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Suggestive evidence implies the existence of either: 1) inconclusive information from peer-reviewed publications or 2) inconclusive or limited information to support the association, but either not published or published somewhere other than in a peer-reviewed journal Unclear evidence implies either directly conflicting information in peer-reviewed publications, or inconclusive information but with some basis for a biological rationale in patients with dry eye has not been associated with a higher risk of complications in dry eye patients; Ram et al reported postoperative punctate epitheliopathy in 8/25 eyes, epithelial defect in 8/25 eyes of 23 patients, and no cases of infection or keratolysis. Future Research Directions A number of questions should be addressed in future research on the epidemiology of dry eye. Do irritative symptoms progress, or might they wane over time with the development of relative corneal anesthesia? Is the amount of corneal staining correlated with visual function/functional visual acuity? What is the incidence of dry eye syndrome in the population, and are there any identifiable demographic correlates (eg, age, sex, race/ethnicity)? It needs to be determined whether predisposing genetic factors contribute to dry eye. The effects of dry eye should be further defined in terms of QoL, impact on vision, impact on driving, psychological issues, cost of care, impact on the health care system, and overall economic impact. New diagnostic tests and disease biomarkers should be developed to facilitate epidemiological and clinical research. The Epidemiology Subcommittee noted that risk factors might differ among certain subtypes of dry eye, which could dilute associations in populationbased studies, in which all forms of dry eye are considered together. Findings from studies in which a purely statistical, non-hypothesis-driven approach was used to study risk factors must be viewed cautiously, as spurious results are likely, and, at the same time, important associations could have easily been overlooked. The Subcommittee recommends that future studies of risk factors for dry eye should concentrate on the examination of biologically compelling hypotheses in a detailed fashion, with appropriate attention to all aspects of good epidemiological study design (including sufficient study power), analysis, and data presentation. Vitamin A deficiency is a well-recognized risk factor for dry eye,55 and the etiology of the nutritional deficiency now extends from inadequate intake due to unavailability of food to alcoholism-related nutritional deficiency, bariatric surgery,56 malabsorption, eating disorders,57 and vegan diet. Conflicting results have been reported on the associations between dry eye and some factors, including alcohol, cigarette smoking, caffeine, acne,63 and menopausal status. Very few reports exist on the risk of dry eye with use of oral contraceptives and pregnancy and the role of ethnicity in dry eye. Bone Marrow transplantation and Cancer Allogeneic bone marrow transplantation has increased in frequency, the indications for the procedure have expanded, and the survival rate is higher than ever before. Conditioning regimens and the use and amount of radiation therapy have also changed, which has altered the clinical spectrum of ocular graft vs host disease. Dry eye due to radiation therapy,65 systemic chemotherapy, or ocular graft vs host disease as a complication of bone marrow transplantation can be seen in cancer survivors. A prospective analysis of data from this study showed that the initiation of estrogen therapy preceded the diagnosis of dry eye syndrome. Sex Hormones the role of sex hormones in ocular surface homeostasis has been recognized and the pathologic mechanism(s) by which disturbances may result in dry eye are being investigated. There are conflicting reports of small studies of the risk of dry eye with oral contraceptive use, and minimal data are available regarding the effect of pregnancy, hysterectomy, oophorectomy and ovarian dysfunction on the ocular surface. Essential Fatty Acids A role for essential fatty acids in dry eye is supported by largely consistent evidence. In a study of over 32,000 women, Miljanovic et al demonstrated about a 30% reduction in risk for dry eye with each additional gram of omega-3 fatty acids consumed per day. Thus, the higher the level of intake of omega-3 fatty acids in relation to the most commonly consumed types of omega-6 fatty acids, the lower the risk of dry eye. Low Humidity Environments Ocular irritative complaints, such as burning, dryness, stinging, and grittiness, are often reported in epidemiologic studies of indoor environment, especially in offices where highly demanding visual and cognitive tasks are performed. Computer Use Computer users often complain of eye strain, eye fatigue, burning, irritation, redness, blurred vision, and dry eyes, among other repetitive strain symptoms. In a study by Prichard and coworkers, 12% of contact lens patients discontinued lens wear within 5 years of the initial fitting due to these symptoms. In one study performed at a university-based ophthalmic clinic, 109 (24%) of 453 subjects with a history of contact lens wear discontinued lens wear permanently and 119 current contact lens wearers expressed contact lens dissatisfaction; both groups ranked dryness as the most common ocular symptom. Alternatively, it has been proposed that this symptomatic condition is due to the disruption of trophic sensory support to the denervated region. Limited epidemiologic data are available on refractive surgeryinduced dry eye, and the magnitude, severity, and duration of the disease require further controlled prospective study. Some authors have reported a greater risk of dry eye and refractive regression in women than in men and a higher prevalence in Asian (28%) than in Caucasian (5%) persons.

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As a result, these gases penetrate the airways down into the deep lung, where they can diffuse across the thin alveoli lung tissue into the blood. The more soluble a gas is in the blood, the more it will be dissolved and transported to other organs. For inhaled solid chemicals, an important factor in determining if and where a particle will be deposited in the respiratory tract is its size. One generalization is that the largest particles (>5 m) are deposited primarily in the nose, smaller particles (1 to 5 m) in the trachea and small airways, and the smallest particles in the alveoli region of the lungs. Thus, depending on the size of an inhaled particle, it will be deposited in different sections of the respiratory tract, and the location affects the local toxicity and the absorption of the material. In general, particles that are water soluble dissolve within minutes or days, and chemicals that are not water soluble but have a moderate degree of fat solubility also clear rapidly into the blood. Those that are not water soluble or highly fat soluble do not dissolve and are retained in the lungs for long periods of time. Metal oxides, asbestos, fiberglass, and silica are examples of water-insoluble inorganic particles that are retained in the lungs for years. A number of factors affect the airborne concentrations of chemicals, but vapor pressure (the tendency of molecules to escape from the liquid or solid phase into the gaseous phase) is the most important characteristic. The higher the vapor pressure is, the greater the potential concentration of the chemical in the air. For example, acetone (with a vapor pressure of 180 mmHg at 20 °C) reaches an equilibrium concentration in air of 240,000 ppm, or approximately 24%. Fortunately, the ventilation system in most laboratories prevents an equilibrium concentration from developing in the breathing zone of laboratory personnel. Even very low vapor pressure chemicals are dangerous if the material is highly toxic. The vapor pressure of a chemical increases with temperature; therefore, heating solvents or reaction mixtures increases the potential for high airborne concentrations. Also, a spilled volatile chemical evaporates very quickly because of its large surface area, creating a significant exposure potential. Clearly, careful handling of volatile chemicals is very important; keeping containers tightly closed or covered and using volatiles in laboratory chemical hoods help avoid unnecessary exposure to inhaled chemicals. Certain types of particulate materials also present potential for airborne exposure. If a material has a very low density or a very small particle size, it tends to remain airborne for a considerable time. For example, the very fine dust cloud generated by emptying a lowdensity particulate. Such operations should therefore be carried out in a laboratory chemical hood or in a glovebox. Operations that generate aerosols (suspensions of microscopic droplets in air), such as vigorous boiling, Copyright © National Academy of Sciences. Prudent Practices in the Laboratory: Handling and Management of Chemical Hazards, Updated Version 58 high-speed blending, or bubbling gas through a liquid, increase the potential for exposure via inhalation. Consequently, these and other such operations on toxic chemicals should also be carried out in a laboratory chemical hood. Many chemicals injure the skin directly by causing skin irritation and allergic skin reactions. In addition to causing local toxic effects, many chemicals are absorbed through the skin in sufficient quantity to produce systemic toxicity. The main avenues by which chemicals enter the body through the skin are the hair follicles, sebaceous glands, sweat glands, and cuts or abrasions of the outer layer. Absorption of chemicals through the skin depends on a number of factors, including chemical concentration, chemical reactivity, and the solubility of the chemical in fat and water. Absorption is also dependent on the condition of the skin, the part of the body exposed, and duration of contact. Although an acid burn on the skin is felt immediately, an alkaline burn takes time to be felt and its damage goes deeper than the acid. Burns and skin diseases are the most common examples of skin damage that increase penetration. Some chemicals such as dimethyl sulfoxide actually increase the penetration of other chemicals through the skin by increasing its permeability.

Never use a screwdriver to pry off a stuck cap or pliers to open a cylinder valve. If valve fittings require washers or gaskets, check the materials of construction before the regulator is fitted. If the valve on a cylinder containing an irritating or toxic gas is being opened outside, the worker should stand upwind of the cylinder with the valve pointed downwind, away from personnel, and warn those working nearby in case of a possible leak. If the work is being done inside, open the cylinder only in a laboratory chemical hood or specially designed cylinder cabinet. Install a differential pressure switch with an audible alarm in any chemical hood dedicated for use with toxic gases. In the event of chemical hood failure, the pressure switch should activate an audible alarm warning personnel. Convenient ways to check for leaks include a flammable gas leak detector (for flammable gases only) or looking for bubbles after application of soapy water or a 50% glycerin­water solution. At or below freezing temperatures, use the glycerin solution instead of soapy water. When the gas to be used in the procedure is a flammable, oxidizing, or highly toxic gas, check the system first for leaks with an inert gas (helium or nitrogen) before introducing Pressure regulators are required to reduce a highpressure supplied gas to a desirable lower pressure and to maintain a satisfactory delivery pressure and flow level for the required operating conditions. They are available to fit many operating conditions over a range of supply and delivery pressures, flow capacities, and construction materials. All regulators are typically of a diaphragm type and are spring-loaded or gas-loaded, depending on pressure requirements. Under no circumstances should oil or grease be used on regulator valves or cylinder valves because these substances may react with some gases. Never tamper with or adapt regulators for use with gases for which they are not designed. Likewise, never substitute the fittings that are on either the cylinder side or downstream (low-pressure) side of a vendor-supplied regulator. Instead, purchase a regulator designed for Copyright © National Academy of Sciences. Prudent Practices in the Laboratory: Handling and Management of Chemical Hazards, Updated Version 170 use with the specific cylinder, and use adapters only on the downstream side of the regulator. Check regulators before use to verify they are free of foreign objects and to correct for the particular gas. Special regulators made of corrosionresistant materials are available for use with such gases as ammonia, boron trifluoride, chlorine, hydrogen chloride, hydrogen sulfide, and sulfur dioxide. Because of freeze-up and corrosion problems, regulators used with carbon dioxide gas must have special internal design features and be made of special materials. Regulators used with oxidizing agents must be cleaned specially to avoid the possibility of an explosion on contact of the gas with any reducing agent or oil left from the cleaning process. All pressure regulators should be equipped with spring-loaded pressure-relief valves (see section 7. When used on cylinders of flammable, toxic, or otherwise hazardous gases, vent the relief valve to a laboratory chemical hood or other safe location. When working with hazardous gases, installing flow-limiting devices after the regulator is recommended in order to add a level of control on the system. Remove regulators from corrosive gases immediately after use and flush with dry air or nitrogen. For many experiments, extremes of both pressure and temperature, such as reactions at elevated temperatures and pressures and work with cryogenic liquids and high vacuum, must be managed simultaneously. Carry out procedures at high or low pressures with protection against explosion or implosion by appropriate equipment selection and the use of safety shields. Provide appropriate temperature control and interlocks so that heating or cooling baths cannot exceed the desired limits even if the equipment fails. Take care to select and use glass apparatuses that can safely withstand thermal expansion or contraction at the designated pressure and temperature extremes. Always keep connections to piping, regulators, and other appliances tight to prevent leakage, and keep the tubing or hoses used in good condition. Do not interchange regulators, hoses, and other appliances used with cylinders of flammable gases with similar equipment intended for use with other gases.

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Genetic Factors the evidence for genetic influences on post-traumatic seizures is conflicting. Some studies (98) reported a higher incidence of seizures in family members of patients with post-traumatic seizures; other research has failed to demonstrate a similar relationship (11,99). According to a recent report, a family history of epilepsy and mild brain injury independently contributed to the risk of epilepsy (13), which supports the concept that genetic factors play a role even in symptomatic focal epilepsies (100,101). The site of injury and the underlying structural damage determine the type of focal manifestations (9,11,102,103). Early post-traumatic seizures are likely to present as generalized tonic­clonic convulsions even in the presence of focal brain damage (26,34,104). Late seizures mostly have a focal onset (9,102,103) and may develop subsequent to early generalized seizures (11). An interaction between the site of injury and the time when seizures are first noticed has been described. Seizures appear earliest after lesions of the motor area, followed by temporal lobe and those in the frontal or occipital areas (105). Chapter 29: Post-Traumatic Epilepsy 365 Diagnostic Pitfalls Nonepileptic Post-Traumatic Seizures Head trauma is a risk factor for epilepsy but is also strongly associated with nonepileptic seizure disorders-presenting in the setting of a somatoform disorder, factitious disorder, or malingering (106,107). Thirty-six out of the 104 patients (35%) were found to have nonepileptic seizures. Trauma is a shared risk factor for epileptic and nonepileptic events, but only two patients (1. The majority of patients had focal onset epilepsy: 54% presenting with temporal, 33% frontal, 5% parietal, and 3% with occipital lobe epilepsy. Secondary generalized convulsions were more common for extratemporal compared to temporal lobe onset epilepsy (19% vs. Half of the patients with temporal lobe epilepsy had mesial temporal lobe sclerosis, most of them with a head injury after the age of 5 years. Interestingly, six patients thought to have symptomatic focal epilepsy for many years were diagnosed as generalized epilepsy; four of them had features of idiopathic generalized epilepsy. This illustrates that the onset of idiopathic generalized epilepsy during teenage years and the high frequency of minor head injuries during the same age can easily delay the diagnosis of the underlying epilepsy syndrome with significant impact on the medical management and outcome. Nonepileptic seizures after head trauma pose a particular challenge to the medical community. On the other hand, nonepileptic seizures are not uncommon after minor head injuries, and a delay in diagnosis and antiepileptic therapy interfers not only with rational treatment, but also negatively affects long-term prognosis (108). There is no clear relationship between the presence of preinjury mental disorders and post-traumatic nonepileptic seizures. However, a high incidence of new psychiatric conditions including post-traumatic stress disorder, depression, and anxiety in up to 75% of patients can be noted, often associated with dissociative symptoms and complaints. Up to one third of patients with nonepileptic seizures have a history of head injury, in 78% to 91% mild injuries (106,107). In regards to disability estimation, nonepileptic seizures can be as disabling as epileptic events. However, the disability claim is based on a completely different diagnostic entity, which may influence the chance of approval. Differentiating epileptic and nonepileptic seizures will pose a diagnostic challenge in Iraq veterans. Nonconvulsive Seizures and Status Epilepticus There is limited literature regarding the incidence of late post-traumatic nonconvulsive seizures and status. Particularly, patients with persistent cognitive impairment after head injuries are at risk of subclinical seizures for a variety of reasons. They have a 20% risk to develop epilepsy and they may not be able to communicate seizure symptoms. The caregivers may confound seizure activity with other causes of impaired or fluctuating cognition and consciousness (21). Patients who are not cognitively impaired do not recognize more than half of their seizures.