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Research, Papers, and Other Resources

The below clinical research, papers, reports, and correspondence use, rely on, or otherwise refer to contrast sensitivity testing.  Some may be provided with direct downloads, while others may link to outside sources.  The contrast sensitivity test, results, and results interpretation are based on this and other like information.

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Environmental Health Perspectives — April, 2001
Possible Estuary-Associated Syndrome: Symptoms, Vision, and Treatment
Author(s):  Ritchie C. Shoemaker, MD; H. Kenneth Hudnell, PhD
The human illness designated as possible estuarine-associated syndrome (PEAS) by the Centers for Disease Control and Prevention (CDC) has been associated with exposure to estuaries inhabited by toxin-forming dinoflagellates, including members of the fish-killing toxic Pfiesteria complex (TPC), Pfiesteria piscicida and Pfiesteria shumwayae. Humans may be exposed through direct contact with estuarine water or by inhalation of aerosolized or volatilized toxin(s). The five cases reported here demonstrate the full spectrum of symptoms experienced during acute and chronic stages of this suspected neurotoxin-mediated illness. The nonspecific symptoms most commonly reported are cough, secretory diarrhea, headache, fatigue, memory impairment, rash, difficulty in concentrating, light sensitivity, burning skin upon water contact, muscle ache, and abdominal pain. Less frequently encountered symptoms are upper airway obstruction, shortness of breath, confusion, red or tearing eyes, weakness, and vertigo. Some patients experience as few as four of these symptoms. The discovery that an indicator of visual pattern-detection ability, visual contrast sensitivity (VCS), is sharply reduced in affected individuals has provided an objective indicator that is useful in diagnosing and monitoring PEAS. VCS deficits are present in both acute and chronic PEAS, and VCS recovers during cholestyramine treatment coincident with symptom abatement. Although PEAS cannot yet be definitively associated with TPC exposure, resolution with cholestyramine treatment suggests a neurotoxin-mediated illness.
Download:   letter-peas-ehp-May2001.pdf (98.24kb)

Keywords:  cholestyramine; chronic neurotoxic illness; harmful algal bloom; Pfiesteria; possible estuary-associated syndrome; visual contrast sensitivity
Environmental Health Perspectives — September, 2001
Residential and Recreational Acquisition of Possible Estuary-Associated Syndrome: A New Approach to Successful Diagnosis and Treatment
Author(s):  Ritchie C. Shoemaker, MD
Evidence suggests that the estuarine dinoflagellates, Pfiesteria piscicida Steidinger & Burkholder and P. shumwayae Glasgow & Burkholder, members of the toxic Pfiesteria complex (TPC), may release one or more toxins that kill fish and adversely affect human health. In the current study we investigated the potential for undiagnosed cases of possible estuary-associated syndrome (PEAS), as termed by the Centers for Disease Control and Prevention (CDC), in a population that had residential and/or recreational exposure to TPC-affected estuaries, but that did not have direct contact with fish kills or lesioned fish. Age-adjusted visual contrast sensitivity (VCS) was significantly lower and the presence of PEAS-associated symptoms was much higher in the estuary cohort (n = 77) than in combined-control cohorts (n = 87), one without exposure to bodies of water (n = 53) and one with exposure to marine waters (n = 34). In the estuary cohort, 37 individuals met the CDC case definition for PEAS and had significantly lower VCS than non-PEAS cases. The VCS improved and symptoms abated after 2 weeks of treatment with cholestyramine. Cholestyramine, the original drug approved for treatment of hypercholesterolemia, has previously been reported to enhance the elimination rates of a variety of toxins, presumably by interruption of enterohepatic recirculation through toxin entrapment in its polymeric structure and/or anion-exchange process. Control studies showed that repeated VCS testing alone did not improve VCS scores and that cholestyramine treatment did not affect VCS in patients with elevated cholesterol levels. These results suggested that a) susceptible individuals may acquire PEAS through residential and/or recreational contact with TPC-affected estuaries in the absence of an active fish kill; b) VCS is a useful indicator in PEAS diagnosis and treatment monitoring; and c) PEAS can be effectively treated with cholestyramine. Because the study did not use population sampling techniques, the results do not indicate PEAS prevalence. Furthermore, definitive diagnosis of PEAS and association with TPC toxin(s) must await identification of, and a serologic test for, the putative TPC toxin(s).
Download:   peas-approach-dx-tx-Oct2001.pdf (563.31kb)

Keywords:  cholestyramine; chronic neurotoxic illness; harmful algal bloom; Pfiesteria; possible estuary-associated syndrome; visual contrast sensitivity
Environmental Health Perspectives — February, 2002
Correspondence: Visual Contrast Sensitivity as a Diagnostic Tool & Response
Author(s):  Marian Swinker; William A. Burke; H. Kenneth Hudnell, PhD; Ritchie C. Shoemaker, MD
In “Possible Estuary-Associated Syndrome: Symptoms, Vision, and Treatment,” Shoemaker and Hudnell (1) advocated use of the visual contrast sensitivity (VCS) test as a biomarker to diagnose possible estuaryassociated syndrome (PEAS) and to assess response to their proposed treatment regimen...

Keywords:  cholestyramine; chronic neurotoxic illness; Pfiesteria; possible estuary-associated syndrome; visual contrast sensitivity
Environmental Health Perspectives — June, 2002
Apartment Residents’ and Day Care Workers’ Exposures to Tetrachloroethylene and Deficits in Visual Contrast Sensitivity
Author(s):  Judith S. Schreiber; H. Kenneth Hudnell, PhD; Andrew M. Geller; Dennis E. House, MS; Kenneth M. Aldous; Michael S. Force; Karyn Langguth; Elizabeth J. Prohonic
Tetrachloroethylene (also called perchloroethylene, or perc), a volatile organic compound, has been the predominant solvent used by the dry-cleaning industry for many years. The U.S. Environmental Protection Agency (EPA) classified perc as a hazardous air pollutant because of its potential adverse impact on human health. Several occupational studies have indicated that chronic, airborne perc exposure adversely affects neurobehavioral functions in workers, particularly visual color discrimination and tasks dependent on rapid visual-information processing. A 1995 study by Altmann and colleagues extended these findings, indicating that environmental perc exposure at a mean level of 4,980 μg/m3 (median=1,360 μg/m3) alters neurobehavioral functions in residents living near dry-cleaning facilities. Although the U.S. EPA has not yet set a reference concentration guideline level for environmental exposure to airborne perc, the New York State Department of Health set an air quality guideline of 100 μg/m3. In the current residential study, we investigated the potential for perc exposure and neurologic effects, using a battery of visual-system function tests, among healthy members of six families living in two apartment buildings in New York City that contained dry-cleaning facilities on the ground floors. In addition, a day care investigation assessed the potential for perc exposure and effects among workers at a day care center located in the same one-story building as a dry-cleaning facility. Results from the residential study showed a mean exposure level of 778 μg/m3 perc in indoor air for a mean of 5.8 years, and that perc levels in breath, blood, and urine were 1–2 orders of magnitude in excess of background values. Group-mean visual contrast sensitivity (VCS), a measure of the ability to detect visual patterns, was significantly reduced in the 17 exposed study participants relative to unexposed matched-control participants. The groups did not differ in visual acuity, suggesting that the VCS deficit was of neurologic origin. Healthy workers in the day care investigation were chronically exposed to airborne perc at a mean of 2,150 μg/m3 for a mean of 4.0 years. Again, group-mean VCS, measured 6 weeks after exposure cessation, was significantly reduced in the nine exposed workers relative to matched controls, and the groups did not differ significantly in visual acuity. These results suggested that chronic, environmental exposure to airborne perc adversely affects neurobehavioral function in healthy individuals. Further research is needed to assess the susceptibility of the young and elderly to perc-induced effects, to determine whether persistent solvent-induced VCS deficits are a risk factor for the development of neurologic disease, and to identify the no observable adverse effect level for chronic, environmental, perc exposure in humans.

Keywords:  color discrimination; human exposure; perchloroethylene; tetrachlorethylene; vision; visual contrast sensitivity
Environmental Heath Perspectives — December, 2002
Correspondence: Neuropsychologic Testing versus Visual Contrast Sensitivity in Diagnosing PEAS & Response
Author(s):  Marian Swinker; H. Kenneth Hudnell, PhD; Ritchie C. Shoemaker, MD
I would like to comment on Hudnell and Shoemaker’s response (Hudnell and Shoemaker 2002) to our letter (Swinker and Burke 2002), both published in the March 2002 issue of EHP...

Keywords:  cholestyramine; chronic neurotoxic illness; Pfiesteria; possible estuary-associated syndrome; visual contrast sensitivity
Neurotoxicology and Teratology — June, 2004
A time-series study of sick building syndrome: chronic, biotoxin-associated illness from exposure to water-damaged buildings
Author(s):  Ritchie C. Shoemaker, MD; Dennis E. House, MS
The human health risk for chronic illnesses involving multiple body systems following inhalation exposure to the indoor environments of water-damaged buildings (WDBs) has remained poorly characterized and the subject of intense controversy.  The current study assessed the hypothesis that exposure to the indoor environments of WDBs with visible microbial colonization was associated with illness.  The study used a cross-sectional design with assessments at five time points, and the interventions of cholestyramine (CSM) therapy, exposure avoidance following therapy, and reexposure to the buildings after illness resolution.  The methodological approach included oral administration of questionnaires, medical examinations, laboratory analyses, pulmonary function testing, and measurements of visual function.  Of the 21 study volunteers, 19 completed assessment at each of the five time points.  Data at Time Point 1 indicated multiple symptoms involving at least four organ systems in all study participants, a restrictive respiratory condition in four participants, and abnormally low visual contrast sensitivity (VCS) in 18 participants.  Serum leptin levels were abnormally high and alpha melanocyte stimulating hormone (MSH) levels were abnormally low.  Assessments at Time Point 2, following 2 weeks of CSM therapy, indicated a highly significant improvement in health status.  Improvement was maintained at Time Point 3, which followed exposure avoidance without therapy.  Reexposure to the WDBs resulted in illness reacquisition in all participants in 1 to 7 days.  Following another round of CSM therapy, assessments at Time Point 5 indicated a highly significant improvement in health status.  The group-mean number of symptoms decreased from 14.9+/-0.8 S.E.M. at Time Point 1 to 1.2+/-0.3 S.E.M., and the VCS deficit of approximately 50% at Time Point 1 was fully resolved.  Leptin and MSH levels showed statistically significant improvement.  The results indicated that CSM was an effective therapeutic agent, that VCS was a sensitive and specific indicator of neurologic function, and that illness involved systemic and hypothalamic processes.  Although the results supported the general hypothesis that illness was associated with exposure to the WDBs, this conclusion was tempered by several study limitations.  Exposure to specific agents was not demonstrated, study participants were not randomly selected, and double-blinding procedures were not used.  Additional human and animal studies are needed to confirm this conclusion, investigate the role of complex mixtures of bacteria, fungi, mycotoxins, endotoxins, and antigens in illness causation, and characterize modes of action.  Such data will improve the assessment of human health risk from chronic exposure to WDBs.

Keywords:  alpha melanocyte stimulating hormone; cholestyramine; fungi; leptin; sick building syndrome; toxins; visual contrast sensitivity; water-damaged indoor environments
Neurotoxicology and Teratology — January, 2005
Chronic biotoxin-associated illness: Multiple-system symptoms, a vision deficit, and effective treatment
Author(s):  H. Kenneth Hudnell, PhD
Blooms of toxigenic organisms have increased in spatial and temporal extent due to human activities and natural forces that alter ecologic habitats and pollute the environment. In aquatic environments, harmful algal blooms pose a risk for human health, the viability of organisms, and the sustainability of ecosystems. The estuarine dinoflagellate, Pfiesteria piscicida, was discovered in the late 1980s at North Carolina State University as a contaminant in fish cultures. P. piscicida was associated with fish death in laboratory aquaria, and illness among laboratory workers who inhaled the mist above aquaria. Both the fish and humans exhibited signs of toxicity. During the 1990s, large-scale mortality among fish and other aquatic organisms was associated with high concentrations of Pfiesteria sp. in estuaries on the eastern seaboard of North America from New York to Texas. Illness among humans was associated with direct exposure to estuaries and exposures to estuarine aerosols around the time of Pfiesteria-related fish kills. This review of the scientific literature on associations between Pfiesteria and human illness identified some of the possible mechanisms of action by which putative Pfiesteria toxins may have caused morbidity. Particular attention was given to the Pfiesteria-associated, human-illness syndrome known as Possible Estuary Associated Syndrome (PEAS). PEAS was characterized by multiple-system symptoms, deficits in neuropsychological tests of cognitive function, and rapid and severe decrements in visual contrast sensitivity (VCS), an indicator of neurologic function in the visual system. PEAS was diagnosed in acute and chronic illness cases, and was reacquired during re-exposure. Rapid normalization of PEAS signs and symptoms was achieved through the use of cholestyramine therapy. Cholestyramine, a non-absorbable polymer, has been used by humans to lower cholesterol levels since it was approved for that use by the U.S. Food and Drug Administration in 1958. When dissolved in water or juice and taken orally, cholestyramine binds with cholesterol, bile acids, and salts in the intestines, causing them to be eliminated rather than reabsorbed with bile during enterohepatic recirculation. Cholestyramine also has been reported to bind and eliminate a variety of toxic substances. The efficacy of cholestyramine therapy in treatment of PEAS supported the hypothesis that PEAS is a biotoxin-associated illness.
Download:   chronic-biotoxin-illness-Jan2005.pdf (515.44kb)

Keywords:  biotoxins; Pfiesteria; possible estuary-associated syndrome; toxigenic microorganisms; visual contrast sensitivity
Bioaerosols, Fungi, Bacteria, Mycotoxins and Human Health — April, 2005
Sick Building Syndrome In Water Damaged Buildings: Generalization of the Chronic Biotoxin-associated Illness Paradigm To Indoor Toxigenic Fungi
Author(s):  Ritchie C. Shoemaker, MD; Judith M. Rash; Elliott W. Simon
There is no academic consensus on whether or not health effects relating to exposure to indoor bioaerosols, sometimes called Sick Building Syndrome (SBS), is a distinct clinical entity (Redd, 2002, Council on Scientific Affairs, 2002). Despite repeated reports of acute and chronic, multi-symptom illnesses acquired by patients following exposure to buildings with both water intrusion and indoor amplification of toxigenic microorganisms (Croft et al. 1986; Johanning et al. 1996; Hodgson et al. 1998; Johanning et al. 1999; Sudakin et al. 1998; Andersson et al. 1997; Dales et al. 1999; Dearborn et al. 1999; Montana et al. 1997; Fung et al. 2003: 18; Trout et al. 2001), including fungi and bacteria, methodological deficiencies in published studies have precluded drawing definitive conclusions on  causation. No studies have identified a robust, objective indicator of neurologic dysfunction to confirm reports of illness. The only medical interventions for SBS to date involved allergy and pulmonary medications or to suggest removal from exposure. The lack of any treatment that could correct the symptoms ascribed to exposure to bioaerosols from water damaged buildings (WDB) has further weakened the contention that SBS is a recognizable illness. Our initial report (43) and the current study addressed the methodological limitations present in the previous studies.
Download:   sbs-wdb-chronic-biotoxin-illness.pdf (183.00kb)

Keywords:  biotoxins; cholestyramine; human exposure; mold illness; sick building syndrome; visual contrast sensitivity
Advances in Therapy — December, 2005
Atovaquone Plus Cholestyramine in Patients Coinfected With Babesia microti and Borrelia burgdorferi Refractory to Other Treatment
Author(s):  Ritchie C. Shoemaker, MD; H. Kenneth Hudnell, PhD; Dennis E. House, MS; Amy van Kempen, MS; Gary E. Pakes, PharmD
Ten percent of US patients with Lyme disease are coinfected with Babesia microti.  A double-blind, placebo-controlled, crossover trial enrolled 25 patients with confirmed Borrelia burgdorferi/B microti coinfection, abnormal visual contrast sensitivity (VCS), and persistent symptoms despite prior treatment with atovaquone and azithromycin.  Patients were randomly assigned to atovaquone suspension or placebo plus cholestyramine for 3 weeks, were crossed over for 3 weeks, and then received open-label atovaquone and cholestyramine for 6 weeks.  Symptoms and VCS scores were recorded at baseline and after weeks 3, 6, 9, and 12. Improvements in symptoms and VCS deficits were observed only after at least 9 weeks of treatment.  At week 12, 5 patients were asymptomatic, and 16 had a notable reduction in the number of symptoms.  The entire cohort demonstrated significant increases in VCS scores.  Adverse effects were rare.  Patients coinfected with B burgdorferi and B microti derive measurable clinical benefit from prolonged treatment with atovaquone and cholestyramine.  Longer-term combination therapy may be indicated.
Download:   atovaquone-csm-lyme-Jan2006.pdf (259.03kb)

Keywords:  atovaquone; babesiosis; cholestyramine; Lyme disease; visual contrast sensitivity
Neurotoxicology and Teratology — July, 2006
Sick building syndrome (SBS) and exposure to water-damaged buildings: Time series study, clinical trial and mechanisms
Author(s):  Ritchie C. Shoemaker, MD; H. Kenneth Hudnell, PhD
Occupants of water-damaged buildings (WDBs) with evidence of microbial amplification often describe a syndrome involving multiple organ systems, commonly referred to as “sick building syndrome” (SBS), following chronic exposure to the indoor air. Studies have demonstrated that the indoor air of WDBs often contains a complex mixture of fungi, mycotoxins, bacteria, endotoxins, antigens, lipopolysaccharides, and biologically produced volatile compounds. A case-series study with medical assessments at five time points was conducted to characterize the syndrome after a double-blinded, placebo-controlled clinical trial conducted among a group of study participants investigated the efficacy of cholestyramine (CSM) therapy. The general hypothesis of the time series study was that chronic exposure to the indoor air of WDBs is associated with SBS. Consecutive clinical patients were screened for diagnosis of SBS using criteria of exposure potential, symptoms involving at least five organ systems, and the absence of confounding factors. Twenty-eight cases signed voluntary consent forms for participation in the time-series study and provided samples of microbial contaminants from water-damaged areas in the buildings they occupied. Twenty-six participants with a group-mean duration of illness of 11 months completed examinations at all five study time points. Thirteen of those participants also agreed to complete a double-blinded, placebo-controlled clinical trial. Data from Time Point 1 indicated a group-mean of 23 out of 37 symptoms evaluated; and visual contrast sensitivity (VCS), an indicator of neurological function, was abnormally low in all participants. Measurements of matrix metalloproteinase 9 (MMP9), leptin, alpha melanocyte stimulating hormone (MSH), vascular endothelial growth factor (VEGF), immunoglobulin E (IgE), and pulmonary function were abnormal in 22, 13, 25, 14, 1, and 7 participants, respectively. Following 2 weeks of CSM therapy to enhance toxin elimination rates, measurements at Time Point 2 indicated group-means of 4 symptoms with 65% improvement in VCS at mid-spatial frequency—both statistically significant improvements relative to Time Point 1. Moderate improvements were seen in MMP9, leptin, and VEGF serum levels. The improvements in health status were maintained at Time Point 3 following a 2-week period during which CSM therapy was suspended and the participants avoid re-exposure to the WDBs. Participants reoccupied the respective WDBs for 3 days without CSM therapy, and all participants reported relapse at Time Point 4. The group-mean number of symptoms increased from 4 at Time Point 2 to 15 and VCS at mid-spatial frequency declined by 42%, both statistically significant differences relative to Time Point 2. Statistically significant differences in the group-mean levels of MMP9 and leptin relative to Time Point 2 were also observed. CSM therapy was reinstated for 2 weeks prior to assessments at Time Point 5. Measurements at Time Point 5 indicated group-means of 3 symptoms and a 69% increase in VCS, both results statistically different from those at Time Points 1 and 4. Optically corrected Snellen Distance Equivalent visual acuity scores did not vary significantly over the course of the study. Group-mean levels of MMP9 and leptin showed statistically significant improvement at Time Point 5 relative to Time Points 1 and 4, and the proportion of participants with abnormal VEGF levels was significantly lower at Time Point 5 than at Time Point 1. The number of participants at Time Point 5 with abnormal levels of MMP9, leptin, VEGF, and pulmonary function were 10, 10, 9, and 7, respectively. The level of IgE was not re-measured because of the low incidence of abnormality at Time Point 1, and MSH was not re-measured because previously published data indicated a long time course for MSH improvement. The results from the time series study supported the general study hypothesis that exposure to the indoor air of WDBs is associated with SBS. High levels of MMP9 indicated that exposure to the complex mixture of substances in the indoor air of the WDBs triggered a pro-inflammatory cytokine response. A model describing modes of action along a pathway leading to biotoxin-associated illness is presented to organize current knowledge into testable hypotheses. The model links an inflammatory response with tissue hypoxia, as indicated by abnormal levels of VEGF, and disruption of the proopiomelanocortin pathway in the hypothalamus, as evidenced by abnormalities in leptin and MSH levels. Results from the clinical trial on CSM efficacy indicated highly significant improvement in group-mean number of symptoms and VCS scores relative to baseline in the 7 participants randomly assigned to receive 2 weeks of CSM therapy, but no improvement in the 6 participants assigned placebo therapy during that time interval. However, those 6 participants also showed a highly significant improvement in group-mean number of symptoms and VCS scores relative to baseline following a subsequent 2-week period of CSM therapy. Because the only known benefit of CSM therapy is to enhance the elimination rates of substances that accumulate in bile by preventing re-absorption during enterohepatic re-circulation, results from the clinical trial also supported the general study hypothesis that SBS is associated with exposure to WDBs because the only relevant function of CSM is to bind and remove toxigenic compounds. Only research that focuses on the signs, symptoms, and biochemical markers of patients with persistent illness following acute and/or chronic exposure to WDBs can further the development of the model describing modes of action in the biotoxin-associated pathway and guide the development of innovative and efficacious therapeutic interventions.
Download:   sbs-wdb-timeseries-Aug2006.pdf (318.14kb)

Keywords:  cholestyramine; fungi; mold; mycotoxins; sick building syndrome; visual contrast sensitivity; water-damaged buildings
Environmental Health Perspectives — February, 2007
Correspondence: Pfiesteria in Esturaine Waters: The Question of Health Risks
Author(s):  Ritchie C. Shoemaker, MD; Wayne Lawson
The conclusion of Morris et al. (2006) that “Exposure to Pfiesteria Species in Estuarine Waters Is Not a Risk Factor for Illness” is
unsupported because a) a description of Pfiesteria-related fish kills in the Chesapeake estuaries during 1999–2002 was omitted; b) quantitative data on Pfiesteria were not collected; c) data on visual contrast sensitivity (VCS) were collected but not reported; d) a comprehensive list of other results was not presented; and e) data were lost due to a 30% attrition rate. These data are needed to justify or negate the conclusion.
Download:   letter-pfiesteria-ehp-Mar2007.pdf (199.31kb)

Keywords:  biotoxins; Pfiesteria; visual contrast sensitivity
New York State Department of Health — February, 2010
Tetrachloroethylene (PERC) Exposure and Visual Contrast Sensitivity Test Performance in Adults and Children Residing in Buildings With or Without a Dry Cleaner
This report presents research findings obtained as part of the New York City (NYC) Perc Project (funded through U.S. EPA STAR Grant #R827446 to the New York State Department of Health (NYS DOH)). Households in residential buildings (with and without a co-located dry cleaner using tetrachloroethylene (perc)) in the NYC Borough of Manhattan with at least one adult and one school-age child, were enrolled in the NYC Perc Project. Adults were about 35–45 years old, and children were 9–11 years old. Perc exposures (indoor air, exhaled breath, and blood perc levels) and measures of visual function (visual contrast sensitivity (VCS) and color vision) were obtained for each participant and associations between all measures of perc exposure and visual function were assessed. The main body of this report describes observed associations between perc exposure and VCS.

Keywords:  neurotoxin; organic solvent; perchloroethylene; tetrachlorethylene; vision; visual contrast sensitivity; visual function; volatile organic compounds
Neurotoxicity and Teratology — May, 2010
Defining the neurotoxin derived illness chronic ciguatera using markers of chronic systemic inflammatory disturbances: A case/control study
Author(s):  Ritchie C. Shoemaker, MD; Dennis E. House, MS; James C. Ryan, PhD
Background: Ciguatoxins are extremely potent neurotoxins, produced by tropical marine dinoflagellates, that persistently enter into our food web. Over 100,000 people annually experience acute ciguatera poisoning from consuming toxic fish. Roughly 5% of these victims will develop chronic ciguatera (CC), a widespread, multisymptom, multisystem, chronic illness that can last tens of years. CC is marked by disproportionate disability and non-specific refractory symptoms such as fatigue, cognitive deficits and pain, and is suggestive of other illnesses. Its unknown pathophysiology makes both diagnosis and treatment difficult.

Objectives: We wanted to compare objective parameters of visual contrast sensitivity testing, measures of innate immune response and genetic markers in cases to controls to assess the potential for the presence of persistent inflammatory parameters that are demonstrated in other biotoxin associated illnesses at a singlespecialty clinic.

Methods: Using 59 CC cases and 59 controls we present in retrospective review, in all cases, abnormalities in immune responses paralleling the chronic systemic inflammatory response syndrome seen in several other chronic diseases.

Results: This study defines a preliminary case definition using medical history, total symptoms, visual contrast sensitivity, HLA DR genotype analysis, reduction of regulatory neuropeptides VIP and MSH, and multiple measures of inflammatory immune response, especially C4a and TGFβ1, thereby providing a basis for identification and targeted therapy.

Conclusions: CC provides a model for chronic human illness associated with initiation of inflammatory responses by biologically produced neurotoxins.

Keywords:  biotoxins; chronic inflammatory response syndrome; ciguatera fish poisoning; ciguatoxin; immune; inflammation
CDC/NIOSH — August, 2010
Comparison of Mold Exposures, Work-related Symptoms, and Visual Contrast Sensitivity between Employees at a Severely Water-damaged School and Employees at a School without Significant Water Damage
Author(s):  Gregory Thomas, MD, MS; Nancy Clark Burton, PhD, MPH, CIH; Charles Mueller, MS; Elena Page, MD, MPH
On January 18, 2005, NIOSH received a request for an HHE at AFSHS in New Orleans, Louisiana. Employees submitted the request because of concerns about exposure to mold and lead paint in their school building. Employees reported a variety of health effects, including difficulty breathing, chronic sinusitis, immune system problems, nosebleeds, skin rashes, irregular menses, headaches, irritable bowel syndrome, and nausea.

We visited AFSHS on April 18–19, 2005. During informal interviews, employees reported possible work-related symptoms, some of which were consistent with symptoms reported by people working in water-damaged buildings. The building had obvious microbial contamination, so we decided that further evaluation was needed. On May 23–24, 2005, we returned to New Orleans for a follow-up evaluation. During this visit we administered a work history and health symptom questionnaire. We also conducted VCS testing using the F.A.C.T.® handheld chart. VCS testing measures the subjects’ ability to determine changes in alternating light and dark bands of varying intensity. Performance on this test has been adversely associated with exposure to neurotoxins such as solvents and lead among many other conditions and exposures such as aging, certain eye conditions, alcohol and medication use, and depression. We used VCS testing for this evaluation to determine if it could serve as a biomarker of effect for occupants who experience adverse effects from a water-damaged building. We also collected environmental samples for culturable and aerosolized fungal spores and measured IEQ parameters (CO2, temperature, and RH). We performed a similar evaluation at WHHS in Cincinnati, Ohio, on February 27–29, 2006. WHHS had no history of ongoing water intrusion or mold growth.

Of 119 employees at AFSHS, 95 (80%) participated in the evaluation. Of 165 employees at WHHS, 110 (67%) participated. Participants at both schools were similar in sex, age, history of psychiatric disease, atopy (the predisposition to allergic disease), smoking history, and having mold or moisture problems in their homes.

Employees at AFSHS had higher prevalences of work-related cough, wheezing, or whistling in the chest; chest tightness; unusual shortness of breath; sinus problems; sore or dry throat; frequent sneezing; stuffy nose; runny nose; fever or sweats; aching all over; unusual tiredness or fatigue; headache; difficulty concentrating; confusion or disorientation; trouble remembering things; change in sleep patterns; and rash, dermatitis, or eczema on the face, neck, or arms than employees at WHHS. At each school, 13 employees reported currently having asthma. A significantly higher percent of the asthmatics at AFSHS reported their asthma was worse at work.

Monocular and binocular VCS values were significantly lower at all spatial frequencies among AFSHS employees. A significantly higher percentage of employees at AFSHS had scores that fell below the average performance for 90% of the population compared to the results found among employees at WHHS.

Keywords:  biotoxins; mold; mold illness; visual contrast sensitivity
PLoS ONE — April, 2015
Exposure to Organic Solvents Used in Dry Cleaning Reduces Low and High Level Visual Function
Author(s):  Ingrid Astrid Jimenez Barbosa; Mei Ying Boon; Sieu K. Khuu
To investigate whether exposure to occupational levels of organic solvents in the dry cleaning industry is associated with neurotoxic symptoms and visual deficits in the perception of basic visual features such as luminance contrast and colour, higher level processing of global motion and form (Experiment 1), and cognitive function as measured in a visual search task (Experiment 2).

The Q16 neurotoxic questionnaire, a commonly used measure of neurotoxicity (by the World Health Organization), was administered to assess the neurotoxic status of a group of 33 dry cleaners exposed to occupational levels of organic solvents (OS) and 35 agematched non dry-cleaners who had never worked in the dry cleaning industry. In Experiment 1, to assess visual function, contrast sensitivity, colour/hue discrimination (Munsell Hue 100 test), global motion and form thresholds were assessed using computerised psychophysical tests. Sensitivity to global motion or form structure was quantified by varying the pattern coherence of global dot motion (GDM) and Glass pattern (oriented dot pairs) respectively (i.e., the percentage of dots/dot pairs that contribute to the perception of global structure). In Experiment 2, a letter visual-search task was used to measure reaction times (as a function of the number of elements: 4, 8, 16, 32, 64 and 100) in both parallel and serial search conditions.

Dry cleaners exposed to organic solvents had significantly higher scores on the Q16 compared to non dry-cleaners indicating that dry cleaners experienced more neurotoxic symptoms on average. The contrast sensitivity function for dry cleaners was significantly lower at
all spatial frequencies relative to non dry-cleaners, which is consistent with previous studies. Poorer colour discrimination performance was also noted in dry cleaners than non dry-cleaners, particularly along the blue/yellow axis. In a new finding, we report that global form
and motion thresholds for dry cleaners were also significantly higher and almost double than that obtained from non dry-cleaners. However, reaction time performance on both parallel and serial visual search was not different between dry cleaners and non dry-cleaners.

Exposure to occupational levels of organic solvents is associated with neurotoxicity which is in turn associated with both low level deficits (such as the perception of contrast and discrimination of colour) and high level visual deficits such as the perception of global form and motion, but not visual search performance. The latter finding indicates that the deficits in visual function are unlikely to be due to changes in general cognitive performance.

Keywords:  dry cleaning; neurotoxin; organic solvent; visual contrast sensitivity; visual function
Medical Research Archives — June, 2021
Treatable metabolic and inflammatory abnormalities in Post COVID Syndrome (PCS) define the transcriptomic basis for persistent symptoms: Lessons from CIRS
Author(s):  Ritchie C. Shoemaker, MD; Scott McMahon, MD; Andrew Heyman, MD; David Lark; Michelle van der Westhuizen, MD; James C. Ryan, PhD
Within three months of the onset of acute SARS-CoV-2 (COVID-19) infections, new and persistent symptoms were noted in survivors. While the world’s medical and research communities focus on saving lives following COVID-19 infection, a relentless march of new cases of Post-COVID Syndrome (PCS) continues to spread around the globe as a second COVID-related pandemic. Efforts to define the physiology of PCS, a multisystem, multisymptom illness, continue without success, in part due to the markedly different case presentations. Using a transcriptomic assessment of persistently ill cases of PCS, we show the presence of (i) molecular hypometabolism (MHM) and proliferative physiology; (ii) elevated levels of ribosomal stress responses and a concomitant increase in gene activation of TGFBR; and (iii) common co-expression of CD14 and Toll Receptor 4, correlated to exposure of amplified microbial growth in a water-damaged environment, specifically Actinobacteria and endotoxin, respectively, compared to recovered PCS cases. Total symptom scores and visual contrast sensitivity (VCS) results showed statistically significant differences. The data reported here supports the concept that PCS occurs in patients with additional environmental exposures and enhanced TGF signaling. In a strikingly similar condition called Chronic Inflammatory Response Syndrome (CIRS), named in 2010, the transcriptomic abnormalities were identified to respond to treatment with FDA-cleared medications, with salutary benefits for affected cases. Though sparsely reported, PCS cases share proteomic findings with CIRS. While additional studies are indicated, a new approach to the treatment of PCS is suggested.
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Keywords:  chronic inflammatory response syndrome; covid; covid-19; endotoxin; pcs; post-covid syndrome; vision; visual contrast sensitivity