High circulating levels of midregional proenkephalin A predict vascular dementia: a population-based prospective study.

Midregional Pro-enkephalin A (MR-PENK A) and N-terminal Protachykinin A (NT-PTA) have been associated with vascular dementia. However, the longitudinal relationship between these biomarkers and incident dementia has not been fully investigated. In the population-based Malmö Preventive Project, circulating levels of MR-PENK A and NT-PTA were determined in a random sample of 5,323 study participants (mean age: 69 ± 6 years) who were followed-up over a period of 4.6 ± 1.6 years. The study sample included 369 patients (7%) who were diagnosed in the same period with dementia. We analyzed relationship of MR-PENK A and NT-PTA with the risk of developing dementia by using multivariable-adjusted Cox regression models adjusted for traditional risk factors. Increased plasma levels of MR-PENK A were associated with higher risk of incident vascular dementia whereas no associations were found with all-cause or Alzheimer dementia. The risk of vascular dementia was mainly conferred by the highest quartile of MR-PENK as compared with lower quartiles. Elevated levels of NT-PTA yielded significant association with all-cause dementia or dementia subtypes. Elevated plasma concentration of MR-PENK A independently predicts vascular dementia in the general population. MR-PENK A may be used as an additional tool for identifying vascular subtype in ambiguous dementia cases.

Beta-blocker therapy and risk of vascular dementia: A population-based prospective study.

There are a few studies that report cognitive impairment as a complication of treatment with beta- blockers. We aimed to evaluate the longitudinal association between use of beta-blockers, as a class, and incident risk of all-cause dementia, vascular dementia, Alzheimer's and mixed dementia in the prospective population-based Malmö Preventive Project. We included 18,063 individuals (mean age 68.2, males 63.4%) followed up for 84,506 person-years. Dementia cases were retrieved from the Swedish National Patient Register and validated by review of medical records and neuroimaging data. We performed propensity score matching analysis, resulting in 3720 matched pairs of beta-blocker users and non-users at baseline, and multivariable Cox proportional-hazards regression. Overall, 122 study participants (1.6%) were diagnosed with dementia during the follow-up. Beta-blocker therapy was independently associated with increased risk of developing vascular dementia, regardless of confounding factors (HR: 1.72, 95%CI 1.01-3.78; p = .048). Conversely, treatment with beta-blockers was not associated with increased risk of all-cause, Alzheimer's and mixed dementia (HR:1.15; 95%CI 0.80-1.66; p = .44; HR:0.85; 95%CI 0.48-1.54; P = .59 and HR:1.35; 95%CI 0.56-3.27; p = .50, respectively). We observed that use of beta-blockers, as a class, is associated with increased longitudinal risk of vascular dementia in the general elderly population, regardless of cardiovascular risk factors, prevalent or incident history of atrial fibrillation, stroke, coronary events and heart failure. Further studies are needed to confirm our findings in the general population and to explore the mechanisms underlying the relationship between use of beta- blockers and increased risk of vascular dementia.

A practical guide to active stand testing and analysis using continuous beat-to-beat non-invasive blood pressure monitoring.

PURPOSE: The average adult stands approximately 50-60 times per day. Cardiovascular responses evoked during the first 3 min of active standing provide a simple means to clinically assess short-term neural and cardiovascular function across the lifespan. Clinically, this response is used to identify the haemodynamic correlates of patient symptoms and attributable causes of (pre-)syncope, and to detect autonomic dysfunction, variants of orthostatic hypotension, postural orthostatic tachycardia syndrome and orthostatic hypertension. METHODS: This paper provides a set of experience/expertise-based recommendations detailing current state-of-the-art measurement and analysis approaches for the active stand test, focusing on beat-to-beat BP technologies. This information is targeted at those interested in performing and interpreting the active stand test to current international standards. RESULTS: This paper presents a practical step-by-step guide on (1) how to perform active stand measurements using beat-to-beat continuous blood pressure measurement technologies, (2) how to conduct an analysis of the active stand response and (3) how to identify the spectrum of abnormal blood pressure and heart rate responses which are of clinical interest. CONCLUSION: Impairments in neurocardiovascular control are an attributable cause of falls and syncope across the lifespan. The simple active stand test provides the clinician with a powerful tool for assessing individuals at risk of such common disorders. However, its simplicity belies the complexity of its interpretation. Care must therefore be taken in administering and interpreting the test in order to maximise its clinical benefit and minimise its misinterpretation.

Postural orthostatic tachycardia syndrome: clinical presentation, aetiology and management.

Postural orthostatic tachycardia syndrome (POTS) is a variant of cardiovascular autonomic disorder characterized by an excessive heart rate increase on standing and orthostatic intolerance. POTS affects younger individuals 15-45 years old with a distinct female predominance (≈80%). The prevalence ranges between 0.2% and 1.0% in developed countries. The onset of POTS is typically precipitated by immunological stressors such as viral infection, vaccination, trauma, pregnancy, surgery or psychosocial stress. The most common complaints are dizziness, weakness, rapid heartbeat and palpitation on standing. Moreover, patients often report physical deconditioning and reduced exercise capacity as well as headache, 'brain fog', dyspnoea, gastrointestinal disorders and musculoskeletal pain. The aetiology of POTS is largely unknown and three main hypotheses include an autoimmune disorder, abnormally increased sympathetic activity and catecholamine excess, and sympathetic denervation leading to central hypovolaemia and reflex tachycardia. The golden standard for POTS diagnosis is head-up tilt test with a non-invasive beat-to-beat haemodynamic monitoring. Although long-term prognosis of POTS is poorly explored, around 50% of patients spontaneously recover within 1-3 years. After the diagnosis has been established, patient should be thoroughly educated about non-pharmacological measures alleviating the symptoms. Exercise training may be very effective and counteract deconditioning. In more symptomatic patients, different drugs directed at controlling heart rate, increasing peripheral vasoconstriction and intravascular volume can be tested. However, the overall effects of pharmacological therapy are modest and the most affected patients remain handicapped. Future efforts should focus on better understanding of POTS pathophysiology and designing randomized controlled trials for selection of more effective therapy.

Monitoring of cerebral oximetry during head-up tilt test in adults with history of syncope and orthostatic intolerance.

Aims: We applied near-infrared-spectroscopy (NIRS) to measure absolute frontal cerebral tissue oxygen saturation (SctO2) during head-up tilt test (HUT) in patients investigated for unexplained syncope. Methods and results: Synchronized non-invasive beat-to-beat haemodynamic monitoring, ECG, SctO2 (NIRS; normal range: 60-80%), and peripheral oxygen saturation (left hand, SpO2) were applied during HUT in a random sample of patients with unexplained syncope. Tracings of 54 patients (mean-age: 55 ± 19 years, 39% male) with negative HUT, vasovagal syncope (VVS), or orthostatic hypotension (OH) were analysed. In 44 patients HUT was diagnostic, in 10 HUT was negative. Thirty-one experienced VVS. Of these, 6 had spontaneous and 25 nitroglycerin-induced syncope. Thirteen patients had orthostatic hypotension (OH). Although there was no significant change in mean-arterial pressure from baseline to 1 min before syncope or end of passive HUT phase (-1.4 ± 13.9 mmHg; P = 0.45), there was a significant fall in SctO2 during the same period (-3.2 ± 3.2%; P ≤ 0.001). Among patients who experienced syncope, a decrease in SctO2 from 71 ± 5% at baseline to 53 ± 9% (P < 0.001) at syncope was observed. During HUT, there was a significant difference in delta SctO2 between spontaneous VVS (-4.5 ± 3.0%) and negative HUT (-1.3 ± 1.9%; P = 0.021), but not between spontaneous VVS and OH (-5.4 ± 4.2%; P = 0.65). In spontaneous VVS, progressive decrease of SctO2 was independent of mean arterial pressure decrease (P = 0.22). Conclusions: Progressive decrease in cerebral tissue oxygenation independent of mean-arterial pressure may precede spontaneous vasovagal reflex during tilt. Patients experience syncope when SctO2 falls below 60%. These data confirm clinical utility of absolute cerebral oximetry monitoring for syncope investigation. We applied NIRS to measure frontal cerebral tissue oxygen saturation (SctO2) during head-up tilt test (HUT) in patients with unexplained syncope. In 44 of 54 patients, HUT was diagnostic. In patients with syncope, a significant SctO2-decrease was observed. Different patterns of SctO2 can be detected.

Biomarkers of microvascular endothelial dysfunction predict incident dementia: a population-based prospective study.

BACKGROUND: Cerebral endothelial dysfunction occurs in a spectrum of neurodegenerative diseases. Whether biomarkers of microvascular endothelial dysfunction can predict dementia is largely unknown. We explored the longitudinal association of midregional pro-atrial natriuretic peptide (MR-proANP), C-terminal endothelin-1 (CT-proET-1) and midregional proadrenomedullin (MR-proADM) with dementia and subtypes amongst community-dwelling older adults. METHODS: A population-based cohort of 5347 individuals (men, 70%; age, 69 ± 6 years) without prevalent dementia provided plasma for determination of MR-proANP, CT-proET-1 and MR-proADM. Three-hundred-and-seventy-three patients (7%) were diagnosed with dementia (120 Alzheimer's disease, 83 vascular, 102 mixed, and 68 other aetiology) over a period of 4.6 ± 1.3 years. Relations between baseline biomarker plasma concentrations and incident dementia were assessed using multivariable Cox regression analysis. RESULTS: Higher levels of MR-proANP were significantly associated with increased risk of all-cause and vascular dementia (hazard ratio [HR] per 1 SD: 1.20, 95% confidence interval [CI], 1.07-1.36; P = 0.002, and 1.52; 1.21-1.89; P < 0.001, respectively). Risk of all-cause dementia increased across the quartiles of MR-proANP (p for linear trend = 0.004; Q4, 145-1681 pmol L-1 vs. Q1, 22-77 pmol L-1 : HR: 1.83; 95%CI: 1.23-2.71) and was most pronounced for vascular type (p for linear trend = 0.005: HR: 2.71; 95%CI: 1.14-6.46). Moreover, the two highest quartiles of CT-proET-1 predicted vascular dementia with a cut-off value at 68 pmol L-1 (Q3-Q4, 68-432 pmol L-1 vs. Q1-Q2,4-68 pmol L-1 ; HR: 1.94; 95%CI: 1.12-3.36). Elevated levels of MR-proADM indicated no increased risk of developing dementia after adjustment for traditional risk factors. CONCLUSIONS: Elevated plasma concentration of MR-proANP is an independent predictor of all-cause and vascular dementia. Pronounced increase in CT-proET-1 indicates higher risk of vascular dementia.

Reflex syncope, anxiety level, and family history of cardiovascular disease in young women: case-control study.

AIMS: Anxiety is an emotion, which stimulates sympathetic nervous outflow potentially facilitating vasovagal reflex syncope (VVS) but reports on anxiety levels in patients with VVS are sparse. METHODS AND RESULTS: We studied anxiety levels in young women (21-40 years) referred for unexplained transient loss of consciousness (TLOC), and age-matched female controls with or without past history of TLOC (≈probable VVS). Referred patients underwent head-up tilt (HUT) according to current ESC Guidelines. State and Trait Anxiety Inventory questionnaire evaluated anxiety levels plus a questionnaire explored risk factors for cardiovascular disease (CVD). Sixty-five of 91 women were diagnosed with VVS on HUT. Among 549 controls, 223 (40.6%) reported at least one episode of TLOC. State-anxiety level in patients with VVS undergoing HUT (42.4 ± 9.3) was higher compared with both controls with (38.3 ± 10.2; P < 0.01) and without past TLOC history (35.9 ± 9.8; P < 0.001). Trait anxiety in patients with VVS (42.7 ± 8.4), and controls with TLOC history (42.4 ± 8.4) was higher compared with controls without TLOC history (39.7 ± 8.5; P < 0.01). In the logistic regression using controls without TLOC as reference, both VVS diagnosis and past history of TLOC were associated with family history of CVD [odds ratio (OR) 2.4, 95% confidence interval (CI), 1.3-4.4; P = 0.007, and 2.3, 1.4-3.6; P = 0.001, respectively], and this association was independent of anxiety level. CONCLUSIONS: Trait anxiety and family history of CVD are increased in both young women with VVS and controls with history of TLOC. However, the height of anxiety level does not explain CVD heredity and other mechanisms may link syncope with CVD.

Novel cardiovascular biomarkers in unexplained syncopal attacks: the SYSTEMA cohort.

OBJECTIVES: The aim of the study was to investigate the resting levels of novel cardiovascular biomarkers in common types of noncardiac syncope. DESIGN AND SETTING: An observational study was conducted including 255 patients (mean age 60 years, range 15-93; 45% men) with unexplained syncopal attacks. Subjects underwent an expanded head-up tilt test including carotid sinus massage, and nitroglycerin provocation if indicated. Using logistic regression, we explored the associations between specific diagnoses of syncope and resting levels of circulating biomarkers: C-terminal pro-arginine vasopressin (CT-proAVP), C-terminal endothelin-1 precursor fragment (CT-proET-1), midregional fragments of pro-atrial natriuretic peptide (MR-proANP) and pro-adrenomedullin (MR-proADM). RESULTS: A total of 142 (56%) patients were diagnosed with vasovagal syncope (VVS), 85 (33%) with orthostatic hypotension (OH) and 47 (18%) with carotid sinus hypersensitivity (CSH); in addition, 74 (29%) patients had more than one diagnosis. Thirty-five patients (14%) demonstrated a cardioinhibitory reflex. The probability of VVS was highest in the first quartile of MR-proANP [Q1 vs. Q4: odds ratio (OR) 5.57, 95% confidence interval (CI) 1.86-16.74; P < 0.001] and CT-proET-1 (OR 7.17, 95% CI 2.43-21.13; P < 0.001). By contrast, the probability of OH was highest in the fourth quartile of CT-proET-1 (Q4 vs. Q1: OR 8.66, 95% CI 2.49-30.17; P < 0.001). Furthermore, CSH was most frequently observed in the first quartile of MR-proANP (Q1 vs. Q4: OR 6.57, 95% CI 1.62-26.62; P = 0.008) among those over 60 years of age, whereas the cardioinhibitory reflex was strongly associated with low CT-proET-1 levels (Q1 vs. Q4: OR 69.7, 95% CI 6.97-696.6; P < 0.001). Moreover, in patients with VVS, a high concentration of CT-proET-1 was predictive of OH (OR per 1 SD 2.4, 95% CI 1.15-5.02; P = 0.02), whereas low CT-proET-1 suggested involvement of the cardioinhibitory reflex (OR per 1SD 0.42, 95% CI 0.25-0.70; P = 0.001). CONCLUSIONS: The levels of MR-proANP and CT-proET-1 are markedly changed in common forms of syncope, suggesting the involvement of novel neurohormonal mechanisms in syncopal attacks.

Syndromes of orthostatic intolerance: a hidden danger.

Orthostatic hypotension (OH) is a relatively common heterogenous and multifactorial disorder, traditionally classified as neurogenic (less common but often more severe) or nonneurogenic (more common, with no direct signs of autonomic nervous system disease). The different clinical variants of orthostatic intolerance include initial, classical and delayed OH as well as postural tachycardia syndrome. Orthostatic instability may induce syncopal attacks either alone or in combination with other mechanisms, and is often dismissed as a precipitating factor. Moreover, prevalent OH is an independent risk factor for all-cause mortality and cardiovascular morbidity, and the majority of patients with OH are asymptomatic or have few nonspecific symptoms. Management of symptomatic orthostatic intolerance includes both nonpharmacological and pharmacological methods, but it is not always successful and may lead to complications. Future studies of OH should focus on mechanisms that lead to neurogenic and nonneurogenic OH, novel diagnostic methods and more effective therapeutic modalities.

Orthostatic hypotension and long-term incidence of atrial fibrillation: the Malmö Preventive Project.

OBJECTIVES: Orthostatic hypotension (OH), a common manifestation of autonomic dysfunction, has been identified as an independent risk factor for all-cause mortality and incident cardiovascular disease. However, the role of OH in the development of atrial fibrillation has not been studied. DESIGN: We investigated the incidence of atrial fibrillation in relation to baseline presence of OH according to international consensus criteria in the Swedish population-based prospective cohort of the Malmö Preventive Project. The study sample consisted of 33,346 individuals (67.3% men; mean age, 45.6 ± 7.4 years; range, 26-61 years). The association between OH and incidence of atrial fibrillation during follow-up was assessed using the Kaplan-Meier method and multivariable Cox proportional hazard models, taking into account conventional risk factors for atrial fibrillation. RESULTS: At baseline, 1987 participants (6.1%) met the diagnostic criteria for OH. Over a follow-up period of approximately 24 years, 2312 individuals (3.0 events/1000 person-years) were diagnosed with new-onset atrial fibrillation. Of these, 196 had OH at baseline (4.6 events/1000 person-years amongst all OH-positive individuals). In a multivariable Cox regression analysis, OH predicted incidence of atrial fibrillation independently of other risk factors (hazard ratio [HR]: 1.30; 95% confidence interval [CI]: 1.05-1.61; P = 0.016), and this association was significant in hypertensive (HR: 1.44; 95%CI: 1.10-1.88; P = 0.008), but not in normotensive participants (HR: 1.10; 95%CI: 0.77-1.58; P = 0.60). CONCLUSIONS: The presence of OH predicts the incidence of atrial fibrillation in middle-aged hypertensive individuals, independently of conventional risk factors. Further studies of the association of autonomic dysfunction and OH with atrial fibrillation are needed.

[Interdisciplinary interventional therapy for tracheobronchial stenosis with modern metal net stents]. / Interdisziplinäre interventionelle Therapie tracheobronchialer Stenosen mit modernen Metallmaschenstents.

STUDY OBJECTIVES: Assessment of the therapeutic potential of tracheobronchial stenting for obstructive tracheobronchial disease, in-vivo comparison of different stent types and development of helpful criteria for choosing the suitable stent type. MATERIAL AND METHODS: Prospective case analysis. Between 1993 and 1999 53 stents were implanted into the tracheobronchial system of 39 consecutive patients with benign or malignant airway obstruction. Every single stent (26 Strecker Stents, 18 Wallstents, 6 Accuflex Nitinolstents, 1 Dumon-, 1 Rüsch- and 1 Palmazstent) was recorded in an unified database. Analysis comprised clinical effectiveness, lung function if possible, relevant complications and radiologic follow-up parameters. The probability of their remaining within the tracheobronchial system, of their remaining undislocated and uncompressed was calculated using Kaplan-Meier analysis for three stent types. RESULTS: Stent placement proved itself to be an effective treatment in 86 % of the patients. Resistance could be normalized in 9/9 patients. Kaplan-Meier analysis clearly revealed a higher probability for the Wall- and Nitinolstent to remain within the tracheobronchial system and to remain uncompressed. Dislocation also occurred more rarely. Explantation of the Wallstent, however, if desired, was much more difficult compared to the Strecker stent. The Wallstent also occasionally led to the formation of granulation tissue especially at the proximal stent end and, as such, required reintervention. CONCLUSION: Any of the 3 stent types proved to be an effective therapeutic option in the management of obstructive tracheobronchial disease. Choise of the stent type should be determined through definition of the therapeutic intention. It is useful to distinguish between (a) benign stenosis, (b) malignant stenosis but curative therapeutic situation and (c) malignant stenosis in a palliative therapeutic situation with limited life expectancy. In spite of its superior mechanical properties the Wallstent is rather suited for a palliative situation because explantation may be difficult. The Strecker Stent requires more reinterventions but removal is easy to perform. The Nitinolstent possibly represents a reasonable compromise.

[Basic fibroblast growth factor (b-FGF) in the perimatrix of cholesteatoma]. / "Basic fibroblast growth factor" (b-FGF) in der Perimatrix des Cholesteatoms.

UNLABELLED: The growth of a cholesteatoma requires angioneogenesis in the connective tissue of the perimatrix. Angioneogenesis is also needed for wound healing as a host response to tissue injury. Normal wound repair is conducted through a wide number of growth factors. Basic fibroblast growth factor (b-FGF) plays a pivotal role in wound repair. This cytokine exerts its effects through stimulation of a wide range of target cells. B-FGF is chemotactic and mitogenic for fibroblasts, endothelial cells and keratinocytes. In addition, b-FGF can stimulate the production of collagenase and plasminogen activators to enhance fibroblast proliferation and angioneogenesis. Its necessity for normal wound repair has been confirmed by several workers. METHOD: In order to demonstrate angioneogenesis in the cholesteatoma perimatrix the distribution of b-FGF as the pivotal cytokine of the process was investigated in the perimatrix of 18 cholesteatoma specimens. RESULTS: B-FGF could be observed in 12 of 18 specimens (66%) in close approximation to histological signs of inflammation and wound healing. Areas with b-FGF also exhibited proliferation of the covering squamous epithelium. Cholesteatoma matrix tissue without inflammation or any sign of wound healing did not express b-FGF (6 of 18). CONCLUSION: Histological changes and distribution pattern of b-FGF in the perimatrix of cholesteatoma in the present study indicate that the perimatrix cells and substances of the wound healing cascade may play an important role in cholesteatoma development, angiogenesis and growth.

[Biological effects of non-ionizing electromagnetic radiation]. / Biologiczne oddzialywanie niejonizujacego promieniowania elektromagnetycznego.

Since the mid 1970's, when Adey discovered that extremely-low-frequency electromagnetic field (ELF EMF) may affect the calcium ions efflux from various cells, bioeffects of non-ionizing radiation (NIR) have become the subject of growing interest and numerous research projects. At present, the fact that NIR exerts both stimulatory and inhibitory effects on different physiological cellular parameters is rather unquestionable. At the same time, some epidemiological studies suggest that exposure to EMF is potentially harmful even if its intensity is very low. It has been proved that thermal factors are not responsible for these effects, therefore nowadays, they are called 'non-thermal effects'. Our paper deals with three different aspects of biological effects of non-ionizing radiation, bioelectromagnetism, electromagnetobiology and electromagnetic bioinformation. Firstly, we describe how EMF and photons can be produced within a living cell, how biological cycles are controlled, and what are the features of endogenous electromagnetic radiation. Secondly, we discuss various facets of external EMF interactions with living matter, focusing on extremely-low-frequencies, radio- and microwaves. Possible mechanisms of these interactions are also mentioned. Finally, we present a short overview of current theories which explain how electromagnetic couplings may control an open and dissipative structure, namely the living organism. The theory of electromagnetic bioinformation seems to explain how different physiological processes are triggered and controlled, as well as how long-range interactions may possibly occur within the complex biological system. The review points out that the presented research data must be assessed very carefully since its evaluation is crucial to set the proper limits of EMF exposure, both occupational and environmental. The study of biological effects of non-ioinizing radiation may also contribute to the development of new diagnostic and therapeutic methods.

[Electrosmog as a health risk factor: sources of artificial electromagnetic fields, evaluation of health risk, prevention methods]. / Elektrosmog jako czynnik zagrozenia zdrowia: zródla sztucznych pól elektromagnetycznych, ocena ryzyka zdrowotnego, metody zapobiegania.

In recent years we have observed how electromagnetic (EM) radiation enters our daily life. The strength of man-made EM field is often far above the natural level and this finding has encouraged a large group of researchers to investigate its possible health effect. Non-ionizing radiation and extremely low-frequency electric and magnetic fields have been the subject of intensive theoretical and experimental works since Adey published his observations concerning non-linear and non-thermal biological effects. At the same time an epidemiological material appeared suggesting that EM field generates various diseases including leukemia and brain tumors. Possible mechanisms of EM field interactions with living matter remain unknown although theoretical models have been proposed by many authors. In vitro and in vivo studies as well as epidemiological data have not provided the ground for decisive conclusions. Nevertheless, the relationship between EM fields and biological effects seems to be most likely. Any international standards for safety limits have not as yet been established and regulations in this regard vary in different countries. However, occupational and residential exposure to EM field can be efficiently measured using an appropriate equipment and such measurements should become a standard procedure wherever electrosmog is suspected to be a pathogenic factor.

Acute toxicity, subchronic dermal toxicity, and delayed contact sensitization evaluations of dicyclopentenyloxyethyl methacrylate in rabbits and guinea pigs.

The subchronic dermal toxicity of dicyclopentenyloxethyl methacrylate (DPOMA) was evaluated in young adult New Zealand White rabbits, and its potential to produce delayed contact sensitization was evaluated in Harley guinea pigs by a modified Buehler's closed patch technique. In addition, studies were conducted to evaluate the acute systemic toxicity of DPOMA in rats (oral) and rabbits (dermal), and its eye and skin irritancy in rabbits. In the subchronic dermal toxicity study, 4 groups of rabbits were treated percutaneously with DPOMA at 0 (acetone), 10, 107, and 1067 (undiluted) mg/kg X day in a volume of 1 ml/kg, over a 4-wk period. The application sites were unoccluded. No deaths occurred, and no signs of systemic toxicity were observed. No treatment-related effects were seen on body weights, hematology, clinical chemistry, urinalysis, organ weights, or histopathology (except the treated skin). The only treatment-related effect was slight to moderate skin irritation in the mid- and high-dose groups. The severity of skin irritaton was dependent on the number of applications and the concentration of DPOMA. Maximal skin irritation occurred after 1 wk. No skin irritation was seen in the control and low-dose group. In the DCS study, guinea pigs received 6 induction doses of 0.5 ml 100% DPOMA and were challenged with 0.5 ml of 50% (w/v) DPOMA in acetone 2 wk after the last induction treatment. No erythema or edema was observed in any of the challenged guinea pigs in either the treated and control groups. These acute toxicity studies indicate that DPOMA is practically nontoxic by a single exposure via both oral and dermal routes (the oral LD50 in rat and dermal LD50 in rabbits were greater than 5.0 g/kg body weight), slightly irritating to the skin, and inconsequentially irritating to the eyes. The no-observed-effect level (NOEL) for systemic toxicity of DPOMA applied repeatedly to rabbits skin is at least 1067 mg/kg X d. DPOMA is not a strong or moderate skin sensitizer in guinea pigs.