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  • Associate Professor of Pharmacy Practice, Butler University, College of Pharmacy and Health Sciences
  • Director of Ambulatory Pharmacy Services, Community Health Network, Indianapolis, Indiana


This memo provides a short summary of the resolution and hyperlink to gastritis in toddlers discount protonix 20mg mastercard the full text and additional materials (if applicable) gastritis symptoms blood purchase protonix 20 mg with mastercard. Carriers will be required gastritis diet journal printable buy protonix 40mg line, within 30 days chronic superficial gastritis definition purchase protonix 40mg otc, to validate reports that directories are inaccurate or incomplete and, when appropriate, to correct the provider information. The transition policy shall be similar to that which was adopted by the Maryland Health Progress Act of 2013, as appropriate. The triggering date is the effective date for the plan in which the individual has been automatically enrolled. Resolution To Establish Outreach Strategies to Promote Tobacco Cessation Programs and Other Preventive Benefits That Are Covered Without Cost Sharing (5/9/2013) 1. Recognizing that carriers now communicate with new enrollees, ensure that carriers include information about tobacco cessation and other preventive services in their new member communication. Note: this recommendation is not intended to duplicate existing communication or add to costs. Recognizing that carriers now communicate with providers, ensure that carrier communications to their providers include up to date information on the preventive benefits and tobacco cessation programs to be provided with no cost sharing. These counselors should stress the importance of enrollees speaking directly with their carrier to obtain more information on these benefits. Utilize alternative vehicles for communication, other than carriers, including providing educational materials to small business owners and benefit administrators on the availability of preventive services including tobacco cessation 6. Maintain ongoing discussions with key stakeholder groups to identify additional opportunities to increase the use of preventive services including tobacco cessation. Stakeholder groups should include at least carriers, providers, and community organizations. Going forward, the proration calculation will be based on Plan M anagem ent Advisory Com m ittee to be the actual number of days in the month, yielding a more precise refreshed in 2018 result. Example of ceasation of invoicing timeline: Introducing assigned Plan M anagem ent team m em bers: May 1, 2018: Group terminated for non-payment with coverage end date of 3/31/2018 (paid through date will be 2/28/2018) and Andre Dixon (andre. Kaiser & Delta Dental st June 1, 2018: Group reinstatement window closes and 1 invoice Brian Schwartz (brian. Health and dental carriers offering coverage in the individual and/or sm all group m arkets are subject to these rules and policies, as w ell as all applicable federal and District law s. If, after initial review, it is determined the requested change in benefit is visible in the O lufunm ilayo Hall O lufunm ilayo. The adoption of rules and policies enables the Exchange to m eet federal and District requirem ents and provides health carriers w ith inform ation necessary to design and develop qualified health plans and qualified dental plans. The last date of the claims grace period will be transmitted as the date of termination for the carrier installation. Consumers will be granted a terimination date as early as the date of the request. Consumers’ requests for a retroactive termination date will continue to be processed via the established tracker process. Health and dental carriers offering coverage in the individual and/or small group markets are subject to these rules and policies, as well as all applicable federal and District laws. The formal request to reopen for submission should be made on company letterhead and describe the changes to the template. The adoption of rules and policies enables the Exchange to meet federal and District requirements and provides health carriers with information necessary to design and develop qualified health plans and qualified dental plans. To terminate a group’s coverage, the employer must provide a written request 30 days in advance Deadline to subm it all 10/1/2017 plan corrections of the desired termination date. For voluntary terminations, the group’s coverage can only be terminated at the end of a calendar month. A request to terminate an entire group that is th submitted after the 15 of the month, will not be effective until the last day of the following month. For example, an employer th who provides a request for termination on August 15 will receive st an August 31 termination date. An employer who provides a th request for termination on August 16 will receive a September th 30 termination date. Code §31-4305 (revocation and appeal language for life insurance) and §31-5111 (applying §31-4305 to health insurance). Department of Health and Human Services, the Anti-Duplication Provision prohibits Q 4 M eeting Scheduled for Novem ber 29, 2017 issuers that have knowledge that an individual is entitled to Medicare Part A or enrolled in Medicare Part B from selling or issuing new policies to that individual an individual market policy that duplicates benefits to which that individual is entitled. However, consistent with the Guaranteed Renewability Provision, it does not prohibit renewal of policies that an individual is already enrolled in, regardless of whether that person is eligible for Medicare Part or enrolled in Part B. Such enrollments are renewals and shall not be rejected or cancelled on the basis on Medicare eligibility or enrollment. In contrast, if a customer is entitled to Medicare Part A or enrolled in Medicare Part B and seeks an initial enrollment into a Qualified Health Plan that duplicates Medicare coverage, carriers may cancel this enrollment within 31 days of receipt. All appropriate refunds shall be made for premiums paid for months that are cancelled. Notably, stand-alone dental coverage does not duplicate Medicare Part A or Part B coverage and thus could not be cancelled under this policy. The Carrier Integration Manual permits carriers to require binder Deadline to submit all 10/1/2016 payments to effectuate coverage, provided that plan corrections carriers afford consumers 30 days to make the binder payment before the carrier is permitted to cancel coverage for nonpayment. However, carriers must apply able to offer to our small business customers,” their binder payment policies uniformly to all of their said Mila Kofman, J. Going forward, the policy is that carriers shall terminate coverage for adult Deadline to submit all 10/1/2016 dependent children at the end of the calendar year plan corrections (December 31st) during which the dependent turns 26 years of age. The scope of these calls is enrollment period on the dependent’s behalf intended to be more policy focused. We will also reach out to these members kindly submitting agenda items via email to regarding this change in their coverage carrier. Fourteen (14) days is considered reasonable notice in advance of a termination request. This creates multiple scenarios depending on when a customer makes the request and for what date the termination is requested. See examples below: Date of Termination Latest Date Term Earliest Date Term Explanation Request Request Date Can Occur Can Occur Customer Provided Reasonable Notice 1/17/2016 1/31/2016 1/31/2016 1/31/2016 (14 days) prior to requested date. Customer Provided Reasonable Notice 1/17/2016 2/8/2016 2/8/2016 2/8/2016 (22 days) prior to requested date. Customer calls carrier call center and/or provides electronic communication indicating that they would like to terminate their coverage. Carrier provides acknowledgement of receipt of termination file and processes in a timely manner (3 business days). The carrier may submit contrary evidence within 7 days of a voluntary termination transmission. For example, if an employee is terminated on 1/1/2015, we allow until 3/1/2015 to be informed and process the termination with the respective carrier(s). Until approximately March 2015, this rule was stretched by certain Congressional terminations due to internal operations within both the House and Senate that often prevented the timely transmission of terminations. Recognizing that the adverse impact this had on carriers we enforced the small group termination policy of 60 days on Congress. To view the full Carrier Reference Manual, click here: 2016 Carrier Reference Manual. The federal regulations provide that a group health plan seeking to take advantage of the exemption for certain religious employers are required to complete a self-certification and provide it to the health insurance carrier or carriers providing coverage in connection with the plan. Alternatively, the group health plan can provide a notice to the Secretary of Health and Human Services that it is an eligible organization. If the group health plan provides the self-certification directly to the issuer, the issuer is solely responsible for providing the coverage the employer has self-certified it has a religious objection to providing in accordance with the preventive health services requirements set forth a 45 C. An updated schedule for completion of the phased approach will be distributed to all carriers. Current Payment Model(s) Description 4 Select the category(ies) of payment models that are used by the issuer across its Marketplace product line. Payment Model Type Payment Model Description Fee for Service – No Link to Payments are based on volume of services Quality or Value and not linked to quality or efficiency. Fee for Service – Linked to At least a portion of payments vary based on Quality or Value the quality or efficiency of health care delivery. Alternative Payment Models Built Some payment is linked to the effective upon Fee for Service Architecture management of a population or an episode of care. Payments still are triggered by delivery of services, but there are opportunities for shared savings or two-sided risk. Population-based Payment Payment is not directly triggered by service delivery, so volume is not linked to payment.

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Varied exposure to gastritis burping buy cheap protonix 40mg a complex set of risk and protective factors at critical life stages can significantly alter individuals’ 5 metabolic health trajectories chronic gastritis h pylori purchase 40 mg protonix with amex, contributing to gastritis diet ideas quality protonix 20mg persistent disparities and increased risk of diabetes among certain groups gastritis diet brat order protonix 40mg. Factors placing individuals at increased risk for diabetes include gestational diabetes, propensity toward bottle feeding for 23,25 infants, poor diet, sedentary lifestyle and unhealthy sleep patterns. Inequities in social, economic, and environmental 25,6 conditions may increase these factors in racial minorities. To illustrate, African American women are less likely to breastfeed, a known protective factor for diabetes, than White or 26 Hispanic women. Lower breastfeeding rates in African American women may be due to cultural norms, negative 26 perceptions about breastfeeding, lack of partner support, or unsupportive work environments. In order to reduce disparities in diabetes and improve health equity, increasing protective factors such as breastfeeding in high-risk populations should be examined. Early onset of diabetes in youth, including type I diabetes, and poor glycemic control have been associated with lower educational attainment and unemployment, which may limit access to health insurance and preventive health care 5 services, as well as impact health-seeking behaviors. For example, low-income families and households with limited access to affordable produce are less likely to maintain a healthy diet than those with higher incomes and who live 27,28 in close proximity to a grocery store. Similarly, individuals who live in unsafe neighborhoods with high crime rates or 29,30 that lack sidewalks, parks and other green space are less likely to maintain recommended levels of physical activity. Diabetes results in a total of $245 billion in direct medical costs ($176 billion) and indirect costs due to disability, work loss, and premature 22 mortality ($69 billion). Type 2 diabetes currently accounts for the majority of diagnosed diabetes cases in adults (90-95 22 percent), and an estimated 1. Onset of type 2 diabetes can be prevented by reducing risk factors such as overnutrition (taking in more calories than required for normal growth and development), 3 physical inactivity, and overweight or obesity. An important predictor of future burden, an estimated 86 million adults in the United States are currently living with 22 prediabetes, or impaired glucose tolerance. This represents a substantial opportunity for impact through public health interventions. In 2010, an evaluation of clinical trials found that a modest weight loss of less than 20 pounds could substantially reduce the risk of diabetes; the study also found that moderate to intense physical activity. In the absence of intervention, it is currently projected that more than 30 percent of individuals in the United States will 32 develop diabetes in their lifetime. Given the increasing prevalence of type 2 diabetes at younger ages, an increasing 37 number of women are entering pregnancy with the disease. Those who enter pregnancy with uncontrolled diabetes are more likely to experience complications, such as preeclampsia, macrosomia (birth weight >4,500 grams), congenital 33 35, 36 malformations, or perinatal death. Obesity and diabetes increase risk for maternal morbidity, which makes prevention of these conditions a valuable preconception health opportunity. Diabetes is a risk factor for two main causes 36 of severe maternal morbidity including cardiac conditions and preeclampsia. Although screening for gestational diabetes 38 is recommended at 24 weeks, greater awareness of diabetes prevention in women of childbearing age could help to 37 reduce the impact diabetes has on women and families. A review of 2004 death certificates revealed that heart disease was reported in 68 percent of 8 diabetes-related deaths. Screening for type 2 diabetes is now recommended for adults with high blood pressure and 9 other cardiovascular risk factors in order to identify and manage undiagnosed cases. The consequences of uncontrolled diabetes can be devastating for individuals, their families, and their communities. In 8 2011, diabetes was the leading cause of blindness among adults age 20 to 74 years. Diabetes also accounted for an 8 estimated 60 percent of non trauma-related lower-limb amputations and 44 percent of end-stage renal failure in adults. A number of other morbidities have been linked to diabetes including gum disease, hearing loss, non-alcoholic fatty liver 17disease, erectile dysfunction, depression, polycystic ovarian disease, complications of pregnancy, and some cancers. Leverage or realign resources Given the complex set of social, economic, and environmental factors associated with the onset of type 2 diabetes, investment in a multi-sector approach offers the most promising route to its prevention and management. State or local level policies such as the New York City local government’s requirement for posting nutrition information on menus and limiting the size of beverage cups make 42 healthy nutrition choices easier and may make consumers more aware of nutrition. Other interventions that are shown to be effective in reducing incidence and effectively managing type 2 diabetes include combined diet and physical activity promotion programs in clinical or community settings, case management to monitor and improve glycemic control, and 39 type 2 diabetes self-management education in community gathering locations. Medicare and Medicaid have a significant interest in diabetes prevention due to health care costs. Currently, Medicare 16 covers diabetes screening tests and tools needed for diabetes self-management such as insulin and other medications. Also, through the Affordable Care Act, preventive services such as type 2 diabetes screening, diet counseling, and blood 16 pressure screening are covered without cost sharing. Beyond nutrition and physical problems, diabetes in school-age children increases risk for academic 11 disadvantage. In addition, adolescents ages 15-17 who are overweight tend to show signs of depression, shame, and being 14 victims and perpetrators of bullying. Many schools already have interventions in place that promote physical activity and behavioral changes. Some have been successful in diet modification and increasing physical activity, but more research is needed about long-term effects of school interventions, and whether or not the interventions are being followed through 15 outside of the school environment. Predict an individual’s health and wellness and/or that of their offspring As noted above, improperly managed diabetes can lead to damage to the heart, blood vessels, eyes, kidneys, mouth, gums, teeth, and nerves leading to multiple serious health problems including cardiovascular disease, blindness, kidney 46,47 failure, and lower limb amputations. Diabetes causes damage to small blood vessels in the kidneys creating high risk 48 for chronic kidney disease, which presents in 35 percent of adult diabetics. Multiple risk factors for cardiovascular 46 disease are common in individuals with diabetes, particularly type 2 diabetes. Type 2 diabetics also have a higher risk 46 for high blood pressure, high cholesterol, obesity, and/or high triglyceride levels. A clustering of three or more of these 46 cardiovascular disease risk factors in an individual is known as metabolic syndrome. In an estimated 50 percent of 46 diabetics, some form of diabetic neuropathy (nerve damage) will occur, with risk increasing with the duration of diabetes. Lastly, there is also evidence that people 5,46 with diabetes are at double the risk of depression compared to people without diabetes. Elevated risk for depression 46 may be due to stress related to having diabetes or could be linked to the effect diabetes has on brain function. Increased health risks for infants born to diabetic mothers may illustrate this hypothesis. Infants born to diabetic mothers are at a high risk for spontaneous abortion, congenital malformations, 18 stillbirth, and perinatal morbidity and mortality. Maternal diabetes may cause infants to produce excess insulin, leading to increased growth rates and macrosomia (birthweight > 4,000 to 4,500 grams). Maternal diabetes also leads to a higher 19 risk for breathing problems and low blood glucose levels in infants. In childhood and adolescence children born to 20 diabetic mothers are at a higher risk for obesity and development of type 2 diabetes. The elevated risk of diabetes in children and adolescents born to mothers with diabetes during pregnancy creates a cycle of diabetes that persists across 37 generations. Greater awareness, prevention and management of diabetes across the lifespan will reduce the impact 37 diabetes has on women, children, and families. Currently, data are collected monthly in all 50 states, the District of Columbia, Puerto Rico, the U. Some of these are core questions asked each year, and some are rotating core questions asked every other year. Juvenile diabetes is also a major public health issue; however, analysts may have insufficient cases and statistical power to make meaningful interpretations of the data. However, refusal to answer generally accounts for a small proportion of responses for most data elements. Quality control computer programs are used to check the raw data for values out of range. Interviewers are monitored during the annual questionnaire pilot period and intermittently during the data collection period to determine whether any interviewer bias exists and to correct any bias that might be found. For 2011, the median weighted response rate for the combined cell phone and landline was 49. The survey adjusts for non-response to reduce the known differences between respondents and non-respondents.

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Anaerobic organisms gastritis diet foods eat protonix 40 mg low price, particularly anaerobic gram-negative rods gastritis diet chocolate cheap 20mg protonix with visa, predominate in more severe disease gastritis diet 5 days generic protonix 20mg without a prescription, especially that which spreads beyond the teeth and alveolar processes gastritis diet 900 cheap 40 mg protonix amex. In addition to surgical drainage of the abscessed tooth, the most appropriate therapy for this patient is ampicillin-sulbactam, because it has activity against fi-lactamase–producing anaerobic and aerobic organisms. Most orofacial infections arise from periapical, periodontal, or pericoronal dental infection that spreads by the path of least resistance into surrounding (potential) spaces and tissues. Spread of infection into the fascial spaces can result in significant facial swelling and fever, such as that described in the vignette. Odontogenic infections in children usually are localized; significant spread can lead to respiratory compromise and life-threatening complications. Serious odontogenic infection should be treated with intravenous antibiotics and, if indicated, surgical drainage. Given the polymicrobial nature of infection, with anaerobic organisms playing an important role in severe disease, broad-spectrum antimicrobial therapy with activity against filactamase–producing anaerobic and aerobic organisms is optimal. Cephalosporins, such as cefotaxime, are second-line agents for the treatment of odontogenic infection. They effectively treat fi-lactamase–producing oral streptococci and gram-negative pathogens such as Eikenella, but must be combined with metronidazole for anaerobic coverage. Metronidazole has excellent activity against anaerobic pathogens but no activity against aerobic gram-positive and gram-negative organisms. In addition, there is increasing resistance to tetracycline among gram-positive and gram-negative organisms. Mild odontogenic infection may be treated with oral penicillin, amoxicillin, or clindamycin, but as resistance to these agents is increasing, patients must be monitored closely for clinical improvement. Her plan of care includes obtaining blood, urine, and cerebrospinal fluid cultures, and initiating empiric intravenous antibiotic therapy. As you discuss this plan with the admitting resident, you ask how she will manage the newborn’s procedure-related pain. The resident replies that she generally does not use any pain management modality when performing procedures in newborns, as they are much less affected by these procedures than older children. The most accurate statement related to pain management in infants is that undergoing painful procedures in infancy may result in long-term changes in pain response. It is imperative for all pediatric providers to understand the effects of patients’ developmental stage on their response to pain and to apply this knowledge in implementing appropriate pain management plans for children of various ages. The field of knowledge related to pain response in children and pediatric pain management techniques has advanced significantly over the past 2 to 3 decades. Regarding newborns specifically, an emerging body of literature highlights the critical importance of appropriate pain management. Historically, analgesics were rarely administered to newborns, based on the theory that they experience less pain because of the immaturity of their nervous systems. Until the late 1980s, in fact, newborns often underwent certain surgical procedures without anesthesia. Recent studies suggest that newborns may actually have an increased sensitivity to pain, which may be attributable to the fact that although their ascending nerve pathways can transmit painful stimuli to the brain, descending inhibitory pathways are not yet established. Data demonstrate that neonates display a more pronounced physiologic response to pain and require higher serum concentrations of analgesics to modulate pain compared with older children. Studies also indicate that repeated exposure to painful stimuli in the neonatal period can increase sensitivity to subsequent painful stimuli as well as routine handling. In addition, infants who experience painful procedures may develop altered responses to future painful episodes, even those that occur well beyond infancy. Pain may even be a contributing factor in the occurrence of intraventricular hemorrhage in preterm infants. A number of general principles should be applied to managing pain appropriately in children: • Pain prevention: Pain should be managed prophylactically, if it can be anticipated. A single modality approach to the management of procedure-related pain is not the best strategy for infants or older children. A multimodal approach incorporating environmental, behavioral, and pharmacologic interventions is much more effective. Current literature contradicts the theory that infants lack the cognitive ability to remember painful experiences. Studies also indicate that compared with older children, newborns may display a greater physiologic response to pain. The pregnancy was complicated by limited prenatal care and maternal substance abuse. Your quick assessment reveals a heart rate of 90 beats/min and a respiratory rate of 50 breaths/min. Physical examination demonstrates a jittery newborn with decreased perfusion, moderate grunting, and cool extremities. A newborn with cold stress will develop tachypnea and peripheral vasoconstriction. The peripheral vasoconstriction leads to decreased perfusion, poor color, and cool extremities. Biochemical findings associated with cold stress include metabolic acidosis and hypoglycemia. All newborns are at risk for convective, evaporative, and conductive heat loss at the time of delivery. This heat loss is exaggerated in newborns born prematurely because of decreased epidermal thickness, decreased brown fat, and increased surface area. Optimizing the temperature in the delivery room, gently drying the neonate, and replacing any wet towels and blankets with dry warm blankets can minimize heat loss in the full-term and late-preterm newborn. Unless clinically unstable, full-term and late-preterm newborns should be placed on the mother’s chest shortly after birth for both bonding and enhanced thermoregulation. A radiant warmer should be available in the delivery room for management of newborns who are unstable or premature. This will provide the resuscitation team ready access to the newborn while minimizing heat loss. Many radiant warmers allow a temperature probe to be placed on the newborn’s skin that allows auto regulation of the overbed heat output. If auto regulation is unavailable, and the radiant warmer temperature is manually set to deliver maximum heat, the newborn’s temperature should be monitored frequently to avoid hyperthermia. The clinical signs and symptoms of cold stress can mimic those of neonatal sepsis or drug withdrawal, though sinus bradycardia is generally not present in those conditions. Cold stress can lead to surfactant deficiency in affected premature infants, but the mild tachypnea without other signs of respiratory distress in the newborn in the vignette makes surfactant deficiency unlikely. Cold stress and hypoglycemia in the late preterm (“nearterm”) infant: impact on nursery of admission. He was referred to an ophthalmologist, who found an unremarkable examination and recommended monitoring. In addition, she feels he looks excessively tired in the afternoons and she is putting him down for naps, but he says he is not tired at all. He goes to sleep easily at night, sleeps through the night, and wakes up without difficulty. His symptoms of intermittent ocular misalignment and ptosis are highly suggestive of this disease. In the classic presentation of myasthenia gravis, the patient has intermittent symptoms that improve with rest. Most patients feel better after rest or a nap, so the clinician has to determine if the improvement is subjective or if the patient has actual weakness that improves. It can also be difficult to differentiate ptosis from drooping eyelids because of fatigue; children with ptosis do not subjectively feel tired. Because the symptoms fluctuate, the examination findings can be normal at times, as in the boy in the vignette. The diagnosis of myasthenia gravis is confirmed with serum myasthenia gravis antibody titers. In hospitalized patients, edrophonium can be given intravenously to help confirm the diagnosis, but is not used as commonly as it was in the past. Edrophonium is a short-acting acetylcholinesterase inhibitor which, when given intravenously, will cause a patient with myasthenia gravis to have a sudden improvement in symptoms. The patient may also experience sudden salivation, and possibly defecation or bradycardia because of its parasympathomimetic effects. Another method used to diagnose myasthenia gravis is a nerve conduction study with repetitive stimulation. Repetitive stimulation is a specialized test that confirms the presence of a defect in signal transmission at the neuromuscular junction.

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The most highly exposed group received doses of 4–7 Sv gastritis eggs cheap protonix 20mg on-line, one receiving up to gastritis information purchase protonix 40mg with visa 10 Sv severe erosive gastritis diet order cheap protonix. The collective external dose amounted to gastritis diet ãóãúë purchase protonix with paypal 56 person–Sv and the internal dose to 4 person–Sv. Four people died within six weeks; of 112 000 people monitored, 249 showed detectable contamination, and 129 of them were found to have internal contamination and were referred for medical care. In order to estimate the absorbed radiation dose, the initial frequencies of chromosomal aberrations (dicentrics and rings) were determined in 110 exposed persons (Natarajan et al. The frequencies of translocations detected years after the accident by fluorescence in situ hybridization were two to three times lower than the initial frequencies of dicentrics, the differences being larger at higher doses (> 1 Gy) (Ramalho et al. The results for visible recessive mutations (specific locus test) indicate a conversion factor of 3 for acute to chronic irradiation (Russell & Kelly, 1982). This is the factor that has often been used to account for the difference between acute and protracted doses in humans, although a factor of 5–10 could equally well be proposed in view of the data shown in Table 42. The mutation rates for skeletal abnormalities in mice after single doses of X-rays were estimated to be 1 fi 10–5 per gamete per cGy for spermatogonia and 3 fi 10–5 per gamete per cGy for the post-spermatogonial cell stages (corrected for unirradiated controls) (Ehling, 1965, 1966). This procedure is often used to increase the mutation yield while avoiding excessive cell killing (Russell, 1962). In Xand fi-irradiated spermatogonia, the mutation rate for abnormalities of the lens was 3–13 fi 10–7 per gamete per cGy (Ehling, 1985; Graw et al. The mutation rate in post-spermatogonial stages appeared to be twoto fivefold higher than that in spermatogonia. Other dominant mutations include those that result in changes in growth rate, coat colour, limb and tail structure, eye and ear size, hair texture and histocompatibility. No significant increase in mutation frequency at histocompatibility loci was detected in irradiated sperm or spermatogonia (Kohn & Melvold, 1976; Dunn & Kohn, 1981). This result could indicate reduced mutability of these loci or a greater susceptibility for lethal mutations than expected on the basis of known mutation rates for visible recessive mutations in mice. The spontaneous rate of visible dominant mutations other than skeletal abnormalities and cataracts is approximately 8 fi 10–6 per gamete per generation (see Table 41). Protracted treatment with 60Co fi-rays yielded a spermatogonial mutation rate of 1. In X-irradiated female mice, the induced rates were between 5 fi 10–7 and 10 fi 10–7 per gamete per cGy for single doses of 2, 4 and 6 Gy (Lyon et al. Studies with a different marker stock suggested a mutation rate as high as 3 fi 10–6 per gamete per cGy, after two doses of 5 Gy of X-rays at a 24-h interval (Searle & Beechey, 1985, 1986). Thus, a deficiency in the number of offspring is measured from conception to the time of weaning, i. Dominant lethal mutations are attributed to the induction of chromosomal aberrations that interfere with cell and tissue differentiation during fetal growth. These aberrations are generally eliminated during mitotic cell division and do not persist in stem-cell populations. In general, mutation rates of about 10 fi 10–4 per gamete per cGy were reported (Ehling, 1971; Schroder, 1971; Grahn et al. At low dose rates of radiation, mutation rates of 5 fi 10–4 per gamete per cGy were observed (Grahn et al. Few data are available on the induction of dominant lethal mutations in irradiated female mice. In one study, the average mutation rate 1–28 days after irradiation was similar to that seen in the male mice, 10 fi 10–4 per gamete per cGy (Kirk & Lyon, 1982). In guinea-pigs, rabbits and hamsters, the rate of dominant lethal mutations in males appeared to be lower than that in male mice, but those in females were similar (Lyon, 1970; Cox & Lyon, 1975). Stem-cell stage: Dominant lethal mutations generally do not persist in stem-cell populations because of chromosomal imbalance; however, balanced chromosomal translocations can be transmitted during the proliferative phase of gametogenesis, and such gametes behave like dominant lethal mutations. The dose-rate effect for fi-rays is significant, as the mutation rate fell to 3 fi 10–5 per gamete per cGy with weekly exposures from 1. The rate of sex-linked lethal mutations was first determined after the detection of a large inversion of the X chromosome. Two doses of 5 Gy of X-rays at a 24-h interval to the spermatogonia of mice gave a mutation rate of 3. Irradiated wild-type male or female mice are crossed with stock bearing these mutations, and new mutations at any of the marker loci are observed in the F1 progeny. Most of the radiation-induced mutations examined at the molecular level appeared to be deletions (Bultman et al. In post-spermatogonial stages, the mutation rate reached 65–70 fi 10–8 per locus per cGy in progeny conceived four weeks after exposure of the male parent to 3 Gy of low dose-rate X-rays (Sega et al. The mutation rate was increased by fractionation of 1 Gy into two equal doses at a 24-h interval, but not by a larger number of fractions or a shorter interval (Russell, 1962). The spontaneous rate of recessive visible mutations in female mice was estimated to be 1. From these results it is clear that the dose-rate factor—the ratio of the mutation rates at high and low dose rates—for females is at least 10, whereas it is 3 for males (Lyon et al. The colours of the spots on the adult fur were due either to expression of the recessive genes or were white because of cell killing. Loss of heterozygosity: Genetic alterations that result in loss of heterozygosity play an important role in the development of cancer. The underlying mechanisms are mitotic recombination, mitotic non-disjunction, gene conversion and deletion (Smith & Grosovsky, 1993). Such events occur not only in genetically unstable cancer cells but also in normal human and mouse somatic cells (Hakoda et al. The mechanisms of loss of heterozygosity have been studied in mice rendered heterozygous for the autosomal Aprt gene by gene targeting (Van Sloun et al. A dose-dependent increase was observed in Hprt mutant frequency, but that for Aprt was no different from that of controls, even though clear induction of mutations at the Aprt locus was observed after treatment with chemical carcinogens. Molecular analysis indicated that 70% of these mutations were caused by loss of heterozygosity. The hemizygous Hprt locus appeared to be a better target for the recovery of X-ray-induced mutants than the heterozygous Aprt locus. This result is unexpected, as X-rays induce predominantly multilocus deletions (Hutchinson, 1995), and deletion of an essential flanking gene from a hemizygous locus would be more detrimental for the cell. The results also suggest that loss of heterozygosity might not occur after ionizing irradiation, at least at the Aprt locus in mice (Wijnhoven et al. The rate of induction cannot be explained by the occurrence of initial radiation damage within the minisatellite sequence, and suggests an unexpected mechanism involving radiation-induced damage elsewhere in the genome (Dubrova et al. Such minisatellite mutations have no known phenotypic effect or any direct relation to carcinogenesis. The responses of Big Blue LacI transgenic mice to ionizing radiation were measured as induction of LacI mutations in the spleen. Of 34 mutations analysed, four were large-scale rearrangements, three of which were deletions within the LacI gene, while the fourth was a deletion that extended from within the fi LacZ gene into downstream sequences. The Big Blue LacI transgenic mouse reporter system was also used to investigate mutation induction in the testis, spleen and liver after whole-body irradiation of the mice with 60Co fi-rays. No statistically significant induction of mutation was observed in testis or spleen 35 days after exposure, although the mutation frequencies tended to be increased by approximately 1. The main obstacles to understanding the fundamental processes involved in radiation-induced cancer in animal models until recently included the long latency and the complexity of the neoplastic process. In an effort to overcome these problems, animal models have been developed for the identification, isolation and characterization of radiation-altered or radiation-initiated cells from irradiated tissues shortly after exposure (Ethier & Ullrich, 1982; Clifton et al. These ‘in-vivo/in-vitro’ systems have been used to show that initiation of cells by ionizing radiation is a frequent event, of the order of 10–2, which is much greater than would be expected if initiation were the result of a simple mutation. Subsequent analysis of initiated cells and detailed study of their progression led to the hypothesis that a critical early event in radiationinduced carcinogenesis is the induction of widespread genomic instability, which is apparent from increased cytogenetic damage and increased mutation rates in the progeny of irradiated cells many cell doublings after exposure (Ullrich & Ponnaiya, 1998). In one model involving transplantation of mammary tissue or mammary cells into syngeneic hosts (DeOme et al. The cell populations that emerged had increased growth potential in vitro and enhanced tumorigenic potential with increasing time in situ (Adams et al.

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