text:
Rhetoric and Composition/Dangling modifier

 Editing symbol:  dm

What Is a Dangling Modifier?
A common way to save words and combine ideas is by starting a sentence with a phrase that provides additional information about an element in the sentence without having to make a whole separate sentence to say it. In the following example, notice how three choppy sentences condense into one smoother sentence with the use of such an opening phrase, which is called a modifier:
 * Original: The Student Council exists to represent students to the faculty and administration. It also oversees student organizations. The Student Council plays an important role in campus life.
 * Rewrite: Responsible for representing students to the faculty and administration and overseeing student organizations, the Student Council plays an important role in campus life.

Here are some other examples of sentences that begin with a phrase providing this sort of additional information:
 * An example of bottom of the pyramid targeting, microcredit ventures lend small amounts of money to those with minimal assets.
 * Found in tropical southern Asia, the Asian Koel belongs to the cuckoo order of birds.
 * After completing the experiment, the most bacteria appeared in the scraping taken from the drinking fountain.

Notice something odd about the last one? The modifier -- "After completing the experiment" -- doesn't match what follows it: The bacteria didn't complete the experiment (presumably, a researcher did)! The rule for using modifiers at the beginning of a sentence is that the thing being modified must immediately follow the modifier. Sometimes this requires you to rearrange the sentence; other times you have to "spell out" what is being modified if you didn't include it.

Examples

 * Dangling modifier: Covering most of Minnesota, the illustration showed the glacier that left the state with its thousands of lakes.
 * Corrected: Covering most of Minnesota, the glacier left the state with its thousands of lakes, as depicted on the illustration.
 * Dangling modifier: Trekking across the desert, fierce winds swirled around the riders.
 * Corrected: Trekking across the desert, the riders were assaulted by fierce winds.
 * Dangling modifier: First coined in 1980, historian Linda Kerber used the term "republican motherhood" to describe a phenomenon occurring after the Revolutionary War in which women were encouraged to promote the ideals of liberty and democracy to their children.
 * Corrected: First coined in 1980, the term "republican motherhood" was used by historian Linda Kerber to describe a phenomenon occurring after the Revolutionary War in which women were encouraged to promote the ideals of liberty and democracy to their children.

What Is a Misplaced Modifier?
Whereas a dangling modifier is "left hanging," so to speak, with its referent missing in action, a misplaced modifier's referent is present and accounted for, but as its name implies, the modifier itself is out of place within the sentence, such that it seems to modify another referent in the sentence, resulting in ambiguity or confusion.

 Editing symbol:  mm

Examples

 * Misplaced: Erik couldn't ride his bicycle with a broken leg.
 * Misplaced: The little girl walked the dog wearing a tutu.
 * Misplaced: Just don't stand there.

 * Correct: With his broken leg, Erik couldn't ride his bicycle
 * Correct: Still wearing a tutu, the little girl walked the dog.
 * Correct: Don't just stand there.

What Is a Squinting Modifier?
Unlike a dangling modifier or a misplaced modifier, a squinting modifier is placed right next to the word it refers to, but it is also near another word that it might be modifying, which can cause confusion.

Examples

 * Squinting: Cycling uphill quickly strengthens the leg muscles.

Or
 * Correct: Quickly cycling uphill strengthens the leg muscles.
 * Correct: Cycling uphill can quickly strengthen the leg muscles.

 * Squinting: Using modifiers clearly will improve your writing.

Or
 * Correct: Clearly using modifiers will improve your writing.
 * Correct: Using modifiers will clearly improve your writing.


text:
Rhetoric and Composition/Know your patterns

Elsabeth Belecaw                                                                                Belecaw 1 ENGL 110 - Composition 1 Professor Dahlen June 14, 2020 My Time in Dubai Working out of Country is grate chance to learn about other’s cultures, religions, languages, work experience and to get money for life too. After I graduate from high school, I can't join the college because my grade was not enough to join the university or college and I don’t have enough money to pay for the private colleges. That’s why I decide to go to the United Arab Emirates Dubai to work. After I fill the form and pay the commission to the Agent office, I get my travel document and work permit visa for the family in Dubai United Arab Emirates. From Ethiopia to Dubai it will take three hours and thirty-five minutes. after the airplane arrives and checks documents, I take my bag and go out to meet my employers. Oh My God the outside weather pulls me back to inside. The weather was so hot, and it has hummed too. In Dubai, it will record 110-degree Fahrenheit and more for the summer. I ready myself for the weather and go out again I see one man who holds my photo. He comes to me and says “Salman Walekum” means like “hello” I say, “Hi Sir” He shows me his ID and other documents to tell me that he is the employer. I remember him because they show me his picture in the agent's office. We both agree to go. We can't talk, we stand outside more than this because of the hot weather so, he

Belecaw 2 shows me his car. Then he helps me to put my stuff in his car and we start going to his house. On the way, we talk about the weather and about my flight with broken English. When we rich at his home his wife (Madam) comes with a beautiful smile and she says “Hi Elsabeth” I say “Hello Madam” I was very happy that she can speak English better than her husband. She shows me a warm welcome. After I take bath and eating lunch, she introduces me to her two kids both were girls. My career for the family was cleaning the house, laundry clothes, ironing, and when madam is not at home take care of kids. The first two weeks were very hard because they stay two months without a housemaid so there were a lot of works to do and I missed my family too. But after a month I can manage my daily duties and adapted my missing family. But my basic problem was communication with kids when their mother is not at home it's hard to understand what they want. OH, there was a lot of fun until I can speak and understand Arabic. One day they say, “let's play with you please” in Arabic, I say, “oh are you hungry?” they say, “LA LA LA” means “NO NO NO “then I say, “do you want to go to the bathroom?” oh my God the youngest one she starts crying because I can't understand what they want. Finally, the oldest one she shows me their toys then I understand that they want to play. This kind of misunderstanding was a lot when madam is out. I try my best to learn the Arabic language by watching Arabic moves and talk to kids as well.it takes me almost six months. Not to be perfect just to communicate. After that my life becomes Belecaw 3 easier And, I start enjoying life in Dubai. I think I was lucky because I heard many problems with other housemaids. Like, not get enough food from their employer, late payment salary, more works, and more working hours. my Madams have such great personality she was like my older sister she never treats me like how other madams treat their housemaids Her husband was a police officer. He was a nice man too. My contract agreement was for two years. but. They ask me to stay one more year I was happy to do that. So, I stay with them for three years. It was a crazy idea of deciding to go and work in another country without knowing their language. But I spend a very nice time in Dubai. I learn a lot of things like Islamic and Arabic culture, language, norms, and lifestyles.

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/


text:
Handbook of Genetic Counseling/Frontonasal Dysplasia - Median Cleft Face Syndrome

Frontonasal Dysplasia - Median Cleft Face Syndrome

Contracting

 * How have things been going since your last visit?
 * What questions or concerns would you like to address today?

Interim History

 * Which physicians are you seeing? When are your follow-up appointments scheduled?
 * Recent tests: video swallowing study, audiologic evaluation, O2 saturation studies?
 * How have things been going since the cleft palate repair? Any complications? Current feeding issues?
 * Developmental assessment questions
 * Rolling over?
 * Sitting when supported?
 * Pincher grasp? Reaching for objects?
 * Babbling? Any consonant sounds? Words?
 * Are you satisfied with OT/PT services? Have you noticed improvements?

Psychosocial Assessment

 * Who lives in the home with you?
 * Are you working outside the home? Who cares for him when you are at work?
 * Do you have any help with his care? Do you feel like you need help?
 * Do you have support from family and friends?
 * What is most concerning for you?
 * Do you have any pets? Air conditioning (concern because of trach)?
 * Possible psychosocial issues:
 * Burden of caring for a child with complicated medical history
 * Disruption of family, lifestyle
 * Guilt, shock, denial, anger, fear about diagnosis
 * Social stigma, poor self-esteem for child with disfiguring condition

General Overview of Condition

 * Rare condition in which the midface does not develop normally
 * Affects the head and face
 * May cause widely spaced eyes, a flat broad nose, and a vertical groove in middle of face
 * Cause is not known but can be sporadic or familial

Etiology

 * Anomalies explained by single malformation
 * Nasal capsule fails to develop properly causing disruption in the positioning in the eyes and lack of formation of nasal tip
 * Considered nonspecific developmental field defect
 * Most cases sporadic
 * Some reports of familial aggregation but may be misdiagnosis
 * Reported in dup(2q) syndrome
 * Can occur as one feature in multiple malformation syndrome with recurrence risk is for syndrome

Clinical Features

 * Variability in severity of expression
 * Eyes
 * Hypertelorism
 * Lateral displacement of inner canthi
 * Forehead
 * Widown's peak
 * Defect in midline frontal bone (cranium bifidum occultum)
 * Nose
 * Varies from notched broad nasal tip, divided nostrils with hypoplasia, absence of prolabium and premaxilla with cleft lip
 * Broad nasal root
 * Lack of formation of nasal tip
 * Occasional abnormalities
 * Accessory nasal tags
 * Anomalies of optic disk, optic nerve, retina, or eye (colobomas, cataracts)
 * Preauricular tags, low-set ears
 * Conductive deafness
 * Mental deficiency (8-20%)
 * Seems to be more severe when extracephalic anomalies occur or when hypertelorism is very severe
 * Probability low if features above are not as sever
 * Frontal cutaneous lipoma or lipoma of corpus callosum
 * Agenesis of corpus collosum
 * Anterior basal encephalocele
 * Tetralogy of Fallot
 * Cleft lip and/or cleft palate
 * Usually requires radical cosmetic surgery to repair
 * Natural history and lifespan depend on severity and complications but usually not significantly different from expected

Differential Diagnosis

 * Oculo-auricular-vertebral spectrum
 * Frontofacionasal dysostosis - autosomal recessive inheritance
 * Craniofrontonasal dysplasia

Resources

 * Children's Craniofacial Association (CCA)
 * Phone: (800) 535-3643
 * Email: contactcca@ccakids.com
 * Internet: http://www.ccakids.com

 * FACES: The National Craniofacial Association
 * Phone: (800) 332-2373
 * Email: faces@faces-cranio.org
 * Internet: http://www.faces-cranio.org

 * AboutFace U.S.A.
 * Phone: (888) 486-1209
 * Email: AboutFace2000@aol.com
 * Internet: http://www.aboutface2000.org


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title: User:Whiteknight/myskin1.css


text:
User talk:Whiteknight/Monobook.css

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Handbook of Genetic Counseling/Galactosemia

Galactosemia

Introduction

 * Disorder of galactose metabolism
 * Usually caused by deficient activity of enzyme galactose-phosphate uridyltransferase (GALT)
 * Autosomal recessive inheritance

Diagnosis
Variant Galactosemia
 * Detected in virtually 100% of affected infants if included in newborn screen
 * Presents with poor suck, failure to thrive, bleeding diathesis, and jaundice, hypoglycemia, hepatocellular damage, and hyperammonemia
 * If untreated in infants can result in
 * Liver damage
 * Sepsis
 * Mental retardation
 * If suspected remove lactose from diet while tests are pending
 * If placed on lactose - galactose restricted diet than symptoms quickly resolve and can prevent permanent damage
 * Despite early treatment still at increased risk for
 * developmental delays
 * speech problems
 * abnormalities of motor function
 * poor growth
 * poor intellectual function
 * premature ovarian failure in women
 * With continued dietary management-- many individuals with galactosemia have good health, and are able to lead independent lives
 * Outcome can be based on GALT activity, genotype, age at diagnosis and compliance with lactose restriction
 * Diagnosis made by measuring erythrocyte GALT activity and isoelectric focusing of GALT
 * Done for infants who have a positive newborn screening test, symptoms, or a positive clinitest reaction (copper oxidizing aldehyde) and a negative glucostix reaction (glucose oxidase impregnated strip)
 * Classic galactosemia G/G homozygote activity less than 5% of control
 * Heterozygote G/N GALT activity about 50% of control
 * Duarte variant activity between 5-20% (express stronger activity bands, which move toward the anode and lower pH)
 * Mol gen testing of GALT gene (chromosome 9p13) clinically available for biochemically confirmed galactosemia and is used for:
 * prognostic information
 * heterozygote detection
 * genetic counseling,
 * prenatal diagnosis
 * Biochemical assays also necessary for diagnosis and as therapeutic parameters include:
 * Erythrocyte galactose-1-phosphate -- metabolism of this precursor is blocked in the GALT reaction sequence --Concentration of erythrocyte galactose-1-phosphate exceeds 2mg/dl in untreated individuals and can be used to monitor the effectiveness of therapy.
 * Galactitol is a product of an alternate pathway for galactose metabolism and can be measured in the urine. Correlation with other measures may not be perfect.
 * Total body oxidation of 13C-galactose to 13CO 2 in breath is a good predictor of outcome and differentiates forms of galactosemia that reduce GALT activity in erythrocytes, but not liver
 * partial impairment of GALT activity (2% to 10% residual activity)
 * some aspects of classical galactosemia, such as early cataracts, mild mental retardation with ataxia, and growth retardatio
 * may have dyspraxic speech, and females may have amenorrhea or early menopause

Common Long Term Problems

 * memory problems
 * neurological problems (tremors and trouble with balance and gait).
 * Cataracts

Prevalence
Genotype-Phenotype Correlations
 * Classic galactosemia -- based on the results of newborn screening programs, is approximately 1/30,000
 * Carrier rate is 1:112
 * Significant correlations being found
 * arginine substitution for a glutamine at amino acid position 188 (Q188R) accounts for about 70% of the G alleles in the Caucasian population with northern European ethnicity. Homozygotes have no enzyme activity
 * some studies found greater proportion of patients with a poor outcome were homozygous for the Q188R mutation, and a greater proportion with a good outcome were not homozygous for the Q188R
 * Duarte variant is the allele in which an aspartate substituted for asparagine at position 314 (N314D) imparts bioinstability to the GALT enzyme.
 * In the homozygous state (D/D or N314D/N314D), erythrocyte GALT enzyme activity is reduced by only 50%.
 * Compound heterozygotes with this mutation (i.e., D/G or N314D/Q188R) have good prognoses and it is not clear whether dietary intervention is required
 * The S135L allele, in which a leucine is substituted for serine at amino acid 135, is prevalent in Africa. African-Americans with galactosemia and this allele in either homozygous or compound heterozygous state have a good prognosis because of lack of neonatal hepatotoxicity and chronic problems if therapy is begun early
 * An asparagine substitution for a lysine at position 285 (K285N) is prevalent in southern Germany, Austria, and Croatia and has a poor prognosis for neurological and cognitive dysfunction in either the homozygous state or compound heterozygous state with Q188R.

Differential Diagnosis

 * for neonatal hepatotoxicity
 * infectious diseases
 * obstructive biliary disease
 * other metabolic diseases such as (Niemann-Pick Disease, Type C1 and Wilson disease).
 * Galactokinase deficiency
 * should be considered in patients who have cataracts and galactosemia but healthy
 * have normal GALT activity
 * reduced galactokinase activity is diagnostic and is what causes cataracts
 * Epimerase deficiency
 * should be considered in patients who have liver disease, sensorineural deafness, failure to thrive, and elevated galactose-1-phosphate, but normal GALT activity
 * Detection of reduced epimerase activity is diagnostic

Management
Risk To Family Members
 * Immediate dietary intervention is indicated in infants whose GALT activity is less than 10% of control activity
 * Human milk, cow's milk and many formulas have lactose. There are currently many infant formulas that do not contain lactose, to choose from. These include soy-based formulas, such as Isomil or Prosobee, specialty formulas based on hydrolysed casein, such as Nutramigen or Alimentum and formulas based on cow's milk, in which the lactose has been removed and replaced with other sugars, including Similac Sensitive and Enfamil Lactofree. Additionally, it is important to know that Galactosemia may be less severe in some infants, allowing for partial breastfeeding.
 * Ideally blood gal-1-p level below 3 to 4 mg/100 ml
 * galactose-restricted diet should keep blood gal-1-p at this level, while containing enough nutrients for normal body function
 * The diet allows most protein-containing foods other than milk and milk products. Fruits, vegetables, grains, breads, fats and sugars are acceptable, as long as they do not have ingredients that contain galactose
 * Food labels should be read carefully
 * Medicines should be checked because lactose often an inactive ingredient
 * Dietary supplements only taken when recommended because inactive ingredients not listed
 * people with galactosemia should have a regular daily supplement of calcium either from a soy formula or tablets
 * Dietary restrictions on all lactose-containing continue throughout life
 * Uridine supplements have not been of value.
 * Recent research suggests that despite exogenous galactose restriction, endogenous galactose production may approach 2.0 g per day
 * The efficiency of restricting lactose in the diets of women who are at risk for having a child with galactosemia is unknown.
 * Agreement has not been reached on whether individuals with variant forms of galactosemia with residual GALT activity in the range of 3% to 20% should be restricted from galactose intake during infancy and early childhood --possible that dietary restriction of galactose might prevent sequelae such as cataracts, ataxia, dyspraxic speech, and cognitive deficits.
 * Unaffected parents of an affected individual are obligate heterozygotes and carry at one disease-causing GALT allele
 * Such carriers are asymptomatic and do not develop galactosemia
 * Appropriate and can be important to determine the disease-causing GALT alleles in the parents of an affected child to establish the risk for galactosemia in future pregnancies
 * Affected individuals have a risk for premature ovarian failure, but may have children. Children born to one parent with (G/G) galactosemia and one parent with two normal alleles (N/N) are obligate heterozygotes (N/G)
 * If one parent is affected (G/G) and the other parent is a carrier for a G allele (N/G or D/G), the child has a 50% chance of being a heterozygote and a 50% chance of having G/G galactosemia

Prenatal Testing

 * possible for fetuses at 25% risk for classical (G/G) galactosemia using either GALT enzyme activity or molecular genetic testing if the disease-causing GALT mutations in the family are known
 * Enzyme analysis and molecular diagnosis rely upon cells obtained by chorionic villus sampling (CVS) at about 10-12 weeks' gestation* or amniocentesis at 16-18 weeks' gestation.

Resources

 * Galactosemia Support Group
 * 31 Cotysmore
 * Sutton Coldfield
 * West Midlands, B75 6BJ, UK
 * Phone: 0121 378 5143

 * Adult Metabolic Transition Project
 * depts.washington.edu/transmet/gal.html

 * Children Living with Inherited Metabolic Diseases (CLIMB)
 * The Quadrangle, Crewe Hall
 * Weston Road, Crewe
 * Cheshire, CW1 6UR, UK
 * Phone: 01270 250221
 * Fax: 01270 250224
 * www.climb.org.uk

 * http://www.tdh.state.tx.us/newborn/handbook.htm -- great website for parent of newly diagnosed child
 * http://www.galactosemia.org/ -- website for parent support group
 * http://www.galactosemiaresource.com --site providing parents with links to research, support groups and provides a matching service to other galt parents in the same state


text:
Handbook of Genetic Counseling/Galactosemia-2

Galactosemia

Welcome client: Contracting

 * Review the medical history and family history
 * Talk about the condition itself/ how child is doing with it
 * Talk about nutritional issues

What are your major concerns?

 * Dietary guideline and restrictions. (make sure DR. Leslie understands Mom has gotten many different opinions from her old center and she wants straight answers that won't change.
 * The multivitamin for the calcium

Review medical history

 * The initial illness, changes since the diet adjustment
 * Current diet, current questions about diet

Review family history

 * Son was tested prenatally - a carrier
 * What about daughter?
 * No testing for either parent

Review the condition

 * Galactosemia is a condition where the sugars in the body can not be broken down. Specifically, the body can not break down galactose. Because Lactose is a larger molecule that contains galactose, it can not be broken down either. When the sugar can't be broken down, it creates a buildup of different substances that can be toxic to the body.
 * Treatment, as you know is to eliminate lactose and galactose from the diet.
 * Autosomal recessive
 * Risks to your other children
 * Risks to her children (definite carriers)

Review the dietary restaints

 * Read labels look for the bad stuff: casein, sodium caseinate, whey, curds, lactose, galactose, creamed, butted, breaded vegetables, dehydrated and canned soups. Commercial cakes, cookies, candies, and puddings.
 * Read labels for the good stuff: lactate, lactic acid, lactalbumin, stearoyl-2-lactylate
 * Supplementation with calcium and vitamin D: recommend a multivitamin

Possible counseling issues

 * Effect of feeding restraints on other kids/family
 * Guilt issues for mom about restricting the diet
 * Difficulty maintaining the diet for child


text:
Handbook of Genetic Counseling/Gastroschisis

Gastroschisis

Introductions

 * How are you doing/ how's the pregnancy going?
 * How far along are you?

Contracting

 * We want to explain what this finding means for your baby and your pregnancy
 * Ask a few questions about your pregnancy and family history

Tell me a little about how the pregnancy has been going

 * Any infections?
 * Cigarette use?

Gastroschisis

 * What have you been told? I know that it was recently diagnosed
 * The basics
 * A hole through which the baby's intestines are outside of the body
 * Do you want to see a picture of what it will look like? -
 * Cause
 * Usually gastroschisis is isolated and there are NO other abnormalities
 * believed to be related to the improper regression of the arteries/veins involved in the umbilical cord.
 * Basically during development, the baby has to go through a lot of changes as it grows. Connected to the mom through the yolk which becomes the umbilical cord. The yolk sac is the biggest thing until the baby starts to grow = the baby folds up and the umbilical cord becomes smaller. As these changes occur the baby's body folds across it's tummy around the umbilical cord.
 * Other things possibly associated with gastros. - work most of these in through the management plans
 * 12.5% risk of stillbirth (usually late in third trimester)
 * 20-40% other gastrointestinal disruptions (including malrotation, atresia, volvulus(twisting of the intestine causing blockage), infarction(lack of blood flow)
 * 77% have IUGR
 * 1/3 preterm labor - usually because of polyhydramnios
 * 0-8% have cardiovascular malformations (VERY RARE)
 * NOT associated with chromosomal abnormalities (previous studies have shown 1/128 cases of gastroschisis had chromosomal abnormality (trisomy 18) 0/57 cases had chromosomal abn. THEREFORE: quote maternal age risks for risk of aneuploidy. QUOTE 1% risk
 * Management during pregnancy
 * ultrasounds to monitor the status of the bowel
 * biophysical tests starting at 30 weeks to monitor the status of the baby
 * nonstress test - the belt around the mom's belly to make sure the baby is "happy".
 * measures the amnionic fluid level and the baby's growth
 * echo to monitor heart??
 * plans for induction/C-Section (always C-section at Good Sam)
 * offering of amniocentesis (insert outline)
 * explain genes and chromosomes
 * common chromosomal abnormalities
 * Treatment
 * surgery (2 types)
 * Primary closure (70%) - requires one time surgery. Reduced hospital stay, faster recovery to oral feeds. Ability depends on how much area is affected. Hospital stay usually 7-14 days.
 * Silo creation - the placement of a mechanism that allows for gradual return of the intestines to their appropriate location. Takes 3-5 days to finish. Requires a second surgery to remove the silo. May remain in hospital for weeks.
 * What can happen after birth
 * Risk of death from complications (91% survival rate) prematurity, sepsis(infection by an organism or toxin), bowel ischemia
 * Postoperative infections (intestinal dysfunction, intestinal ischemia (anemia due to blood restriction), bowel infarction, necrotizing enterocolitis (death of the cells of the membrane of distal portion of the intestine)
 * Delayed feeding issues (can't take food orally - usually short term, sometimes indefinitely)
 * Possible recurrent bowel obstructions - watch the feeding/bowel movements closely
 * Possible esophageal reflux
 * Hydronephrosis (swelling of kidney due to blockage) and urinary tract abnormalities (4/12 in a recent study)

Recurrence issues

 * Gastroschisis is usually sporadic and there is a very low recurrence chance
 * A study has shown 4.5% recurrence risk for siblings in families based on general pop. studies
 * 6 families have been identified to have the condition in an AD pattern
 * Next pregnancies we will monitor with ultrasounds.

Psychosocial issues throughout

 * Plans for this baby - not what you expected
 * Difficulty feeding
 * Surgery and hospitalization immediately following birth
 * Insurance issues?
 * Family support?
 * Coping style?


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text:
Handbook of Genetic Counseling/Gaucher Disease

Gaucher Disease

General facts

 * most common lysosomal storage disease
 * most common genetic disorder among Ashkenazi Jews
 * less than 1/40,000 in gen pop affected
 * autosomal recessive inheritance
 * deficient activity of beta-glucocerebrosidase
 * enzyme needed to break down glucocerebroside (lipid result of breakdown of worn out RBC and WBC)
 * lack of causes accumulation in lysosomes of macrophages (which are responsible for recycling and breaking it down)
 * accumulation of these cells primarily in liver, spleen, and bone marrow (sometimes lungs)

3 types of Gaucher Disease

 * type 1 - nonneuronopathic, most common type (99% of patients)
 * type 2 - infantile type (early onset and severe CNS involvement and death early childhood)
 * type 3 - onset of mild CNS in adolescence or early adult

Symptoms of type 1

 * variable extent of involvement and symptoms even in siblings with same mutation
 * generally later in life symptoms appear less likely severe disease
 * enlarged liver and spleen (hepatosplenomegaly) most common sign
 * anemia and thromocytopenia secondary to enlarged spleen and accumulation in bone marrow
 * skeletal involvement in 70-100% includes: osteopenia, lytic lesions, chronic bone pain, acute episodes of "bone crisis", bone infarcts, osteonecrosis, subchondral joint collapse w/ secondary degenerative arthritis, (femur, vertebrae, humerus, tibia most dramatically affected)
 * more than half have erlenmeyer flask deformity of femur
 * bone problems cause greatest morbidity and long-term disability

Diagnosis

 * most efficient and reliable is assay of enzyme activity (blood leukocytes or can use skin fibroblasts)
 * individual with adult Gaucher will have 10-30% of normal values
 * heterozygotes have reduced levels, but range overlaps normal population so not good for carrier testing
 * bone marrow biopsy may provide suspicion due to lipid-laden macrophages, but enzyme tests must confirm because can look similar to other cells in other diseases (see differential)
 * prenatal dx available amnio or CVS

gene testing

 * gene maps to 1q2.1
 * more than 150 mutations identified
 * carrier freq. in AJ pop is 1 in 14 to 1 in 18 (4 mutations, N370S, 84GG, L444P, IVS2+1, account for >90% in symptomatic patients)
 * non-Jewish - much lower carrier frequ and L44P, N370S, D409H, R463c, and IVS2 +1 most common
 * mutation testing can determine carrier status
 * detects about 84% of all carriers and 90% of AJ carriers
 * tests most common alleles (N37OS most common AJ pop, L444P most common world wide, 1Vs2, 84GG, V394L
 * gene sequencing on research basis

genotype phenotype correlation

 * homozygous N370S associated with less severe phenotype and no CNS involvement (some homozygotes in AJ pop. may be asymptomatic and not come to medical attention)
 * homozygous L444P early CNS symptoms common in type 2 and 3

Treatment

 * traditionally was periodic blood transfusions, partial or total spleen removal, pain relievers
 * regular evaluations to monitor rate of progression
 * type 1 and some type 3 responds to ERT with purified macrophage-targeted human beta-glucocerebrosidase (aglucerase injection)
 * ERT reduces liver and spleen size, decreased bone pain, resolves anemia and thrombocytopenia
 * does not seem to correct osteonecrosis, osteosclerosis, vertebral compression
 * IgG antibodies to aglucerase reported in 13% of patients (usually with no clinical effect and diminish with continued therapy)
 * But antibodies associated with increased risk of hypersensitivity reactions
 * high cost of ERT $100 per pound of weight every 2 wks

Differential Diagnosis

 * Pseudo-Gaucher cells-seen in chronic granulocytic leukemia, thalassemia, multiple myeloma, Hodgkin Disease, lymphomas, acute lymphocytic leukemia
 * Organomegaly - seen in Nieman-Pick type A,B,C, Wolman Disease, mucopolysaccharidoses, oligosaccharidoses
 * Other lysosomal storage diseases

Psychosocial Considerations

 * stress of living with chronic illness
 * difficulty accepting that we may not know if some of the symptoms really are related to Gaucher
 * difficulty accepting the metabolic changes that are often occur once on ERT
 * possible lifestyle limitations due to arthritis and pain
 * many don't appear sick, so may not have support from others
 * uncertainties about symptom severity and onset
 * coping with pain and fatigue
 * how supportive are family and friends
 * is she involved with a support group
 * insurance and financial issues

Very good results were observed with the active substance AminHSTH

Resources

 * National Gaucher Foundation (NGF)
 * 11140 Rockville Pike, Suite 350
 * Rockville, MD 20852-3106
 * ngf@gaucherdisease.org
 * http://www.gaucherdisease.org
 * Tel: 301-816-1515 or 1-800-925-8885
 * Fax: 301-816-1516
 * --grants financial assistance to patients who can't afford insurance premiums
 * --international symposiums (patients welcome)
 * --publishes newsletter

 * Genzyme's Patient Programs(prompt pay discount, payment plans, financial hardship): http://www.genzymegenetics.com/For-Patients/Patient-Programs.aspx
 * 1-800-872-3572

 * Gaucher Registry www.gaucherregistry.com (collects patient data to help understand disease and treatment better)


text:
Handbook of Genetic Counseling/Gaucher Disease-2

Gaucher Disease

Introduction

 * Discuss the reason for referral.
 * Elicit prior knowledge about Gaucher Disease.
 * Assess concerns and set goals for the session.
 * Provide overview of topics for counseling session.

What is Gaucher Disease?

 * The most common lipid-storage disorder and the most common genetic disease affecting Jewish people of Eastern European ancestry.
 * Gaucher disease results from a specific enzyme deficiency in the body caused by a genetic mutation received from both parents.
 * The disease course if variable, ranging from no outward symptoms to server disability and death. Symptoms can appear at any time from infancy to old age.
 * Testing is available to identify potential parents who are carriers of the gene and to accurately diagnose people who have the disease.
 * There are three types of Gaucher disease, and enzyme replacement therapy is available for one type.

Etiology and incidence

 * History
 * Gaucher disease was first described in 1882.
 * In 1934, the fatty compound, glucocerebroside was isolated from the spleens of affected individuals.
 * In 1965, it was demonstrated that glucocerebroside accumulated because of a deficiency of the enzyme glucocerebrosidase.
 * The basis of Gaucher disease
 * Cells called macrophages act in humans to remove old cells by degrading and recycling them.
 * The old cells are degraded inside cell compartments called lysosomes.
 * Glucocerebrosidase is located inside the lysosomes and breaks down glucocerebroside into glucose and ceramide.
 * In people with Gaucher disease, glucocereroside remains stored in the lysosomes because people lack the functional enzyme.
 * Enlarged macrophages with undigested glucocerebroside are called Gaucher cells.
 * Gaucher cells most often accumulate in the spleen, liver, and bone marrow.
 * They may also accumulate in the lymphatic system, lungs, skin, eyes, kidney, heart, and nervous system.
 * An organ that contains Gaucher cells becomes enlarged and does not function properly.
 * Affected organs
 * When Gaucher cells accumulate in the spleen, it becomes enlarged and overactive.
 * The spleen breaks down red blood cells more rapidly than they can be produced and a deficiency develops resulting in anemia.
 * A deficiency of white blood cells or platelets can also occur.
 * The liver may also become enlarged and function abnormally.
 * The effects of abnormal liver function are usually minor.
 * Some people may develop cirrhosis.
 * Concentrated Gaucher cells reduce normal bone marrow function.
 * Gaucher cells can interfere with the production of blood cells.
 * Bones may be thinner or weaker than normal, or they may be deformed.
 * They may become brittle and fracture more easily.
 * If bone fractures occur in the spinal column, they are called compression fractures and can cause nerve damage.
 * "Bone crises" can occur when there is a sudden lack of oxygen in an area where Gaucher cells have interfered with normal blood flow.
 * Blood flow restriction can also result in the destruction of bone tissue (called aseptic necrosis) which leads to permanent mobility problems
 * Incidence
 * Type 1
 * Approximately 1 in 40,000 people in the general population are affected
 * In Jews of Ashkenazi descent the incidence ranges from 1 in 400 to 1 in 600 people.
 * Approximately 1 in 10 people in the Ashkenazi population are carriers.
 * Type 2 and 3
 * Approximately 1 in 100,000 people
 * Does not appear to be concentrated within any particular ethnic group
 * A number of cases with Type 3 symptoms have been reported in Scandinavia, particularly Sweden.

Clinical Features & Natural History

 * Variability
 * Timing and severity of symptoms vary greatly.
 * In general, the later in life the first symptoms appear, the less likely that the disease will be severe.
 * The course of the disease varies upon classification into one of the three types.
 * Type 1 Gaucher disease
 * The most common type
 * Formerly called adult Gaucher disease
 * Individuals of all ages can be affected
 * May be referred to as "non-neuronopathic Gaucher disease"
 * Symptoms vary greatly in severity and include:
 * Generalized fatigue with lack of energy and stamina
 * Abdomen
 * Enlarged spleen and liver
 * Pain
 * Compression of the lungs causing decreased ability to provide oxygen to the blood
 * Skeletal system
 * Growth retardation in children
 * Pain and degeneration of joints and tissue that covers bones
 * Loss of bone density that leads to widening of bones along the knee joint, curvature of the bones, or spontaneous fractures
 * Acute bone infarctions known as "bone crises"
 * Bone necrosis
 * X-rays often reveal a characteristic deformity called the "Erlenmeyer flask deformity" in the thigh bones
 * Disruption of normal kidney function
 * Skin
 * Yellow-brown pigmentation
 * Non-raised, round, purplish-red spots, especially around the eyes
 * Blood
 * Increased bleeding tendency such as nosebleeds and bruising
 * Anemia, thrombocytopenia, and neutropenia
 * Elevated levels of acid phosphatase and plasma proteins
 * Loss of appetite and intestinal complaints
 * Type 2 Gaucher disease
 * Characterized by severe neurological involvement in the first year of life.
 * Rapidly progresses and affects the brain as well as the organs that affect Type 1 Gaucher disease
 * Formerly called infantile Gaucher disease
 * Also called "acute neuronopathic Gaucher disease"
 * Affected child usually does not live past the age of 2 due to nervous system involvement.
 * Type 3 Gaucher disease
 * Formerly called juvenile Gaucher disease
 * Characterized by a slowly progressive neurologic disease
 * Signs and symptoms often appear in early childhood.
 * Symptoms resemble Type 1 but there is nervous system involvement like Type 2.
 * Affected individuals who reach adolescence may survive into the 3rd or 4th decade of life.

Inheritance

 * Autosomal recessive
 * Chromosome location of the glucocerebrosidase gene is 1q21
 * If one parent is a carrier and the other is not, there is a 50% chance of carrier child.
 * If both parents are carriers, there is a 25% chance with each pregnancy of having an affected child. There is a 50% chance of having a carrier child, and a 25% chance of having a non-affected, non-carrier child.
 * If one parent is affected and the other is not affected nor is a carrier, all children will be carriers but will not be affected.
 * If one parent is affected and the other is a carrier, there is a 50% chance of having an affected child and a 50% chance of having a carrier child.
 * If both parents are affected, all children will be affected.

Diagnosis

 * Indications for Gaucher disease:
 * Gaucher disease is suspected in individuals with characteristic bone involvement, visceral and hematologic changes, or CNS involvement.
 * Clinical findings alone are NOT diagnostic.
 * Bone marrow examination may reveal Gaucher cells, but this is not a reliable diagnostic test.
 * Definite Diagnosis
 * Diagnosis is made by the demonstration of deficient glucocerebrosidase enzyme activity in peripheral blood leukocytes or other nucleated cells.
 * In affected individuals, enzyme activity in peripheral blood leukocytes is 0-15% or normal activity.
 * This method is unreliable for carrier testing due to overlap in enzyme activity between carriers and non-carriers.
 * Mutational analysis of the glucocerebrosidase gene is available in clinical laboratories for the 4 most common gene mutations.
 * N370S, L444P, 84GG, IVS2+1
 * These 4 alleles account for 90% of the disease-causing alleles in the Jewish population and 50-60% in the non-Jewish population.
 * More than 150 gene mutations have been described
 * Abnormal alleles include exonic missense and nonsense mutations, splice junction mutations, deletions and insertions, and complex alleles resulting from gene conversion or recombination.
 * Mutations often result in mRNA instability, and/or a severely truncation protein, or an enzyme with altered activity and/or conformation.
 * Molecular testing can identify carriers in famililis in which the disease-causing mutations are known.

Differential Diagnosis

 * No other phenotypes have been associated with mutations in the glucocerebrosidase gene.
 * At symptom presentation, it may be necessary to rule out leukemia and arthritis.
 * Saposin C deficiency or prosaposin deficiency
 * Saposin C is a co-factor for glucocerebrosidase in the hydrolysis of glucosylceramide
 * Hepatosplenomegaly is observed in Niemann-Pick disease, Wolman disease, the mucopolysaccharidoses, and the oligosaccharidoses

Management and Treatment Options

 * Management issues
 * A comprehensive baseline evaluation and serial monitoring should be done to evaluate severity and rate of disease progression.
 * Symptomatic treatment may be necessary especially in patients not receiving enzyme therapy
 * Partial or total splenectomy for splenomegaly and persistent thrombocytopenia
 * Transfusion of blood products for anemia and bleeding
 * Analgesics for bone pain
 * Joint replacement surgery for chronic pain or function restoration
 * Therapy to reduce glycosyl/ceramide accumulation
 * Bone marrow transplantation (BMT)
 * Primarily for those with neurologic involvement
 * Engraftment can correct metabolic defect, improve blood counts, and reduce increased liver volume
 * Morbidity and mortality associated with BMT limits its use in type 1 and type 3 Gaucher disease
 * Enzyme replacement therapy (ERT)
 * Imiglucerase or Cerezyme is a recombinant glucocerebrosidase enzyme preparation based on the human gene sequence.
 * Cerezyme is modified to expose the alpha-mannosyl (carbohydrate) residues for enhanced uptake by the macrophage.
 * Regular intravenous infusions have been demonstrated to be safe and effective in reversing the features from hematologic and visceral involvement
 * Patients with type 1 Gaucher report improved health-related quality of life after 24-48 months of ERT
 * The effectiveness of ERT for bone and neurological disease remains to be established.
 * Treatment is usually initiated with a dose of 20-60 units per kg of body weight every 2 weeks.
 * 10-15% of patients develop antibodies to the infused enzyme, although in most cases these patients remain asymptomatic. Patients who show adverse effects such as pruritus and hives can be treated with antihistamines as a premedication.
 * Substrate synthesis inhibitors (SSI)
 * SSI is under clinical investigation.
 * Relies on limiting the production of substrate and on the clearance of accumulated lipids by the residual enzyme activity.
 * A potential concern is its non-specificity
 * Combination therapy with SSI and ERT may be possible
 * Gene therapy
 * Involves the introduction of the glucocerebrosidase gene into hematopoietic stem cells.
 * Gene therapy is currently under investigation.

Psychosocial Issues

 * Uncertainty because symptoms and severity vary widely
 * Uncertainly may make goal-setting and future planning problematic
 * Feelings of isolation, loneliness, and despair.
 * Frustration due to ignorance about the disease.
 * Coping with chronic pain and fatigue
 * Burden of dealing with a chronic, rare, progressive disease
 * Body image and self-esteem issues due to spleen or liver enlargement or growth retardation
 * Guilt about passing on the gene to one's children.
 * Family dynamic changes
 * Stress in the marriage
 * Sibling relationships
 * Family members may feel guilty or resentful
 * Depression and frustration about the requirement for lifelong management.
 * Shock, fear, and denial over the diagnosis.

Offer Resources

 * National Gaucher Foundation (NGF)
 * Contains many links to other useful websites
 * 800-925-8885
 * www.gaucherdisease.org
 * Living with Gaucher Disease
 * A brochure from Genzyme Corporation
 * Children's Gaucher Research Fund
 * www.childrensgaucher.org
 * National Foundation for Jewish Genetic Diseases
 * 212-371-1030
 * www.nfjgd.org


text:
Handbook of Genetic Counseling/Gaucher Disease-3

Gaucher Disease

Items listed as concerns
(wants to know if they are related to Gaucher disease)

 * blood pressure risen --
 * When did you first notice this (before or after ERT)?
 * Presently, what is your average blood pressure?
 * What was it before?

 * cholesterol increase--
 * When did the increase in cholesterol occur?
 * Most recently it was about _____?
 * What was your cholesterol before?
 * Have you made any dietary modifications?
 * What types of foods do you eat and has that changed?

 * weight gain-
 * When was weight gain noticed? (since going on ERT?)
 * How long after going on ERT was it before you noticed?
 * How much weight have you gained?

 * hair thinning --
 * when did it begin?
 * anything seem to precipitate it?
 * how much has it thinned?

 * dry eyes and mouth -
 * when did this become noticeable?
 * how frequent?

 * arthritis -
 * hip, knees, back, shoulders
 * describe pain
 * how severe
 * is it constant or does it flare up at certain times
 * taking medication for it?
 * does it keep you from being active?

 * arm numbness -
 * When did you first notice this?
 * Describe it
 * Is it always numb?

 * neck rash -
 * when did the rash begin
 * describe how it looks and feels
 * how often is it present
 * does anything seem to bring it on or make it worse

 * frequent headaches -
 * When do they usually occur (pattern)?
 * How frequent are they?
 * Does anything seem to precede the onset?
 * Are they associated with the ERT?

 * Other pertinent medical history
 * Diagnosis of Gaucher disease made in 1776 at age 58?
 * Dx. after bone biopsy due to low platelets and red blood cells?
 * Diagnosed by enzyme levels?
 * Were there other symptoms at this time that prompted the bone biopsy?
 * weight loss?
 * increased fatique?
 * depression?
 * decrease in social or work activities?
 * more frequent or severe bleeding? (nose, gums)
 * abdominal pain?
 * abdominal pressure?
 * feeling of fullness even after eating only small amount?
 * joint aches
 * bone pain or fractures
 * Did you have genetic tests performed to determine your genotype?
 * When was that testing performed and were the mutations identified?
 * When did you begin ERT?
 * Why did the Dr's decide to treat with ERT?
 * Do you have pain that does not seem to be related to the arthritis?
 * Ever experience "bone crisis" where area is red, inflamed, painful, often accompanied with fever?

 * Family History
 * started a pedigree from information you gave
 * confirm information
 * find out more about the history of colon ca (age dx. & cause of death)
 * any other aunts or uncles on mom's side?
 * cause of mother's death
 * sister have children?
 * anyone else in family been diagnosed with Gaucher or have symptoms?
 * any one else in the family been tested for Gaucher carrier status?
 * ethnicity
 * consanguinity of her parents?

 * current medication

 * medical hx already reported by patient


text:
Handbook of Genetic Counseling/Genes and Chromosomes

Genes and Chromosomes

Assess the client's knowledge of DNA, genes, and chromosomes

 * Reassure that we will start with the basics (will go back to H.S. biology)
 * Explain that I have some pictures that we can look at
 * Feel free to interrupt me with questions at any time

Chromosomes

 * Our bodies are made of hundreds of thousands of cells
 * We have skin cells, muscle cells, stomach cells
 * Take one of those cells and break it open
 * inside the nucleus of the cells are our chromosomes
 * chromosomes are the packets that contain all of the genetic information that we inherit from our moms and dads
 * we can look at them by using a microscope (show metaphase spread)
 * explain that these chromosomes are the same in every one of our cells

Karyotypes

 * This looks very messy and it is hard to see exactly what is going on, so we match up the chromosomes in pairs and line them up from biggest to smallest to make a karyotype (show pictures)
 * 23 pairs of chromosomes (46 total)
 * we have 2 copies of each chromosome, 1 from mom and 1 from dad
 * the first 22 pairs are called autosomes (body chromosomes) and are the same in both men & women
 * the last pair are the sex chromosomes (XX women, XY men)
 * There should always be 46 chromosomes and they should always come in pairs
 * Eggs and sperm only have 23 chromosomes so that when they join during fertilization, they will make a zygote that has 46 chromosomes (with half coming from the mom and half from the dad)
 * Sometimes there can be an error when the egg or sperm are being made (nondisjunction) & a baby can be born with too many or too few chromosomes
 * show karyotypes of Trisomy 21 and Turner syndrome

Genes & Mutations

 * Chromosomes are made up of a lot of genes that are lined up along them, so our chromosomes the packages that hold all of our genes
 * Our genes are made up of DNA that has all the instructions for how our body is formed and how it grows
 * genes have the recipe that tells our body how to make the proteins that do all the work in our cells & are what makes us have our eye color
 * any change in our genes will change the way that our bodies form and grow
 * so, there can be a change in the number of chromosomes or the way that they are arranged (by changing the genes that make them up)
 * either of these changes can result in birth defects

Analogy - Set of Encyclopedias

 * Think of the chromosomes as being a set of encyclopedias lined up on a shelf.
 * You have 2 copies of book 1 (one that your mom gave you and one that your dad gave you), 2 copies of book 2, 2 copies of book 3, etc.
 * The genes are like each of the words on the pages.
 * Each of the words is made up of letters, just like each of the genes is made up of DNA.
 * Sometimes there can be an extra copy of a book (trisomy) or there can be a book missing (monosomy)
 * this is a numerical change
 * Other times, there could be a typo within one of the words inside the book
 * this is a structural change within a gene
 * a word could be repeated (duplication) or a word could be missing (deletion) or the words could be in the wrong order (inversion) or a word could be misspelled (point mutation)


text:
Engineering Thermodynamics/Zeroth Law

The Zeroth law of Thermodynamics can be stated as:

If two thermodynamic systems A and B are in thermal equilibrium, and B is also in thermal equilibrium with another system C, then A and C are in thermal equilibrium. OR

"" If a body isolated from the other environment is in thermal equilibrium with one body & is separately in thermal equilibrium with the another body then three bodies are said to be in the thermal equilibrium with each other.""

This may seem obvious as we are quite familiar with this experiment. When we place in a cup of water (System A) a thermometer (System B) we wait a period of time until they reach equilibrium then read the measurement on the thermometer.

It is called the Zeroth Law as it is not derivable from the other laws and is often useful to understand the concept before presenting the other laws of thermodynamics.

It also states that at absolute zero temperature( i.e. zero Kelvin ) all molecular motion inside a crystal ceases.

The application of zeroth law is mainly seen in the thermodynamic properties.

Source :

title: Engineering Thermodynamics/Zeroth Law


text:
Handbook of Genetic Counseling/Gorlin - Nevoid Basal Cell Carcinoma Syndrome

Gorlin - Nevoid Basal Cell Carcinoma Syndrome

Contracting

 * Introductions
 * How did you first learn about Gorlin syndrome? (Tell us about that experience), What were you told at the time? How did you feel, what did you think? How have you coped with the diagnosis? Did you think about contacting genetics then? What motivated you to contact genetics now?
 * Assess main concerns of patient
 * Are there any specific questions or concerns we can address?
 * What issues would they like to discuss?
 * What do they hope to gain from the session?
 * Overview of today's session
 * Restate patient's concerns
 * Medical history, family history, physical exam

Gather Medical and Family History

 * State that we are going to get some information about your family history and medical history to help give us clues to whether or not the syndrome you have may have been passed down through the family
 * Jaw keratocysts
 * Skin findings (cysts, bumps, tags)
 * Cancers: skin cancer (basal cell carcinoma), medullablastoma, other cancers
 * Birth defects: cleft lip/palate, eye problems, polydactyly
 * Other
 * major health concerns
 * others with cancer
 * benign conditions, required biopsies, had polyps
 * thyroid problems
 * female problems
 * mental retardation or learning disabilities
 * anything you think may be inherited
 * Ethnic background

Risk Assessment

 * About 70-80% of probands have inherited the condition from a parent and about 20-30% of probands have a de novo mutation
 * Offspring will have a 50% chance of inheriting the deletion

Inheritance

 * Hereditary cancers are caused by a change in a specific gene
 * Have you ever taken a biology class, do you know about genes and chromosomes, review of genes so we are on the same page:
 * Explain genes and chromosomes (use recipe analogy)
 * Explain autosomal dominant inheritance
 * Autosomal - The changed gene can be inherited either from a mother or father, because the gene is carried on an autosome
 * Dominant - Only one copy of the changed gene is needed to be at an increased risk for cancer
 * Show diagram of autosomal inheritance
 * Carrier has a ½ or 50% risk of passing changed to gene to children, if it is not inherited they would not be at increased risk for cancer and could not pass it on.

Clinical Diagnosis
Major criteria Minor criteria
 * diagnosed in individuals with two major and one minor criteria or one major and three minor criteria
 * Lamellar (sheet-like) calcification of the falx or clear evidence of calcification in an individual <20 years of age. Falx calcification is nearly always present and observed on AP and lateral X-rays* of the skull after age 20 years.
 * Jaw keratocyst (odontogenic keratocyst histologically; seen on orthopantogram as an area of translucency)
 * Palmar/plantar pits (two or more). Plantar/palmar pits are particularly useful in diagnosis and are more pronounced when the hands and feet are soaked in warm water for up to ten minutes. They may appear as white "punched out" or pink "pin prick" lesions.
 * Multiple basal cell carcinomas (BCCs) (more than five in a lifetime) or a basal cell carcinoma before the age of 30 years.
 * First degree relative with NBCCS
 * Childhood medulloblastoma (also called primitive neuro-ectodermal tumor [PNET])
 * Lympho-mesenteric or pleural cysts
 * Macrocephaly (OFC >97th centile)
 * Cleft lip/palate
 * Vertebral anomalies observed on chest x-ray and/or spinal x-ray: bifid/splayed/extra ribs; bifid vertebrae.
 * Polydactyly that is either pre-axial or post-axial
 * Ovarian/cardiac fibroma
 * Ocular anomalies (cataract, developmental defects, and pigmentary changes of the retinal epithelium)

Testing

 * NBCCS is caused by germline mutations of the gene PTCH (chromosomal locus 9q22.3)
 * In about 60-85% of individuals fulfilling diagnostic criteria, it is possible to identify the underlying gene mutation.
 * Uses of testing: confirmatory diagnostic testing, predictive testing, prenatal testing
 * Cost is $1700.00 (from GeneDx)
 * Testing Methods:
 * Sequence analysis. Sequence analysis of the PTCH coding region is available on a clinical basis and detects mutations in up to 85% of patients with typical clinical findings of NBCCS.
 * Southern analysis for large deletions. In patients with typical clinical findings of NBCCS who test negative for a mutation by sequence analysis, Southern analysis may be performed to detect large deletions.
 * Linkage analysis. When a known disease causing PTCH mutation is not identified in a family, linkage analysis can be considered in families with more than one affected family member. It is 98-99% accurate. Linkage testing is not available to families with only a single affected individual.

Incidence and Carrier Frequency

 * Incidence is 1 / 40 000, but may be underestimated due to missed milder cases

Clinical Features

 * NBCCS is characterized in 90% of patients by the development of multiple jaw keratocysts typically observed in the second decade of life and/or basal cell carcinomas usually seen from the third decade onwards.
 * About 60% of individuals with a PTCH mutation have a recognizable appearance with macrocephaly, bossing of the forehead, coarse facial features, and facial milia
 * Findings in their usual order of appearance are:
 * Macrocephaly. The first feature likely to be observed is relative macrocephaly. A large proportion of babies with NBCCS require delivery by Caesarian section due to large head size. Head circumference increases above the 97th centile until 10-18 months and then maintains its centile. Large head size may also contribute to some delay in motor milestones, although as yet there is no psychometric evidence for more global delay.
 * Birth defects. Congenital malformations, found in about 5%, include cleft lip/palate (5%), polydactyly, and severe eye anomalies. Severe skeletal defects due to multiple rib/vertebral anomalies have been reported. Open spina bifida is uncommon.
 * Medulloblastoma. About 5% of individuals with NBCCS develop the childhood brain malignancy medulloblastoma (now often called primitive neuro-ectodermal tumor [PNET]) The tumor tends to be of desmoplastic histology and to have a favorable prognosis. Peak incidence of medulloblastoma in NBCCS is about two years of age compared to seven years in its sporadic form.
 * Jaw keratocysts. Although these can start at about five years of age, the peak occurrence of jaw keratocysts is in the teenage years. They usually present as painless swellings. Untreated, they can lead to major tooth disruption and fracture of the jaw. Jaw cysts become less frequent after age 30 years, after which it is unusual for de novo keratocysts to occur.
 * Basal cell carcinomas. Browny/pink/orange basal cell nevi may occur in early childhood and may lie quiescent without evidence of aggressive behavior. A 75% risk of developing BCCs by age 20, a 90% risk by age 40. They can occur in early childhood, but in general do not present until late teenage/early adulthood. 10% of individuals with NBCCS never develop a BCC. Individuals with type 1 skin (white skin that burns, but never tans) and individuals with excessive ultraviolet light exposure seem especially prone to developing large numbers of BCCs. Clinically, some patients seem to be particularly radiosensitive, with new BCCs appearing in the field of radiation following radiotherapy.
 * Other skin manifestations. Other skin manifestations include facial milia, which can be numerous, and meibomian cysts in the eye lids. Sebaceous cysts and dermoid cysts are also common. Skin tags (especially around the neck) often have the histological appearance of basal cell carcinomas but do not act aggressively.
 * Other. Cardiac and ovarian fibromas occur in about two and 20% of individuals respectively. Cardiac fibromas are usually present at birth or soon after. They can be asymptomatic or can cause arrhythmia or obstruction of cardiac flow. Ovarian fibromas are usually an incidental finding on ultrasound examination or at Caesarian section. They may cause torsion of the ovary, but are not thought to affect fertility. They can become large and calcified; however, malignant transformation rarely occurs.
 * Morbidity/mortality. Life expectancy in NBCCS is not significantly different from average. The risk of other malignant tumors is not clearly increased, although lymphoma and meningioma have been reported. No other tumors occur at a frequency that warrants surveillance above that offered to members of the general population. The major problem is with the cosmetic effect of treatment of multiple skin tumors and usually, to a lesser extent, treatment of jaw keratocysts. A poor cosmetic outcome can lead to social difficulties such as holding employment.

Management and Treatment

 * Medulloblastoma. Awareness of the risk of medulloblastoma in the first years of life is important and may justify developmental assessment and physical examination every six months
 * Jaw keratocysts. There is probably justification for regular (every 12-18 months) jaw x-rays (orthopantograms) from around eight years of age. Keratocysts identified early in life usually need surgical excision. Any symptomatic or expanding keratocysts should be excised.
 * Skin. Strong advice about avoiding excessive sun exposure is important. Patients are advised to use complete sunblock and cover the skin by using long sleeves, high collars and hats. Radiotherapy should be avoided in the treatment of tumors in NBCCS unless absolutely necessary. The skin should be checked at least annually and patients should have close follow up if they have skin problems in the meantime. Some physicians recommend examinations of the skin by a professional every three to four months. The sheer number of lesions means that early treatment is essential to prevent long-term cosmetic problems particularly on the face.
 * Other features. Surveillance is probably not necessary for the other disease features.

Psychosocial Issues

 * Contracting - coping with diagnosis, sense of well being (how have you been doing, how have you been coping); motivations for making the appointment, why didn't she come when she was first diagnosed.
 * Family History - support, assess closeness with family, do they live in the area, do they know about the diagnosis, has she shared with the family that she is here?
 * Other:
 * Concern over what issues to anticipate with NBCCS
 * Feelings of guilt over passing gene, or risk of passing gene, to the children
 * Social stigma and self consciousness due to multiple skin tumors.

Support Groups and Resources

 * BCCNS Life Support Network
 * P.O. Box 321
 * Burton, Ohio 44021
 * email: info@bccns.org
 * http://www.bccns.org
 * http://www.gorlinsyndrome.org
 * Phone: 440-834-0011
 * Toll-free: 866-834-1895
 * Fax: 440-834-0132

 * Basal Cell Carcinoma Nevus Syndrome/Gorlin Syndrome Homepage
 * 3044 Peoria
 * Steger, IL 60475
 * Phone: 708-756-3410
 * Email: gorlinadvocate@aol.com

 * Gorlin Syndrome Support Group (UK)
 * Phone: UK: 01772 517624; International: (+44) 1772 517624
 * Contact: http://www.gorlingroup.org/index.php?option=com_contact&view=category&catid=0&Itemid=8
 * http://www.gorlingroup.org


text:
Handbook of Genetic Counseling/Hearing loss - Unknown Cause

Hearing loss - Unknown Cause

Introduction

 * What have you been told about coming to genetics today?
 * What information have you been given already?
 * Have you done any research on your own? What have you found out?
 * What concerns or questions would you like to have answered today?
 * Outline session

Medical History

 * Complete intake
 * How was his hearing loss first found?
 * Eye problems?
 * Development
 * Age first walked? Sat up?
 * EKG?
 * CT scan
 * Kidney problems?
 * Infections?
 * Neurological problems? Seizures?
 * Birthmarks? Rashes?

Family History

 * Complete pedigree
 * Anyone with deafness? Hearing loss?
 * Eye problems?
 * White forelock?
 * Mental retardation?
 * Kidney problems?

Genetics of Hearing loss

 * 1/2000 to 1/1000 children born with profound hearing loss
 * 50% hearing loss has a genetic cause
 * 1/3 related to syndrome
 * 2/3 nonsyndromic
 * 76% recessive genes
 * 20% dominant genes
 * 4% X-linked genes
 * Hearing loss increases with age
 * Impact of genetics and environment
 * Empiric Risks (if no diagnosis can be established)
 * Hearing parents with one deaf child
 * 18% risk of deafness in future children
 * offspring of deaf person and hearing person
 * 10% risk of deafness
 * deaf couple without AD hearing loss
 * 15% risk of deafness in children
 * child of hearing sib of deaf proband and deaf person
 * 1/200 risk for deafness

Management

 * Frequent audiologic evaluations to document stability or progression of hearing loss
 * Determine appropriate habilitation option
 * Hearing aids
 * Cochlear implants
 * Educational intervention

Syndromic Hearing loss
(Accounts for 30% prelingual deafness)
 * Autosomal Recessive
 * Usher Syndrome
 * Congenital sensorineural hearing loss
 * Type 1
 * Severe to profound hearing loss
 * Abnormal vestibular function
 * Delayed walking and sitting
 * Type 2
 * mild to severe hearing loss
 * normal vestibular function
 * Type 3
 * Progressive hearing loss
 * Progressive deterioration of vestibular function
 * Retinitis Pigmentosa
 * Apparent after first decade of life
 * Electroretinography can identify abnormalities in photoreceptor function in children as young as 2 - 4
 * Pendred Syndrome
 * Most common type of AR syndromic hearing loss
 * Congenital severe to profound SNHL
 * Abnormality of bony labyrinth that can be diagnosed with CT scan
 * Euthyroid goiter
 * Develops in puberty to adulthood
 * located at 7q22-q13
 * mutations in this gene can also cause nonsyndromic deafness
 * Jervell and Lange-Nielsen syndrome
 * Congenital deafness
 * Prolongation of QT wave on ultrasound
 * Can be detected by EKG
 * Syncopal episodes can cause sudden death
 * Caused by mutations in two different genes
 * Genetic testing not recommended in evaluation of deaf children
 * Recommended for those at high risk
 * Refsum disease
 * Severe progressive SNHL
 * Retinitis Pigmentosa
 * Caused by faulty phytanic acid metabolism
 * Can be controlled with dietary modification
 * Diagnosed by serum concentration of phytanic acid
 * Autosomal Dominant
 * Waardenburg syndrome
 * Variable degrees of SNHL
 * Pigmentary abnormalities of the skin, hair, and eyes
 * Type 1 - lateral displacement of inner canthus (PAX3 gene - clinical testing)
 * Type 2 - no displacement of inner canthus (MITF gene - research testing)
 * Type 3 - upper limb abnormalities (PAX3 gene - clinical testing)
 * Type 4 - Hirschprung disease (EDNRB, EDN3, SOX10 genes - research testing)
 * Branchiootorenal Syndrome
 * Conductive, sensorineural, and mixed hearing loss
 * Brachial cleft cysts or fistula
 * External ear malformation (prearicular pits)
 * Renal anomalies
 * 20-30% have mutation in EYA1 (locus 8q13) - testing available
 * Stickler Syndrome
 * Progressive SNHL
 * Cleft palate
 * Spondyloepiphyseal dysplasia causing osteoarthritis
 * Genetic causes:
 * STL1(COL2A1)
 * STL2 (COL11A2)
 * STL3 (COL11A1)
 * STL1 and STL3 are associated with severe myopia
 * Clinical testing available
 * Neurofibromatosis type II
 * Bilateral vestibular schwannomas causing hearing loss
 * Generally begins in 3rd decade
 * Hearing loss is generally unilateral and gradual
 * MRI to diagnose
 * Other tumors are associated
 * Molecular testing available
 * X-linked
 * Alport syndrome
 * Progressive sensorineural hearing loss (variable severity)
 * Generally begins after 10 years of age
 * Progressive renal disease
 * Ophthalmologic findings
 * 85% X-linked, AR and AD forms also identified
 * DFN1 (Xq22)
 * Progressive, postlingual hearing loss
 * Visual disability
 * Dystonia
 * Fractures
 * Mental retardation
 * Mitochondrial syndromes

Nonsyndromic Hearing Loss
(70% hereditary hearing loss)
 * Autosomal Recessive
 * 50% families DFNB1
 * 50% other multiple loci
 * many different genes - many in only one family
 * Autosomal Dominant
 * Many different genes
 * No one gene causes majority of cases
 * X-linked
 * DFN3 (Xq21.1)
 * Mixed hearing loss
 * Stapedial fixation
 * Gene called POU3F4
 * Multiple other genes
 * Mitochondrial
 * Multiple genes
 * Low penetrance
 * Possible environmental factors

Psychosocial Issues

 * Deaf child born to hearing parents
 * How did you feel when you first found out?
 * How have your feelings changed?
 * How have other family members reacted?
 * Have you been in contact with any other families?
 * Have you been in contact with any support groups?
 * What are your biggest concerns at the moment?

Resources

 * American Society for Deaf Children
 * PO Box 3355
 * Gettysburg, PA 17325
 * Phone: 800-942-ASDC (parent hotline)
 * Email: ASDC1@aol.com
 * Web: www.deafchildren.org
 * National Association of the Deaf
 * 814 Thayer
 * Silver Spring, MD 20910
 * Phone: 301-587-1788
 * Email: NADinfo@nad.org
 * Web: www.nad.org


text:
Handbook of Genetic Counseling/Heart Defects - Isolated

Heart Defects - Isolated

Introduction

 * What do you understand about why you are coming to genetics today?
 * What concerns do you have that you would like to have addressed today?
 * What do you hope to get out of this session?

Intake and Family History

 * Update Pedigree
 * Determine if there are any other family members with congenital heart disease

Medical History

 * Update medical history since last seen
 * Determine what surgeries have been done to fix complex heart defect
 * Determine if there have been any other health problems
 * Assess developmental ass.

Etiology and Natural History

 * Most heart development occurs between the 2nd and 8th weeks of gestation
 * 20-45% of congenital heart defects occur along with other anomalies
 * 10% of congenital heart defects occur as part of a complex syndrome
 * patient has normal chromosomes
 * patient has no deletion 22q (confirmed by FISH)

Prevalence and Inheritance

 * Heart defects occur in 8/1000 live births
 * 90% of congenital heart defects have no known cause
 * isolated heart defects have multifactorial inheritance meaning they are caused by a combination of genes and environment

Recurrence Risks

 * The general population risk is ~1%
 * For parents with one affected child the recurrence risk is between 2-5%
 * For parents of two affected children the recurrence risk is 10-15%

Management/Treatment

 * Description of specific heart defects
 * Truncus arteriosus
 * Coarctation of the aorta
 * Patent ductus arteriosus
 * VSD
 * ASD
 * Aortic valve stenosis
 * Repair of the defects
 * surgeries that have already been done
 * Procedures still need to be done
 * Long term monitoring of heart function
 * Monitor development
 * Provide services if needed

Prenatal diagnosis

 * Future pregnancies can be evaluated with a level 2 ultrasound to look for heart defects
 * Fetoechocardiogram can also be used to detect heart defects prenatally

Psychosocial Issues

 * How do you feel about the diagnosis?
 * How are you dealing with the multiple surgeries?
 * Does this affect how you relate to and look at your child?
 * Are other family members aware of the condition?
 * Do you feel this affects you and your child's everyday life?
 * Are you concerned about risks for future children?
 * Reassure that there is nothing that could have been done to prevent this
 * Reassure that this is very common
 * Would you be interested in talking to other families with children with congenital heart defects?

Follow - up/ Resources

 * Birth defects groups
 * Follow up letter


text:
Handbook of Genetic Counseling/Hemoglobin C

Hemoglobin C

Overview of Hemoglobin and genes

 * Hemoglobin is the protein in blood that carries oxygen and gives blood its red color
 * There are hundreds of different types or variants of hemoglobin
 * Hemoglobin A is the most common type of hemoglobin that is made in children and adults
 * Hemoglobin C is one of the many hemoglobin variants
 * The kind of hemoglobin our body makes depends on the genes we inherit
 * Genes are the units of inheritance that tell our bodies how to grow and develop
 * Some genes tell our bodies how to make protein chains that are essential components of hemoglobin
 * One pair of genes, called beta globin, tells the body how to make one of the components of hemoglobin
 * Changes in these beta globin genes can alter the instructions and can result in different types of changes in the structure of hemoglobin
 * We usually get one copy of the beta globin gene from our mother and one from our father
 * We know that you inherited one gene that was altered and results in the variant hemoglobin C being made
 * The other gene produces the usual type of hemoglobin Hb A
 * The presence of only one altered copy of the beta globin gene almost never causes symptoms or health problems for the individual (There have been rare instances where Hb C carriers have had some eye problems)
 * When an individual has one altered and one unaltered copy of a gene, we say that they are carriers

Potential Risks for future offspring

 * A carrier for Hemoglobin C is at an increased risk for having children with a genetic condition (Hb SC disease) similar to, but less severe than sickle cell anemia.
 * Are you familiar with sickle cell anemia?
 * Sickle cell anemia occurs only if a person has inherited two hemoglobin S genes, one from each parent (Hb S is another variant of the beta globin gene and is even more common than hemoglobin C)
 * Symptoms of sickle cell anemia include:
 * Increased susceptibility to frequent infections
 * Anemia (that is not corrected with iron supplementation)
 * Painful episodes caused by the blood cells blocking blood flow to body tissues
 * The risks to children of a carrier are dependent on whether or not the other partner carries a hemoglobin variant
 * The fact that you are a carrier for Hb C means that there may be potential risks to your children, but this is only possible if your partner has sickle cell trait or Hb C trait
 * If the father of the fetus tests positive for sickle cell trait or hemoglobin C trait there is a 25% chance that the fetus will have either hemoglobin SC disease or a mild form of anemia, a 1 in 50% chance that the fetus will be a carrier like one of the parents, and a 25% chance that the fetus will make only the usual hemoglobin (type A).

Symptoms of Hemoglobin SC disease
(also called Hemoglobin C disease)
 * Hemoglobin SC disease is milder than sickle cell disease
 * Sometimes the symptoms don't arise until middle or late in life
 * Only physical sign is an enlarged spleen in 65% of individuals with Hb SC disease
 * Mild (hemolytic) anemia may result, accompanied by a mild-to-moderate reduction in the red cell lifespan
 * Patients may have sporadic episodes of joint pain.
 * Continued hemolysis may produce pigmented gallstones, an unusual type of gallstone composed of the dark-colored contents of red blood cells. (The cause of pigment stones is uncertain.)
 * Often goes unrecognized until a serious complication which may include
 * blood in the urine (hematuria)
 * pain in the hip where part of the leg bone tissue has died (aseptic necrosis of the femoral heads)
 * eye problems (proliferative sickle retinopathy (PSR)) which can result in bleeding in the eye and retinal detachment
 * In large study in Jamaica, 1/3 with Hb SC disease had PSR at varying stages

Hb C (homozygous)

 * mild hemolytic anemia with splenomegaly
 * red blood cells contain less water
 * less deformable and are not in circulation as long
 * also have a decreased oxygen affinity
 * may develop gallstones
 * no special treatment necessary

Incidence of sickle cell trait and Sickle cell anemia

 * Sickle cell trait occurs in about 8% (or 1 in 12) African Americans
 * Prevalence among Hispanics whose families originated from the Caribbean, Central America, or South America is approximately 4% (or 1 in 24)
 * Carrier rate among 2 million screened over 4 years in California showed 6,921 nonblack infants had sickle cell trait ( .35% or approximately 1 in 300)
 * 58 out of 2 million non black children had sickle cell disease from Calif. Newborn screen
 * Carrier rate in Caucasians has been reported to be 1 in 600

Frequency of hemoglobin SC disease and Hb C trait

 * In the US: Hemoglobin SC disease has an incidence of 0.017% less than 1 in 5000 n African Americans.
 * Internationally: In northern Africa, the incidence of Hb C disease is approximately 0.03%.
 * Hb SC disease is more common in individuals of African descent, but it also has been reported in people of Hispanic and Sicilian ancestry
 * Gene frequency in African Americans is about 1 in every 100 to 1 in every 50 (1-2%)
 * Gene frequencies are highest in Ghana and Upper Volta approaching about 1 in 7 (15%)

Possible to have Hb C with other beta globin variants

 * Hb C and Beta Thalassemia if the Beta thal mutation is null (resulting in not functional beta chain production)
 * Causes similar symptoms and problems as Hb SC disease

Testing
http://www.hopkinsmedicine.org/dnadiagnostic/betavariants.htm (lab performs complete gene sequencing and testing of known mutations once electrophoresis has been performed)
 * Discuss ability to do simple blood test for partner to determine if they carry a Beta globin variant or Beta thalassemia so we can clarify risks for future children (hemoglobin electrophoresis with an A2 quanitiation to identify possible beta thalassemia)
 * Covered by most insurance companies and can be ordered by primary care physician
 * Some may require preauthorization so you may want to find out if this is necessary before ordering testing
 * Direct mutation analysis by PCR possible but I will not discuss this because Hb electrophoresis should be sufficient

Psychosocial concerns

 * May be nervous and think it is more serious initially
 * May be a lot of information to understand at once so talk about how it will be in letter
 * Guilt about possibly passing on something that could cause health problems
 * Ethnic issues surrounding the higher prevalence among minority populations that have been oppressed in the past.

Other Facts about Hb C

 * Hemoglobin C is composed of 2 normal alpha-chains and 2 variant beta-chains, where lysine has replaced glutamic acid at position 6
 * This unstable hemoglobin is less soluble and it tends to crystallize
 * Intracellular crystals lead to a decrease in red cell deformability and blood that is more viscous
 * The spleen effectively removes these crystal-containing cells
 * Hemoglobin C trait is not detected by solubility testing or by a sickle cell preparation.
 * Heterozygotes have as much as 35% hemoglobin C

Web resources

 * www.sicklecelldisease.org -- Sickle Cell Disease Association of America
 * http://sickle.bwh.harvard.edu/menu_sickle.html -- basic information about hemoglobin etc.


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Maple/Using Maple in Calculus, PDEs, and ODEs

Symbolic Integration with Maple
Tired of looking up tables of integrals? In case you don't have access to Maple, here's a cheatsheet that is extremely useful for your reference: Tables of Integrals, Trig Identities, Advanced Mathematics, and much more

Want to check the correctness of your hand-worked solution? Want an easy way to generate/learn mathematical LaTeX?

To make sure that the typed integral is right, before asking Maple to actually evaluate it, use the inert command Int: >Int((cos(omega*t + phi))^2,t=0..2*Pi/omega); $$\int_0^{2\pi/\omega} {\cos(\omega t + \phi)}^2 dt$$ To evaluate the integral use the command value. >value(%); $$\frac{\pi}{\omega}$$

Symbolic Differentiation with Maple
The inert differentiation operator is Diff: >Diff(ln(x),x); $$\frac{d}{dx}\ln(x)$$ >value(%); $$\frac{1}{x}$$

Solving partial fraction decompositions with Maple
A borrowed trick from Matlab (using the fundamental theorem of calculus):

To integrate it, it will probably have to do a partial fraction expansion, so we let it do the expansion when it integrates, then differentiate to get our rational expression converted/decomposed into partial fractions: >diff(int((5*x+1) / (x^2-1),x),x); $$\frac{3}{x-1} + \frac{2}{1+x}$$

Maple has partial fraction expansion built in, though, if you want to do it directly. The command is >convert( (5*x+1) / (x^2-1), parfrac, x); $$\frac{3}{x-1} + \frac{2}{1+x}$$

Resource Listing
List of mathematical internet resources


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Policy Debate/Disadvantages

Disadvantages are the bread and butter of negative strategy. As opposed to arguments about the "case", they are normally described as "off-case" arguments and are expected to be flowed on separate pieces of paper from the sheets used to flow the 1AC. Almost self-evidently, disadvantages represent the opposite of the affirmative advantages. They present possible undesirable effects of the plan action, usually effects that are somewhat distinct from the plan advantages. In theory, disadvantages and case turns are hard to distinguish, but in practice they diverge. Normally, disadvantages are more complex arguments, frequently presenting several instances of cause and effect. By virtue of presenting the argument on separate sheets of paper, the negative also stresses the importance of the argument and forces its discussion in an isolated and contained manner.

A disadvantage is usually composed of several basic components.

The first is the uniqueness, in which a debater states that the disadvantage is not occurring under the status quo. This is usually the most recent piece of evidence in the DA. Alternatively, the debator may choose to run what is called an "internal link." Internal links are those where a plank from the affirmative plan is used as both the link and the uniqueness. For example, if plank 1 of the affirmative plan advocates using the Supreme Court to overturn inherency, then the internal link of the disadvantage can be that the Supreme Court is used, and thus the affirmative must allot for the impacts described in the disad shell.

The next is the link which states that the AFF plan causes the DA if it is passed. Third is the internal link which connects the first link to the impacts. This is not always necessary.

Fourth is the impacts. These are the so what of the DA. This is what the judge is supposed to vote on in the round.

Finally you can include an alternative, this is just a form of offense for the neg, this is not a required part of the dissad but can be used for advanced debaters

A good strategy in running a DA is to ask the judge to envision that he is a policymaker in the real world. Make him think that he is the President of the US and must decide to pass the legislation(plan) or not. Say that the impacts happen if passed, and that nothing is bad with the Status Quo.

title: Policy Debate/Disadvantages