Abstract Background Gulf War exposures in 1990 and 1991 have caused 25% to 30% of deployed personnel to develop a syndrome of chronic fatigue, pain, hyperalgesia, cognitive and affective dysfunction. Methods Gulf War veterans (n = 31) and sedentary veteran and civilian controls (n = 20) completed fMRI scans for diffusion tensor imaging. A combination of dolorimetry, subjective reports of pain and fatigue were correlated to white matter diffusivity properties to identify tracts associated with symptom constructs. Results Gulf War Illness subjects had significantly correlated fatigue, pain, hyperalgesia, and increased axial diffusivity in the right inferior fronto-occipital fasciculus. ROC generated thresholds and subsequent binary regression analysis predicted CMI classification based upon axial diffusivity in the right inferior fronto-occipital fasciculus. These correlates were absent for controls in dichotomous regression analysis. Conclusion The right inferior fronto-occipital fasciculus may be a potential biomarker for Gulf War Illness. This tract links cortical regions involved in fatigue, pain, emotional and reward processing, and the right ventral attention network in cognition. The axonal neuropathological mechanism(s) explaining increased axial diffusivity may account for the most prominent symptoms of Gulf War Illness.

 Citation: Rayhan RU, Stevens BW, Timbol CR, Adewuyi O, Walitt B, et al. (2013) Increased Brain White Matter Axial Diffusivity Associated with Fatigue, Pain and Hyperalgesia in Gulf War Illness. PLoS ONE 8(3): e58493. doi:10.1371/journal.pone.0058493 Editor: Yu-Feng Zang, Hangzhou Normal University, China Received: December 12, 2012; Accepted: February 7, 2013; Published: March 20, 2013 Copyright: © 2013 Rayhan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Sources of funding were provided by the Department of Defense Congressionally Directed Medical Research Program (CDMRP) award W81-XWH-09-1-0526. Research support for the Clinical Research Unit at Georgetown University Medical Center was funded in whole or in part with federal funds (Grant # UL1TR000101, previously UL1RR031975) from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), through the Clinical and Translational Science Awards Program (CTSA), a trademark of DHHS, part of the Roadmap Initiative, “Re-Engineering the Clinical Research Enterprise.” The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist.

 Introduction Over 25% of the 697,000 veterans deployed to the 1990–1991 Persian Gulf War and 15% of nondeployed veterans have developed a symptom complex of widespread pain, fatigue, headache, gastrointestinal, bladder, and other “functional” nociceptive and interoceptive complaints [1]–[4]. Gulf War veterans were exposed to a wide variety of exposures that include binary nerve agents, acetylcholinesterase inhibitors, organophosphates, other pesticides and herbicides that may have initiated their symptom complex [3]. This syndrome has been termed Gulf War Illness (GWI). An initial analysis defined these subjects as Chronic Multisymptom Illness (CMI) [1], [2] based on ≥2 complaints of (i) fatigue, (ii) musculoskeletal or (iii) mood and cognitive dysfunction for ≥6 months [2]. Deployed Gulf War veterans met criteria for Chronic Fatigue Syndrome (CFS) (odds ratio = 40.6) and Fibromyalgia (FM) (odds ratio = 2.32) indicating extensive symptom overlap [5], [6], [7]. All of the veterans who met CMI criteria in this study also met CFS criteria, and 52% met FM criteria. A striking clinical observation in our GWI subjects has been that their chronic pain and fatigue fluctuate in parallel [1]. Fatigue represents an increase in the presumed effort required to perform usual activities, and is not the same as tiredness or sleep deprivation [5]. Pain is the subjective sensory and affective perception reported by subjects in response to a potentially harmful stimulus [8]. Pain and fatigue have been associated with structural and functional alterations of cortical regions in chronic regional pain syndrome, penetrating brain injury, migraine, irritable bowel syndrome and chronic pelvic pain [9]–[13]. Efforts have been made to define both fatigue and pain in terms of functional neurobiology [14], [15]. Activity in the orbitofrontal cortex (OFC) has been associated with both the fatigue sensation induced by a prolonged cognitive task and with accurate discrimination between painful and non-painful perceptions [16], [17]. The OFC has strong reciprocal projections with the adjacent ventromedial prefrontal cortex (vmPFC). The severity of damage to the vmPFC correlates with fatigue [10]. Further, increased functional connectivity between the right vmPFC, nucleus accumbens and anterior insula, mediated via the inferior fronto-occipital fasciculus (IFOF), contributes to the development and maintenance of chronic pain. [18], [19]. The prefrontal cortex is the only cortical area to receive direct projections from the spinal cord [20]. Central sensitization mechanisms that alter the spinal cord dorsal horn gating of pain transmission lead to increased perceptions of pain after an aversive, physical stimulus such as cutaneous pressure (hyperalgesia) or an innocuous stimulus such as light touch (allodynia) [21], [22]. These molecular events may sensitize prefrontal regions of the brain’s “pain matrix” leading to structural and functional reorganization associated with chronic symptom complaints [23]. Brain dysfunction in CMI may involve changes in white matter integrity. White matter function can be analyzed using diffusion tensor imaging (DTI) which assesses the random Brownian motion and the orientation of water molecules in a strong magnetic field [24]–[27]. Fractional anisotropy (FA) is the most commonly reported index. A decrease in FA indicates loss of white matter integrity [28]. FA is defined as the inverse of the 3 eigenvectors that describe the potential diffusion of water in nerve bundles [28]. The primary eigenvector describes water diffusivity in the direction of the fiber tract and is called the axial diffusivity (AD). Histological information indicates AD assesses axonal function [29]. Diffusion of water perpendicular to axons is defined by two eigenvectors and reported as the radial diffusivity (RD). RD has been associated with demyelination, neuroinflammation with edema or macrophage infiltration [30]–[32]. Mean diffusivity (MD) is the average of the AD and 2 RD eigenvectors. AD, RD, MD and FA can be correlated with subjective and objective outcomes to determine their relationships with tract integrity. White matter integrity and CMI symptoms have not been investigated. Given the concomitant chronic fatigue and pain, we hypothesized CMI may have significant white matter dysfunction compared to control subjects in tracts connecting the prefrontal areas involved in pain and fatigue. Correlations of fatigue, pain and hyperalgesia with AD and RD of specific white matter tracts were expected to implicate alterations of axonal or dysmyelination processes, respectively, to brain regions responsible for these clinical features. Two possible outcomes were envisioned. Significant correlations between fatigue, pain, hyperalgesia, and DTI variables for specific tracts that are distinct from control subjects would support the hypothesis that CMI is a disease with characteristic central nervous system pathology with bimodal distribution. Alternatively, these correlations may occur across both the CMI and control populations. This would suggest that CMI represents a highly skewed population distribution selected by symptom severity; any neurologic alterations seen in CMI would be interpreted as the far end of the distribution of a normal physiological process. There is no data regarding white matter integrity in CMI. Our findings advance current knowledge by investigating/integrating objective DTI outcomes into CMI neuropathology.

 Materials and Methods Subjects, Ethics Statement and Recruitment Protocols were approved by the Georgetown University Institutional Review Board and USAMRMC Human Research Protection Office (HRPO #A-15547.0) (clinicaltrials.gov identification number NCT01291758). All participants signed an informed consent. The subject pool was composed of 31 veterans who met CMI and CFS criteria, and 12 sedentary control veterans and civilians not meeting CMI or CFS criteria (Georgetown University IRB #2009–229) All of these subjects completed psychometric questionnaires and physical examinations (n = 43). For the initial DTI analysis (n = 51), 8 additional age - matched, healthy sedentary female control civilians(#2010–050 and #2010–356) were recruited. Complete details involving recruitment and retention of all participants can be found in Table B in File S1. On – line questionnaires (Table B in File S1) assessed an extensive set of psychometric qualities to investigate the distinctions between CMI, CFS and control subjects [33]. The current study focused only on fatigue, pain and hyperalgesia. Other data will be reported elsewhere. Fatigue was assessed with the ordinal fatigue rating, Chalder fatigue scale and the Multidimensional Fatigue Inventory (MFI) [34], [35]. The ordinal fatigue assessment was anchored with 0 = no complaint, 1 = trivial, 2 = mild, 3 = moderate or 4 = severe intensity [36]–[38]. Inclusion of “trivial” allowed participants to verify complaints that were present but not bothersome enough to warrant treatment and/or other lifestyle changes [39]. Subjective pain perceptions were quantified using the McGill short form with its sensory, affective and total scores [40] and nominal analysis of widespread pain in 4 quadrants and the axial skeleton [7]. Relative disability and quality of life were compared using the Medical Outcomes Survey Short Form 36 (SF-36) [41]. Subjects on medications (analgesics, sedative, tricyclic and other antidepressant drugs) had their medications tapered over a 2 week period. Protocol Upon arrival to the Georgetown University Clinical Research Unit, participants reviewed and signed their informed consent forms. All subjects had history and physical examinations to assess CMI [2], CFS [5], and fibromyalgia criteria [7], [42]. The protocol also included clinical assessments, blood tests, dolorimetry [43], and had a tour of the facilities to familiarize themselves with the fMRI and other equipment. Hyperalgesia in fibromyalgia has traditionally been ascertained by tenderness to manual thumb pressure of about 4 kg at ≥11 of 18 tender points [7]. We adapted this concept by pressing a pressure strain gauge dolorimeter at the 18 sites at a rate of 1 kg/sec [43]. Subjects were instructed that they were in control of the pressure, and to report the point when the pressure sensation switched to become painful. The average of the dolorimetry pressures has been used as a measure of systemic hyperalgesia [43]. Diffusion Tensor Imaging (DTI) Data was acquired on a Siemens 3T Tim Trio scanner equipped with transmit-receive body coil and commercial 12-element head coil array. Two DTI scans were acquired for each subject with parameters of TE = 101 ms, TR = 7900 ms, FOV = 240 mm, 55 slices, slice resolution = 2.5 mm, voxel size = 2.5×2.5×2.5 mm. For each scan, 5 non-diffusion weighted volumes (b = 0 s/mm2) and 30 diffusion-weighted volumes (b = 1000 s/mm2) were acquired. For each subject, the two DTI scans were concatenated to increase the signal-to-noise ratio. All MR images were screened for abnormal radiological/structural appearances by a trained technician. Preprocessing of the individual subject’s DTI data was performed with the TORTOISE (version 1.1.2) processing pipeline [44]. Default settings were used except where noted otherwise. Eddy current distortion and motion correction were applied [45]. Susceptibility-induced EPI distortion correction was performed using the first B0 image as a target for registration [46]. Rigid reorientation was applied to the subject’s diffusion weighted images, bringing them into a common final space as defined by the registered first B0 image. All corrections were performed in the native space of the diffusion weighted images, all transformations were applied in a single interpolation step, and the b-matrix was reoriented appropriately [47]. In preparation to calculate the FA image, the signal standard deviation was calculated with the automatic method option, and then the diffusion weighted images were masked with the masking tool. FA and eigenvalue images were calculated using the iRESTORE algorithm provided with TORTOISE, which is a non-linear least squares method of tensor estimation [48]. Subject specific maps for FA and MD were direct outputs from the TORTOISE program. The AD maps were the first eigenvalue images, while RD maps were calculated by taking the average of the second and third eigenvalue images. Tract-Based Spatial Statistics (TBSS), which is part of the FSL software package [49], [50] was used to transform the images into common Montreal Neurological Institute (MNI) space. All default settings were used. The subjects’ FA data were imported into TBSS, and then aligned into MNI space using the nonlinear registration tool FNIRT [50], [51], which uses a b-spline representation of the registration warp field [51]. This transformation was subsequently applied to the AD, RD, and MD images. The Johns Hopkins University white-matter tractography atlas was used to create masks to extract mean values for each tract [52]–[54]. Brain extraction was performed, using the brain extraction tool implemented in FSL [55]. Statistical Analysis SPSS for Windows version 20 (Armonk, New York) and Microsoft Excel 2007 (Redmond, Washington) were used for database and statistical analysis. Ordinal fatigue, McGill total score and dolorimetry were compared between the 31 CMI and 12 control subjects and reported as means with 95% confidence intervals. Significant differences between groups (P≤0.05) were identified by two-tailed unpaired Student’s t-tests or Fisher’s exact tests, with all P values corrected for multiple comparisons by Bonferroni corrections and false discovery rate [56]–[58]. Ordinal fatigue, McGill total score and dolorimetry were evaluated by receiver – operator curve (ROC) analysis as predictive measures. Clinical data from the eight control participants recruited under protocols #2010-050 and #2010-356 were not included in this analysis but will be reported separately. FA, MD, AD, and RD for each tract were correlated in univariate fashion with ordinal fatigue by one - tailed Spearman’s function, and for McGill total pain and average dolorimetry pressures using one - tailed Pearson’s function based upon previous studies [9], [13], [18]. The clinical variables with significant DTI correlates were then assessed by separate step-wise multivariate linear regression analyses that included age and gender to identify significantly associated tracts and clinical features across all subjects. Average white matter diffusivity parameters (FA, MD, AD and RD) were compared between all CMI and control participants (n = 51) and in 20 white matter tracts by two-tailed unpaired Student’s t-tests. ROC analysis of each tract identified the sensitivity, specificity, area under the curve (AUC), and asymptotic significance of each diffusivity parameter. The thresholds were used to define dichotomous variables for stepwise forward binary logistic regression to predict CMI status.

 Discussion All of the veterans recruited for this protocol met CMI and CFS criteria [2], [5]. To understand the pathophysiological principles behind these case designation criteria, we examined the underlying complaints that were most strongly reported by our subjects. Dolorimetry, fatigue, and pain ratings were highly correlated with each other and with elevated AD in cortico-cortical association and corticospinal tracts. These analyses identified four significant correlates of CMI status that were significantly different from controls: ordinal fatigue, McGill total pain scores, dolorimetry (kg) and AD of the right IFOF. The salutary observation was that CMI status was associated with increased axial diffusivity in the right IFOF with non-significant trends for increased FA and MD in the same tract (Table C in File S1) (Table D in File S1). Multi-variate and binary logistic regression analysis identified the right IFOF as the only tract to correlate with all three clinical parameters and may provide diagnostic utility in predicting CMI versus control status. The right IFOF connects multiple frontal, sublobar, temporal and occipital cortical regions that are involved in the perception of pain, fatigue and cognitive dysfunction that are symptom constructs in the case designation criteria for CMI [2] and CFS [5]. Anatomically, the tract originates from the vmPFC, inferior frontal gyrus, frontal pole and OFC [59]. As it leaves the prefrontal area it courses adjacent to the insula [60] and through the temporal lobe to terminate in the posterior fusiform, cuneus, and lateral cortices of the occipital lobe [59]. The OFC and vmPFC are intimately associated with the severity of fatigue [10], [16] and communicate with the nucleus accumbens via corticostriatal IFOF fibers [18]. During the onset of noxious stimuli these regions coordinate responses that provide a punishing teaching signal that leads to altered decision making based upon these painful cues [61]. Increased structural connectivity between the regions linked by the right IFOF is predictive of increased blood flow to the nucleus accumbens which represents amplified sensitivity to punishment during reward-related behavior [18]. Sensory and other processing through the anterior insula directly contributes to the vmPFC - nucleus accumbens interactions which are causally associated with the transition from subacute to chronic low back pain [19]. Because the right IFOF is a critical component of the structural circuitry that facilitates communication between these regions, increased AD in the right IFOF may play a central role in the adaptation and maintenance of chronic pain and fatigue in CMI. Attention and focus are other functions mediated via the right IFOF. This tract connects the right inferior frontal gyrus and right temporal parietal junction that form the ventral attention network (VAN) [62]. VAN maintains surveillance for unexpected environmental cues that may be salient. Maintaining focus on goal – directed behavior is the function of the dorsal attention network (DAN) [63]. Anatomically, DAN includes the frontal eye fields, supplementary motor cortex and dorsolateral prefrontal cortex. DAN generates top – down managerial control to complete specific tasks [63]. Activation of VAN creates an interruptive signal that decouples DAN activity so that attention must be reoriented towards the newly identified, task – relevant stimulus. Increased VAN activity has been linked to decreased activity in the DAN [64]. Nociceptive stimuli can involuntarily capture attention and interfere with on – going behavior [65], [66]. Building on this notion, elevated AD in the right IFOF in CMI may signify increased structural connectivity with a heightened propensity to activate VAN, interrupt DAN activity, and cause reorientation of attention to pain signals. Increased connectivity may explain the reported surveillance and hyperarousal behaviors of CMI subjects [1], [67]. The left CST and right SLF had higher diffusivity measures between CMI and control groups. Increased AD in the left CST, which sends collaterals into the spinal cord dorsal horn, may suggest potential dysfunction of descending anti-nociceptive pathways that may contribute to hyperalgesia [68]. MD was increased in the right SLF and correlated with greater fatigue and lower dolorimetry pain pressures. This tract connects the dorsolateral prefrontal cortex and DAN to inferior parietal working memory regions [69]. This is of relevance to CMI since increased MD in the SLF has been correlated with language impairment and cognitive deficits [70], [71]. Increased AD was correlated with fatigue and pain measures in several other tracts when all subjects were assessed. The right cingulum links the anterior and posterior cingulate gyrus and was associated with nociceptive processing in several chronic pain states [9], [12], [72]. Elevated AD was correlated with the McGill total score and lower dolorimetry pressures. The forceps minor connects regions in the left and right anterior prefrontal lobes that are implicated in pain and fatigue processing [10], [13], [16], [17], [19].The uncinate fasciculus links prefrontal and limbic regions involved in pain, emotion and affect [73]. The increase and discriminatory potential in AD suggests DTI analysis may have value as a research tool to identify longitudinal changes and to test the efficacy of novel therapies in clinical trials in CMI. This pilot study has several limitations. The magnitudes of the differences in AD between groups were not large, but were statistical significant after correction for multiple comparisons. Correlations of AD for various tracts with fatigue, pain and dolorimetry measures identified significant relationships within the entire study population. The control group was not entirely Gulf War veterans who shared the same exposures and experiences as the CMI subjects. However, our subjects (Table A in File S1) were representative of the 1995 Gulf War National Health Survey and other population based studies [1], [6], [74]. Prospective epidemiological studies using the variables identified here will be required to firmly resolve this issue. Correlations between the increased AD in right IFOF, fatigue, pain, and hyperalgesia may have been an artifact of selecting subjects with similar complaints who represented a distal end of a spectrum found in the general population. Our sample size was not large enough to adequately assess this possibility. However, the binary logistic regression analysis significantly distinguished CMI from control subjects. This suggests a bimodal rather than unimodal distribution. Tractography and analysis of gray matter volume loss in regions linked by the dysfunctional white matter tracts were not investigated, but may provide important information about the heterogeneity and extent of CMI dysfunction. Reduced midbrain white matter volume was correlated with duration of fatigue in CFS [75], but DTI was not performed. Tractography offers a complementary approach to TBSS. TBSS may underestimate DTI indices since it relies on the white matter skeleton with highest FA values [76]. Axonal atrophy may lead to an artifactual increase in AD since smaller axonal caliber may increase absolute neuron densities within pixels that are mathematically transformed into higher diffusivity measurements when mapped onto a standard white matter skeleton [77]. TBSS processing as used here may reduce this potential bias [76]. This and other explanations for elevated AD await histological verification from surgical or autopsy studies of GWI veterans. The cross - sectional design cannot address longitudinal changes or temporal reproducibility. Future longitudinal DTI studies will be needed to confirm if the defect of elevated AD correlates with fatigue, pain and hyperalgesia as it changes over time. Conclusion The right inferior fronto-occipital fasciculus links cortical regions involved in fatigue, pain, emotional and reward processing, and the right ventral attention network in cognition. Axial diffusivity of this region was significantly different between CMI and controls and the degree of difference was found to correlate to fatigue and pain symptoms. The axonal neuropathological mechanism(s) explaining the objectively measured increase in axial diffusivity may contribute to Gulf War Illness.

 Supporting Information File S1. Supporting information tables. Table A: Extended and detailed demographics information. Table B: Detailed recruitment strategies and retention during protocol. Table C: Average fractional anisotropy (FA) for 20 white matter tracts between groups. Table D: Average mean diffusivity (MD) for 20 white matter tracts between groups. Table E: Average axial diffusivity (AD) for 20 white matter tracts between groups. Table F: Average radial diffusivity (RD) for 20 white matter tracts between groups. doi:10.1371/journal.pone.0058493.s001 (DOCX) ||||| A destroyed Iraqi tank sits near oil well fires in northern Kuwait during the Gulf War in 1991. Gulf War illness has affected more than 250,000 veterans of the 1991 war against Iraq. (Photo: AP file photo by David Longstreath) Story Highlights Findings may eventually help those suffering from chronic fatigue or fibromyalgia

 Veterans studied say the illness has wrecked their lives

 More than 250,000 veterans of the 1991 war have reported some symptoms

 WASHINGTON — Researchers say they have found physical proof that Gulf War illness is caused by damage to the brain — and that proof may ultimately help civilians who suffer from chronic fatigue syndrome and fibromyalgia.

 Using fMRI machines, the Georgetown University researchers were able to see anomalies in the bundle of nerve fibers that interpret pain signals in the brain in 31 Gulf War veterans. The research will be published Wednesday in PLOS ONE journal.

 The findings are "huge," because an fMRI allows doctors to diagnose a person with Gulf War illness quickly, said James Baraniuk, senior author and professor of medicine at Georgetown University Medical Center. The research, he said, also shows that Gulf War illness is not psychological.

 An fMRI, or "functional" MRI, is a scan that measures activity by detecting how blood flows through the brain.

 Many veterans have had difficulties getting benefits and treatment for a service-connected condition because doctors assumed they were either faking it or suffering from post-traumatic stress. "That's a problem with all physicians — VA, military or civilian," Baraniuk said. "If it doesn't fall within their small world of known diseases, then the patient is nuts."

 Gulf War illness is a series of symptoms that has affected more than 250,000 veterans of the 1991 war against Iraq in response to Iraq's invasion of Kuwait.

 Baraniuk said the correlation of anomalies in the brain's white matter with Gulf War illness has not been studied before. Researchers, he said, also found that fatigue and pain worsen congruently in the veterans.

 To test the veterans, they watched the way liquid moved through brain nerve cells at rest and while the veterans were exercising. They could locate the nerves' axons and determine how healthy they were, said Rakib Rayhan, lead author of the study.

 "We're able to say, 'There is something here,' " Rayhan said. " 'Take these veterans seriously when they come in.' "

 In particular, John VanMeter, director of Georgetown's Center for functional and molecular imaging, said they looked at the fibers that process pain.

 "The fibers in the Gulf War veterans have deteriorated compared to the control," he said. Those fibers interpret environmental pain, but in the case of the veterans, a tiny pulse of pressure is interpreted as a painful pinch, or normal muscle fatigue from walking a flight of stairs could be interpreted as climbing to the fourteenth floor. "They get, 'I'm in pain! I'm in pain! I'm in pain!' all the time."

 He said that most hospitals already have the MRI equipment they need to do the exam, but they may need to purchase or install fMRI software, as well as to be trained to use it.

 The researchers do not know whether the veterans' symptoms will continue to worsen, though it appears they have from their onset 22 years ago until now.

 "The guys who were robust and leading the charge on this 10 years ago are now using canes," Baraniuk said.

 This research appears to correlate with previous research on Gulf War Illness, including a major study this year that showed problems in involuntary function, and a second that showed that as many as 100,000 troops may have been doused with Sarin gas when the U.S. Air Force bombed a munitions factory during the war.

 The researchers suspect the damage came from environmental factors. Other researchers have found that as many as 100,000 troops were exposed to Sarin gas when the U.S. Air Force bombed an Iraqi munitions plant, and other researchers have found a connection between the symptoms and the ACHL-inhibitors found in nerve agents, the anti-nerve-agent pills servicemembers took, and the industrial-strength bug spray troops used on their clothing and skin.

 Baraniuk believes that the three areas of symptoms seen in Gulf War veterans are all different stages of the same disease — and he will be able to show that in a future paper.

 Veterans who participated in the study said the illness has hurt them but they were optimistic about the survey's findings.

 Army veteran Robert Ward's symptoms began while he was still in the Middle East. He felt tired and his gums started to swell and bleed. He figured it was a fluke, until he read a newspaper article in 1993 and discovered he was one of many. Soon, he suffered irritable bowel syndrome, constant headaches, muscle twitches, rashes and muscle fatigue. For 18 months, he found himself bedridden. He moved in with his parents so they could help care for him.

 "This is a big deal," he said. "This has ruined my life. I'm thankful that Gulf War illness patients will be able to get the help that they deserve."

 Denise Nichols, an Air Force veteran, also had symptoms while she was still in the Middle East, including irritability, hair lossand sensitivity to light and noise. When she came home, she had blurred vision and tight muscles.

 "I quit nursing because I was afraid of making errors or exposing patients to whatever I had," she said. When she learned the results of the study, she yelled, "Yes! Yes! Yes! We're finding real proof."

 Still, she said, it's bittersweet to wait 22 years.

 The researchers themselves said they've been surprised by how little attention this group of veterans has received.

 "If 30% of Congress got sick, or 30% of Manhattan got sick, there would have been an outcry," Baraniuk said.

 Read or Share this story: http://usat.ly/ZdGhZr

Summary: – Scientists now know that Gulf War Syndrome is more than just a psychological condition—it's actually tied to brain damage. But for the first time, they have zeroed in on physical proof that this is the case. The Georgetown researchers used fMRI machines on 31 Gulf War vets and were able to spot abnormalities in the bundles of nerve fibers that process pain. They "have deteriorated compared to the control," says a researcher, and USA Today explains the impact thusly: "a tiny pulse of pressure is interpreted as a painful pinch, or normal muscle fatigue from walking a flight of stairs could be interpreted as climbing to the fourteenth floor." The discovery is "huge," says another researcher, because it will allow veterans to be quickly diagnosed via the fMRI scan. Most hospitals are equipped with the necessary MRI machines, and would just need to install the proper software and train their technicians on its use. "We're able to say, 'There is something here,'" says the study's lead author. "'Take these veterans seriously when they come in.'" You can check out PLoS ONE to see the original paper.


What you need to know about the BOOK of ENOCH and the AGE of the FALLEN

 - Duration: 13:06.

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 2,731,708 views ||||| Sen. Ted Cruz, speaking as the results of the Nevada caucuses were being tallied, argued Tuesday evening that he was the only Republican left in the race who could beat Donald Trump.

 “They’re still counting the ballots so we don’t know the exact results, but I want to congratulate Donald Trump on a strong evening tonight and I want to congratulate the grass roots – the conservatives across this country who have come together behind this campaign,” Cruz told supporters at a YMCA in Las Vegas.

 Cruz, who was battling with Sen. Marco Rubio for a second-place finish, argued that he had history on his side since he won the Iowa caucuses, the first of the GOP presidential nominating contests.

 “When we started this campaign nearly a year ago, there were 17 candidates in the race. The role of the first four primaries historically has been to narrow the field and we have seen the first four states do exactly that – narrow the field,” Cruz said. “Now at this point we’ve had four primaries, history teaches us no one has ever won the nomination without winning one of the first three primaries. And there are only two people who have won one of the first three primaries – Donald Trump and us.”

 “The first four states has shown the only campaign that has beaten Donald Trump and the only campaign that can beat Donald Trump is this campaign,” he said, urging conservatives and those who want to beat Hillary Clinton to consolidate behind him.

 He never mentioned Rubio by name, but he slashed at him as a Washington insider and over his positions on issues such as immigration. And he set sky-high expectations for Super Tuesday, one week from today, when 11 states including his home state of Texas will go to the polls.

 “One week from today will be the most important night of this campaign,” Cruz said at the rally, his last event before flying to Houston to start a day of campaigning there Wednesday.

Summary: – How big a hit is Beyoncé's Formation? So big it got it's own question during Tuesday's Democratic town hall in South Carolina. "Let's talk about Beyoncé for a second, because why not?" Chris Cuomo introduced a question for Hillary Clinton about policing in the US. Some law enforcement groups see the video for Formation as overly critical of police and led them to call for a boycott of the pop star, the Los Angeles Times reports. Clinton responded that it's important to "respect the police" while recognizing those officers "who are doing the right things and protecting us." But she also acknowledged the difficulty many officers having interacting with minority communities. "Let’s hold police behavior accountable, so there’s an incentive for people to change how they’re doing police practices," she said. (Formation also sent sales skyrocketing at one seafood chain.)


The royal couple will travel more than 14,000 miles (22,530km) in 11 days during next month’s tour of Canada and America, in what will be the new bride’s first visit to both countries.

 St James’s Palace on Monday released a brief itinerary of the couple’s trip, which will take in nine cities throughout the region from June 30 to July 10.

 A royal source said the couple were “very much looking forward to their first joint royal tour”.

 It is understood that the Canadian government will foot the two million dollar bill for that part of the tour as the Commonwealth country is one of the Queen's realms – meaning she is not a foreign monarch but the country's sovereign and head of state.

 This means that Prince William , 28, and the former Kate Middleton , 29, are members of the Canadian royal family and the country's authorities are taking the lead in organising the trip.

 The newly married pair, who are said to be “eagerly anticipating” their summer tour, will be flown by the Royal Canadian Air Force during their nine days in Canada before they are flown to Los Angeles for their three day tour.

 Covering more than 5100 miles across the continent’s vast open spaces, the pair will visit destinations including Charlottetown on the shores of Prince Edward Island in the east, to the remote settlement of Yellowknife in the Northwest Territories, in the far north.

 They will also visit Canada's capital, Ottawa and the surrounding region, Montreal and Quebec City in the francophone province of Quebec and the oil boom town of Calgary, Alberta.

 Officials confirmed that security will be beefed up for their visit In Quebec amid fears nationalists will protest the royals' stop in the mostly French-speaking province.

 One of the tour’s highlights will be the royal couple's appearance at Canada Day celebrations in the Ottawa on July 1.

 The visit to Alberta, during their final leg, also coincides with the opening of the city's world-famous rodeo event, the Calgary Stampede – an annual rodeo, exhibition and festival dubbed the "Greatest Outdoor Show on Earth".

 The pair will then take in a glimpse of Hollywood, when they travel to Los Angeles and the surrounding area on a three-day official visit supporting Britain's interests in America.

 That leg of the tour will also involve promoting charities the Prince is patron of, including Tusk Trust, and will almost certainly include a function on behalf of Bafta, of which the Duke is President.

 While the Duchess has never touched down on American soil, it will also be the first time her husband has visited the country in an official capacity.

 The pair, who married last month at Westminster Abbey, will then take a “scheduled” flight home from Los Angeles.

 Asked whether a Bafta event would mean the couple meeting Hollywood A-listers, a St James's Palace spokesman said: "They may well bump into one or two stars at some point.

 “But there are different types of functions you could organise to promote Bafta, such as a reception for up and coming talent, so it would be wrong to assume they will be in a room full of celebrities.

 "The visit to California is very much about promoting charities."

 The visit had originally been planned as a solo trip for the duke but after last November's engagement announcement the duchess was added to the arrangements.

 The Canadian Government has themed the tour "'Moving Forward Together' from past accomplishments to current service and future achievements”.

 James Moore, Canada’s Heritage Minister, confirmed the entire visit will cost Canadian taxpayers just under two million dollars.

 Stephen Harper, the Prime Minister, added: "Canadians hold the Duke and Duchess of Cambridge in very high esteem and look forward to welcoming them as they embark on their first official royal tour as newly-weds.

 "The couple's decision to visit Canada first is a testament to our country’s close relationship with the Crown and Royal family, and an opportunity for all Canadians to take pride in our traditions, history, and institutions.

 "I am confident that, in coming to know this country and its people better, the Duke and Duchess will develop their own enduring bonds of affection for Canada and Canadians as has been the case with Her Majesty The Queen over sixty years, which began with her own very first tour as Princess Elizabeth at the age of 25 in 1951."

 The royal family have been regular visitors to Canada during the Queen's reign, with the Queen travelling there more than 20 times.

 The Duke last visited Vancouver aged 15 in 1998 with his father, the Prince of Wales and brother Prince Harry.

 The trip will be the duchess's first overseas tour as a member of the royal family.

 But she has a family connection to the Commonwealth country as her grandfather Peter Middleton, who died last year aged 90, served as an RAF flight instructor during the Second World War training Canadian pilots in Calgary from 1942 to 1944.

 It is thought the duchess may pay tribute to her grandfather while in Canada.

 According to reports, the duchess is a fan of Lucy Maud Montgomery's book Anne of Green Gables, which is set in Prince Edward Island, and so she may visit those sites while William, a search and rescue pilot, takes a Coast Guard helicopter out.

 Further details are expected to be released later. ||||| Duke and Duchess of Hazard: Wills and Kate to visit largest rodeo during north American tour

 By Rebecca English

 Last updated at 3:08 PM on 31st May 2011

 The new Duke and Duchess of Cambridge are to visit the world’s largest – and richest – rodeo during their first foreign tour together.

 The couple plan to visit the legendary Calgary Stampede when they fly to Canada next month.

 Billed as the greatest outdoor show on earth, it offers $2 million in prize money to competing cowboys and attracts some of the top names in the field.

 Daring: Cowboy Jake Vold rides in the Novice Saddle Bronc riding event at the Calgary Stampede

 Cropper: Cowboy Gavin DeRose is bucked off the back of a horse in the Novice Bareback Bucking event in 2008

 They are also likely to view the controversial sport of ‘chuckwagon’ racing, which involves a team of horses pulling a large wagon, the kind used to carry food and cooking equipment on the prairies of the United States and Canada, supported by a group of four outriders.

 The outriders have to throw two tent poles and a barrel, representing a camp stove, into the back of their wagon before mounting their horses and following the wagons as they circle a race track.

 The rodeo sport, which is particularly popular on the Canadian prairies, is controversial as horses and drivers are sometimes killed or injured, prompting animal welfare groups to call for the sport to be banned.

 Three horses died following chuckwagon races at the 2009 Calgary Stampede and a spectacular wagon crash during the event in 2007, in which three horses were killed and a driver hospitalized, led officials in Calgary to review the safety of the sport.

 Chuckwagon: Dirt and mud fly as a chuckwagon driver and outriders try to catch the other three wagons at a previous Calgary Stampede

 The couple will be in Calgary, Alberta, from July 7 to 8, the last stop on their nine-day whirlwind tour through Canada which takes in eight major cities: Ottawa (June 30-July2), Montreal (July 2), Quebec (July 3), Charlottetown and Summerside on Prince Edward Island (July 3 and 4) and Yellowknife in the Northwest Territories (July 4-6).

 During their visit, which is being paid for by the Canadian government, the newly-weds will make an emotional visit to the Canadian airfield where Kate’s late grandfather, Peter Middleton, was based as an RAF pilot during the Second World War.

 Kate was very close to Mr Middleton, who died at the age of 90 last year, and even delayed the announcement of her engagement so that she could attend his funeral.

 Flying Officer Middleton was posted to the No37 Service Flying School in Calgary in 1942 (now home to Calgary International Airport) when he was a volunteer reservist aged just 22. He spent two-and-a-half years as an instructor there training Spitfire, Hurricane and Lancaster pilots.

 We're going to America: The young Royal couple meet U.S. President Barack Obama, left, and first lady Michelle Obama, right

 They will also make a trip to the country’s smallest province, Prince Edward Island, which features in Kate’s favourite childhood book, Anne of Green Gables.

 A royal source explained that the trip had been organised to allow William – who visited the country in 1991 and 1998 - to ‘get to know Canada better’.

 ‘The duchess’s late grandfather was stationed near Calgary as a trainee bomber pilot and therefore the country is very much part of her own family’s story too even though this will be her first visit to the country,’ they said.

 ‘The trip is designed to show them the diversity and vibrancy of Canada and its people, visiting provinces and territories that aren’t so often visited by the Royal Family. There will be both traditional and formal elements and more informal elements appropriate to their age and interests.’

 After Canada, the couple fly to LA for three days at the request of the Foreign and Commonwealth Office.

 The Hollywood leg of their trip has created huge excitement in Tinsel Town where stars are said to be falling over themselves to meet the Cambridges.

 And this is how father did it: Prince Charles, in a white stetson and western outfit complete with polo (strings) tie, rides in the Calgary Stampede parade in 1977

 But a royal aide warned that they wanted to concentrate on issues such as armed forces, veterans, vulnerable people, the arts and William and Harry’s own charitable foundation.

 ‘Unfortunately it is unlikely to feature many celebrities and there will be no down time. The trip isn’t about that. It was very much generated by the FCO and has an official itinerary,’ he said.

 The cost of flying William and Kate to Canada on an airforce jet will be shouldered by the country’s government and the couple will take scheduled flights back from LA.

 ‘They are keen to keep their costs down and will keep their entourage to a minimum. They haven’t made any decisions yet on who will travel with them and whether this will include hairdressers or anything like that,’ said a source.

 A spokesman for the Canadian Department of Heritage said: ‘The 2011 Royal Tour of Canada by the Duke and Duchess of Cambridge will give the royal couple the opportunity to visit every region of the country – east, centre, west and north – on their first official tour as a married couple.

 'It will enable them to meet as many Canadians as possible and, in the process, come to know Canada even better.

 ‘It is hoped that, upon their departure, they will come to regard Canada as their second home – a term of endearment often used by the Queen to describe her special bond of affection for and pride in this country.’

Summary: – Royal newlyweds William and Kate will be touching down in Los Angeles for a few days in early July as part of their first official overseas trip. The California destination was revealed in the just released itinerary of earlier announced trip to North America that will also include an eight-city tour of Canada, reports the Telegraph. The trip will be Kate's first visit to either country and William's first visit to the US in an official capacity. The Canadian tour will include a stop in Ottawa on July 1, and a visit to Calgary on the opening day of the Calgary Stampede rodeo festival. The couple also plan to visit the airfield where Kate's grandfather served as a trainee pilot during World War II, the Daily Mail reports. Royal sources say the Los Angeles visit will be more about promoting charities, including the British Academy of Film and Television Arts, than hobnobbing with Hollywood A-listers. "The couple view this as a working visit, not as an opportunity for them to meet celebrities," a palace source tells People.


Tweet with a location

 You can add location information to your Tweets, such as your city or precise location, from the web and via third-party applications. You always have the option to delete your Tweet location history. Learn more ||||| MarShawn M. McCarrel II, a young Ohio activist involved with the Black Lives Matter movement committed suicide on the steps of the Statehouse in Columbus. (WBNS-10TV http://www.10tv.com/)

 A prominent young activist killed himself on the steps of the Ohio statehouse Monday.

 MarShawn M. McCarrel II, a leading member of the state’s Black Lives Matter movement, shot himself outside the capitol’s entrance about 6 p.m. The 23-year-old was pronounced dead at the scene, State Highway Patrol spokesman Lt. Craig Cvetan told the Columbus Dispatch.

 “We don’t have any evidence to know the reason why he did it,” Cvetan said.

 There were signs on social media that McCarrel had been struggling lately. His Twitter feed oscillated between joy and despair, and on the morning of his death, he tweeted an emotional goodbye.

 “I love y’all,” he wrote. “All of you.”

 Moments later, the message turned darker.

 “If we don’t have to live through hell just to get to heaven,” he wrote.

 By the afternoon, his social media postings had darkened further.

 “My demons won today,” he wrote on his Facebook page. “I’m sorry.”

 Just days before his apparent suicide, McCarrel had attended the NAACP Image Awards with his mother. A picture posted to Instagram showed him dressed in a red suit jacket and matching bow tie.

 McCarrel helped coordinate Black Lives Matter protests in Ohio following the death of Michael Brown, the unarmed black teenager killed in 2014 by a police officer in Ferguson, Mo. He also founded a youth mentorship program and anti-homelessness efforts, according to the New York Daily News.

 On Wednesday, Black Lives Matter Cincinnati’s Facebook page was flooded with tributes to McCarrel.

 “An activist to his soul,” wrote fellow activist Shaun King. “Fought tirelessly in Ohio and beyond for the rights of oppressed people.

 “Brother – we’ll keep fighting,” King wrote. “You rest, now.” ||||| A Franklin Township man killed himself outside the front door of the Statehouse Downtown on Monday evening. Authorities were called just after 6 p.m. to a shooting, which occurred up the steps and at the entrance to the Statehouse, on the S. High Street side. MarShawn M. McCarrel II, 23, was pronounced dead at the scene, said Lt. Craig Cvetan of the State Highway Patrol.

 A Franklin Township man killed himself outside the front door of the Statehouse Downtown on Monday evening.

 Authorities were called just after 6 p.m. to a shooting, which occurred up the steps and at the entrance to the Statehouse, on the S. High Street side.

 MarShawn M. McCarrel II, 23, was pronounced dead at the scene, said Lt. Craig Cvetan of the State Highway Patrol.

 >>> Update:Family remembers activist who took own life outside Statehouse on Monday

 McCarrel II, 23, lived on Eastbrook Drive North in Franklin Township. He was not employed by the state, Cvetan said.

 "We don't have any evidence to know the reason why he did it," Cvetan said.

 Posted on his Facebook page shortly after 3 p.m., however, was "My demons won today. I'm sorry."

 No one witnessed McCarrel shoot himself. He was seen on the Statehouse grounds just moments before the gunshot, Cvetan said.

 S. High Street was shut down for a short time and then the sidewalk in front of the Statehouse, and the COTA bus stop, were closed for the investigation.

 If you or someone you know is considering suicide, call Franklin County Suicide Prevention Hotline at 614-221-5445; the Teen Suicide Prevention Hotline, 614-294-3300; or the Lifeline national organization for suicide prevention, 1-800-273-8255.

 jwoods@dispatch.com

 @Woodsnight ||||| ...

 belonging to two children. When two brothers see it, they stop to intervene and make sure the officer and the kids know their rights.

 I love this video. This officer is trying to take and keep backpacks

Summary: – A Black Lives Matter activist is dead after shooting himself outside the entrance of the Ohio Statehouse where he previously attended protests. Police say MarShawn McCarrel II was pronounced dead on the scene around 6pm Monday. "We don't have any evidence to know the reason why he did it," a State Highway Patrol rep tells the Columbus Dispatch. But the Washington Post notes McCarrel's social media posts "oscillated between joy and despair." "I love y'all," the 23-year-old tweeted Monday morning. At noon came his final tweet: "Let the record show that I pissed on the statehouse before I left." Then this Facebook post around 3pm: "My demons won today. I'm sorry." A former teacher describes McCarrel as the student he was proudest of in his 27 years on the job. "I saw him as a shining star in the future of civil rights." Indeed: McCarrel was named one of just 15 Radio One Hometown Champions, attended the NAACP's Image Awards on Friday, helped organize Black Lives Matter protests in Ohio after the shooting of Michael Brown, founded a youth mentorship program, and worked with the homeless. "He had so much to do," his mom tells the Dispatch. "He forgot to take time for himself." A fellow activist says "the statehouse was no accident. We've been working so hard, and yet the conditions for the people in our community ... are still so hard." McCarrel was "an activist to his soul," a friend adds on Facebook. He "fought tirelessly in Ohio and beyond for the rights of oppressed people … Brother—we'll keep fighting. You rest, now."


[Fort Cumberland, Md., 18 July 1755] To Mr Jno. Auge Washington Mount Vernon

 Dear Jack Brother

 As I have heard since my arrivl at this place,1 a circumstantial acct of my death and dying Speech, I take this early oppertunity of contradicting both the first , and of assuring you that I ⟨ illegible ⟩2 of the livg by the miraculous care of I have not, as yet, composed the latter. But by the all powerful dispensatns of Providence, that I have been protected me beyond all human expectation ; probability & expectation for I had 4 Bullets through my Coat, and two Horses shot under and yet me yet although death was levelling my companions on every side of me. escaped unhurt.

 We have been most scandalously beaten by a trifling body of men; but fatiegue, and the want of tim⟨e⟩, will prevent s me from ⟨erasure⟩ give ing you any of the ⟨erasure⟩ details un till I have the happiness of seeing you at home Mount Vernon ; which I now most ardently wish d for, since we are drove in thus far. A Weak, and Feeble State of Health, obliges me to halt here for 2 or 3 days, to recover a little strength, that I may thereby be enabled to proceed homewards with more ease; You may expect to see me there on Saturday or Sunday Se’night,3 which is as soon as I can well be down as I shall take my Bullskin Plantation’s in my way. Pray give my Compts to all my Fds. I am Dr Jack Yr most Affecte Brothr |||||

 This vintage portrait features George Washington, the first president of the United States. (iStock)

 Today is George Washington’s Birthday. It’s something of a political miracle that the man indispensable to the founding of his country came into the world just at the right time, in 1732, so that when he reached manhood, he was there when we needed him.

 More miraculous still is that he survived so long, until 1799.

 During the course of his 67 years on Earth, the father of our country survived smallpox, bouts of malaria, multiple infections and abscesses, tuberculosis, dysentery and in the first six months of his presidency, an extraordinarily painful boil “the size of two fists” accompanied by a fever.

 So worrisome was his health at that point that some feared a “dreadful calamity,” and as James Madison wrote, a “crisis” in the affairs of the new nation, which had given no thought to anyone else as president. The presidency, indeed, was designed with Washington in mind.

 “Were we to be deprived of his influence,” wrote Rep. William Smith at the time, “I much fear no other man could hold us together.”

 As a young man, Washington fought with the British army during the French and Indian War. While not wounded, he became so ill and so close to being shot that before he returned home to Virginia, rumors were already circulating of his death.

 “I have heard,” he wrote upon his return from battle in July, 1755, “a circumstantial account of my death and dying speech.

 “I take this early opportunity,” he wrote his brother, John Augustine Washington, “of contradicting the first, and of assuring you, that I have not, as yet, composed the latter.

 “But by the all powerful dispensations of Providence, I have been protected beyond all human probability or expectation; for I had four Bullets through my Coat, and two Horses shot under me; yet escaped unhurt.”

 He had also fallen victim to dysentery, which produced extreme diarrhea in a man with hemorrhoids. “At first the stoic young aide tried to conceal the malady,” writes Washington biographer Ron Chernow, “but he soon found it so debilitating that he had to travel lying down in a covered wagon.”

 It was not dignified. But he survived.

 He had an iron constitution, which can only be fully fathomed by considering the state of medicine at the time.

 “There was no well-defined concept of infection or immunity,” Anthony Fauci and David M. Morens wrote in a 2012 article in the New England Journal of Medicine, “no vaccines, almost no specific or effective treatments for infectious diseases and little idea that any treatment or public health measure could reliably control epidemic diseases … During Washington’s lifetime, infectious diseases were the defining challenges of human existence.”

 Perhaps the most defining challenge to Washington’s health was his first known confrontation with infectious disease, when he contracted smallpox at the age of 19 while visiting Barbados. And as debilitating as it was, the immunity it conferred upon him would prove vital at another pivotal moment in American history nearly three decades later, a “powerful dispensation” for him and for the nation.

 It was the spring of 1749 when George’s older half brother, Lawrence, contracted tuberculosis, a disease for which there was then no certain cure. In search of relief, he first traveled to England. Finding no reprieve in the treatments of English doctors, he returned to Virginia, where he only deteriorated further. He then decided to try Barbados, in hopes that the warmth there would help.

 “Because Lawrence’s wife had just given birth to a daughter,” writes Chernow, it “fell upon George, nineteen, to accompany his thirty-three-year-old-brother, acting as both nursemaid and companion” on the 37-day voyage and while Lawrence got treatment.

 Shortly after they arrived, the brothers received an invitation to visit Gedney Clarke, an uncle of Lawrence’s wife. Washington was reluctant to accept, because Clarke’s wife was confined with smallpox. Smallpox was “extraordinarily virulent; individuals exposed to the virus, which passes by contact, were almost certain to be infected,” wrote historian Jack Warren, unless through some previous exposure they developed an immunity to the disease.

 As Virginia had not been touched by smallpox during Washington’s lifetime, he caught it. It’s not established that Mary Clarke, Gedney Clarke’s wife, was the source of Washington’s smallpox. But as Washington wrote in his diary on Nov. 16, 1751 he “was strongly attacked” with the lethal disease. Washington was housebound for 25 days with the painful pustules and fever and managed to survive.

 Lawrence returned to Virginia and died of tuberculosis at his home in Mount Vernon in 1752.

 Washington would soon become a soldier and “where soldiers go, plagues follow,” says the old axiom.

 The American Revolution brought with it soldiers from England and Germany carrying smallpox, facing American forces largely unexposed to the disease, and therefore greatly vulnerable. By the fall of 1775, Boston, then under British occupation, “suffered from a widespread smallpox epidemic that threatened to spread throughout the ranks of Washington’s army,” according to the Mount Vernon digital research library.

 The disease “spread like wildfire through the weakened soldiers and crowded army camps, leaving death and devastation in its wake,” writes Jeanne E. Abrams in “Revolutionary Medicine: The Founding Fathers and Mothers in Sickness and Health.”

 “We should have more to dread” from the disease “than from the Sword of the Enemy,” Washington wrote.

 Because Washington had already had smallpox, he was safe.

 Despite the risks of spreading the disease by undertaking to inoculate the soldiers in the army he commanded, in 1777 he took the momentous decision to undertake the first mass military inoculation in history. By the end of that year, with some 40,000 troops inoculated, infection rates fell from 17 percent to 1 percent.

 “It averted another health crisis within the Continental Army and dramatically altered the outcome of the Revolutionary War,” as Benjamin A. Drew wrote in JAMA Dermatology in July, 2015.

 Washington, of course, lived on to become the nation’s first president, albeit one still plagued by the other diseases of his era and ultimately by the state of what was then modern medicine. White McKenzie Wallenborn, a physician, described his last days in an article supplementing the Washington papers at the University of Virginia:

 On December 12th, 1799, George Washington in his 68th year of life, rode out around his farms on horseback from ten a.m. until about three p.m. The weather that day according to General Washington was snowing in the morning and about three inches deep. Wind at NE and mercury at 30 (30 degrees Fahrenheit). Continued snowing until about one o’clock, and at about four o’clock it became perfectly clear. Wind at same place-not hard. Mercury 28 (28 degrees Fahrenheit) at night. Colonel Tobias Lear, George Washington’s secretary, stated that the weather that day was bad, rain, hail, and snow falling alternately with a cold wind. When George Washington returned from his ride, the General’s neck appeared wet, snow was hanging from his hair, and he came to dinner without changing his dress (clothes wet?). The next day, Friday December 13th, 1799, the General did not go out as usual for he had taken cold and complained of a severe sore throat. He did go out in the afternoon to mark some trees which had to be cut down. He now had hoarseness which increased in the evening. He spent the evening reading the papers, and when he met anything interesting, he read it as loud as his hoarseness would permit. On the next day, Saturday the 14th, at three o’clock in the morning, he told Mrs. Washington that he was very unwell and that he had an “ague” (paroxysmal chills). It was observed that he could hardly speak and that he breathed with difficulty. At daybreak on the 14th, Colonel Tobias Lear came in and found the General breathing with difficulty and hardly able to utter a word intelligently. A mixture of molasses, vinegar, and butter was given but he (GW) could not swallow a drop and when attempted, he appeared to be distressed, convulsive, and almost suffocated. Later he tried to use a gargle of vinegar and sage tea but in attempting to gargle, he almost suffocated and when the gargle came back from the throat some phlegm followed. At eleven a.m., his swallowing had not improved. After the last bleeding it was noted that the blood came “slow and thick” but there was no fainting (his physicians had ordered that he be bled a number of times in the course of his illness and an incredible amount about eighty two ounces or about five pints or units of blood were removed from him).

 Doctors now believe Washington had acute epiglottitis, a life-threatening condition, caused by injury or infection, that causes the epligottis to swell, blocking the airways to the lungs. It was, and is still today, potentially life-threatening.

 Today, Wallenborn writes, doctors would perform a tracheostomy, creating a surgical airway to allow air to flow to the patient’s lungs. While one of Washington’s three doctors suggested such a procedure, it was new and controversial and “might not have worked anyway,” Wallenborn writes.

 His friend, Lear, described his last moments.

 “At his bedside,” Lear wrote, “I reached for his hand. ‘My breath cannot last long,'” Washington told him. “‘I believed from the first that the disorder would prove fatal,’ he said. He seemed so perfectly resigned — dignified even — despite his gasping breaths …’I am just going,’ he said. After uttering some instructions, he whispered finally, ‘Tis well.’ And then he expired.” ||||| Interactive Timeline The Perpetual Challenge of Infectious Diseases.

 Among the many challenges to health, infectious diseases stand out for their ability to have a profound impact on the human species. Great pandemics and local epidemics alike have influenced the course of wars, determined the fates of nations and empires, and affected the progress of civilization, making infections compelling actors in the drama of human history.1-11 For 200 years, the Journal has captured the backdrop to this human drama in thousands of articles about infectious diseases and about biomedical research and public health efforts to understand, treat, control, and prevent them.

 The Uniqueness of Infectious Diseases Infections have distinct characteristics that, when considered together, set them apart from other diseases (Table 1Table 1 Characteristics of Infectious Diseases That Set Them Apart from Other Human Diseases.). Paramount among these characteristics is their unpredictability and their potential for explosive global effect, as exemplified by the bubonic–pneumonic plague pandemic in the 14th century,1,12 the 1918 influenza pandemic,13,14 and the current pandemic of human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS),15 among others. Infectious diseases are usually acute and unambiguous in their nature. The onset of an infectious illness, unlike the onset of many other types of disease, in an otherwise healthy host can be abrupt and unmistakable. Moreover, in the absence of therapy, acute infectious diseases often pose an all-or-nothing situation, with the host either quickly dying or recovering spontaneously, and usually relatively promptly, often with lifelong immunity to the specific infecting pathogen. Not only are some infectious diseases transmissible to others, a unique characteristic among human diseases, but their transmission mechanisms are relatively few (including inoculation and airborne and waterborne transmission), well understood, and comparatively easy to study, both experimentally and in the field. In addition, such transmission is generally amenable to medical and public health interventions. Unlike many chronic and lifestyle-associated diseases resulting from multiple, interacting risk cofactors, most infectious diseases are caused by a single agent, the identification of which typically points the way not only to general disease-control measures (e.g., sanitation, chemical disinfection, hand washing, or vector control) but also to specific medical measures (e.g., vaccination or antimicrobial treatment). Given their nature, infectious diseases are potentially preventable with personal protection, general public health measures, or immunologic approaches such as vaccination. As preventive measures have become more effective and efficient, history has shown that certain infectious diseases, particularly those with a broad global health impact and for which there is no nonhuman host or major reservoir, can be eliminated. Such diseases include poliomyelitis, which has been eliminated in the Western Hemisphere,16 and smallpox, which has been eliminated globally.9 Another unique aspect is that the extraordinary adaptability of infectious pathogens (i.e., their replicative and mutational capacities) provides them with a temporary evolutionary advantage against pressures aimed at their destruction. These pressures include environmental factors and antimicrobial drugs, as well as the human immune response. At the same time, such adaptations provide us with opportunities to respond with new vaccine antigens, such as annually updated influenza vaccines,17 or new or different anti-infective agents. This back-and-forth struggle between human ingenuity and microbial adaptation reflects a perpetual challenge.12,18,19 Infectious diseases are closely dependent on the nature and complexity of human behavior, since they directly reflect who we are, what we do, and how we live and interact with other people, animals, and the environment.19-30 Infectious diseases are acquired specifically and directly as a result of our behaviors and lifestyles, from social gatherings, to travel and transportation, to sexual activity, to occupational exposures, to sports and recreational activities, to what we eat and drink, to our pets, to the environment — even to the way we care for the ill in hospitals and other health care environments. Moreover, microbial colonizing infections that lead to long-term carriage without disease (e.g., within the endogenous human microbiome) may influence the development of infections with exogenous microbes31,32 and also have an effect on general immunologic and physiologic homeostasis,33,34 including effects on nutritional status. Human microbiomes seem to reflect, and may even have helped to drive, human evolution.35 In this struggle, infectious diseases are intimately and uniquely related to us through our immune systems. The human immune system, including the primitive innate system and the specific adaptive system,36 has evolved over millions of years from both invertebrate and vertebrate organisms, developing sophisticated defense mechanisms to protect the host from microbes.37 In effect, the human immune system evolved as a response to the challenge of invading pathogens. Thus, it is not by accident that the fields of microbiology and immunology arose and developed in close association long before they came to be considered distinct disciplines.

 Disease Emergence and Reemergence Because infectious pathogens are evolutionarily dynamic, the list of diseases they cause is ever-changing and continually growing. Since newly emerging infectious agents do not arise spontaneously, they must recently have come from somewhere else, usually from animal infections, as occurred with HIV infection, influenza, and the severe acute respiratory syndrome. This interspecies transmission underscores the importance of interdigitating the study of human and animal diseases19,23,38-40 and recognizing the central role that microbial reservoirs, including those in animals, vectors, and the environment, play in human infectious diseases.19,38 Preexisting or established infectious diseases also may reemerge in different forms, as in extensively drug-resistant tuberculosis,41 or in different locations, as in West Nile virus infection in the United States,42 to cause new epidemics (Table 2Table 2 Broad Categories of Infectious Diseases.). Indeed, many human infectious diseases seem to have patterns of evolution, sometimes played out over thousands of years, in which they first emerge and cause epidemics or pandemics, become unstably adapted to human populations, undergo periodic resurgences, and eventually become endemic with the potential for future outbreaks (Figure 1Figure 1 Leading Causes of Global Deaths from Infectious Diseases.Of an estimated 58.8 million annual deaths worldwide, approximately 15.0 million (25.5%) are believed to be caused by infectious diseases. Cause-specific mortality estimates are provided by the World Health Organization.43,44 The data do not include deaths from secondary infectious causes, such as rheumatic fever and rheumatic heart disease, liver cancer and cirrhosis, or other chronic diseases. ).12,19,43,44

 Historical Perspectives and Current Status Just over a decade before the publication of the first issue of the Journal, President George Washington died of an acute infectious disease believed to have been bacterial epiglottitis.45 Washington's life reflects the history of his era and provides both a window into infectious diseases two centuries ago and a benchmark for measuring our remarkable progress since then. Washington was born in 1732, just before the deadliest diphtheria epidemic on the North American continent. He was scarred by smallpox, survived multiple debilitating bouts of malaria, suffered wound infections and abscesses, nursed his brother on a tropical island as he died of tuberculosis, and even had an influenza pandemic named after him (the Washington influenza of 1789–1790). During his presidency, he stayed in the then-capital city of Philadelphia while most of the government fled during the nation's deadliest yellow fever epidemic.5,12 At the time of Washington's birth, there was no well-defined concept of infection or immunity, no vaccines, almost no specific or effective treatments for infectious diseases,3,46 and little idea that any treatment or public health measure could reliably control epidemic diseases. During Washington's lifetime, infectious diseases were the defining challenges of human existence. No one alive then could have imagined the astonishing breakthroughs that lay ahead. In this regard, it is noteworthy that almost all the major advances in understanding and controlling infectious diseases have occurred in the past two centuries (Table 3Table 3 Selected Infectious Diseases of Importance from 1812 to the Present. and interactive timeline). Experimental animal-transmission studies that were conducted soon after the War of 1812 were followed by the development of better microscopes, which linked fungi to skin diseases and protozoa to mucosal diseases — for example, Alfred Donné's 1836 work with Trichomonas vaginalis and David Gruby's studies of Candida albicans in the early 1840s. The breakthroughs in the late 1800s, which taken together provided the compelling unifying principle of infectious diseases and must surely rank among the most important advances in the medical sciences, were the characterization of specific cultivatable microorganisms and proof of their association with specific diseases. This triumph was led by the work of Davaine and Koch in establishing anthrax as the first fully characterized infectious disease.47,48 This seminal process was facilitated by the development of defined criteria for establishing causality (Koch's postulates). Additional breakthroughs followed quickly, including the discovery and characterization of pathogen-specific immune responses; the demonstration that when inactivated by heat or chemicals or grown under limiting conditions that changed certain biologic properties (e.g., attenuation), organisms or their products could safely stimulate protective responses in a host; and development of anti-infective serums and chemicals to destroy pathogens. Over the next 135 years, a wide array of vaccines and antibiotics and, more recently, antiviral agents have saved hundreds of millions of lives, greatly extended the human life span, and reduced untold suffering. Undeniably, these countermeasures against infectious disease rank among the greatest achievements in public health and medicine. History reminds us that new challenges in infectious diseases will continue to emerge and reemerge. We must be prompt in identifying them and devising new countermeasures. In this effort, we still follow the familiar pathway that was set down in the late 1800s for the identification and characterization, both clinical and epidemiologic, of the causative agent; the characterization of the human immune response to the pathogen; and the development of pathogen-specific diagnostic tests, treatment strategies, and public health prevention strategies such as vaccinations.49

 Diagnosis and Characterization of Pathogens In the late 1800s, the realization that identifiable microbes caused specific diseases led to pathogen-specific medical diagnosis. Although the time-honored techniques of growing bacteria in broth or solid cultures and staining and examining them under microscopes are still important today, newer technologies have transformed the field of microbial diagnosis. Among the first emerging epidemic diseases to be identified by one such method was the hantavirus pulmonary syndrome, a centuries-old disease caused by an unknown phlebovirus (Sin Nombre) that was discovered unexpectedly in 199350 by the application of a then-novel molecular genetic technique, polymerase chain reaction (PCR). This followed quickly on the 1992 discovery of the previously unknown agent causing an infectious chronic condition, Whipple's disease.51 Less than a year later, PCR-related subtraction techniques solved a century-old mystery of the cause of Kaposi's sarcoma, human herpesvirus 8.52 Now, less than two decades later, sophisticated, high-throughput, rapid sequencing of the genomes of pathogens not only dramatically hastens initial identification but also detects individual genetic variants,53 facilitating identification of the genetic basis of drug resistance. Additional gene-based diagnostic tools include microchips and other technologies that detect short sequences of many different genes or their proteins, allowing simultaneous diagnosis or diagnostic elimination of multiple pathogens. New serologic techniques such as enzyme-linked immunosorbent assay can be many times more sensitive than traditional techniques in detecting and measuring antibodies to pathogens. Furthermore, monoclonal antibody techniques, which involve the use of cellular clones to produce antibodies against specific pathogen epitopes, have been adapted for the purposes of diagnosis, identification of the molecular structures of pathogens, elucidation of the natural history and pathogenesis of infectious diseases, development of conformationally accurate immunogens to be used as vaccine candidates,54 and even treatment.55 Many of these data-rich approaches require sophisticated bioinformatics systems (e.g., phylogenetic comparisons and genome construction analyses).

 Vaccine Development Vaccines against infectious diseases such as anthrax and rabies have been produced since the late 1870s. Only in the past half century, however, have technological advances in vaccination led to dramatic changes in the field of disease prevention. The World Health Organization now estimates that each year more than 120 different types of vaccines save 2.5 million lives and with optimal uptake could save an additional 2 million.56 Trivalent combined inactivated and live attenuated poliomyelitis vaccines were licensed in 1955 and 1962, respectively; a live attenuated trivalent vaccine against three unrelated diseases (measles, mumps, and rubella) was licensed in 1971; and a variety of vaccine approaches and platforms have been introduced since then. It is now possible to determine high-resolution crystallographic structures of pathogens and use this information to design vaccines directed at the most relevant epitopes in the microbe's complex structure, an approach known as structure-based vaccine design.57

 Treatment Successful treatment with pathogen-immune serum was another critical breakthrough of the late 19th century.55 This approach to therapy also encouraged scientists to develop chemicals to kill the specific pathogens that they were regularly identifying. Ehrlich succeeded first in 1910 with his magic bullet against syphilis (arsphenamine, or salvarsan58). Within two decades, a new generation of scientists was working on what would eventually be called antibiotics. As a result of these efforts, sulfa drugs were developed in 1936, and penicillin in 1943.59,60 In the United States, tuberculosis had been only partially controlled by public health measures and incompletely effective vaccines.61 It was not until the introduction of specific antituberculosis therapy in the 1950s62 that sanatoriums were emptied and cases of active disease were substantially reduced. Antibiotics have revolutionized the treatment of many other important bacterial infections and have saved many millions of lives since their introduction. When antiviral drugs were first developed in the 1960s, they did not seem to be particularly promising, with a few exceptions. In response to the HIV/AIDS pandemic, however, the development of antiretroviral drugs markedly expanded the arsenal of available antiviral agents and invigorated the research-and-development pathway for these important drugs. Effective combinations of powerful antiretroviral drugs have led to substantial prolongation of the lives of millions of persons with previously almost invariably fatal HIV infection, a true landmark in therapies for infectious diseases.15,63 All antibiotic and antiviral drugs, however, share an inherent weakness: the organisms against which they are directed almost invariably evolve mechanisms of resistance. Bacteria become resistant by a variety of mechanisms.64 The evolution of antimicrobial resistance is enhanced by overuse of antibiotics in animals and by inappropriate use in humans. Many viruses, particularly RNA viruses such as influenza virus, rapidly develop mutations even in a single brief replication cycle. A number of approaches have been pursued to meet the ever-present challenge of antimicrobial resistance. The development of new classes of antibiotic, antiviral, and antiparasitic agents aimed at diverse microbial targets, often with the use of high-throughput screening of compounds,65 is strengthening and broadening the therapeutic armamentarium. In addition, combination therapies (e.g., antiretroviral agents for HIV infection and multidrug approaches to tuberculosis) have proved to be successful in slowing the emergence of resistance.

 Public Health Achievements Breakthroughs in the field of infectious diseases have had far-reaching effects, including the realization of the critical importance of clean water and basic sanitation and hygiene for the prevention of a great number of infectious diseases. In addition, disease-specific approaches to prevention and treatment have led in many cases to the widespread control of diseases that historically have caused substantial morbidity and mortality.66 The treatment of infectious diseases is in itself a prevention measure, limiting or preventing transmission to others. Eradication, the ultimate goal in facing the threat of an established or emerging infectious disease, is no longer unrealistic. Specifically, in addition to the millions of lives saved by vaccines and antibiotics, certain infectious diseases have been eliminated from large regions of the world or even completely eradicated, an accomplishment rarely, if ever, seen in other medical disciplines. In 1980, smallpox became the first eradicated disease,9 making this among the most momentous achievements in human disease control. In May 2011, the veterinary morbillivirus disease rinderpest was declared eradicated, and its presumed descendant, human measles virus, is now being targeted for eradication.67 Poliomyelitis has been eliminated from several regions of the world, and it is hoped that within a reasonable period, it will be eradicated globally.68 Dracunculiasis (guinea worm disease) is also almost completely eradicated.69 These are just a few examples of what has been and can be accomplished by aggressive and concerted public health measures using the tools provided by basic and clinical research.

 New Vistas An unanticipated outcome of the explosion of information concerning the microbial world is the recognition that a growing number of chronic diseases that were once attributed to host, environmental, or lifestyle factors or to unknown causes are actually directly or indirectly caused by infectious agents that potentially can be controlled through prevention and treatment. For example, liver cancer and cirrhosis are complications of hepatitis B and C infections, cervical cancer is a complication of human papillomavirus (HPV) infection, and gastric and duodenal ulcers may result from Helicobacter pylori infection.70-72 Vaccines against two of these agents, hepatitis B and HPV, are already in use, exemplifying the concept of cancer-preventing vaccines. H. pylori infection can be cured with antibiotics, and chronic hepatitis B and C infections are being treated by means of antiviral regimens with growing success rates. Certain autoimmune conditions have also been attributed to infections. For example, enteric microbes have been associated with inflammatory arthritides, and Campylobacter jejuni and certain viruses have been associated with the Guillain–Barré syndrome.73 In addition, with new technologies and approaches, scientists are exploring new facets of microbiology, including the role of the human microbiome in maintaining homeostasis in the ecosystems of our bodies and its possible relationship to conditions such as obesity and inflammatory bowel disease.74

 The Perpetual Challenge We are living in a remarkable era. Almost all the major advances in understanding and controlling infectious diseases have occurred during the past two centuries, and momentous successes continue to accrue. These breakthroughs in the prevention, treatment, control, elimination, and potential eradication of infectious diseases are among the most important advances in the history of medicine. Nevertheless, because of the evolutionary capacity of infectious pathogens to adapt to new ecologic niches created by human endeavor, as well as to pressures directed at their elimination, we will always confront new or reemerging infectious threats. Our successes in meeting these threats have come not just from isolated scientific triumphs but also from broad approaches that complement the battle against infectious diseases on many different fronts, including constant surveillance of the microbial landscape, clinical and public health efforts, and efficient translation of new discoveries into disease-control applications. These efforts are driven by the necessity of expecting the unexpected and being prepared to respond when the unexpected occurs. It is a battle that has been well fought for more than two centuries but that will almost certainly still be raging, in now-unimagined forms, two centuries from now. The challenges are truly perpetual. Our response to these challenges must be perpetual as well.

 Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. ||||| By White McKenzie Wallenborn, M.D.

 On December 12th, 1799, George Washington in his 68th year of life, rode out around his farms on horseback from ten a.m. until about three p.m. The weather that day according to General Washington was snowing in the morning and about three inches deep. Wind at NE and mercury at 30 (30 degrees Fahrenheit). Continued snowing until about one o’clock, and at about four o’clock it became perfectly clear. Wind at same place-not hard. Mercury 28 (28 degrees Fahrenheit) at night. Colonel Tobias Lear, George Washington’s secretary, stated that the weather that day was bad, rain, hail, and snow falling alternately with a cold wind. When George Washington returned from his ride, the General’s neck appeared wet, snow was hanging from his hair, and he came to dinner without changing his dress (clothes wet?).

 The next day, Friday December 13th, 1799, the General did not go out as usual for he had taken cold and complained of a severe sore throat. He did go out in the afternoon to mark some trees which had to be cut down. He now had hoarseness which increased in the evening. He spent the evening reading the papers, and when he met anything interesting, he read it as loud as his hoarseness would permit.

 On the next day, Saturday the 14th, at three o’clock in the morning, he told Mrs. Washington that he was very unwell and that he had an “ague” (paroxysmal chills). It was observed that he could hardly speak and that he breathed with difficulty. At daybreak on the 14th, Colonel Tobias Lear came in and found the General breathing with difficulty and hardly able to utter a word intelligently. A mixture of molasses, vinegar, and butter was given but he (GW) could not swallow a drop and when attempted, he appeared to be distressed, convulsive, and almost suffocated. Later he tried to use a gargle of vinegar and sage tea but in attempting to gargle, he almost suffocated and when the gargle came back from the throat some phlegm followed. At eleven a.m., his swallowing had not improved. After the last bleeding it was noted that the blood came “slow and thick” but there was no fainting (his physicians had ordered that he be bled a number of times in the course of his illness and an incredible amount about eighty two ounces or about five pints or units of blood were removed from him). At half past four o’clock, Washington gave directions about his will and at about five he again tried sitting up but remained so only half an hour. In the course of the afternoon, he appeared in great pain and distress from difficulty in breathing, and frequently changed his position in bed. At about eight o’clock it was noted that his condition remained unchanged and did so until about ten minutes before his decease (death) when breathing became easier. He died between ten and eleven p.m. December 14th, 1799.

 His primary symptoms in the order of their occurrence were – severe sore throat; hoarseness; cough, chills, difficulty with breathing; difficulty with swallowing; expectoration (spitting-? drooling); fever; loss of voice-, and suffocation.

 From the observations of Colonel Lear, Dr. James Craik, Dr. Elisha Cullen Dick, an Dr. Gustavus Richard Brown, and the clinical course of his illness, I think that it is very reasonable and possible to make a determination of the disease process that was the cause of George Washington’s death. He had acute epiglottitis (supraglottitis) which is a severe, rapidly progressing infection of the epiglottis and surrounding tissues that may be quickly fatal because of sudden respiratory (airway) obstruction by the inflamed structures. The epiglottis is located at the base of the tongue and is the most superior part of the larynx (voice box). It is at the very entrance to the airway which goes through the larynx to the trachea and lungs. Swelling of this structure is painful and tends to rapidly obstruct the airway and also the entrance to the hypopharynx (area just above the esophagus) and the esophagus (gullet). With acute epiglottitis, George Washington would have had great difficulty breathing, talking, and swallowing and these he certainly had.

 The onset of epiglottitis is usually acute and fulminating. Sore throat, hoarseness, dysphagia (difficulty swallowing) , and respiratory distress accompanied by drooling, shortness of breath, rapid pulse, and inspiratory stridor (harsh high pitched respiratory noise heard while the patient is inhaling [breathing in]) develop in rapid order. Death from this dysorder is caused by obstruction of the patient’s airway and is very painful and frightening.

 The other possible dysorders suggested by some as being the disease process that caused George Washington’s death were acute diphtheria (laryngeal diphtheria), quinsy, acute laryngitis, and Ludwig’s angina. However none of these diagnoses quite fit the description of Washington’s terminal illness but on the other hand acute epiglottitis does explain all of his symptoms and his demise. His illness is a classic “textbook” case of acute epiglottitis.

 Laryngeal diphtheria is an unlikely diagnosis for several reasons. General Washington was reported to have survived a case of “black canker” as a child. This would have been diphtheria and would have given him lifetime immunity against future attacks of diphtheria more than likely. There were no other reported cases of diphtheria in his household or farm population so the likelihood that he would have picked up a case of diphtheria was remote. Diphtheria in an adult is a very rare occurrence. Although this diagnosis is a possibility because it can produce laryngeal obstruction and respiratory distress, it just doesn’t fit the picture.

 Quinsy is the term used to describe a peritonsillar abscess. Quinsy produces a sore throat but it is almost always unilateral (on only one side of the throat) and produces symptoms referable to that side only e.g. soreness; swelling of the neck on that side; and another symptom: trismus (a lockjaw-like symptom where the patient cannot open their mouth). This diagnosis also does not fit the disease process from which General Washington died.

 Acute laryngitis in an adult is not usually a life threatening dysorder.

 Ludwig’s Angina is an infection in the floor of the mouth in front of or lateral to the tongue. It usually results from a dental or periodontal infection. George Washington had no teeth..ergo.. not a likely diagnosis.

 It would be improper for today’s medical practitioners to be critical of the physicians of George Washington’s day if they were delivering the standard of care that other physicians of that era were giving to their patients. It would appear that Dr. James Craik, Dr. Elisha Cullen Dick, and Dr. Gustavus Richard Brown were well trained as physicians, were honest and caring, and gave the kind of medical care that their peers would have given. Today we know that many of their methods were wrong and we would do things differently. If Drs. Craik and Brown would have encouraged Dr. Dick to perforate Washington’s trachea (tracheostomy), it might have allowed him to survive the acute illness and live on for sometime afterwards. However this procedure was new and controversial so they were not totally wrong to oppose it. Technically it might not have worked anyway … but who knows? Today we find the removal of about eighty two ounces of blood (about five pints or units of blood) from a sick patient in less than sixteen hours to be incredible. However this was the method of treatment being taught in those days. It was the treatment of choice for many diseases and the complications of using this method were not comprehended by the physicians of that day. I certainly have a great deal of compassion for George Washington’s physicians who were attempting to save his life by using the methods that they thought best for him. I am also filled with sadness that such a remarkable man and leader should have such a painful and frightening end to his life.

 White McKenzie Wallenborn, M.D.

 Clinical Professor (Ret.)

 Department of Otolaryngology-Head & Neck Surgery

 University of Virginia School of Medicine

 November 5, 1997

 References

 In the study of George Washington’s terminal illness, a number of textbooks of Otolaryngology were consulted. William Abbot and Dorothy Twohig, Editor in Chief of The Papers of George Washington at the University of Virginia, provided a number of valuable articles written about George Washington’s death and his overall medical history. By combining the textbook articles, the journal articles, and my own clinical experiences, I was able to reach the conclusions noted above. The journals used are listed below:

 Barker, Creighton. “A Case Report,” The Yale Journal of Biology and Medicine, 9 (1936), 185-87.

 Blanton, Wyndham B. “Washington’s Medical Knowledge and Its Sources,” Annals of Medical History, 4 (1932), 52-61.

 Brickell, John. “Observations on the Medical Treatment of General Washington in His Illness,” Transactions of the College of Physicians, 25 (1903), 90-93.

 Courtney, John F. “George Washington’s Final Illness,” Resident and Staff Physician, 15 (1969), 84-.

 Knox, J. H. Mason, Jr. “The Medical History of George Washington, His Physicians, Friends and Advisers,” Bullentin of the Institute of the History of Medicine, 1 (1933), 174-91.

 Lewis, Fielding 0. “Washington’s Last Illness,” Annals of Medical History, 4 (1932), 245-48.

 Nydegger, James A. “The Last Illness of George Washington,” Medical Record, 92 (1917), 1128.

 Wells, Walter A. “Last Illness and Death of Washington,” Virginia Medical Monthly, 53 (1926-27), 629-42.

 Willius, F. A., and Keys, T. E. “The Medical History of George Washington (1732-1799),” Proceedings of the Staff Meetings of the Mayo Clinic, 17 (1942), 92-96, 107-112, 116-121.

 © 1999 White McKenzie Wallenborn

Summary: – "I have been protected beyond all human probability or expectation," the National Archives quote George Washington in a letter to his brother following the French and Indian War. He wasn't kidding. In a piece written for Washington's birthday this week, the Washington Post reveals America's first president was nigh indestructible. In his lifetime, Washington bested smallpox, malaria, infections, abscesses, tuberculosis, dysentery, and a boil "the size of two fists." And that's not even mentioning the battles he survived. Washington claimed that during the French and Indian War, four bullets ripped through his coat and two horses were shot while he rode them. He apparently had so many close calls he was rumored to be dead. Yet somehow he managed to live to 67. Washington's resilience was all the more impressive as he was living at time with, as the New England Journal of Medicine puts it, "no well-defined concept of infection...no vaccines, almost no specific or effective treatments for infections diseases." As an illustration of this point, Washington finally died in 1799 when he came down with a sore throat and chills after riding around his property in the snow, according to the Washington Papers. Doctors tried everything to cure him—from molasses mixed with butter, to vinegar mixed with sage tea, to removing five pints of blood from the former president. None of it worked. A friend described Washington's "dignified" final words, which were—frankly—a long time coming: "I am just going...Tis well." (Thomas Jefferson's home is getting a renovation with slave Sally Hemings in mind.)