BIOE 301 Lecture Three Review of Lecture Two

BIOE 301 Lecture Three

Review of Lecture Two n Developing world 1. 2. 3. 4. n Perinatal conditions Lower respiratory infections Diarrheal diseases Malaria Developed world 1. 2. 3. 4. Perinatal conditions Congenital anomalies Lower respiratory infections Unintentional injuries

Leading Causes of Mortality Ages 15 -44 n Developing World 1. 2. 3. 4. n HIV/AIDS Unintentional injuries Cardiovascular diseases Tuberculosis Developed World 1. 2. 3. 4. Unintentional injuries Cardiovascular diseases Cancer Self-inflicted injuries

Burden of HIV/AIDS n Worldwide n n n 40 million people are living with HIV/AIDS 20 million people have been killed by the disease 2003: 3 million deaths n 5 million new HIV infections n n n 2/3 of those with AIDS are in Africa 1 in 12 African adults has HIV/ AIDS

AIDS has Reduced Life Expectancy

Burden of HIV/AIDS n United States n n n 0. 8 -1. 2 million people have HIV/AIDS (prevalence) 30, 000 -40, 000 new HIV infections per year (incidence) Annual cost to treat: $15 billion

Clinical Course of HIV/AIDS n HIV Infection n n n n Spread by sexual contact with infected person or sharing needles with infected person or by transmission from mother to child Virus deposited on mucosal surface Acute infection (flu like symptoms) Viral dissemination HIV-specific immune response Replication of virus Destruction of CD 4+ lymphocytes Rate of progression is correlated with viral load Latent Period

Clinical Course of HIV/AIDS

Clinical Course of HIV/AIDS n n n Immunologic dysregulation Opportunistic infections and cancers Risk of infections is correlated with number of CD 4+ lymphocytes Average patient with AIDS dies in 1 -3 years Within 10 years of infection (w/o Rx): n n n 50% of patients develop AIDS 40% develop illness associated with HIV 5 -10% remain asymptomatic

HIV/AIDS Historical Perspective n 1981 n n n 1981 -1982 n n CDC reported unexplained PCP in 5 previously health, homosexual men CDC reported Kaposi’s sarcoma in 26 previously healthy, homosexual men Increased association with IV drug use, recipients of blood transfusions, hemophiliacs 1983 n Virus isolated

HIV/AIDS Historical Perspective n 1984 n n 1985 n n ELISA test developed 1996: n n Virus shown to be causative agent HAART developed Today: n Broad spectrum of disease n n Asymptomatic infection Clinical latency Advanced disease (AIDS) Clearly sexually transmitted, and transmitted through blood products

Pathophysiology of HIV/AIDS http: //health. howstuffworks. com/aids 3. htm

Pathophysiology of HIV/AIDS http: //www. roche. com/pages/facets/ 4/hiv_life_cycle 2. jpg

HAART Treatments for HIV/AIDS n Inhibit reverse transcriptase enzymes (1987) n n n Inhibitors of HIV protease (1995) n n n HIV proteases are distinct from mammalian proteases Most significant advance in HIV therapy yet Highly Active Antiretroviral Therapy (HAART) n n Enzyme is specific to HIV Combinations of RTIs appear effective Combination of three or more drugs Fusion inhibitors (2003) n Subject of new research

HAART n n n HIV can rapidly mutate to quickly develop resistance to a single drug Resistance develops much more slowly to drug combinations Goal of HAART: n n Reduce viral levels undetectable levels Has reduced death rate in US and Europe by 80% to

http: //www. npr. org/templates/story. php? story. Id=4724368

Unintentional Injuries n n n More than 1. 25 million people aged 15 -44 die as a result of unintentional injuries each year Major cause of disability Leading cause is road traffic injuries: n n 500, 000 deaths per year in his age group 90% of these deaths occur in developing countries

US Burden of Disease: Road Accidents n n n Rates declining steadily Leading cause of potential years of life lost 2004: n n n 42, 636 Americans killed 2, 788, 000 Americans injured Fatal accident rates >4 X higher for males than for females Motorcycles: 40 X higher death rate per mile traveled 39% of fatalities related to alcohol use

Prevention: Road Accidents n Legislation: n n n Engineering: n n n Speed Seat belts, Car seats, Air Bags Alcohol use Motorcycle helmets Restraints Safety standards Education: n n Seat belts, Car seats, Air Bags Alcohol use

Accident Physics n Newton’s 2 nd Law: n n In a crash: n n n F=ma a = dv/dt a = initial velocity/time to come to rest Velocity slows to zero in a very short time Generates large forces How can we reduce these forces? n n Reduce initial velocity of impact Extend time that it takes passengers to come to rest

Reducing Initial Velocity n Excessive speed contributes to: n n 30% of deaths in developed countries 50% of deaths in developing countries

Physics of Accidents/Restraints

Slowed Driver Reaction Time n n When drivers anticipate a crash, they have time to brake and reduce initial velocity Factors which slow driver reaction time: n n n Alcohol use Cell phone use Poor visibility

Alcohol Use n n Alcohol impaired drivers have 17 X increased risk of being in fatal crash Alcohol use increases risk more in younger drivers

Mobile Phone Use n At any given daylight moment in US: n n Cell phone use: n n 10% of drivers are using a cell phone Increases driver reaction time by 0. 5 -1. 5 sections Risk of crash is 4 X higher when using a mobile phone Same as driving with a BAC of 0. 09 g/ dl 3 states have banned use of hand held phones while driving

Alcohol Related Deaths

Extending Time to Come to Rest n Crumple zones n n Allow passengers additional time to decelerate Seat belts n n n Keep occupants in the passenger compartment Stretch during impact Reduce risk of death in crash by 40 -60% n n n Air bags n n http: //www. regentsprep. org/Regents/physics/phys 01/accident/nobelt. htm http: //www. regentsprep. org/Regents/physics/phys 01/accident/withbelt. htm When combined with seat belts, reduce risk of serious and fatal injuries by 40 -65% http: //www. nhtsa. dot. gov/staticfiles/DOT/NHTSA/Communication%20&%20 Consumer%20 I nformation/Multimedia/Associated%20 Files/crashdum 2. ram http: //www. accidentreconstruction. com/movies/5 thper. mov Child restraints: n n Reduce risk of infant death by 71% and toddler death by 54$ http: //www. nhtsa. dot. gov/staticfiles/DOT/NHTSA/Communication%20&%20 Consumer%20 I nformation/Multimedia/Associated%20 Files/crashdum 3. ram

Helmet Laws

Cardiovascular Diseases n n 768, 000 people aged 15 -44 die as a result of cardiovascular disease every Most common causes: n n Ischemic heart disease (286, 000 deaths) Cerebrovascular disease (159, 000 deaths)

Ischemic Heart Disease: Epidemiology n United States n n n 11 million people have coronary artery disease Causes more deaths, disability and economic cost than any other illness Risk factors n n n Positive family history Diabetes Hyperlipidemia Hypertension Smoking

Ischemic Heart Disease: Pathogenesis n Atherosclerosis n Causes a decrease in myocardial perfusion n Stable angina n n n Typically a 50 -60 yo man or 65 -75 yo woman Heaviness, pressure, squeezing, smothering or choking Localized to chest Lasts 1 -5 minutes Radiates to left shoulder and both arms Unstable angina n Patients with angina that is: n New onset and severe and frequent n Accelerating n Angina at rest

Ischemic Heart Disease: Diagnosis n n Usually made by history Physical exam may reveal other disorders n n Lipid disorders Hypertension Diabetes Testing n n n EKG Stress Testing Coronary arteriography

http: //www. columbiasurgery. org/divisions/cardiac/im ages/novartis_207 B. jpg

Ischemic Heart Disease: Treatment n Medical management n Nitrates n n Increase myocardial oxygen supply, systemic vasodilation Beta blockers Inhibit increases in heart rate and contractility n Decrease myocardial oxygen demand n n Calcium channel agonists n n n Coronary vasodilators CABG PTCA

CABG PTCA

Cerebrovascular Disease: Epidemiology n n Third leading cause of death in the US Most prevalent neurologic disorder n n Morbidity Mortality

Cerebrovascular Disease: Stroke n Abrupt onset with focal neurologic deficit n Usually mini-event or warning signs n n Reversible ischemia n n 5 -20% transient ischemic attacks Some lasting 24 -72 hours Completed stroke Maximal deficit within hours n Often patient awakens with completed stroke n Usually preceded by TIA Progressive stroke n Ischemia worsens min. to min. or hour to hour n

Cerebrovascular Disease: Pathogenesis n Causes of stroke: n n n Blood vessel supplying the brain is blocked Thrombosis (clot in vessel) Embolism (clot breaks off and lodges in blood vessel in brain) Vasoconstriction or spasm Venous collapse

Cerebrovascular Disease: Diagnosis n n n History Exam Imaging n n n CT Scan MRI CT/MR Angiography

Cerebrovascular Disease: Treatment n n n Thrombolysis Rehabilitation Experimental n n Angioplasty Heparin Coumarin Aspirin

Tuberculosis n n 600, 000 people ages 15 -44 die each year from TB 2003: n n n 8. 8 million new cases Growing 1%/year 1. 5 million deaths 98% of deaths occur in developing world Estimated that TB will kill 35 million people in next 20 years if situation does not change

Tuberculosis n n n Bacterial infection of the lungs caused by mycobacterium tuberculosis Drugs which cure TB were discovered in 1940 s If untreated, results in death in 5 years in half of all cases

Tuberculosis n 1/3 of world’s population is infected with TB n n n Not all have active TB Most have latent TB - Immune system has walled off bacilli with waxy coat 5 -10% of people with normal immune systems will go on to develop active TB n n Higher in people with compromised immune systems (10 X higher in people with AIDS) TB is leading cause of death among people with HIV/AIDS n http: //www. npr. org/rundowns/segment. php? wf. Id=1520699

Tuberculosis n Symptoms n n n n Fever Night sweats Weight loss Weakness Coughs (productive with bloody sputum) Airborne transmission Left untreated, one person with active TB can infect 10 -15 people each year

Tuberculosis: Diagnosis n n n Skin test Serum test CXR n Shows nodules in active TB

Tuberculosis: Treatment n Latent TB: n n Treated with isoniazid, prevents development of active TB Active TB: n n n Can almost always be cured by taking several antibiotics in combination Stay home for several weeks while contagious Take drugs for 6 months

Tuberculosis n Resistant TB: n n Can develop if patients do not take all medicine Growing problem n n n 425, 000 new cases per year In Russia and China, 14% of new cases are resistant Must be treated with special medicines Poorly supervised Rx is worse than no Rx DOTS: n n 6 month supply is $10 Cure rates of up to 95% even in poorest countries 17 million patients worldwide have been treated with DOTS since 1995 25% of world’s population does not have access to DOTS.

Cancer n n 580, 000 people aged 15 -44 die every year due to cancer Cancer is a group of diseases characterized by uncontrolled cell growth Cancer cells usually form a tumor Cancer cells can spread from tumor to other sites in the body

Cancer n 2 nd n 1 leading cause of death in US of every 4 deaths is from cancer n 5 -year survival rate: 59% n Annual costs: $107 billion

Cancer n Tumor n n Types of Tumors: n n n Abnormal mass of tissue Growth exceeds that of normal tissue Purposeless and preys on host Benign Malignant Only malignant tumors can spread (Metastasize)

Microscopic Appearance

2004 Estimated US Cancer Deaths* Lung & bronchus 32% Prostate 10% Colon & rectum Men 290, 890 Women 272, 810 25% Lung & bronchus 15% Breast 10% Colon & rectum Pancreas 5% 6% Ovary Leukemia 5% 6% Pancreas Non-Hodgkin lymphoma 4% 4% Leukemia Esophagus 4% 3% Non-Hodgkin lymphoma Liver & intrahepatic bile duct 3% 3% Uterine corpus Urinary bladder 3% 2% Multiple myeloma Kidney 3% 2% Brain/ONS All other sites 21% ONS=Other nervous system. Source: American Cancer Society, 2004. 24% All other sites

Differentiation and Anaplasia n Benign tumors n n Malignant tumors n n Range from well to poorly differentiated Hallmarks of anaplasia: n n n Well differentiated Cells and nuclei show pleomorphism Cells contain abundant DNA, coarse, clumped chromatin Large NC ratio (1: 1) rather than (1: 4) Large nucleoli Large # of mitoses Dysplasia n n n Precancerous condition in epithelial tissue Anaplastic cells in epithelium Dysplasia does not always progress to cancer

Carcinogensis n Carcinogenesis: n n Result of non-lethal genetic damage Tumor masses result from the clonal expansion of a single progenitor cell that has incurred genetic damage

Biology of Tumor Growth n Natural hx of most cancers has 4 phases: n n Malignant transformation in target cell Growth of transformed cells Local invasion Distant metastases

Fig 7. 33 – The Metastatic cascade Neoplasia

Tissue Invasion n n Metastasis causes 90% of cancer death How do tumors invade: n n n Detach from primary tumor Degrade surrounding matrix Migrate

Importance of Cancer Screening

Burden of Self-Inflicted Injuries n n 480, 000 people aged 15 -44 take their own lives each year Highest rate of completed suicides n n Men >65 years old Highest rate of attempted suicides n Men and women ages 20 -24

Risk Factors Associated with Suicide n Psychiatric illness n n Affective, substance abuse, personality, other mental disorders Other risk factors n n n n Social adjustment problems Serious medical illness Living alone Recent bereavement Personal history of suicide attempt or completion Divorce or separation Unemployment

Methods of Suicide n Most common: n n 2 nd leading cause: n n n Firearms are used in 60% of suicides Men: Hanging Women: Drug overdose or poison Alcohol is involved in 25 -40% of suicides

Screening and Prevention n 50 -66% of all suicide victims visit physician <1 month before event 10 -40% in the preceding week Hard to identify who is at risk n n n Direct questioning has low yield General questions about sleep disturbance, depressed mood, guilt and hopelessness Survey instruments aren’t good at predicting what will happen

Screening for Suicide Risk n How do we quantify the efficacy of such questionnaires? n Goal of screening: n n Sensitivity: n n Catch as many positives as possible, even at the risk of some false positives Se = probability of testing positive if you will commit suicide Sensitivity of best questionnaires: 56% (low)

Screening for Suicide Risk n How many false positives result? n Positive predictive value: n n PPV=probability of committing suicide if you test positive PPV of best questionnaires: 3% (pathetic)

Summary of Lecture Two n n Developing countries Leading causes of mortality: ages 15 -44 n Developing world 1. 2. 3. n HIV/AIDS Road Accidents Interpersonal violence Developed world 1. 2. 3. Road accidents Self-inflicted injuries Interpersonal violence

Summary of Lecture 3 n Developing World 1. 2. 3. 4. n HIV/AIDS Unintentional injuries Cardiovascular diseases Tuberculosis Developed World 1. 2. 3. 4. Unintentional injuries Cardiovascular diseases Cancer Self-inflicted injuries

Assignments Due Next Time n HW 3

Infectious Diseases Malaria and Tuberculosis

What is Malaria? n n Periodic episodes of severe chills and high fevers along with profuse sweating at 4872 hour intervals, anemia. Plasmodium, a protozoa n n n P. falciparum – Coma and death P. malarium P. ovali and vivax – latent stage in the liver Deaths in children <5 y/o in sub-Saharan Africa Infection does not necessarily cause symptoms

Malaria is a disease of the tropics Source: CDC

Impact of Malaria n Enormous economic burden n Direct costs n n Drugs, doctors’ fees, lost wages, insecticide treated mosquito nets Indirect costs Pain and suffering, hampered schooling n Reduced tourism and business investments n n n “Growth penalty” of 1. 3% per year Disease of poverty and a cause of poverty

How Do We Control Malaria? n Prevent mosquito bite n n Eliminate vector (Anopheles mosquito) with pesticides at dusk in living and sleeping areas Use insect repellants and mosquito nets, and wear long-sleeved shirts and long pants n n Expensive Treat those will malaria n n n Treatment prevents spread of disease Not all infected have symptoms Treatment depends on species and strain Insecticide-treated mosquito net

Who pays for treatment and control? n n Local governments, Non-profits, governments of developed countries Private sector n Supporting malaria control helps boost profit

What is the role of technology? n n Develop a vaccine Better diagnostic techniques n n Low cost, rapid, user-friendly (e. g. dipstick test) Pre-packaging drugs Mapping of the Plasmodium falciparum genome -> better drugs Mapping malaria vectors

Who pays for technology development? n n n US Govt gives tax credits for companies that develop new vaccines World Bank may create a revolving fund to subsidize purchase of new vaccines Roll Back Malaria n WHO-founded global partnership

Disease Burden and Funding SOURCE: MALARIA R&D ALLIANCE

Where is the malaria vaccine? n What is stopping us? n n n Funding Thousands of antigens to the human immune system -> which ones are useful targets? Plasmodium has several life stages -> different antigens at each stage Plasmodium has several strategies to confuse, hide, and misdirect human immune system Multiple malaria infections of the different species and different strains of the same species in one host!

Tuberculosis n n Bacterial infection of the lungs and occasionally other body parts caused by Mycobacterium tuberculosis Incidence: 7. 5 million people (WHO) Deaths: 2. 5 million people/year. TB infects one-third of all humans. Follow poverty and urban crowding Particularly severe in: n n n AIDS patients Those who can't afford medical care Noncompliant patients.

Stages of Tuberculosis Illness n n n Primary TB Latent TB Secondary, or reactivation, TB

Stop TB Partnership n n Goal: Reduce the global burden of the disease by half by the year 2010. How: A broad commitment from governments and NGOs.

What is the role of technology? n n Vaccine development and evaluation Early diagnosis and monitoring n n Epidemiology n n New molecular tools Drug development and treatment n n n Drug-sensitive v. drug-resistant strains of TB Mechanisms of drug resistance and activity Discovery and development of new candidate antibiotics Basic Research n Molecular biology, genetics, immunology and pathogenic mechanisms of TB

Overlapping Epidemics n Malaria and HIV n n For people with HIV, especially pregnant women, episodes of acute malaria are complicated and more serious. TB and HIV n n TB is the leading killer of people with HIV In Africa, half of all TB cases are associated with HIV.

Who is helping? n n World Health Organization Global Fund for AIDS, Tuberculosis and Malaria (GFATM) n n Responds to intertwining threats by underwriting expanded treatment programs Gates Foundation n n $186 million to fight malaria $200 million with NIH for childhood vaccines, insect control, nutrition, new treatments

Drug Resistance and Tuberculosis

Drug Resistance n n n Selective pressure –Darwin’s theory of survival of the fittest Resistance is expected Factors can reduce development of resistance n n n Finish a course of antibiotics Only those who need antibiotics Narrow spectrum

How does an organism acquire resistance? n n Mutation and selection Exchange of genes between strains and species Source: Essential Biochemistry

You be the Doctor n n You are the health care provider and you have a patient with active TB TB strain in patient is susceptible to isoniazid, rifampin, ethambutal Poll: Which drug(s)? How long? 2 weeks, 6 months or 2 years?

Choices to treat TB n Isoniazid: n n n Rifampin n 1 in 106 organisms is resistant to isoniazid Adverse: liver toxicity 1 in 108 organisms is resistant Adverse: liver toxicity, interactions with other meds Ethambutol n n 1 in 106 organisms is resistant Adverse: eye damage Poll: Which drug(s)? How long? 2 weeks, 6 months or 2 years

Treat with Isoniazid n n 1 in 106 organisms is resistant to isoniazid At 2 weeks, 25% chance of resistant organisms n n At 6 months, 60% chance n n Not Cured! At 2 years, 80% chance n Not cured! Resistance to isoniazid! 999, 999 1 > x x x

Treat with Rifampin n 1 in 108 organisms is resistant to rifampin 99, 999 1 n At 2 weeks, 25% chance of resistant organisms n n At 6 months, 60% chance n n Not cured! Resistance to rifampin! At 2 years, 80% chance n Not cured! Resistance to rifampin! > x x

Treat with Ethambutol n 1 in 106 organisms is resistant to ethambutol 999, 999 1 n At 2 weeks, 25% chance of resistant organisms n n At 6 months, 60% chance n n Not cured! Resistant to ethambutol! Not cured! Resistance to ethambutol! At 2 years, 80% chance n Not cured! Resistance to ethambutol! x x x

Treat with Isoniazid and Rifampin n n The probability of developing resistance to 2 unrelated agents is the product of probabilities 1 in 106 x 1 in 108 = 1 in 1014 n Spontaneous evolution of multidrug-resistant bacillus is exceedingly rare

Solution n n Always treat with at least two drugs for which the strain is susceptible. If resistance develops, add at least two drugs for which the strain is susceptible

Case 2 – Two patients with TB resistant to Isoniazid n Which drug combination?

6 month Check-up n n Patient 1 has no active TB infection Patient 2 has TB resistant to all three drugs. n Why?

TB in the Last Century n n n TB incidence declined in the 1960’s and 1970’s. Incidence increased in the 1980’s. Drug prescription practices followed the previously mentioned guidelines. Why did therapy fail? n Compliance.

Directly Observed Therapy Shortcourse (DOTS) n n A health care worker watches and helps as the patient swallows anti-TB medicines in his/her presence. DOTS shifts responsibility for cure from patient to health care system Requires political commitment, accurate diagnosis, quality drugs, observation, follow up DOTS works well in many developing countries

Directly Observed Therapy with HIV n Controversial n n n Requiring DOT may impose substantial barriers to drugs in resource-poor countries HIV is more stigmatizing than TB Does directly observed therapy prevent more HIV mortality and transmission than selfadministered therapy? n How would you find out?

Clinical Trial n n Question: Does combined directly observed therapy for HIV and TB decrease HIV mortality in a resource-limited developing country? NIH study in resource-poor Durban, South Africa 2 groups of patients: Group 1 will undergo DOT for HIV and TB simultaneously. Group 2 will undergo DOTS for TB and HIV therapy without DOT Primary outcome: Diagnosis of an AIDS-defining illness; 18 -month mortality http: //clinicaltrials. gov/show/NCT 00091936

Back Up

Malaria Control n Reduce human/insect contact n n Prevent mosquito breeding Use insect repellents, mats, coils, bednets Residual treatment of interior walls Insecticide-treated mosquito nets n Expensive. Any solutions?

What are the Challenges for Malaria? n n n Mapping areas that are difficult to access Poor communication Direction – Transfer of vector control efforts from malaria control authorities to local primary health care center Financial support – decreased standard of living from wars, environmental factors, migration Corruption, graft

HIV, TB, and Malaria Selected Preventable Causes of Death n HIV/AIDS 2, 886, 000 n TB 1, 664, 000 n Malaria 1, 124, 000 n Diarrheal diseases 2, 001, 000 n Perinatal conditions 2, 504, 000 n Childhood diseases 1, 318, 000 n Lung cancer 1, 213, 000 n Traffic accidents 1, 194, 000 n Suicide 849, 000 n War 230, 000 Source: The World Health Report 2002, WHO