of the lung are more prone to injury and that rapid inflation may be cytoprotective. Repeated reopening events and subconfluent conditions resulted in significant cellular detachment. In addition, we observed a larger percentage of dead cells under subconfluent conditions. Analysis of this data suggests that in addition to the magnitude of the hydrodynamic stresses generated during reopening, EpC morphological, biomechanical, and microstructural properties may also be important determinants of cell injury.
Arterial baroreflex control of heart rate during exercise in postural tachycardia syndrome
Authors: Masuki Shizue , Eisenach John H. , Schrage William G. , Dietz Niki M. , Johnson Christopher P. , Wilkins Brad W. , Dierkhising Ross A. , Sandroni Paola , Low Phillip A. , Joyner Michael J.
Published: August 2007

Patients with postural tachycardia syndrome (POTS) have excessive tachycardia without hypotension during orthostasis as well as exercise. We tested the hypothesis that excessive tachycardia during exercise in POTS is not related to abnormal baroreflex control of heart rate (HR). Patients ( n = 13) and healthy controls ( n = 10) performed graded cycle exercise at 25, 50, and 75 W in both supine and upright positions while arterial pressure (arterial catheter) and HR (ECG) were measured. Baroreflex sensitivity of HR was assessed by bolus intravenous infusion of phenylephrine at each workload. In both positions, HR was higher in the patients than the controls during exercise. Supine baroreflex sensitivity (HR/systolic pressure) in POTS patients was −1.3 ± 0.1 beats·min−1·mmHg−1 at rest and decreased to −0.6 ± 0.1 beats·min−1·mmHg−1 during 75-W exercise, neither significantly different from the controls ( P > 0.6). In the upright position, baroreflex sensitivity in POTS patients at rest (−1.4 ± 0.1 beats·min−1·mmHg−1) was higher than the controls (−1.0 ± 0.1 beats·min−1·mmHg−1) ( P < 0.05), and it decreased to −0.1 ± 0.04 beats·min−1·mmHg−1 during 75-W exercise, lower than the controls (−0.3 ± 0.09 beats·min−1·mmHg−1) ( P < 0.05). The reduced arterial baroreflex sensitivity of HR during upright exercise was accompanied by greater fluctuations in systolic and pulse pressure in the patients than in the controls with 56 and 90% higher coefficient of variations, respectively ( P < 0.01). However, when baroreflex control of HR was corrected for differences in HR, it was similar between the patients and controls during upright exercise. These results suggest that the tachycardia during exercise in POTS was not due to abnormal baroreflex control of HR.
Antiapoptotic Effects of Progastrin on Pancreatic Cancer Cells Are Mediated by Sustained Activation of Nuclear Factor-κB
Authors: Rengifo-Cam William , Umar Shahid , Sarkar Shubhashish , Singh Pomila
Published: August 2007

Progastrin (PG) exerts proliferative and antiapoptotic effects on intestinal epithelial and colon cancer cells via Annexin II (ANX-II). In here, we show that ANX-II similarly mediates proliferative and antiapoptotic effects of PG on a pancreatic cancer cell line, AR42J. The role of several signaling molecules was examined in delineating the biological activity of PG. PG (0.1–1.0 nmol/L) caused a significant increase (2- to 5-fold) in the phosphorylation of phosphatidylinositol 3-kinase (PI3K), Akt (Thr308), p38 mitogen-activated protein kinase (MAPK; Thr180/Tyr182), extracellular signal-regulated kinases (ERK; Thr202/Tyr204), IκB kinase α/β (IKKα/β; Ser176/180), IκBα (Ser32), and p65 nuclear factor-κB (NF-κB; Ser536). Inhibition of p44/42 ERKs (PD98059), p38 MAPK (SB203580), Akt, and PI3K (LY294002), individually or combined, partially reversed antiapoptotic effects of PG. The kinetics of phosphorylation of IKKα/β in response to PG matched the kinetics of phosphorylation and degradation of IκBα and correlated with phosphorylation, nuclear translocation, and activation of p65 NF-κB. NF-κB essential modulator–binding domain peptide (an inhibitor of IKKα/β) effectively blocked the activity of p65 NF-κB in response to PG. Activation of p65 NF-κB, in response to PG, was 70% to 80% dependent on phosphorylation of MAPK/ERK and PI3K/Akt molecules. Down-regulation of p65 NF-κB by specific small interfering RNA resulted in the loss of antiapoptotic effects of PG on AR42J cells. These studies show for the first time that the canonical pathway of activation of p65 NF-κB mediates antiapoptotic effects of PG. Therefore, targeting PG and/or p65 NF-κB may be useful for treating cancers, which are dependent on autocrine or circulating PGs for their growth. [Cancer Res 2007;67(15):7266–74]
Genetic Abnormalities Associated with Chemoradiation Resistance of Head and Neck Squamous Cell Carcinoma
Authors: van den Broek Guido B. , Wreesmann Volkert B. , van den Brekel Michiel W.M. , Rasch Coen R.N. , Balm Alfons J.M. , Rao Pulivarthi H.
Published: August 2007

Purpose: To identify reliable predictors of chemoradiation resistance of advanced head and neck squamous cell carcinoma (HNSCC).

Experimental Design: We did a matched-pair analysis of 20 chemoradiation-resistant and 20 sensitive HNSCCs, identified among a series of 104 consecutively treated cases. We compared the global DNA copy number profiles derived from comparative genomic hybridization analysis of both groups to identify genetic markers associated with chemoradiation resistance.

Results: Although sensitive and resistant case groups were characterized by a similar total number of genetic aberrations, high-level amplifications were more frequent in resistant tumors. Resistant tumors were characterized by a different profile of genetic changes. Gains of 3q11-q13, 3q21-q26.1, and 6q22-q27 and losses of 3p11-pter and 4p11-pter were significantly associated with chemoradiation resistance. High-level amplifications unique to resistant cases involved the chromosomal regions 1p32, 3q24, 7p11.1, 7p11.2-12, 8p11.1, 8p11.1-12, 12q15, 13q21, 15q12, 18p11.3, and 18q11.

Conclusions: Sensitive and resistant HNSCCs are characterized by divergent genomic profiles. These profiles may be valuable as predictive markers of treatment failure.
Toll-like Receptor 3 Expressed by Melanoma Cells as a Target for Therapy?
Authors: Salaun Bruno , Lebecque Serge , Matikainen Sampsa , Rimoldi Donata , Romero Pedro
Published: August 2007

Purpose: The immunomodulatory properties of Toll-like receptors (TLR) agonists have inspired their use as experimental adjuvants for vaccination of cancer patients. However, it is now well recognized that TLR expression is not restricted to immune cells but can also be found in many cell types, including those giving rise to tumors. It is therefore mandatory to explore the potential effects of TLR triggering directly on tumor cells.

Experimental Design: In the present work, we have investigated TLR3 protein expression in melanoma cell lines derived from patients, and analyzed the effects of TLR3 agonists on tumor cell survival. Moreover, we used RNA interference to stably knock down TLR3 expression and study the involvement of this receptor in dsRNA-induced effects on melanoma cells viability.

Results: Human melanoma cells can express functional TLR3 protein. Interestingly, the engagement of the receptor by TLR3 agonists can directly inhibit cell proliferation and induce tumor cell death when combined to treatment with either type I IFN or protein synthesis inhibitors. These effects were shown by RNA interference to be largely dependent on TLR3. Moreover, TLR3-mediated cell death involves the activation of caspases and engages both extrinsic and intrinsic apoptotic pathways.

Conclusion: TLR3 protein can be expressed in human melanoma cells, where it can deliver proapoptotic and antiproliferative signaling. Altogether, these results suggest that TLR3 agonists represent very promising adjuvants for cancer vaccines not only based on their well-described immunostimulatory properties, but also due to their newly identified cytostatic and cytotoxic effects directly on tumor cells.
Selecting Patients for Treatment with Epidermal Growth Factor Tyrosine Kinase Inhibitors
Authors: Bonomi Philip D. , Buckingham Lela , Coon John
Published: August 2007

Identification of objective tumor regressions with epidermal growth factor receptor tyrosine kinases (EGFR TKI) in non–small cell lung cancer (NSCLC) patients has resulted in intense, worldwide clinical and basic research directed toward finding the optimal use of EGFR TKIs in NSCLC. EGFR TKI clinical trials have shown that higher response rates and longer survival are associated with specific patient characteristics and that using conventional chemotherapy simultaneously with EGFR TKIs in unselected patients does not increase survival. Molecular studies have revealed that EGFR-activating mutations and high EGFR gene copy number are frequently found in patients who have the best outcomes with EGFR TKIs. More recent studies suggest that KRAS mutations may identify the subset of patients who have the worst outcome with the EGFR TKI treatment. Currently, investigators are trying to determine the optimal approach to selecting patients for treatment with EGFR TKIs. Studies that have evaluated the potential predictive value of clinical features and/or molecular profiles in EGFR TKI-treated NSCLC patients are discussed in this review.
The Role of Psychological Stress in Inflammatory Bowel Disease
Authors: Mawdsley Joel E. , Rampton David S.
Published: August 2007

Inflammatory bowel disease (IBD) is an idiopathic inflammatory condition of the gastrointestinal tract whose natural history is one of periods of remission and relapse. The aetiology is complex and reflects an interaction between genes and environment. Psychological stress has long been reported by both doctors and patients as worsening disease activity in IBD. Prospective studies of the relationship between disease relapse and adverse life events have produced conflicting results, in part due to the inherent difficulties of such studies. However, several more recent analyses have suggested that both adverse life events and chronic perceived stress can contribute to disease relapse. There is also an increasing body of evidence to suggest that experimental stress can increase mucosal inflammation both in patients with IBD and in animal models of colitis. Despite this increase in understanding the pro-inflammatory effects of stress in IBD, thus far only a few limited studies have examined stress reduction as a therapeutic modality.
Usefulness of Simple Measures of Temporal Lobe Atrophy in Probable Alzheimer's Disease
Authors: Frisoni Giovanni B. , Beltramello Alberto , Weiss Claudia , Geroldi Cristina , Bianchetti Angelo , Trabucchi Marco
Published: August 2007

Diagnosis of Alzheimer''s disease is made on clinical grounds, and the availability of a simple and sensitive quantitative index of the disease might aid in the routine diagnosis. The aim of this study was to assess whether linear measures of brain atrophy as detected by magnetic resonance imaging can be helpful in the differentiation of mild to moderate Alzheimer''s disease from nondemented elderly. Measures of global (bifrontal index and interuncal distance) and hippocampal (minimum thickness of the medial temporal lobe, hippocampal height, width of the choroid fissure, and width of the temporal horn) atrophy were taken from 26 cases and 21 controls. Measures of hippocampal atrophy were the most sensitive in the differentiation of cases from controls, and among them width of the temporal horn yielded the highest sensitivity, predicting the disease in 73% of cases with 95% specificity. A compound measure comprising width of the temporal horn, width of the choroid fissure, and hippocampal height increased sensitivity to 85%. These results suggest that selected simple indices of hippocampal atrophy might be useful in the diagnosis of Alzheimer''s disease.
Aphasia, Apraxia, and Agnosia in the Diagnosis of Dementia
Authors: Kramer Joel H. , Duffy Jennifer M.
Published: August 2007

The association of aphasia, apraxia and agnosia with cortical but not subcortical dementias, is a widely held belief. The purpose of the present study was to determine the frequency of aphasia, apraxia, and agnosia in groups of cortical and subcortical dementia patients, and to assess the diagnostic utility of these symptoms. Subjects were 64 patients with subcortical dementias (Parkinson''s disease and normal pressure hydrocephalus) and 192 patients with cortical dementia (probable Alzheimer''s disease) matched for sex, age, and Mini-Mental State Examination score. Each patient was evaluated for the presence of aphasia, apraxia, and agnosia. Results indicated that only aphasia was reported significantly more often in cortical dementia patients than in subcortical dementia patients. The presence of either of these three symptoms has very low diagnostic sensitivity, specificity, and total predictive value. The severity of the patient''s dementia was predicted whether the patient had aphasia or apraxia; type of dementia had no predictive value. These data led to the conclusion that cortical and subcortical dementias cannot be reliably dissociated on the basis of aphasia, apraxia, or agnosia.
The Effects of Nicotine in Dermal Plaster on Cognitive Functions in Patients with Alzheimers Disease
Authors: Snaedal J. , Johannesson T. , Jonsson J.E. , Gylfadottir G.
Published: August 2007

Eighteen patients with probable Alzheimer’s disease (NINCDS/ADRDA criteria) participated in a placebo-controlled, double-blind study, with a crossover design. The patients had mild or moderate dementia (MMSE = 20.3 ± 4.6, range 12–28). The trial consisted of two 4-week periods with a 2-week washout period in between. Nicotine was given in the form of dermal plasters. Most of the patients tolerated the highest doses of 21 mg nicotine/24 h, but some received 14 mg/24 h. The effect was monitored with tests of short-term memory, verbal fluency, attention and psychomotor speed. Nicotine was also determined in the blood. Short-term memory improved significantly after 4 weeks of treatment, both on nicotine and placebo (p < 0.05/p < 0.01). The results of our study thus do not indicate that nicotine applied in the form of dermal plasters is of any significance in the treatment of memory deficits in patient with Alzheimers disease.
Cognition-Related EEG Abnormalities in Nondemented Down Syndrome Subjects
Authors: Politoff Alberto L. , Stadter Richard P. , Monson Nancy , Hass Patricia
Published: August 2007

Down Syndrome (DS) subjects develop Alzheimer disease (AD) histopathology before they develop dementia. We compared the resting and flash stimulated electroencephalogram (EEG) of nondemented adult DS and age-matched control subjects, in search of EEG abnormalities that might correlate with AD histopathology. DS subjects had increased absolute power in all the EEG bands, independent of cognition functions measured by the Mini Mental State Examination and Picture Absurdities Test scores. In the power spectrum of the resting EEG, we found a cognition-related increase in power at 4.5 and 8.8 Hz, indicative of a-slowing, as in AD patients. In the stimulated EEG, we found several cognition-related abnormalities, such as decreased responses to 12-Hz Stimulation and decreased integral of β- and γ-band responses, indicative of decreased responsiveness to photic stimulation, as in AD patients. Therefore, nondemented DS and AD patients share several cognition related EEG abnormalities which are probably due to AD histopathology.
Hippocampal Pathology Reflects Memory Deficit and Brain Imaging Measurements in Alzheimers Disease: Clinicopathologic Correlations Using Three Sets of Pathologic Diagnostic Criteria
Authors: Nagy Z. , Jobst K.A. , Esiri M.M. , Morris J.H. , King E.M.-F. , MacDonald B. , Litchfield S. , Barnetson L. , Smith A.D.
Published: August 2007

Neurofibrillary tangles (NFT), neuritic plaques and amyloid load were quantified in sections of the hippocampus at the level of the lateral geniculate body in 41 consecutive cases fulfilling pathological criteria for diagnosis of Alzheimer’s disease (AD) and coming to autopsy after longitudinal study during life. A strong correlation was found between NFT density in the hippocampus and cognitive impairment scores obtained shortly before death, particularly with scores of memory impairment. Weaker and less consistent correlations were found for hippocampal neuritic plaques and amyloid load with cognitive/ memory deficits. No significant correlations were found between hippocampal pathology and either age of onset or disease duration. All three measures of hippocampal pathology were inversely correlated with the minimum medial temporal lobe (MTL) width, a measure of the MTL atrophy made from temporal-lobe-oriented X-ray computed tomography scans performed during life; the strongest correlation being between atrophy of the MTL and NFT density in the hippocampus.
Alterations in Tau Protein Metabolism during Normal Aging
Authors: Mukaetova-Ladinska E.B. , Harrington C.R. , Roth M. , Wischik C.M.
Published: August 2007

It is unknown whether aging and Alzheimer’s disease (AD) are on the same continuum, or whether they are qualitatively distinct. Tau protein has been identified as a major constituent of paired helical filaments (PHFs) and AD is characterised by a major redistribution of the normal tau protein pool into PHFs. Little is known about the changes in tau protein distribution that occur in the course of normal aging. We have examined PHF-bound and normal tau fractions in frontal, temporal, parietal and occipital neocortex, cerebellum, hippocampus and entorhinal cortex in 15 cognitively unimpaired individuals aged 19–88 years at death. Insoluble tau protein in the PHF fraction did not increase with aging in any brain region, despite the appearance of neurofibrillary pathology at low density in the more elderly cases. By contrast, normal tau protein decreased with aging (r = 0.32, p < 0.001), with an average loss of 14% of soluble tau per decade after the age of 20 years. This was unrelated either to neurofibrillary or β-amyloid pathology. Frontal grey matter and hippocampus were most vulnerable to age-related tau loss, decreasing by as much as 90% in the older subgroup. These findings contrast with those we have previously reported in AD, where the redistribution of tau protein into the PHF-bound fraction was highly correlated with the extent of neurofibrillary pathology, and suggest that the mechanisms of tau loss in aging and AD are distinct. Age-related tau loss may underlie the neuropsychological impairments seen in the non-demented elderly.
Steady-State Pharmacokinetics of Tacrine in Long-Term Treatment of Alzheimer Patients
Authors: Johansson Monika , Hellström-Lindahl Ewa , Nordberg Agneta
Published: August 2007

The pharmacokinetics of the cholinesterase inhibitor tacrine was studied in 5 Alzheimer patients during 12–31 months of treatment. A mean average steady-state concentration in plasma ranging from 1.1 to 30ng/ml was obtained with doses ranging from 40 to 160 mg of tacrine daily. During treatment with 80 mg daily a maximal plasma concentration of tacrine (8.7 ± 0.6 ng/ml) was obtained 1.3 ± 0.2 h after intake of the morning dose. The mean elimination half-life was estimated at 5–7 h and remained unchanged when the tacrine dose was increased. The plasma concentration of tacrine was stable during long-term treatment with tacrine and no tolerance was observed regarding its cholinesterase inhibitory effect. A maximal 40% inhibition of plasma cholinesterase (ChE) activity and 60% inhibition of acetylcholinesterase activity in red blood cells was measured following treatment with the highest dose of 160 mg tacrine daily. A significant correlation was obtained between the plasma concentration of tacrine and the inhibition of ChE activity (p < 0.001). The tacrine concentration in CSF was measured in each patient on 1–3 occasions during the treatment and the ratio CSF/plasma concentration was estimated to be 0.47 ± 0.09 (n = 11).
Differential Susceptibility to Neurofibrillary Pathology among Patients with Down Syndrome
Authors: Wegiel J. , Wisniewski H.M. , Dziewiatkowski J. , Popovitch E.R. , Tarnawski M.
Published: August 2007

Individual differences in the development of neurofibrillary changes were examined in eight cortical regions in the brains of 43 subjects with Down syndrome (DS; age range, 15-69 years) using sections stained with monoclonal antibodies (mAb) tau-1 and 3-39. Neurofibrillary pathology was found in 4 cases below 36 years of age and in all 20 cases above that age. In the 24 positive cases, numerical density of pretangles stained with tau-1 and 3-39, respectively, was 6.1/mm2 and 0/mm2; early tangles, 5.0/mm2 and 5.3/mm2; mature tangles, 4.0/mm2 and 5.0/mm2 (p < 0.01); and end-stage tangles, 0.04/mm2 and 2.5/mm2 (p < 0.001). Numerical density of pretangles stained with mAb tau-1 and tangles and plaques stained with mAb 3-39 correlates weakly with age (r = 0.43; p < 0.02), and together with the wide range of numerical densities suggested heterogeneity of the population examined. Cluster analysis based on two variables – i.e., numerical density of pretangles stained with mAb tau-1 and neurofibrillary tangles (NFTs) and plaques stained with mAb 3-39, distinguished three groups of subjects with severe, moderate and weak changes. The severely affected group of 5 subjects (21%) had an average 54.6/mm2 of neurons and 13.9/mm2 plaques with neurofibrillary changes, whereas the moderately affected group (6 subjects; 25%) showed a significantly lower numerical density of neurons and plaques with neurofibrillary changes (25.7/mm2 and 8.1/mm2, respectively) as compared with the most affected group. Most of the subjects (13; 54%) belong to the third group with only 2.2/mm2 of neurons and 1.4/mm2 plaques with neurofibrillary pathology. Comparison of these three groups of Down syndrome subjects representing high, moderate, and low susceptibility to neurofibrillary changes with the general population suggests that the risk of Alzheimer disease is similar but the onset of pathological changes is earlier in DS.
Cerebral Ischemia: Pharmacological Bases of Drug Therapy
Authors: Ferger Dorothee , Krieglstein Josef
Published: August 2007

The cascade of reactions caused by ischemia in brain tissue is complex and not completely understood, but intensive investigation has led to convincing hypotheses. A disturbed calcium homeostasis and oxygen radicals seem to play a major role in postischemic neuronal damage. In accordance to these hypotheses drugs with different mechanisms of action have been developed. The aim of this paper is to give an overview over pathobiochemical mechanisms in cerebral ischemia and possibilities of pharmacological intervention.
Intact Brain Serotonin System in Vascular Dementia
Authors: Hansson Gunilla , Alafuzoff Irina , Winblad Bengt , Marcusson Jan
Published: August 2007

Pre- and postsynaptic elements of the 5-hydroxytryptamine (5-HT, serotonin) system were studied in a control group and in patients with vascular dementia (VAD). The 5-HT uptake site was used as a presynaptic marker for 5-HT terminals and 5-HT1A and 5HT2 receptors were used as postsynaptic markers. The binding sites were quantified with radioligand binding techniques, where the radioligands used were [3H]paroxetine, [3H]8-OH-DPAT and [3H]ketanserin, respectively. The presynaptic uptake site was studied in frontal and temporal cortices and caudate nucleus. 5-HT1A and 5-HT2 receptors were studied only in frontal and temporal cortices. There were no differences between control and VAD groups in any of the regions investigated with respect to the number of binding sites (Bmax) and binding affinity (Kd). This indicates that both pre- and postsynaptic parts of the 5-HT system are intact in these brain areas in VAD.
Neurochemical and Pathological Alterations following Infusion of Leupeptin, a Protease Inhibitor, into the Rat Brain
Authors: Kuki Katsutoshi , Maeda Kiyoshi , Takauchi Shigeru , Kakigi Tatsuya , Maeda Sakan , Tanaka Chikako
Published: August 2007

It is known that proteases participate in cellular protein turnover and eliminate abnormal and potentially toxic proteins. Disturbed proteolysis may be responsible for generating the pathological features of some neurodegenerative disorders. Alzheimer disease, for instance, is the most common neurodegenerative disorder and a condition in which proteins of the cell membrane and cytoskeleton are abnormally processed and accumulated in the brain. It is of interest to investigate the effect of protease inhibitors on neurons and neurotransmitter systems in the brain. We examined neurochemical and morphological neuronal changes in the rat brain following long-term intracerebroventricular infusion of leupeptin, a potent calcium-activated protease (calpain) inhibitor. Leupeptin (5 mg) was infused into the lateral ventricle using an osmotic minipump for 14 days. We found a significant reduction of regional choline acetyltransferase activities in the hippocampus, and of somatostatin concentrations in the hypothalamus and entorhinal cortex. Moreover, leupeptin caused a wide-spread, highly significant decrease in neuropeptide-Y concentrations. Leupeptin infusion produced severe degeneration of neuronal processes in both axons and dendrites, and accumulation of electron-dense bodies in the hippocampus. The results indicate that long-term intracerebro-ventricular infusion of leupeptin in the rat produces neurochemical and morphological changes resembling those of some neurodegenerative disease and aging. Abnormal proteolysis caused by either reduced protease or enhanced protease inhibitor activities might play an important role in these conditions.