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[1] This study investigates the magnitude and spatial extent of extreme summer temperature and specific humidity events in the extratropical northern hemisphere (NHEXT) using the NCEP Reanalysis (1979–2012) and the 20th century reanalysis (1871–2010). Specifically, we look at the percentage of area exceeding standard deviation thresholds in layer-averaged (500 mb–1000 mb) temperature and surface-level specific humidity to classify extremes. We find that: (1) areas of the NHEXT, including the southwestern tip of Greenland, experienced a summer heat wave during 2012 that was almost as extreme in spatial extent and magnitude as the Russian heat wave of 2010, (2) there is an increasing trend in summer heat waves and positive specific humidity anomalies and a decreasing trend in summer cold waves and negative specific humidity anomalies, and (3) while similar patterns in the global trend (1979–2012) in variability exist for both temperature and specific humidity, areas of increased variability are not necessarily the areas that have experienced extreme heat waves.

Continental temperature inversions significantly influence air quality, yet little is known about their variability in frequency and intensity with time or sensitivity to dynamical changes with climate. Inversion statistics for six upper-air stations in the American Southwest are derived for the period 1994–2008 from radiosonde data reported by the Global Telecommunication System (GTS) and National Climatic Data Center (NCDC), which use different significant level standards. GTS data indicate that low-level elevated inversions have increased in frequency at four of six sites, consistent with enhanced regional stagnation projected by models. NCDC data, in contrast, show remarkable declines in weak, near-surface inversions through 2001, indicating local surface conditions may counteract atmospheric dynamics in regulating inversion activity and air quality. To further test the sensitivity of inversion activity to climate, associations between wintertime inversion frequency and large-scale circulation are quantified using the self-organizing map technique. Twenty-four representative circulation patterns are derived from North American Regional Reanalysis (NARR) 500-hPa geopotential height fields, and these patterns are correlated with inversion frequency at each site. Inversion activity in Salt Lake City, Utah, and Albuquerque and Santa Teresa, New Mexico, is found to correspond well with large-scale anticyclonic ridging; however, sensitivities to large-scale circulation in Denver, Colorado, and Flagstaff and Tucson, Arizona, are weak. Denver stands out in exhibiting a higher percentage of near-surface inversions in winter than the other southwestern sites. These findings indicate that dynamical changes with climate will not uniformly influence inversions and hence urban air quality conditions in the American Southwest.

Clear-sky, upwelling shortwave flux at the top of the atmosphere (S(sub TOA raised arrow)), simulated using the atmospheric and land model components of the Community Climate System Model 3 (CCSM3), is compared to corresponding observational estimates from the Clouds and Earth's Radiant Energy System (CERES) sensor. Improvements resulting from the use of land surface albedo derived from Moderate Resolution Imaging Spectroradiometer (MODIS) to constrain the simulations are also examined. Compared to CERES observations, CCSM3 overestimates global, annual averaged S(sub TOA raised arrow) over both land and oceans. However, regionally, CCSM3 overestimates S(sub TOA raised arrow) over some land and ocean areas while underestimating it over other sites. CCSM3 underestimates S(sub TOA raised arrow) over the Saharan and Arabian Deserts and substantial differences exist between CERES observations and CCSM3 over agricultural areas. Over selected sites, after using groundbased observations to remove systematic biases that exist in CCSM computation of S(sub TOA raised arrow), it is found that use of MODIS albedo improves the simulation of S(sub TOA raised arrow). Inability of coarse resolution CCSM3 simulation to resolve spatial heterogeneity of snowfall over high altitude sites such as the Tibetan Plateau causes overestimation of S(sub TOA raised arrow) in these areas. Discrepancies also exist in the simulation of S(sub TOA raised arrow) over ocean areas as CCSM3 does not account for the effect of wind speed on ocean surface albedo. This study shows that the radiative energy budget at the TOA is improved through the use of MODIS albedo in Global Climate Models.

Recently, (Pitman et al., 2009) found a wide range of bio-geophysical climate impacts from historical land cover change when modelled in a suite of current global climate models (GCMs). The bio-geophysical climate impacts of human land cover change, however, have been investigated by a wide range of general circulation modelling, regional climate modelling, and observational studies. In this regard the IPCC 4th assessment report specifies radiative cooling of 0.2 W/m2 as the dominant global impact of human land cover change since 1750, but states this has a low to medium level of scientific understanding. To further contribute to the understanding of the possible climatic impacts of anthropogenic land cover change, we have performed a series of land cover change experiments with the community land model (CLM) within the community climate system model (CCSM). To do this we have developed a new set of potential vegetation land surface parameters to represent land cover change in CLM. The new parameters are consistent with the potential vegetation biome mapping of (Ramankutty and Foley, 1999), with the plant functional types (PFTs) and plant phenology consistent with the current day Moderate Resolution Imaging Spectroradiometer (MODIS) land surface parameters of (Lawrence and Chase, 2007). We found that land cover change in CCSM resulted in widespread regional warming of the near surface atmosphere, but with limited global impact on near surface temperatures. The experiments also found changes in precipitation, with drier conditions regionally, but with limited impact on average global precipitation. Analysis of the surface fluxes in the CCSM experiments found the current day warming was predominantly driven by changes in surface hydrology through reduced evapo-transpiration and latent heat flux, with the radiative forcing playing a secondary role. We show that these finding are supported by a wide range of observational field studies, satellite studies and regional and global climate modelling studies. Copyright © 2010 Royal Meteorological Society

Several recommendations have been proposed for detecting land use and land cover change (LULCC) on the environment from, observed climatic records and to modeling to improve its understanding and its impacts on climate. Researchers need to detect LULCCs accurately at appropriate scales within a specified time period to better understand their impacts on climate and provide improved estimates of future climate. The US Climate Reference Network (USCRN) can be helpful in monitoring impacts of LULCC on near-surface atmospheric conditions, including temperature. The USCRN measures temperature, precipitation, solar radiation, and ground or skin temperature. It is recommended that the National Climatic Data Center (NCDC) and other climate monitoring agencies develop plans and seek funds to address any monitoring biases that are identified and for which detailed analyses have not been completed.

In recent climate sensitivity experiments with the Community Climate System Model, version 3 (CCSM3), a wide range of studies have found that the Community Land Model, version 3 (CLM3), simulates mean global evapotranspiration with low contributions from transpiration (15%), and high contributions from soil and canopy evaporation (47% and 38%, respectively). This evapotranspiration partitioning is inconsistent with the consensus of other land surface models used in GCMs. To understand the high soil and canopy evaporation and the low transpiration observed in the CLM3, select individual components of the land surface parameterizations that control transpiration, canopy and soil evaporation, and soil hydrology are compared against the equivalent parameterizations used in the Simple Biosphere Model, versions 2 and 3 (SiB2 and SiB3), and against more recent developments with CLM. The findings of these investigations are used to develop new parameterizations for CLM3 that would reproduce the functional dynamics of land surface processes found in SiB and other alternative land surface parameterizations. Global climate sensitivity experiments are performed with the new land surface parameterizations to assess how the new SiB, consistent CLM land surface parameterizations, influence the surface energy balance, hydrology, and atmospheric fluxes in CLM3, and through that the larger-scale climate modeled in CCSM3. It is found that the new parameterizations enable CLM to simulate evapotranspiration partitioning consistently with the multimodel average of other land surface models used in GCMs, as evaluated by Dirmeyer et al. (2005). The changes in surface fluxes also resulted in a number of improvements in the simulation of precipitation and near-surface air temperature in CCSM3. The new model is fully coupled in the CCSM3 framework, allowing a wide range of climate modeling investigations without the surface hydrology issues found in the current CLM3 model. This provides a substantially more robust framework for performing climate modeling experiments investigating the influence of land cover change and surface hydrology in CLM and CCSM than the existing CLM3 parameterizations. The study also shows that changes in land surface hydrology have global scale impacts on model climatology.

We examined the effects of land cover change over the Indian subcontinent during pre-monsoon season (March, April, and May—MAM) on early Indian summer monsoon (ISM) rainfall using observed Normalized Difference Vegetation Index (NDVI) and July precipitation for the period of 1982–2003. MAM NDVI anomalies have increased in the Indian subcontinent and the increases are significantly correlated with increases in the irrigated area, not preceding rainfall. July rainfall significantly decreased in central and southern India, and the decrease is statistically related to the increase in the preceding MAM NDVI anomalies. Decreased July surface temperature in the Indian subcontinent (an expected result of increased evapotranspiration due to irrigation and increased vegetation) leads to a reduced land–sea thermal contrast, which is one of the factors driving the monsoon, and therefore weakens the monsoon circulation. A weak early ISM appears to be at least partially a result of irrigation and the resultant increased vegetation and crop activity prior to the monsoon. Copyright © 2008 Royal Meteorological Society

A potent 5-hydroxytryptamine (5-HT)2A receptor inverse agonist and antagonist, ACP-103 [N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1, active:salt)], was evaluated for its ability to reduce the primary motor symptom of tremor using tacrine-induced tremulous jaw movements in rats, which is an animal model of parkinsonian tremor. Furthermore, ACP-103 was evaluated for its ability to reduce levodopa-induced dyskinesias in monkeys rendered parkinsonian with MPTP [1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine]. ACP-103 reduced tacrine-induced tremulous jaw movements in rats. In addition, ACP-103 administered in combination with levodopa caused a dose-related reduction in dyskinesias in monkeys. These data suggest that ACP-103 may have the potential to reduce tremor and levodopa-induced dyskinesias in Parkinson's disease.

We use the upper-level divergence zone at 150 hPa to define the areas of study for the East Asian summer monsoon (EASM) and to show the advances and retreats of the EASM. We find that the EASM can be subdivided into a northern and southern component with distinctly different driving mechanisms. The northern EASM (NEASM) is affected by heat sources in the tropical oceans related to El Nino events while the southern EASM (SEASM) is affected by the subtropical oceans related to a North Pacific sea surface temperature (SST) dipole mode. A stronger NEASM is related to above-normal western North Pacific (WNP) anticyclonic anomalies, while a stronger SEASM is related to below-normal WNP anticyclonic anomalies. These WNP anticyclonic anomalies are connected to SST anomalies in the tropical and subtropical Pacific during the pre-monsoon season (December∼May). We also find that NEASM precipitation can be predicted from regional oceanic heat sources, i.e. SST and ocean heat content, in the tropical Pacific and Indian Oceans during the pre-monsoon season using a linear regression model. SEASM precipitation can be predicted from pre-monsoon SST in the eastern North Pacific. The NEASM forecast model is more skillful than that for the SEASM. Copyright © 2007 Royal Meteorological Society

This paper discusses the diverse climate forcings that impact agricultural systems, and contrasts the current paradigm of using global models downscaled to agricultural areas (a top-down approach) with a new paradigm that first assesses the vulnerability of agricultural activities to the spectrum of environmental risk including climate (a bottom-up approach). To illustrate the wide spectrum of climate forcings, regional climate forcings are presented including land-use/land-cover change and the influence of aerosols on radiative and biogeochemical fluxes and cloud/precipitation processes, as well as how these effects can be teleconnected globally. Examples are presented of the vulnerability perspective, along with a small survey of the perceived drought impacts in a local area, in which a wide range of impacts for the same precipitation deficits are found. This example illustrates why agricultural assessments of risk to climate change and variability and of other environmental risks should start with a bottom-up perspective.

The contribution of striatal protein kinase C (PKC) isoform changes in levodopa (L-DOPA) induced motor response complications in parkinsonian rats was investigated and the ability of tamoxifen, an antiestrogen with a partial PKC antagonist property, to prevent these response alterations in 6-hydroxydopamine (6-OHDA) lesioned rats as well as in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated cynomologous monkeys was studied. Following treatment of adult male rats with L-DOPA twice daily for 3 weeks, protein levels of left (lesioned) and right (intact) striatal PKC isoforms were measured. Western blot analysis showed increased protein expression of both the novel PKC epsilon isoform and the atypical PKC lambda isoform ipsilateral to the lesion (174 � 17% for epsilon, 140 � 9% for lambda, of intact striatum in 6-OHDA lesioned plus chronic L-DOPA treated animals) in acute L-DOPA treated rats. No enhancement was observed in PKC immunoreactivity for other isoforms. Tamoxifen (5.0 mg/kg p.o.) significantly attenuated the L-DOPA induced augmentation of protein expression of PKC epsilon and PKC lambda, but had no effect on immunoreactivity for other PKC isoforms. In chronic L-DOPA treated parkinsonian rats, tamoxifen prevented (5.0 mg/kg p.o.) as well as ameliorated (5.0 mg/kg p.o.) the characteristic shortening in duration of motor response to L-DOPA challenge. In MPTP lesioned primates, similar to the ameliorative effect seen in rats, tamoxifen (1 and 3 mg/kg p.o) reduced the appearance of L-DOPA induced dyskinesia by 61% and 55% respectively (p < 0.05). These results suggest that changes in specific striatal PKC isoforms contribute to the pathogenesis of L-DOPA induced motor complications and further that drugs able to selectively inhibit these signaling kinases might provide adjunctive benefit in the treatment of Parkinson’s disease. Published by Elsevier Ltd.

Cell cycle reentry has been found during apoptosis of postmitotic neurons under certain pathological conditions. To evaluate whether nuclear factor-kappaB (NF-kappaB) activation promotes cell cycle entry and neuronal apoptosis, we studied the relation among NF-kappaB-mediated cyclin induction, bromodeoxyuridine (BrdU) incorporation, and apoptosis initiation in rat striatal neurons following excitotoxic insult. Intrastriatally injected N-methyl-D-aspartate receptor agonist quinolinic acid (QA, 60 nmol) elicited a rise in cyclin D1 mRNA and protein levels (P

Aberrant protein aggregation has been recognized as an important factor in the degeneration of melanized dopaminergic neurones in Parkinson's disease (PD). The constitutive (HSP73) and (heat)-inducible (HSP72) proteins of the heat shock 70 family form a major defence system against pathological protein aggregation. However, the distribution patterns of these chaperones in nigral neuromelanin-laden neurones are largely unknown. The present study determined the distribution of HSP72 and HSP73 in control and Parkinsonian substantia nigra, using immunohistochemistry. In the neuromelanin-laden neurones of controls, HSP72 was nondetectable, whereas HSP73 was weakly expressed in both the cytosol and the nucleus. Surprisingly, in PD subjects, marked nuclear HSP73, but not HSP72 immunoreactivity was observed, while cytosolic immunoreactivity of the two chaperones resembled the labelling pattern observed in controls. Furthermore, HSP73 immunoreactivity was observed in a subset of the Lewy bodies (LBs) detected in the substantia nigra of PD subjects, whereas only few of these LBs were labelled with HSP72. Interestingly, HSP72 and to a lesser extent HSP73 immunoreactivity was much stronger in nonmelanized neurones as compared with melanized neurones in this area. Thus, we conclude that the distribution pattern of HSP73 rather than HSP72 is changed in the nigral neuromelanin-laden neurones of PD subjects as compared with control subjects. The impaired ability of aged, dopaminergic neurones to express high levels of chaperones, may contribute to the preferential vulnerability of the latter cells in PD.

Reported benefits of various glutamatergic receptor antagonists in Parkinson's disease (PD) prompted an evaluation of the antidyskinetic effect of a putative glutamate release inhibitor in 15 moderately advanced patients. In a 3-week, double-blind, proof-of-concept study, riluzole (200 mg/day) failed to alter parkinsonian or levodopa-induced motor complication severity. Opposing effects of a generalized inhibition of glutamate-mediated synaptic transmission may limit the usefulness of this approach to treat PD.

We present the construction of a dynamic area fraction model (DAFM), representing a new class of models for an earth-like planet. The model presented here has no spatial dimensions, but contains coupled parameterizations for all the major components of the hydrological cycle involving liquid, solid and vapor phases. We investigate the nature of feedback processes with this model in regulating Earth's climate as a highly nonlinear coupled system. The model includes solar radiation, evapotranspiration from dynamically competing trees and grasses, an ocean, an ice cap, precipitation, dynamic clouds, and a static carbon greenhouse effect. This model therefore shares some of the characteristics of an Earth System Model of Intermediate complexity. We perform two experiments with this model to determine the potential effects of positive and negative feedbacks due to a dynamic hydrological cycle, and due to the relative distribution of trees and grasses, in regulating global mean temperature. In the first experiment, we vary the intensity of insolation on the model's surface both with and without an active (fully coupled) water cycle. In the second, we test the strength of feedbacks with biota in a fully coupled model by varying the optimal growing temperature for our two plant species (trees and grasses). We find that the negative feedbacks associated with the water cycle are far more powerful than those associated with the biota, but that the biota still play a significant role in shaping the model climate. third experiment, we vary the heat and moisture transport coefficient in an attempt to represent changing atmospheric circulations.

The present study evaluated the neuroprotective potential of prostaglandin A1 (PGA1) in rodent models of focal cerebral ischemia. PGA1 33 nmol reduced infarction volume by about 43% (P < 0.05) when administered intracerebroventricularly before and after transient ischemia in mice. PGA1 16.5–66 nmol diminished infarction volume by 18% to 27% (P < 0.01) when administered immediately following permanent ischemia in rats. PGA1 treatment also significantly ameliorated motor dysfunction after brain ischemia. These results suggest that PGA1 protects neurons from ischemic injury.

Dopamine reuptake blockers, by enhancing and stabilizing intrasynaptic transmitter levels, could help palliate motor dysfunction in Parkinson's disease. This randomized, double-blind, placebo-controlled study compared the acute effects of the monoamine uptake inhibitor NS 2330 to those of placebo in 9 relatively advanced parkinsonian patients. At the dose administered, no change in parkinsonian scores was found when NS 2330 was given alone or with levodopa. Moreover, NS 2330 coadministration did not appear to alter dyskinesia severity or the duration of the antiparkinsonian response to levodopa. The drug was well tolerated. Under the conditions of this study, the present results failed to support the usefulness of dopamine reuptake inhibition in the treatment of advanced Parkinson's disease.

Recent model simulations of the effects of increasing greenhouse gases combined with other anthropogenic effects predicted larger rates of warming in the mid and upper troposphere than near the Earth's surface. In multiple model comparisons we find that accelerated upper-level warm- ing is simulated in all models for the greenhouse-gas/direct-aerosol forcing representative of 1979-2000. However, in a test of model predictive skill, a comparison with observations shows no warming of the free troposphere over this period. We assessed the likelihood that such a disparity between model projection and observations could be generated by forcing uncertainties or chance model fluctuations, by comparing all possible 22 yr temperature trends in a series of climate simula- tions. We find that it is extremely unlikely for near-surface air temperatures (surface temperatures) to increase at the magnitude observed since 1979 without a larger warming in the mid-troposphere. Warming of the surface relative to the mid-troposphere was also more likely in control simulations than under anthropogenic forcing. Because errors in the vertical temperature structure would be expected to create errors in water-vapor feedback, cloud cover and moisture content, these results suggest the need for great caution when applying the simulations to future climate predictions and to impact assessments.

Adenosine A(2A) receptors, abundantly expressed on striatal medium spiny neurons, appear to activate signaling cascades implicated in the regulation of coexpressed ionotropic glutamatergic receptors. To evaluate the contribution of adenosinergic mechanisms to the pathogenesis of the response alterations induced by dopaminergic treatment, we studied the ability of the selective adenosine A(2A) receptor antagonist KW-6002 to prevent as well as palliate these syndromes in rodent and primate models of Parkinson's disease. In rats, KW-6002 reversed the shortened motor response produced by chronic levodopa treatment while reducing levodopa-induced hyperphosphorylation at S845 residues on AMPA receptor GluR1 subunits. In primates, KW-6002 evidenced modest antiparkinsonian activity when given alone. Once-daily coadministration of KW-6002 with apomorphine prevented the development of dyskinesias, which appeared in control animals 7-10 days after initiating apomorphine treatment. Animals initially given apomorphine plus KW-6002 for 3 weeks did not begin to manifest apomorphine-induced dyskinesias until 10-12 days after discontinuing the A(2A) antagonist. These results suggest that KW-6002 can attenuate the induction as well as the expression of motor response alterations to chronic dopaminergic stimulation in parkinsonian animals, possibly by blocking A(2A) receptor-stimulated signaling pathways. Our findings strengthen the rationale for developing A(2A) antagonists as an early treatment strategy for Parkinson's disease.

The neuronal protein alpha-synuclein has been implicated in the pathogenesis of Parkinson disease and other neurodegenerative diseases. Although many studies report that alpha-synuclein expression is restricted to neuronal presynaptic terminals, this protein aggregates in Lewy bodies in somata that are typically distant from their axon terminals. Few studies have addressed this paradox and there has been no compelling explanation proposed for the apparent discrepancy between the locus of neuronal alpha-synuclein expression and the loci of Lewy bodies in the majority of Parkinson disease cases. We explored this issue by extensively characterizing the monoclonal antibody Synuclein-1 (Syn-1) and using this highly selective antibody to map the distribution of alpha-synuclein throughout rat brain and in human substantia nigra (SN). Additionally, alpha-synuclein expression in rat SN detected by 2 polyclonal antibodies against alpha-synuclein was compared with that detected by the Syn-1 antibody. In contrast with many previous reports, alpha-synuclein was detected by Syn-1 in neuronal somata and dendrites in restricted brain regions, as well as more ubiquitously in axons and terminals. The strongest alpha-synuclein neuronal expression in rat was found in brainstem and cortical regions that are homologous to regions prone to Lewy body formation in humans. The Syn-1 antibody labeled abundant somatodendritic alpha-synuclein in both rat and human SN, a major locus of Lewy body formation and neurodegeneration in Parkinson disease. By contrast, very few immunoreactive somata in the rat SN were labeled by the 2 polyclonal antibodies. We explore possible explanations for the differences in conflicting reports of patterns of alpha-synuclein expression in brain, including differences among antibodies.

We examined changes in several independent intensity indices of four major tropical monsoonal circulations for the period 1950-1998. These intensity indices included observed land surface precipitation and observed ocean surface pressure in the monsoon regions as well as upper- level divergence calculated at several standard levels from the NCAR/NCEP reanalysis. These values were averaged seasonally over appropriate regions of southeastern Asian, western Africa, eastern Africa and the Australia/Maritime continent and adjacent ocean areas. As a consistency check we also examined two secondary indices: mean sea level pressure trends and low level convergence both from the NCEP reanalysis. We find that in each of the four regions examined, a consistent picture emerges indicating signi- ficantly diminished monsoonal circulations over the period of record, evidence of diminished spatial maxima in the global hydrological cycle since 1950. Trends since 1979, the period of strongest reported surface warming, do not indicate any change in monsoon circulations. When strong ENSO years are removed from each of the time series the trends still show a general, significant reduc- tion of monsoon intensity indicating that ENSO variability is not the direct cause for the observed weakening. Most previously reported model simulations of the effects of rising CO2 show an increase in monsoonal activity with rising global surface temperature. We find no support in these data for an increasing hydrological cycle or increasing extremes as hypothesized by greenhouse warming scenarios.

The nonphysiologic stimulation of striatal dopaminergic receptors, as a result of disease- or drug-related denervation or intermittent excitation, triggers adaptive responses in the basal ganglia which contribute to the appearance of parkinsonian symptoms and later to the dyskinesias and other alterations in motor response associated with dopaminergic therapy. Current evidence suggests that these altered responses involve activation of signal transduction cascades in striatal medium spiny neurons linking dopaminergic to coexpressed ionotropic glutamatergic receptors of the N-methyl-D-aspartate (NMDA) and Alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) classes. These intraneuronal signaling pathways appear capable of modifying the phosphorylation state of NMDA and AMPA receptor subunits; resultant sensitization enhances cortical glutamatergic input which in turn modifies striatal output in ways that compromise motor behavior. The regulation of these spiny neuron glutamate receptors can also be affected by the activation state of coexpressed nondopaminergic receptors as well as by changes associated with Huntington's disease. These observations lend new insight into molecular mechanisms contributing to the integration of synaptic inputs to spiny neurons. They also suggest novel approaches to the pharmacotherapy of extrapyramidal motor dysfunction.

In addition to classic motor signs and symptoms, Parkinson's disease (PD) is characterized by neuropsychological and emotional deficits, including a blunted emotional response. In the present study, we explored both the neural basis of abnormal emotional behavior in PD and the physiological effects of dopaminergic therapy on the response of the amygdala, a central structure in emotion processing. PD patients and matched normal controls (NCs) were studied with blood oxygenation level-dependent functional magnetic resonance imaging during a paradigm that involved perceptual processing of fearful stimuli. PD patients were studied twice, once during a relatively hypodopaminergic state (i.e.,or =12 hr after their last dose of dopamimetic treatment) and again during a dopamine-replete state. The imaging data revealed a robust bilateral amygdala response in NCs that was absent in PD patients during the hypodopaminergic state. Dopamine repletion partially restored this response in PD patients. Our results demonstrate an abnormal amygdala response in PD that may underlie the emotional deficits accompanying the disease. Furthermore, consistent with findings in experimental animal paradigms, our results provide in vivo evidence of the role of dopamine in modulating the response of the amygdala to sensory information in human subjects.

The contribution of serotoninergic mechanisms to motor dysfunction in Parkinson's disease (PD) has yet to be fully elucidated. Recent clinical observations increasingly suggest that drugs able to block serotonin 5HT2A/C receptors can benefit patients with certain extrapyramidal movement disorders. To further explore the roles of these and other neurotransmitter receptors in the pathogenesis of parkinsonian signs and levodopa-induced dyskinesias; we evaluated the effects of quetiapine, an atypical antipsychotic with 5HT2A/C and D2/3 antagonistic activity, on motor behavior in 6-hydroxydopamine-lesioned rats and MPTP-lesioned nonhuman primates. In hemiparkinsonian rats, quetiapine (5 mg/kg, po) reversed the shortened motor response to levodopa challenge produced by 3 weeks of twice-daily levodopa treatment (P < 0.01). Quetiapine (5 mg/kg po) also normalized the shortened response to the acute injection of either a dopamine D1 receptor agonist (SKF 38392) or a D2 agonist (quinpirole) in rats that had received chronic levodopa treatment. Quetiapine had no effect on parkinsonian dysfunction when given alone or with levodopa to parkinsonian rats and monkeys. Quetiapine (4 mg/kg, po) did, however, substantially reduce levodopa-induced dyskinesias when coadministered with levodopa (P < 0.05). These results suggest that quetiapine could confer therapeutic benefits to patients with levodopa-induced motor complications. Moreover, our findings may indicate that 5HT2A/C receptor-mediated mechanisms, alone or in combination with other mechanisms, contribute to the pathogenesis of the altered motor responses associated with the treatment of PD.

The increasing global demand for food will be met chiefly by increased intensification of production. For crops, this will be achieved largely by increased yields per area with a smaller contribution from an increased number of crops grown in a seasonal cycle. Production systems show a spectrum of intensification practices characterised by varying methods of site preparation and pest control, and inputs of germplasm, nutrients and water. This paper highlights three main types of intensification (based largely on the quantity and efficiency of use of external inputs) and examines both the on- and off-site environmental consequences of each for soils, water quantity and quality, and climate forcing and regional climate change. The use of low amounts of external inputs is generally regarded as being the most environmentally-benign although this advantage over systems with higher inputs may disappear if the consequences are expressed per unit of product rather than per unit area. The adverse effects of production systems with high external inputs, especially losses of nutrients from fertilisers and manures to water courses and contributions of gases to climate forcing, have been quantified. Future intensification, including the use of improved germplasm via genetic modification, will seek to increase the efficiency of use of added inputs while minimising adverse effects on the environment. However, reducing the loss of nutrients from fertilisers and manures, and increasing the efficiency of water utilisation in crop production, remain considerable challenges.

Patients with idiopathic Parkinson's disease suffer not only from classic motor symptoms, but from deficits in cognitive function, primarily those subserved by the prefrontal cortex as well. The aim of the current study was to investigate the modulatory effects of dopaminergic therapy on neural systems subserving working memory and motor function in patients with Parkinson's disease. Ten patients with stage I and II Parkinson's disease were studied with functional magnetic resonance imaging, during a relatively hypodopaminergic state (ie, 12 hours after a last dose of dopamimetic treatment), and again during a dopamine-replete state. Functional magnetic resonance imaging was performed under three conditions: a working memory task, a cued sensorimotor task and rest. Consistent with prior data, the cortical motor regions activated during the motor task showed greater activation during the dopamine-replete state; however, the cortical regions subserving working memory displayed greater activation during the hypodopaminergic state. Interestingly, the increase in cortical activation during the working memory task in the hypodopaminergic state positively correlated with errors in task performance, and the increased activation in the cortical motor regions during the dopamine-replete state was positively correlated with improvement in motor function. These results support evidence from basic research that dopamine modulates cortical networks subserving working memory and motor function via two distinct mechanisms: nigrostriatal projections facilitate motor function indirectly via thalamic projections to motor cortices, whereas the mesocortical dopaminergic system facilitates working memory function via direct inputs to prefrontal cortex. The results are also consistent with evidence that the hypodopaminergic state is associated with decreased efficiency of prefrontal cortical information processing and that dopaminergic therapy improves the physiological efficiency of this region.

The value of the analyses of the 200 mbar zonal winds is proposed as a particularly effective tool to assess variability and trends in atmospheric circulation. Using the thermal wind relation, the 200 mbar zonal wind results from the vertically integrated north-south temperature gradient between the Earth's surface and 200 mbar. We found a tendency for the 200 mbar winds to become somewhat stronger at higher latitudes since 1958.

The close correspondence between the distribution of brain alpha-synuclein and that of muscarinic M1 and M3 receptors suggests a role for this protein in cholinergic transmission. We thus examined the effect of muscarinic stimulation on alpha-synuclein in SH-SY5Y, a human dopaminergic cell line that expresses this protein. Under basal conditions, alpha-synuclein was detected in all subcellular compartments isolated as follows: plasma membrane, cytoplasm, nucleus, and two vesicle fractions. The lipid fractions contained only a 45-kDa alpha-synuclein oligomer, whereas the cytoplasmic and nuclear fractions contained both the oligomer and the monomer. This finding suggests alpha-synuclein exists physiologically as a lipid-bound oligomer and a soluble monomer. Muscarinic stimulation by carbachol reduced the alpha-synuclein oligomer in plasma membrane over a 30-min period, with a concomitant increase of both the oligomer and the monomer in the cytoplasmic fraction. The oligomer was associated with a light vesicle fraction in cytoplasm that contains uncoated endocytotic vesicles. The carbachol-induced alteration of alpha-synuclein was blocked by atropine. Translocation of the alpha-synuclein oligomer in response to carbachol stimulation corresponds closely with the time course of ligand-stimulated muscarinic receptor endocytosis. The data suggest that the muscarine receptor stimulated release of the alpha-synuclein oligomer from plasma membrane, and its subsequent association with the endocytotic vesicle fraction may have a role in muscarine receptor endocytosis. We propose that its function may be a transient release of membrane-bound phospholipase D2 from alpha-synuclein inhibition, thus allowing this lipase to participate in muscarinic receptor endocytosis.

The NCAR Community Climate Model (version 3), coupled to the Biosphere Atmosphere Transfer scheme and a mixed layer ocean model is used to investigate the impact on the climate of a conservative change from natural to present land cover. Natural vegetation cover was obtained from an ecophysiologically constrained biome model. The current vegetation cover was obtained by perturbing the natural cover from forest to grass over areas where land cover has been observed to change. Simulations were performed for 17 years for each case (results from the last 15 years are presented here). We find that land cover changes, largely constrained to the tropics, SE Asia, North America and Europe, cause statistically significant changes in regional temperature and precipitation but cause no impact on the globally averaged temperature or precipitation. The perturbation in land cover in the tropics and SE Asia teleconnect to higher latitudes by changing the position and strength of key elements of the general circulation (the Hadley and Walker circulations). Many of the areas where statistically significant changes occur are remote from the location of land cover change. Historical land cover change is not typically included in transitory climate simulations, and it may be that the simulation of the patterns of temperature change over the twentieth century by climate models will be further improved by taking it into account.

Land cover change (LCC) simulations were performed at 3 different carbon dioxide lev- els (280, 355 and 430 ppmv) using the standard version of the NCAR CCM3 at T42 resolution coupled with the Biosphere-Atmosphere Transfer Scheme (BATS) and a mixed-layer ocean model. We follow the evolution of the initial temperature perturbation within the horizontal and vertical structure of the atmosphere and then examine the 15 yr average of near-surface air temperature and meridional stream function differences between current and natural land cover at the 3 different CO2 levels. Results show that LCC caused temperature perturbations which initially affected only those regions where the land cover was modified. After a short period, however, the effects of LCC propagated to remote regions. While the remote effects of LCC were generally different at each CO2 level, 4 com- mon remote regions of sensitivity were identified in these simulations (North Pacific, North America, northeast Asia and the Indian Ocean). The main factor in explaining the differing remote responses was the change in the zonally averaged background circulation resulting from circulation changes caused by LCC, CO2 level, and the interaction between these 2 forcings. The 15 yr average seasonal results indicate that LCC may have impacts on surface air temperature which vary in sign between seasons, depending on the character of the initial land cover perturbation as well as local meteoro- logical conditions. We find no evidence that the impacts of LCC decrease with increasing CO2, rather we show that LCC does appear to affect regional climate at a statistically significant level.

Chronic dopaminomimetic administration to parkinsonian animal models or Parkinson's disease patients leads to characteristic alteration in motor response. Previous studies suggested that the nonphysiologic stimulation of dopaminergic receptors on striatal medium spiny neurons enhances the synaptic efficacy of juxtaposed glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype. Resultant NMDA receptor sensitization due to differential changes in subunit phosphorylation appears to favor alterations in striatal output in ways that influence motor function. To detail the involvement of NMDA receptors further as well as to determine whether similar functional changes might develop in α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors, the effects of selective antagonist of AMPA receptors (6-nitro-7-sulfamoyl-benzo[f]-quinoxaline-2,3 (1H,4H)-dione sodium salt, NBQX, 10 mg/kg) on levodopa-induced response alterations in 6-hydroxydopamine (6-OHDA) lesioned rats were compared with drugs which act competitively (3-(±)-2-carboxypiperazin-4-yl)-propyl-1-phosphonicacid, CPP, 6.25 mg/kg) or noncompetitively (dextromethorphan, 40 mg/kg) to block NMDA receptors, or a nonselective inhibitor of glutamatergic transmission (2-amino-6-trifluoromethoxy benzothiazole, riluzole, 5 mg/kg). We found that the shortened duration of the motor response to levodopa, which underlies human wearing-off fluctuations, was reversed to a similar degree by the acute coadministration of CPP, NBQX, or riluzole (n = 4–6) but dextromethorphan did not. These observations strengthen the possibility that a reduction in levodopa-associated changes in motor response by inhibitors of glutamatergic transmission acting generally or selectively at the glutamate binding-sites may relate to their ability to attenuate pathologic gain in striatal glutamatergic function. The capacity of NBQX to reverse these altered responses suggests that an enhanced synaptic efficacy of striatal AMPA receptors may also participate in the generation of these motor response changes in levodopa-treated parkinsonian rats. Synapse 36:267–274, 2000. © 2000 Wiley-Liss, Inc.

OBJECTIVE: To evaluate the contribution of amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) glutamate receptors to the pathogenesis of parkinsonian signs and levodopa-induced dyskinesias. BACKGROUND: Motor fluctuations and dyskinesias reflect, in part, altered function of glutamate receptors of the NMDA subtype. The possible role of AMPA receptors, however, has not yet been examined. METHODS: The authors compared the ability of an AMPA agonist (CX516) and a noncompetitive AMPA antagonist (LY300164) to alter parkinsonian symptoms and levodopa-induced dyskinesia in MPTP-lesioned monkeys. Eight levodopa-treated parkinsonian monkeys received rising doses of each drug, first in monotherapy and then in combination with low-, medium-, and high-dose levodopa. RESULTS: CX516 alone, as well as when combined with low-dose levodopa, did not affect motor activity but induced dyskinesia. Moreover, following injection of the higher doses of levodopa, it increased levodopa-induced dyskinesia by up to 52% (p < 0.05). LY300164 potentiated the motor activating effects of low-dose levodopa, increasing motor activity by as much as 86% (p < 0.05), and that of medium-dose levodopa as much as 54% (p < 0.05). At the same time, LY300164 decreased levodopa-induced dyskinesia by up to 40% (p < 0.05). CONCLUSIONS: AMPA receptor upregulation may contribute to the expression of levodopa-induced dyskinesia. Conceivably, noncompetitive AMPA receptor antagonists could be useful, alone or in combination with NMDA antagonists, in the treatment of PD, by enhancing the antiparkinsonian effects of levodopa without increasing and possibly even decreasing levodopa-induced dyskinesia. Neurology

Motor dysfunction produced by the chronic non-physiological stimulation of dopaminergic receptors on striatal medium spiny neurons is associated with alterations in the sensitivity of glutamatergic receptors, including those of the N-methyl-D-aspartate (NMDA) subtype. Functional characteristics of these ionotropic receptors are regulated by their phosphorylation state. Lesioning the nigrostriatal dopamine system of rats induces parkinsonian signs and increases the phosphorylation of striatal NMDA receptor subunits on serine and tyrosine residues. The intrastriatal administration of certain inhibitors of the kinases capable of phosphorylating NMDA receptors produces a dopaminomimetic motor response in these animals. Treating parkinsonian rats twice daily with levodopa induces many of the characteristic features of the human motor complication syndrome and further increases the serine and tyrosine phosphorylation of specific NMDA receptor subunits. Again, the intrastriatal administration of selective inhibitors of certain serine and tyrosine kinases alleviates the motor complications. NMDA receptor antagonists, including some non-competitive channel blockers, act both palliatively and prophylactically in rodent and primate models to reverse these levodopa-induced response alterations. Similarly, in clinical studies dextrorphan, dextromethorphan, and amantadine have been found to be efficacious against motor complications. Recent observations in animal models further indicate that certain amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) antagonists alleviate, while others exacerbate, these complications. Thus, it appears that the denervation or intermittent stimulation of striatal dopaminergic receptors differentially activates signal transduction pathways in medium spiny neurons. These in turn modify the phosphorylation state of ionotropic glutamate receptors and consequently their sensitivity to cortical input. These striatal changes contribute to symptom production in Parkinson's disease, and their prevention or reversal could prove useful in the treatment of this disorder.

This study examines regional temperature trends during the period 1979–1997 from the Microwave Sounding Unit (MSU) 2r satellite measurements and compares them with the same trends in depth-averaged tropospheric temperatures derived from the National Center for Environmental Prediction (NCEP) reanalysis, in an attempt to determine whether regional trends exist which are larger than known inhomogeneities in the data. Large, statistically significant regional trends were found in both the NCEP and the MSU data that are of both signs and have larger magnitude than documented biases in the data. The datasets have overall agreement on the location and strength of these significant regional trends at mid and high latitudes but agreement decreases in the tropics. A global annual average of the significant regional trends with larger amplitudes than reported data biases and areally weighted over the globe yields −0.02°C over the 19-year period of the record in the MSU 2r Version C dataset, and −0.05°C/19 years in the NCEP data in the 1000–500 mb layer. Increasing the bias threshold by as much as five times still results in an average cooling in both datasets. Subjecting the surface temperature record to the same regional analysis yields a regionally significant trend of 0.17°C/19 years, approximately halving the trend obtained when all regions, regardless of significance, are considered. In addition, many regions with significant warming trends in the surface network occur in areas with limited observations over oceans and are not confirmed by the other datasets. Discrepancies between significant regional trends in the surface record and the upper-air observations are not systematic. In no case are regionally significant, tropical, warming trends at the surface magnified at higher levels in the MSU and NCEP tropospheric data. In the case of the NCEP reanalysis, both warming and cooling trends on average become larger, more significant, and cover larger areas in shallower tropospheric layers. These results suggest that the disparity between global trends in satellite/rawinsonde/reanalysis datasets and those of the surface record are not simply the result of large-scale changes in the vertical structure of the atmosphere or to large-scale biases in the satellite observations, but instead are linked to processes which are regional in nature. Copyright © 2000 Royal Meteorological Society

This ten-year general circulation model experiment compared a simulation where land surface boundary conditions were represented by observed, present day land cover to a simulation where the surface was represented by natural, potential land cover conditions. As a result of these estimated changes in historical land cover, significant temperature and hydrology changes affected tropical land surfaces, where some of the largest historical disruptions in total vegetation biomass have occurred. Also of considerable interest because of their broad scope and magnitude were changes in high-latitude Northern Hemisphere winter climate which resulted from changes in tropical convection, upper-level tropical outflow, and the generation of low-frequency tropical waves which propagated to the extratropics. These effects combined to move the Northern Hemisphere zonally averaged westerly jet to higher latitudes, broaden it, and reduce its maximum intensity. Low-level easterlies were also reduced over much of the tropical Pacific basin while positive anomalies in convective precipitation occurred in the central Pacific. Globally averaged changes were small. Comparisons of recent, observed trends in tropical and Northern Hemisphere, mid-latitude climate with these simulations suggests an interaction between the climatic effects of historical land cover changes and other modes of climate variability.

Mutations in alpha-synuclein are known to be associated with Parkinson's disease (PD). The coexistence of this neuronal protein with ubiquitin and proteasome subunits in Lewy bodies in sporadic disease suggests that alterations of alpha-synuclein catabolism may contribute to the pathogenesis of PD. The degradation pathway of alpha-synuclein has not been identified nor has the kinetics of this process been described. We investigated the degradation kinetics of both wild-type and A53T mutant 6XHis-tagged alpha-synuclein in transiently transfected SH-SY5Y cells. Degradation of both isoforms followed first-order kinetics over 24 h as monitored by the pulse-chase method. However, the t((1)/(2)) of mutant alpha-synuclein was 50% longer than that of the wild-type protein (p0.01). The degradation of both recombinant proteins and endogenous alpha-synuclein in these cells was blocked by the selective proteasome inhibitor beta-lactone (40 microM), indicating that both wild-type and A53T mutant alpha-synuclein are degraded by the ubiquitin-proteasome pathway. The slower degradation of mutant alpha-synuclein provides a kinetic basis for its intracellular accumulation, thus favoring its aggregation.

Using identical observed meteorology for lateral boundary conditions, the Regional Atmospheric Modeling System was integrated for July-August 1973 for south Florida. Three experiments were performed-one using the observed 1973 landscape, another the 1993 landscape, and the third the 1900 landscape, when the region was close to its natural state. Over the 2-month period, there was a 9% decrease in rainfall averaged over south Florida with the 1973 landscape and an 11% decrease with the 1993 landscape, as compared with the model results when the 1900 landscape is used. The limited available observations of trends in summer rainfall over this region are consistent with these trends.

The analysis of thickness derived from the National Center for Environmental Prediction (NCEP) reanalysis indicates that there has been no statistically significant warming trend in layer-averaged global tropospheric temperatures during the period 1979–1996. While this result is at variance with data based on surface information, NCEP trends and interannual variations are closely related to tropospheric mean-layer temperatures obtained from the satellite-based microwave sounding unit (MSU) lower-tropospheric data set. When a longer period, 1973–1996, is used for the NCEP analysis, a warming trend within a 95% confidence interval is derived. However, it is nearly half the magnitude of the surface-derived trends. Strong correlations of the yearly global surface temperature anomalies and those calculated for several layers in the NCEP data indicate coincident interannual temperature variations throughout the depth of the troposphere. The disagreement of both our analysis and satellite-derived estimates with surface data could be due to a land surface measurement bias, a result of land use changes such as deforestation and agricultural expansion whose effects are not yet accounted for in the global temperature records, and/or a decoupling between surface and lower-tropospheric temperature over the last several years.

Levodopa continues to be the most effective agent for the symptomatic treatment of Parkinson's disease. No other drug matches its ability to suppress parkinsonian symptoms, especially in patients with advanced disease. But over time, initial benefits begin to wane, not so much because of a decline in efficacy against core symptoms, but rather because of a rise in adverse effects. Most common are the motor response complications that appear within a few years of treatment initiation and ultimately affect most parkinsonian patients. These progressively disabling complications include response fluctuations and abnormal involuntary movements. Current evidence indicates that 'wearing-off' fluctuations, typically the first motor complication to become clinically evident, initially reflect the loss of buffering normally provided by striatal dopaminergic terminals. Thus, with increasing degeneration of the nigrostriatal system, swings in plasma levodopa concentrations associated with standard dosage regimens produce nonphysiological fluctuations in intrasynaptic dopamine. As a result of long term discontinuous stimulation, secondary changes occur at sites downstream from the dopamine system and now appear to underlie the progressive worsening of 'wearing-off' phenomena as well as the eventual appearance of other response complications. Chronic intermittent stimulation of normally tonically active dopaminergic receptors activates specific signalling cascades in striatal dopaminoceptive medium spiny neurons, and this evidently results in long term potentiation of the synaptic efficacy of glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype on these GABAergic efferents. As a consequence of their increasing sensitivity to excitation by cortical glutamatergic projections, it would, however, appear that medium spiny neuron function changes to favour the appearance of response fluctuations of the 'on-off' type and peak dose dyskinesias. The inability of standard levodopa treatment to restore striatal dopaminergic function in a more physiological manner clearly contributes to the appearance of motor complications. Continuous dopaminergic replacement not only reverses these complications in parkinsonian patients but also prevents their development in animal models of Parkinson's disease. Thus, pharmaceutical approaches that provide relatively continuous dopamine receptor stimulation might confer both prophylactic and palliative benefit to parkinsonian patients. Several such strategies are currently under development, and include various methods to prolong the duration of action of levodopa as well as the use of transdermally administered or very long acting dopamine agonists.

Glutamate metabotropic receptor mediated mechanisms have been implicated in both neuroprotection and neurotoxicity. To characterize these mechanisms further in vivo, the effects of an intrastriatally injected metabotropic receptor agonist, trans-(1S,3R)-1-amino-1,3-cyclopentanedicarboxylic acid (1S,3R-ACPD), were studied alone and together with N-methyl-D-aspartate (NMDA) or kainic acid (KA) receptor agonists on DNA fragmentation and nerve cell death. 1S,3R-ACPD induced internucleosomal DNA fragmentation of striatal cells in a dose-dependent manner. TUNEL and propidium iodide staining showed DNA fragmentation and profound nuclear condensation around the injection site. Fragmented nuclei were occasionally seen under light microscopy. Internucleosomal DNA fragmentation induced by 1S,3R-ACPD was attenuated by the protein synthesis inhibitor cycloheximide as well as by the non-selective and selective metabotropic receptor antagonists L-(+)-2-amino-3-phosphonopionic acid (L-AP3), (RS)-aminoindan-1,5-dicarboxylic acid and (RS)-alpha-methylserine-o-phosphate monophenyl ester, respectively. The 1S,3R-ACPD (100-900 nmol) induced death of striatal neurons was suggested by the reduction in NMDA and D1 dopamine receptors by up to 13% (P0.05) and 20% (P0.05) as well as by the decline in GAD67 mRNA (25%, P0.01) and proenkephalin mRNA levels (35%, P0.01). Interestingly, 1S,3R-ACPD attenuated internucleosomal DNA fragmentation induced by NMDA, but potentiated that induced by KA. These results suggest that metabotropic receptor stimulation leads to the death of striatal neurons by a mechanism having the biochemical stigmata of apoptosis. Moreover, metabotropic receptor stimulation evidently exerts opposite effects on pre- or postsynaptic mechanisms contributing to the NMDA and KA-induced apoptotic-like death of these neurons.

We examined 50 patients with parkinsonism-dementia complex of Guam (Guam PDC), 10 Guamanian patients with amyotrophic lateral sclerosis (ALS), 5 patients with combined PDC and ALS (PDC-ALS), and 20 non-PDC non-ALS Guamanians, who had been autopsied between 1979 and 1982, paying special attention to glial inclusions. Gallyas-positive and tau-immunopositive intracytoplasmic inclusions were observed in many of the glial cells, in addition to extensive neurofibrillary tangles (NFTs) in the brains of Guam PDC and PDC-ALS patients. Granular hazy inclusions were seen in the astrocytes, and some crescent/coiled inclusions were observed in the oligodendroglia. Many granular hazy inclusions were observed in the amygdaloid nucleus, inferior olivary nucleus, and lateral funiculus of the spinal cord. The crescent/coiled inclusions were observed predominantly in the anterior nucleus of the thalamus, motor cortex, midbrain tegmentum, pyramids of the medulla oblongata, and lateral funiculus of the spinal cord. The granular hazy inclusions have never been reported previously, and the topographic distribution of the crescent/coiled inclusions in Guam PDC and PDC-ALS differs from those reported previously in other NFT-forming diseases. These findings indicate that Guam PDC and PDC-ALS involve not only neurons but also glia, and that their morphological and topographic differences from other NFT-forming diseases may provide further insights into their distinct etiopathogenesis, and thus prove useful for diagnosis.