NR507 FINAL EXAM STUDY GUIDE

Endometrial cycle and occurrence of ovulation Manifestation of female reproductive functioning is menstrual bleeding, which starts with menarche (1st period) and ends with menopause (cessation of menstrual flow for 1 y ...

Endometrial cycle and occurrence of ovulation Manifestation of female reproductive functioning is menstrual bleeding, which starts with menarche (1st period) and ends with menopause (cessation of menstrual flow for 1 year). Average age of menarche is 12 with a range of 9-17. Appears to be r/t body weight, especially body fat ratio. At first cycles are anovulatory and vary from 10-60 days or >. Then in adulthood range form 25-35 days. Length varies considerably. Cycle and regular ovulation are dependent on  The activity of gonadostat  Initial pituitary secretion of gonadotropin FSH  Estrogen positive feedback for the preovulatory FSH and LH surge, oocyte maturation, and corpus luteum formation and production of progesterone. The average menstrual cycle lasts 27 to 30 days and consists of three phases, which are named for ovarian and endometrial changes: the follicular/proliferative phase, the luteal/secretory phase, and the ischemic/menstrual phase. Phase 1-is the follicular phase in which begins on day one of one’s menstrual cycle. It lasts until about day 14. -In phase 1 the endometrium grows to form a lush lining inside of the uterus. Phase 2: Luteal phase-this is where the body secretes the hormones estrogen and progesterone. -These hormones work together to prepare the lining of the uterus for implantation. -This last for 12 days. Phase 3: Menstrual phase-The estrogen and progesterone start to decline and the endometrial lining begins to shed. This lasts for 3-5 days and the process restarts. Ovulation -Release of ovum -Present at the beginning of the luteal/secretory phase. -The ovarian follicle begins to transform into the corpus luteum. -Pulsatile secretion of the LH from the anterior pituitary stimulates the corpus luteum to secrete progesterone. -This will initiate the secretory phase of endometrial development. -Glands and blood vessels in the endometrium branch and curl through a functional layer, and the glands begin to secrete a thin glycogen-containing fluid= the secretory phase. *If conception occurs the nutrient-laden endometrium is ready for implantation. *The HCG hormone is secreted 3 days after fertilization by blastocytes and maintains the corpus luteum once implantation occurs at day 6 or 7. *HCG can be detected in maternal blood or urine about 8-10 days after ovulation. *Production of estrogen and progesterone continue until placenta can adequately maintain hormonal production. *Ovulatory cycles have a length of 24-26.5 days. *The primary ovarian follicle requires 10-12.5 days to develop. *The luteal phase appears at 14 days. Ovarian events of the menstrual cycle are controlled by gonadotropins. High FSH levels stimulate follicle and ovum maturation (follicular phase), then a surge of LH causes ovulation, which is followed by development of the corpus luteum (luteal phase). Ovarian hormones control the uterine (endometrial) events of the menstrual cycle. During the follicular/proliferative phase of the ovarian cycle, estrogen produced by the follicle causes the endometrium to proliferate (proliferative phase) and induces the LH surge and progesterone production in the granulosa layer. During the luteal/secretory phase, estrogen maintains the thickened endometrium, and progesterone causes it to develop blood vessels and secretory glands (secretory phase). As the corpus luteum degenerates, production of both hormones drops sharply, and the “starved” endometrium degenerates and sloughs off, causing menstruation, the ischemic/menstrual phase. Cyclic changes in hormone levels also cause thinning and thickening of the vaginal epithelium, thinning and thickening of cervical secretions, and changes in basal body temperature. Uterine Prolapse descent of cervix or entire uterus into vaginal canal. In severe cases the uterus falls completely through the vagina and protrudes from the introitus. Symptoms of other pelvic floor disorders may also be present. Tx depends on severity of symptoms and physical condition of woman. First line treatment is often a pessary- removable mechanical device that holds uterus in position. The pelvic fascia may be strengthened through kegels or by estrogen therapy in menopausal women. Healthy BMI, preventing constipation, and treating chronic cough may also help. Surgical repair with or without hysterectomy is the last resort. Page-771 fig 25.11 -Dropping of the cervix or the entire uterus into the vaginal canal. -In severe cases the uterus completely through the vagina and protrudes from the introitus. -Symptoms of other pelvic floor disorders may also be present. Symptoms: urinary-sensation of incomplete emptying of bladder, incontinence,frequency,bladder splinting to accomplish voiding. Bowel-constipation or feeling of rectal fullness, difficult defecation, stool or flatus incontinence. *Pain or bulging includes pelvic pressure, low back pain, and vagina, bladder or rectum bulging. *Sexual-decreased sensation, lubrication or arousal. -Dyspareunia Treatment: -Depends on age and severity. -Isometric exercise-strengthen the pubococcygeal muscle. KEGELS* -Estrogen-to improve tone and vascularity of fascial support POSTMENOPAUSAL* -Pessary—a removable device to hold pelvic organs in place. -Weight loss -Stool softeners to avoid constipation -tx of lung and cough conditions PCOS Polycystic ovary syndrome (PCOS) is a difficult syndrome to diagnose because several factors are involved. It is a syndrome in which at least two of the following are present: oligo-ovulation or anovulation, elevated levels of androgens, or clinical signs of hyperandrogenism and polycystic ovaries. Prolonged anovulation leads to infertility, menstrual bleeding disorders, hirsutism, acne, endometrial hyperplasia, cardiovascular disease, and diabetes mellitus in women with hyperinsulinemia. Presenting s/s: obesity, menstrual disturbance, oligomenorrhea, amenorrhea, regular menstruation, hyperandrogenism, infertility or they could be asymptomatic. Diagnosis of PCOS is based on evidence of androgen excess, chronic anovulation, and inappropriate gonadotropin secretion. Tests for impaired glucose tolerance are recommended. As stated, polycystic ovaries do noT have to be present and, conversely, their presence alone does not establish the diagnosis. Goals of treatment include reversing signs and symptoms of androgen excess, instituting cyclic menstruation, restoring fertility, and ameliorating any associated metabolic or endocrine, or both, disturbances. *Most common cause of anovulation and ovulatory dysfunction in women. *Leading cause of infertility and most common endocrine disturbance. *Mostly common in younger women *Usually has two/three of the following: irregular ovulation, elevated levels of androgens (testosterone), and the appearance of polycystic ovaries on ultrasound. *Polycystic ovaries do not need to be present to dx POS. *Thyroid dysfunction, hyperprolactinemia, and congenital adrenal hyperplasia must be ruled out first. *Associated with metabolic dysfunction, dyslipidemia, insulin resistance, and obesity. *Strong genetic component and possibly differentially inherited. *Difficult to diagnose as symptoms may change over time. *80% of women have one or more of the symptoms with normal ovaries. *More prominent sx as we age. *May be associated with Cushing’s syndrome, acromegaly, premature ovarian failure, obesity, congenital adrenal hyperplasia, thyroid disease and androgen producing adrenal tumors. Pathophysiology: *Underlying cause is unknown *Genetic involvement suggested because of steroid and androgen biosynthesis. *No single factor accounts for abnormalities of pcos. ***A HYPERANDROGENIC STATE IS A CARDINAL GEATURE IN THE PATHOGENSIS OF PCOS*** -3 X LIKELY TO HAVE INSULIN RESISTENCE. *Insulin stimulates androgen secretion by the ovarian stroma and reduces the serum sex hormone-binding globulin. * Free testosterone levels increase *Excessive androgens affect follicular growth and insulin affects follicular decline by suppressing apoptosis Decreased intraovarian receptors for estrogen receptor -a- or insulin like growth factor 1, increased leptin levels, or direct infrared redaction select ovarian cells. *Intrauterine and early child enviroment contribute to childhood development. *Weight gain aggravates symptoms and women will have an increased leptin level. *Leptin levels are increased in thin women as well *Leptin influences the hypothalamic pulsatility of GNRH and interaction with HPO. *Dysfunction in ovarian follicle development results from inappropriate gondatropin secretes and triggers the beginning of anovulation. *FSH is low and LH are high. *Persistent LH elevation causes an increase in androgens *DHEA (in adrenal glands and testosterone). And Androstenedione and dhea in the ovary. *Characterized by excessive levels of androgen and estrogen. -increased androgen contributes to a premature follicular failure (anovulation). -Persistent anovulation causes the pearly white smooth capsules (polycystic ovaries). -Thickening of the tunica, increased cortical stromal thickening, and hyperplasia. -**Women with PCOS 3 x greater of developing uterine cancer. Clinical Manifestations: *Appear within 2 years of puberty. *May not present until normal menstrual function or pregnancy. *Obese *Anovulation, hyperandrogenism, insulin resistance *infertility, hirsutism, acne, dysfunctional bleeding. *More likely to experience sleep apnea. Evaluation and Treatment: *dx is made based on androgen excess, chronic anovulation, and sonographic evidence of polycystic ovaries. *Must have 2 -3 of these. *Impaired glucose tolerance test is recommended *Goals are to suppress androgen, instituting menstruation, restore fertility, and reduce endocrine disturbance. **FIRST LINE TREATMENT= COMBINED ORAL CONTRACEPTIVES** -This helps to initiate regular menses. -Lifestyle modifications= exercise and weight loss. --Insulin resistance= metformin -If pregnancy is not desired- progesterone therapy is important to oppose estrogen effects on the endometrium to help monthly bleeding. **FOR OBESE WOMEN LIFESTYLE MODIFICATIONS ARE FIRST LINE** -CLOMIPHENE CITRATE CAN BE USED TO FACILITATE OVULATION* Testicular cancer & Risk factors Highly treatable, usually curable cancer most often develops in young and middle aged men. Rare, but most common form of cancer between young men 15-35. More common on R side than left. Germ cell tumors arising from male gametes: seminomans and nonseminomas. Seminomas are most common, least aggressive. Nonseminomas include embryonal carcinomas, teratomas, and choriocarcinomas, most aggressive but rare. Neoplasm cause is unknown. Genetic predisposition is suggested d/t incidence in brothers, identical twins and close male relatives. Risk factors: cryptochordism- neoplasms develop more commonly in contralateral testis. Abnormal testicular development, HIV and AIDS, Klinefelter syndrome, and hx of testicular cancer. Symptoms that require evaluation for Breast Cancer Clinical manifestation Pathophysiology Chest pain Metastasis to lung Dilated blood vessels Obstruction of venous return by fast growing tumor Dimpling of skin Can occur with invasion of dermal lymphatics because of retraction of cooper ligament Edeme of arm Local inflammation of lymphatic obstruction Hemorrhage Erosion of blood vessels Local pain Local obstruction by tumor Nipple/areolar eczema Paget disease Nipple discharge in a nonlactating woman Spontaneous and intermittent d/c caused by tumor obstruction Nipple retraction Shortening of mammary ducts Pitting of the skin Obstruction of subq lymphatics, resulting in fluid accumulation Reddened skin, local tenderness, warmth Inflammation Skin retraction Involvement of suspensory ligaments Ulceration Tumor necrosis Signs of premenstrual dysphoric disorder (PMDD)  The cyclic recurrence (in the luteal phase of the menstrual cycle) of distressing physical, physical, psychologic, or behavioral changes that impair interpersonal relationships or interfere with usual activities.  Neurotransmitters, GABA, and noradrenaline may have mediating or moderating roles on symptom manifestation. These neurotransmitters have demonstrated interactions with estrogen and progesterone and all of these are neuroactive with known mood and behavior effects, including negative mood, irritability, aggression, and impulse control.  Symptoms usually appear a week before menstruation and end a few days after your period starts. When this happens, some women have trouble functioning at home, at work and in relationships during this time.  Women show symptoms of irritability, nervousness, anger, insomnia, anxiety, paranoia, trouble sleeping, N&V, headaches, fainting. Dysfunctional uterine bleeding  DUB is heavy or irregular bleeding in the absence of organic disease, such as submucous fibroids, endometrial polyps, blood dyscrasias, pregnancy, infection, or systemic disease.  This accounts for 70% of all hysterectomies and almost all endometrial ablation procedures.  Caused by the lack of ovulation. Normal periods result in the complex interplay of the hypothalamus, the pituitary, the ovary, and the uterine endometrium. Disruptions in this system can affect the amount and structure of the uterine endometrium causing it to shed irregularly or heavily.  Occurs more in women ages 40-50 because they are at the end of their reproductive years and are more likely to ovulate irregularly.  PCOS can lead to irregular heavy uterine bleeding  The formation of the follicle and its rupture release an ovum which is a very important part of the menstrual cycle. As the follicles forms it produces estrogen. Following ovulations, the remain portions of the follicle, known as the corpus luteum, releases progesterone. Progesterone acts on the endometrium to limit growth and causes, which helps limit bleeding during endometrial shedding.  If a follicle forms but never releases in the ovum, the follicle may continue to produce estrogen which causes thickening of the endometrium. This causes the endometrium to be able to shed in a predictable fashion. Pathophysiology of prostate cancer  More than 95% of prostatic neoplasms are adenocarcinomas and most occur in the periphery of the prostate. Prostatic adenocarcinoma is a heterogenous group of tumors.  Estrogen receptor -a has shown evidence to participate in the pathogenesis of prostate cancer.  This ER-a receptor leads to inflammation, proliferation and development of premalignant lesions. ER-B leads to antiproliferative, anti-inflammatory, and potentially anticarcinogenic effect that tries to balance ER-a and the androgens involved.  Increased expression of ER-a has been shown to increase prostate cancer progression, metastasis.  The prostate glands require male hormones, known as androgens, to work properly. Androgens include testosterone, which is made in the testes, dehydroepiandrosterone, made in the adrenal glands; and dihydrotestosterone, which is converted from testosterone within the prostate itself. Androgens are also responsible for secondary sex characteristics such as facial hair and increased muscle mass. Prostate cancer is classified as an adenocarcinoma, or glandular cancer, that begins when normal semen- screening prostate gland cells mutate into cancer cells. The region of prostate gland where the adenocarcinoma is most common is the peripheral zone. Initially, small clumps of cancer cells remain confined to otherwise normal prostate glands, a condition known as carcinoma in situ or prostate intraepithelial neoplasia (PIN). Although there is no proof that PIN is a precursor, it is closely associated with cancer. Overtime, these cancer cells begin to multiply and spread to the surrounding prostate tissue (the stroma) forming a tumor. Eventually, the tumor may grow large enough to invade nearby organs such as the seminal vesicles, or the rectum, or the tumor cells may develop the ability to travel in the blood stream and lymphatic system HPV and development of cervical cancer  Cervical cancer is almost exclusively caused by cervical human papillomavirus (HPV) infection.  Infection with “high-risk” (oncogenic) types of HPV (predominately 16 and 18) is necessary precursor to development of precancerous cell changes, known as dysplasia of the cervix that leads to invasive cancer.  With these cell changes, they can be detected noninvasively through examination of the cervical cells. The cells can be destroyed to prevent cancer development if dysplasia can be detected early.  The line where two cell types meet, known as the transformation zone, is very vulnerable to oncogenic effects of HPV. In girls and young woman, a large portion of the cervix is covered with columnar epithelium, a condition called squamous metaplasia. As women age the transformation zone moves as the squamous epithelium covers the surface of the cervix. The younger the woman is when she contracts HPV, the more sensitive cervical cells are exposed.  Vaccinating against HPV early before the initiate of sexual activity is important  Normally, women can clear most HPV infections by the immune system. But some cannot which contributes to the develop of cervical cancer. ENDOCRINE Body’s process for adapting to high hormone levels: Negative-feedback systems are important in maintaining hormone concentrations within physiologic ranges. The lack of negative-feedback inhibition on hormonal release often results in pathologic conditions. hormonal imbalances and related conditions are caused by excessive hormone production, which is the result of failure to “turn off” the system. High concentrations of hormone decrease the number of receptors, called down-regulation. Thus the cell can adjust its sensitivity to the concentration of the signaling hormone. The receptors on the plasma membrane are continuously synthesized and degraded, so that changes in receptor concentration may occur within hours. Various physiochemical conditions also can affect both the receptor number and the affinity of the hormone for its receptor. Some of these physiochemical conditions are the fluidity and structure of the plasma membrane, pH, temperature, ion concentration, diet, and the presence of other Cushing’s Syndrome: overproduction of anterior pituitary ACTH by a pituitary adenoma; chronic excess cortisol (at any age) With ACTH-dependent hypercortisolism, the excess ACTH stimulates excess production of cortisol and there is loss of feedback control of ACTH secretion. Whatever the cause, two observations consistently apply to individuals with Cushing syndrome: (1) they do not have diurnal or circadian secretion patterns of ACTH and cortisol, and (2) they do not increase ACTH and cortisol secretion in response to a stressor. Exogenous result from administration of glucocorticoids. Endogenous either corticotropin dependent (most common & caused by ACTH-secreting pituitary tumor) or corticotropin independent (usually caused by an adrenal cortical tumor). Clinical features: weight gain in trunk, face, and cervical areas. “truncal obesity, moon face, buffalo hump”. Transient weight gain from sodium and water retention may be present because of the mineralocorticoid effects of cortisol, exhibited when cortisol is present in high levels. Glucose intolerance occurs because of cortisol-induced insulin resistance and increased gluconeogenesis and glycogen storage by the liver. Protein wasting is caused by the catabolic effects of cortisol on peripheral tissues. Muscle wasting leads to muscle weakness and is especially obvious in the muscles of the extremities with thinning of the limbs. In bone, loss of the protein matrix and increases in bone resorption lead to osteoporosis and can result in pathologic fractures, vertebral compression fractures, bone and back pain, kyphosis, and reduced height. Hypercalciuria may result in renal stones, which are experienced by approximately 20% of individuals with this disease. Loss of collagen also leads to thin, weakened integumentary tissues through which capillaries are more visible; the tissues are easily stretched by adipose deposits. Hypoparathyroidism CX: low PTH levels. Usually caused by damage to the PT glands during thyroid surgery & anatomic proximity of PT glands to thyroid. Assoc c genetic syndromes, including familial HX & DiGeorge syndrome (velocardiofacial syndrome) & idiopathic or autoimmune form of the disease. Low mag can cause a decrease of PTH secretion & function Lab results point to primary hypothyroidism: caused by a deficient production of TH by the thyroid gland. Primary hypothyroidism the loss of functional thyroid tissue leads to a decreased production of TH. Causes in adults include autoimmune thyroiditis (Hashimoto disease), iatrogenic loss of thyroid tissue after surgical or radioactive treatment for hyperthyroidism, head and neck radiation therapy, medications, and endemic iodine deficiency. Primary hypothyroidism DX: is made by documentation of the clinical symptoms of hypothyroidism, and by measurement of increased levels of TSH and decreased levels of TH (total T3 and both total and free T4). When hypothyroidism is caused by pituitary deficiencies, serum TSH levels are decreased or are inappropriately normal in the face of low levels of TH. Pathophysiology of thyroid storm: (Thyrotoxic Crisis) rare but dangerous worsening of thyrotoxic state. Death within 48hr without treatment. Occurs in individuals who have undiagnosed or partially treated severe hyperthyroidism & subjected to excessive stress. CX: infection, pulmonary/cardiac disorder, trauma, burns, seizures, SX (esp thyroid surgery), OB complications, emotional distress, or dialysis. Symptoms: ↑thyroxine action(T4) & triiodothyronine (T3) exceeding metabolic demands. Signs of thyrotoxicosis: Excessive concentrations of thyroid hormones. Symptoms: ↑metabolic rate, hyperthermia (heat intolerance), tachycardia (esp atrial tachydysrhythmias), high-output HF; agitation or delirium, goiter, reproductive disorders, excessive sweating, nausea, vomiting, diarrhea (n/v/d=fluid volume depletion) NEURO Dermatomes Specific areas of cutaneous (skin) innervation at these spinal cord segments. The dermatomes of various spinal nerves are distributed in a fairly regular pattern, although adjacent regions between dermatomes can be innervated by more than one spinal nerve. Substance release at synapse The region between adjacent neurons is called a synapse. Impulses are transmitted across the synapse by chemical and electrical conduction. The conducting substance is called a neurotransmitter and it is often formed in the neuron, transported to the synaptic knobs (boutons) of the presynaptic neuron’s axon, and stored in synaptic vesicles within the knobs. Action potentials in the presynaptic neuron cause the synaptic vesicles to release their neurotransmitter(s) through the plasma membrane into the synaptic clef (the space between the neurons), where they bind to specific neurotransmitter (protein) receptor sites on the plasma membrane of the postsynaptic neuron Spondylolysis Degenerative process of the vertebral column and associated with soft tissue. Characterized by a structural defect of spine involving lamina or neural arch of vertebra. Most common site affected is the lumbar spine. This defect occurs in the portion of the lamina between the superior and inferior articular facets called the pars interarticularis. Mechanical pressure may cause a forward displacement of the deficient vertebra called spondylolisthesis. Heredity plays a significant role, and spondylolysis is associated with an increased incidence of other congenital spinal defects. As a result of torsional and rotational stress, “microfractures” occur at the affected site and eventually cause dissolution of the pars interarticularis. Location of motor and sensory areas of the brain The special senses of vision, hearing, touch, smell, and taste are the means by which individuals perceive stimuli that are essential for interacting with the environment. Special sensory receptors are connected to specific areas of the brain through the afferent pathways of the peripheral and central nervous system (CNS). Each of the special senses thus involves a connected system of organs and tissues that receives stimuli and sends sensory messages to areas of the CNS, where they are processed and guide behavior. Patho of cerebral infarction and excitotoxins results when an area of the brain loses supply and becomes ischemic because of vascular occlusion embolic or thrombotic. 1. Abrupt vascular occlusion (embolus) 2. Gradual vessel occlusion (atheroma) 3. Vessels thats are stenosed but not completely occluded (atherosclerosis/hypotension) are the dominant underlying processes (Textbook) Release of excitatory neurotransmitters after brain injury causes secondary neural injury known as excitotocity. (Workbook pg. 86) Agnosia Impaired/defect of recognition and may be tactile, visual or auditory stimuli. Caused by dysfunction in the primary sensory area or the interpretive areas of the cerebral cortex Accumulation of blood in a subarachnoid hemorrhage (SAH) Hemorrhage from a defective or injured vasculature into the subarachnoid space. The blood is extremely irritating to the meningeal and other neural tissues and so produces an inflammation & impairs circulation of cerebrospinal fluid. Additionally, the blood coats nerve roots, clogs arachnoid granulations (impairing CSF reabsorption), and clogs foramina within the ventricular system (impairing CSF circulation). ICP immediately increases to almost diastolic levels within 10 mins. ICP returns to near baseline in about 10 minutes. Cerebral blood flow and cerebral perfusion pressure (CPP) decrease. The expanding hematoma acts like a space-occupying lesion, compressing and displacing brain tissue. Granulation tissue is formed and scarring of the meninges, with resulting impairment of CSF reabsorption and secondary hydrocephalus, often results. Most common cause of meningitis Meningitis is inflammation of the brain or spinal cord. Infectious meningitis may be caused by bacteria, viruses, fungi, parasites, or toxins. Bacterial & viral meningitis is the most common. Bacterial infection may be due to Neisseria meningitis, Haemophilus influenza, streptococcus pneumoniae, or Escherichia coli. Sometimes, no causative organisms can be found. In most patients, the infections that cause meningitis is secondary to another bacterial infection, such as bacteremia. Respiratory infections increase the risk. It may follow a skull fracture, a penetrating head wound, lumbar puncture, ventricular shunting, or neuro procedure. Viral meningitis aka aseptic viral meningitis may result from a direct infection or secondary to disease such as mumps, herpes, measles, or leukemia. (Textbook) GENITOURINARY Diet and prevention of prostate cancer Evidence exists that dietary factors play a role in prostate cancer development. The lack of biomarkers for certain nutrients, difficulty measuring and quantifying diet, and limitation of clinical trials all make the understanding of the relationship difficult. Dietary intake effects the signaling pathways, hormones, oxidative stress, and reactive oxygen species (RDS). Nutrients most associated with cancer are carotenoids, fat, vit E, vit D/calcium, and selenium. Less studied are isoflavones, curcumin, lycopene, zinc, green tea, omega 3 polyunsaturated fats, and sulforaphane. The hypothesis for MEAL is that a change in diet of higher intake of animal products to vegetables and fruits will slow the progression of the indolent to the aggressive form of prostate cancer. As adipose tissue is increasingly being regarded as hormonally active tissue, high body fat and obesity need in-depth exploration to understand the associated risk of prostate problems Obesity has a positive association with aggressive prostate cancer and worse outcomes but a negative association with indolent (slow growing) prostate cancer. Adipose tissue is considered hormonally active tissue. It effects circulating bio-active messengers therefore influences the risk of developing prostate problems. - Consumption of excess calories increases the need for insulin and IGF-1 which is a powerful carcinogenic. Total fat intake, animal and saturated fat, red meat and dairy all increase the risk for prostate cancer High calorie and high carb diet increase the risk for prostate cancer Monosaturated fats decrease the risk for prostate cancer. Linoteic acid and high ratios of omega 6/omega 3 are all proinflammatories - This promotes cell proliferation and angiogenesis (new flood vessel formation) but inhibits apoptosis (cell death). Cooking meat at high temperatures produces heterocyclic amines and aromatic hydrocarbons. Both are carcinogenic. Vitamin E is a fat-soluble vitamin found in vegetable oils, nuts, and egg yolks. It is a intracellular antioxidant which inhibits peroxidation and DNA change. Studies have shown it reduces incidence of prostate CA in smokers, kills cancer cells, and inhibits androgen receptors. Selenium is a trace mineral found in food. Essential for functioning of antioxidant enzymes and proteins in body. It inhibits cell proliferation, kills prostate cells, stops angiogenesis, and sensitizes cells for radiation-induced killing. It is capable of activating intrinsic and extrinsic pathways for apoptosis. Vitamin E in combination with selenium does not reduce cancer incidence or provide any type of defense. Separately they decrease the risk but together they do not. Vitamin D/Zinc/Tomatoes/Tomato products- may be important but lack data Soy will inhibit cell proliferation and angiogenesis but can also reduce the PSA and androgen receptor level Vegetables including broccoli, cabbage, cauliflower, brussel sprouts, and turnips all protect against prostate cancer. However, broccoli will decrease the growth of cancer cells. Green tea contains polyphenols and has been associated with decrease incidence of several cancers including prostate cancer. It helps improve antioxidant potential, binds directly to carcinogens, inhibits IGF-1 which results in decreased development and progression of prostate cancer. Black tea also decreases the risk for prostate cancer. As you can see multiple signaling pathways such as proliferation, angiogenesis, and apoptosis, are all involved in the development and progression of prostate cancer and closely related to dietary factors. Impact of BPH on the Urinary System Benign Prostate Hyperplasia is an enlargement of the prostate gland. As the prostatic tissue enlarges is compresses the urethra, where it passes through the prostate, causing lower urinary tract symptoms. At birth the gland is pea sized and growth is gradual until puberty. Development continues until 3rd decade of life. Benign hyperplasia begins around age 40-45 and continues until death. Bladder outflow obstruction occurs as the hypertrophy continues and the urethra is compressed. - Symptoms sometimes called spectrum of lower urinary tract symptoms (LUTS) are: urge to urinate often, delay in starting urination, decrease in force of stream. As this progresses over years the bladder cannot empty leading to long term urinary retention. The overload of volume may cause “overflow incontinence” if intra-abdominal pressure occurs. The stream force is significantly reduced and much more time is required to initiate and complete urination at this stage. Hematuria, bladder or kidney infection, bladder calculi, acute urinary retention hydroureter, hydronephrosis, and renal insufficiency are other common complication of BPH. Sometimes the initial signs may be uremia and renal failure. The palpated prostate does not always reflect the degree of BPH because a large portion of enlargement is intravesicular. On digital rectal exam the prostate may be soft or firm enlargement with smooth muscle surface. Asymmetry is common. Digital exam and PSA are used to determine BPH. Cannot use PSA only because it is also elevated in prostate cancer. If enlargement is noted and symptoms are severe a transrectal ultrasound is performed to determine residual urine. BPH can be treated successfully with drugs that relax the smooth muscle of the bladder and prostate (adrenergic blockers). Other medications can block androgens at the cellular level and cause the prostate gland to shrink (antiandrogen agents). Surgical removal of the hyperplastic tissue to prevent the serious consequences of urethral obstruction is an option if medication is ineffective. If medication is ineffective and an individual cannot tolerate surgery a permanent indwelling catheter is placed. GENETICS The role of DNA in genetics – Genes are composed of DNA Chromosomes are composed of many genes = basic units of inheritance, carrying information for synthesis of specific proteins. Genes are composed of the chemical deoxyribonucleic acid (DNA). the replication of DNA occurs a finite number of times per chromosome due to the presence of telomeres = short nt/protein segments on the ends of chromosome arms that protect DNA and prevent chromosome fusions during the cell division cycle. Telomeres gradually erode away with each cell division until DNA unravels and chromosome disintegrates. This is an important way to help eliminate chromosomes (and cells) carrying accumulated undesirable mutations! DNA is the genetic basis of life = the “blueprint of life" Transcription –Transcription is the process by which DNA specifies a sequence of mRNA. RNA is synthesized using DNA as the template via the process of transcription. However, unlike the replication process where an exact copy is made of all the DNA within the nucleus, only small portions of DNA are transcribed at a time to make RNA. Each transcribed segment of DNA corresponds to one of the 1000’s of genes that make up our chromosomes. Several 100-1000 DNA nt comprise a gene = information for synthesis of a specific protein. Effects of genetic mutations – Changes in the DNA can also occur as the result of a mutation = inheritable alteration of genetic material. Mutations can occur either spontaneously or as a result of exposure to external mutagens such as radiation, chemicals, and even certain infectious agents (eg – viruses). Mutations in individual genes can also result in single gene disorders. (e.g. sickle cell anemia, cystic fibrosis, hemophilia) Depending on the location of the mutated gene, and whether or not it is a dominant or recessive allele, disorders are classified as: autosomal dominant, autosomal recessive, sex-linked Most diseases (including diabetes, dementia, cardiovascular conditions, cancer) have a genetic component and are classified as multi-factorial: mutations occur at multiple (polygenic) chromosomal sites that have a cumulative effect to cause disease. Down syndrome/ Trisomy: Trisomy is a type of aneuploidy in which one chromosome is present in three copies in somatic cells. A partial trisomy is one in which only part of a chromosome is present in three copies. Down Syndrome- pg. 146 – aneuploidy in an autosome is trisomy of the 21 chromosome, low nasal bridge, epicanthal folds, protruding tongue, flat low set ears. Down syndrome, a trisomy of chromosome 21, is the most well-known disease caused by a chromosome aberration. It affects 1 in 800 live births and is much more likely to occur in the offspring of women older than 35 years of age.  Failure of the homologous chromosome pairs to separate during meiosis is called nondisjunction and also results in abnormalities of chromosome number.  Aneuploidy: gamete cell that does not have 23 chromosomes so resulting embryo will have fewer or extra chromosome (not all abnormal chromosomes may even survive). Cells with fewer than normal chromosomes are less likely to survive than cells that have more than normal chromosomes.  Aneuoploidy of sex chromosomes results in conditions: o Klinefeiter symdrome (XXY) o Turner syndrome (XO)  Aneuoploidy of autosomal chromosomes results in conditions such as: o Down syndrome (trisomy 21) o Or Edwards syndrome (trisomy 18) Aneuploid cells are those that do not contain a multiple of 23 chromosomes. An aneuploid cell containing three copies of one chromosome is said to be trisomic (a condition termed trisomy) o The only trisomies frequent in live births are trisomy 13, 18 and 21. Fetuses with other trisomies do not survive to term, trisomy 16 most common trisomy among abortuses. o Partial trisomy: extra portion of a chromosome is present in each cell. o Most well-known example of aneuploidy in an autosome is trisomy 21= Down Syndrome o IQs between 25-70 Facial appearance: low nasal bridge, epicanthal folds, protruding tongue, flat low-set ears, poor muscle tone. Congenital heart defects are common with inability to fight off respiratory tract infections and increased susceptibility to leukemia. o After age of 40, develop symptoms similar to Alzheimer disease because gene of Alzheimer disease is located on chromosome 21. o 97% of Down Syndrome cases are caused by nondisjunction during the formation of one of the parents games or early embryonic development. Remaining 3% is translocation. 90-95%, nondisjunction occurs in formation of mothers egg cell. o 1% of individuals with ds are known to be mosaics, the effects of the trisomic cells are attenuated and symptoms are less severe. Klinefelter syndrome: smallness of testes with fibrosis and hyalinization of seminiferous tubules, variable degrees of masculinization, azoospermia, infertility, and increased levels of urinary gonadotropins; associated typically with an XXY chromosome complement although variants include XXYY, XXXY, and XXXXY - Diagnosed in individuals with at least 2 X chromosomes and a Y chromosome - Individuals have a male appearance - Usually sterile - About half develop female-like breasts (condition called gynecomastia_ - Testes are small, body hair is sparse, voice is often high pitched, stature is elevated, and a moderate degree of mental impairment is present - 1 in 1000 male births - About 2/3rd are caused by nondisjunction of the x chromosomes in the mother and frequency rises with increased maternal age - XXXY and XXXXY karyotypes are also considered to have Klinefelter syndrome, the degree of physical and mental impairment increases with each additional X chromosome - Those with an extra Y chromosome produce the 47,XYY karyotype: these individuals are taller than average, and have a 10-15 point reduction in IQ; condition causes few serious physical problems but evidence shows increased behavioral disorders Duchenne muscular dystrophy Duchenne muscular dystrophy, is the most common of the muscular dystrophies. The X-linked inherited type of Duchenne muscular dystrophy is thought to be caused by deletion of a segment of deoxyribonucleic acid (DNA) or a single-gene defect on the short arm of the X chromosome. A protein encoded by the Duchenne muscular dystrophy gene, called dystrophin, has been identified. Dystrophin is present in normal muscle cells and absent in Duchenne muscular dystrophy (it is present in reduced amounts in Becker dystrophy). Dystrophin mediates anchorage of the actin cytoskeleton of skeletal muscle fibers to the basement membrane through a membrane glycoprotein complex. The complete lack of dystrophin in severe Duchenne dystrophy means that poorly anchored fibers tear themselves apart under the repeated stress of contraction. Free calcium then enters the muscle cells, causing cell death and fiber necrosis. An X-linked genetic disorder in which fat and fibrous tissue infiltrate and weaken muscle tissues such as in the legs and pelvis, lungs, and heart; usually results in death before adulthood. - X-linked recessive disorder - 1 in 3500 males - Progressive muscle degeneration; affected individuals are unable to walk by the age 10 to 12 - Disease affects the heart and respiratory muscles, and death caused by respiratory or cardiac failure usually occurs before the age of 20 - Dystrophin: muscle protein o Dystrophin plays an important role in maintaining the structural integrity of muscle cells: one end of the protein binds to actin filaments in the cytoplasm of the cell, and other end binds to a group of membranespanning proteins known as dystrophin-associated glycoproteins o When Dystrophin is absent, as in individuals with DMD, the muscle cell cannot survive, and muscle deterioration ensues - Most cases of DMD is caused by deletions of portions of the DMD genes Neurofibromatosis Neurofibromatosis (NF) is an inherited autosomal dominant disorder accounting for 5% of all neuromas and is divided into two types: NF1 and NF2, which are clinically and genetically distinct disorders. The gene products are neurofibromin and merlin (schwannomin), both of which are thought to be tumor suppressors - Inherited autosomal dominant disorder accounting for 5% of all neuromas and is divided into two types: NF1 and NF2 - NF1 is associated with cutaneous manifestations, iris hamartomas, and tumors primarily involving the peripheral nervous systems and occasionally the CNS - NF2 is associated with cataracts, hearing loss, and tumors primarily in the CNS; most commonly vestibular schwannoma and meningioma - The tumors most commonly affect people older than 50, women more than men - The tumor originates most commonly just distal to the junction between the nerve roots and the brainstem o As the tumor grows, it extends into he posterior fossa to occupy the cerebropontine angle and compress adjacent nerves o Eventually, the brainstem is displaced, and the CSF flow is obstructed - Clinical manifestations: headache, tinnitus, hearing loss, impaired balance, unsteady gait, facial pain, and loss of facial sensations o Later, vertigo with nausea, vomiting, a sense of pressure in the ear, and moderate to severe unsteadiness with rapid position changes may appear - CT or MRI help diagnose o Posterior fossa dye studies maybe required - Treatment o Surgical excision o Radiotherapy of the neuroma diseases that have multifactorial traits/multifactorial inheritance - When environmental factors are also believed to cause variation in the trait, which is usually the case, the term multifactorial trait is used. Blood pressure is another example of a multifactorial trait. A correlation exists between parents’ blood pressures (systolic and diastolic) and those of their children. The evidence is good that this correlation is partially caused by genes, but blood pressure is also influenced by environmental factors, such as diet, exercise, and stress. Two goals of genetic research are the identification and measurement of the relative roles of genes and environment in the causation of multifactorial diseases. - Hypertension, dementia, coronary heart disease, stroke, diabetes mellitus (1 and 2), and some cancers - Autism, pyloric stenosis, cleft lip, cleft palate, neural tube defects, clubfoot, and congenital heart disease - Definition: when genes +environmental factors cause a disease - Read pages 165-168 - Criteria used to define multifactorial inheritance o The recurrence risk becomes higher if more than one family member is affected o If the expression of the disease in a proband is more severe, the recurrence risk is higher o The recurrence risk is higher if the proband is of the less commonly affected sex o The recurrence risk for the disease usually decreases rapidly in more remotely related relatives o If the prevalence of the disease in a population is f, the risk for offspring and siblings of probands is approx. square root of f What is multifactorial inheritance?  Multifactorial inheritance means that "many factors" are involved in causing a birth defect. The factors are usually both genetic and environmental, where a combination of genes from both parents, in addition to unknown environmental factors, produce the trait or condition. Often one gender is affected more frequently than the other in multifactorial traits. There appears to be a different "threshold of expression", which means that one gender is more likely to show the problem over the other gender. For example, hip dysplasia is nine times more common in females than males. Multifactorial traits do recur in families, because they are partly caused by genes. The chance for a multifactorial trait or condition to happen again depends upon how closely the family member with the trait is related to you.  Some disorders, such as sickle cell disease and cystic fibrosis, are caused by mutations in a single gene. The causes of many other disorders, however, are much more complex. Common medical problems such as heart disease, type 2 diabetes, and obesity do not have a single genetic cause—they are likely associated with the effects of multiple genes (polygenic) in combination with lifestyle and environmental factors. Conditions caused by many contributing factors are called complex or multifactorial disorders. MUSCULOSKELETAL Ions that initiate muscle contraction: (page 1533) Calcium is the main ion that initiates muscle contraction, 4-step process: excitation, coupling, contraction, and relaxation. Initial contraction process is the excitation-contraction coupling (ECC) series involving the electrical properties of all cells and the movement of ions across the plasma membrane. Specific intracellular receptors with skeletal muscle sarcoplasmic reticulum, called ryanodine receptors (RyRs) are primary ion channels that control calcium release. RyRs are the largest known channels, allowing rapid movement of calcium. RyRs1 is predominantly found in skeletal muscle. Excitation – the first step of muscle contraction, begins with the spread of an action potential from the nerve terminal to the neuromuscular junction. The rapid depolarization of the membrane initiates an electrical impulse in the muscle fiber membrane called the muscle fiber action potential. The action potential spreads to the T-tubules. An action potential triggers receptors in the T-tubule wall, opening the RyR channels, releasing calcium from the sarcoplasmic reticulum. The second stage, Coupling, consists of the migration of calcium ions to the myofilaments. Calcium affects troponin and tropomyosin, muscle proteins that bind with actin when the muscle is at rest. In the presence of calcium, both of these proteins are attracted to calcium ions, leaving actin free to bind with myosin. Contraction begins as the calcium ions combine with troponin, a reaction that overcomes the inhibitory function of the troponin-tropomyosin system (troponin is attached to the protein tropomyosin and lies within the groove between actin filaments in muscle tissue. In a relaxed muscle, tropomyosin blocks the attachment site for the myosin crossbridge, preventing contraction). The thin filament actin then slides toward the thick filament myosin. The two ends of the myofibril shorten after contraction when the myosin heads attach to the actin molecules, forming a crossbridge that constitutes an actin-myosin complex. ATP, located on the actin-myosin complex, is released when the cross-bridges attach. *the useful distance of contraction of a skeletal muscle is approximately 25-35% of the muscles length. The last step, Relaxation, begins as the sarcoplasmic reticulum absorbs the calcium molecules, removing them from interaction with troponin. Calcium is pumped back into the sarcoplasmic reticulum by means of an active transport process. The cross-bridges detach, and the sarcomere lengthens. Growth of long bones in children: 1592 Long bones of the body include: clavicles, humeri, radii, ulnae, metacarpals, femurs, tibiae, fibulae, metatarsals, and phalanges. Endochondral formation of bone is the development of new bone from cartilage. First, mesenchymal tissue forms a cartilage anlage, which defines the shape of the bone by 6 weeks of gestation. Blood vessel invasion to inside the anlage brings osteoprogenitor cells leading to primary centers of calcification by 8 weeks. Endochondral bone formation begins in the outer layer of the cartilage model, which consists of a layer of dense connective tissue called perichondrium. The perichondrium contains cells that develop into osteoblasts, forming a collar of bone, termed the periosteal collar, around the cartilage model. Cartilage enclosed within the periosteal collar degenerates, and capillaries from outside the perichondrium invade the degenerating cartilage cells, carrying with them osteoblast precursors from the inner layer of the perichondrium and osteoclast precursors from the blood itself. Endochondral bone formation progresses at the primary center of ossification in the middle of the cartilage model and extends toward either end of the developing bone. At the same time, the periosteal collar thickens and becomes wider toward the epiphyses. By the end of gestation secondary centers of ossification begin to lay down bone at both ends of the cartilage model. Here, too, cartilage within the periosteal collar degenerates, and blood vessels grow inward, delivering bone cell precursors. Once the osteoblasts begin to secrete osteoid, ossification spreads from the secondary centers in all directions until all the cartilage within the model is replaced by bone. Two regions of cartilage remain at the ends of long bones: (1) articular cartilage over the free ends of the bone, and (2) the physeal plate, a layer of cartilage between the metaphysis and epiphysis. The physeal plate retains the ability to form and calcify new cartilage and deposit bone until the skeleton matures approximately 1 year after sexual maturity (11-15 yrs. in females, 15-18 yrs. in males). Bones belonging to the appendicular skeleton: pg. 1519 Appendicular skeleton has 126 bones and supports the appendages of the body. Pectoral Girdle – total of 4 bones Clavicle (2) - braces the shoulder joint against the sternum, it articulates with the scapula Scapula (2) - flat, triangular bones, lateral angle articulates with the head of the humerus and forms the shoulder joint Upper Extremities – total of 60 bones Humerus (2)- only long bone of the arm, articulates at the proximal end with the glenoid cavity of the scapula Radius (2) – the lateral forearm bone. Proximal end articulates with the capitulum of the humerus, distal end widens and forms primary articulation with proximal carpal bones. Ulna (2) – medial bone of the forearm. Proximal end forms the olecranon process (the point of the elbow) Carpals (16) – (wrist) each bone has a unique shape and name. Metacarpals (10) – (palm) associated with a number starting with the thumb on lateral side Phalanges (28) – (fingers) thumb has two phalanges and each finger has three Pelvic Girdle– total of 2 bones Coxal (hip) bone (2) – results from the fusion of three bones Ilium, Ischium, and Pubis Ilium – large flaring bone that forms the superior part of hip. Upper edge is the iliac crest, crest ends anteriorly in the anterior superior iliac spine (can be felt easily in thin people). Ischium – inferior part of coxal bone. Inferior surface has roughened part called the ischial tuberosity, they are the parts of the hip bones that press against objects you sit on. Pubis – (pubic bone) most anterior part of hip. **the ilium, ischium and pubis together form a deep socket called acetabulum which articulates with the head of the femur Lower Extremities – total of 60 bones Femur (2) – only long bone of the thigh, heaviest and strongest bone in the body. Proximal end has ball like head (greater trochanter) that fits into the acetabulum of the coxal (hip) bone. Patella (2) – (kneecap) small, freestanding bone that rests between the femur and tibia. Femur has a dedicated groove which the kneecap slides. Tibia (2) – (shinbone) is the larger, medial bone of lower leg. Anterior surface forms an anterior border that can be easily felt, distally there is a process called the medial malleolus that forms the inner bulge of the ankle. Fibula (2) – long, slender bone lateral to the tibia. Distal part forms the lateral malleolus (outer part of ankle) Tarsals (14) – 2 notable tarsal bones are the calcaneus (heel bone), and the talus which articulates with the tibia to form hingelike ankle joint Metatarsals (10) - form the sole of the foot Phalanges (28) – similar to phalanges of hand, great toe, like thumb, has only two phalanges. IMMUNITY How vaccines are performed – A vaccine is a biological preparation that provides active acquired immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from weakened or killed forms of the microbe, its toxins, or one of its surface proteins. Vaccines are like a training course for the immune system. They prepare the body to fight disease without exposing it to disease symptoms. When foreign invaders such as bacteria or viruses enter the body, immune cells called lymphocytes respond by producing antibodies, which are protein molecules. Antigens are present in extremely small quantities to elicit an immune response through a vaccine. The most common routes of administration are intravenous, intraperitoneal, subcutaneous, intranasal, and oral. Each route stimulates a different set of lymphocyte-containing tissues and therefore results in the induction of different types of cell-mediated or humoral immune responses. Vaccines are considered nonimmunogenic. Populations are risk for getting systematic fungal infections and parasitic infections- In immunocompromised individuals, particularly those with diminished levels of neutrophils (neutropenia), fungal infections may occur. Candida is the most common fungal infection in people with cancer (particularly acute leukemia and other hematologic cancers) transplantation (bone marrow and solid organ), and HIV/AIDS. Almost 90% of people with AIDS have candida at least one time (usually thrush or vaginitis) because of their decreased number of neutrophils. Invasive candidiasis may also be secondary to indwelling catheters, intravenous lines, or peritoneal dialysis which provided direct entrance into the blood. Disseminated candidiasis may involve several internal organs, including abscesses in the kidney, brain, liver, and heart. It is characterized by a persistent fever and gram-negative shock like symptoms (hypotension, tachycardia), DIC, and death. The mortality rates of sepsis or disseminated candidiasis are in the range of 30-40%. Parasitic infections are uncommon in the United States, with significant mortality and morbidity of individuals in developing countries. Malaria is most common in Africa. Systematic manifestations of infection – Systematic infection is the term used to describe an infection that is circulating in the blood. This means it affects the entire body. Signs/symptoms of this can be fever, tachycardia, hypotension, septic shock, toxic shock, hypovolemia, respiratory alkalosis, and hyperventilation, neutropenia, thrombocytopenia, and DIC. Alterations in sensorium may occur in severe infection and may cause anxiety, confusion, delirium, stupor, seizures, and coma. Mechanism responsible for the increase in antimicrobial resistance worldwide – Antimicrobial resistance occurs naturally overtime, usually through genetics. However, the misuse and overuse of antimicrobials is accelerating this process. In many places antibiotics are overused and misused. Example of misuse include they are taken by people with viral infections such as the flu. Poor infection control, inadequate sanitary conditions and inappropriate food handling encourage the spread of antimicrobial resistance. Functions of normal body flora The normal microbiome provides protection by inhibiting colonization by pathogens and by releasing chemicals that prevent infection. Each surface including the skin, mucous membranes of the eyes, upper and lower GI, urethra and vagina are all colonized by combo of bacteria (mostly bacteria) and fungi that are unique to the particular location. The relationship between this “good” bacteria and humans is both commensal (to the benefit of one organism without affecting the other) and mutualistic (to the benefit of both). Many of these microorganisms help digest fatty acids, large polysaccharides and other dietary substances. They also produce biotin and Vit K, assist in the absorption of various ions: such as calcium, iron and magnesium. These good bacteria compete with pathogens for nutrients and block attachment to the epithelium. They produce chemicals (ammonia, phenols, and indoles). Treatment with broad spectrum abx can alter this normal flora, decreasing its protective activity, leading to overgrowth of yeast Candida Albicans or C Dif. The good flora trains the adaptive immune system by growth of gut-associated lymphoid tissue (where cells of adaptive immunity reside). Desensitization therapy Also known as allergen Immunotherapy. This is where minute quantities of the allergen are injected in increasing doses over a prolonged period. The therapy may reduce the severity of the allergic reaction in the treated individual. This therapy is associated with a risk of systemic anaphylaxis, which can be life threatening. This approach works best for routine respiratory allergies and biting insect allergies (80-90% rate of desensitization over 5 years of treatment). The mechanisms by which desensitization occurs may be several, one of which is the production of large amounts os so called blocking antibodies, usually circulating IgG. A blocking antibody presumably competes in the tissues or in the circulation for binding with antigenic determinants on the allergen so the allergen is “neutralized” and is unable to bind with IgE on the mast cells. Desensitization injections may also stimulate the generation of clones of T- regulatory lymphocytes which inhibit hypersensitivity by suppressing the production of IgE and anti-inflammatory cytokines.