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146 Cards in this Set

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1. What are two determinants in the transmission of STDs?
1. Transmission between heterosexuals or male homosexuals can take place following oral or anal intercourse. The gonococcus, for instance, causes pharyngitis and proctitis, although it infects stratified squamous epithelium less readily than columnar epithelium.

2. Condo usage - condoms have been shown to retain gonococci, HSV, HIV, and chlamydia in simulated coital tests.
2. What is syphilis?
Syphilis is caused by the spirochete treponema pallidum and is less common than other STDs.

Treponema pallidum also causes the non-venereal infections of pinta and yaws.
3. How does T. pallidum enter the body?
T. pallidum enters the body thru minute abrasions on the skin or mucous membranes. Transmission of T. pallidum requires close personal contact b/c the organism does not survive well outside the body and is very sensitive to drying, heat, and disinfectants.

*Local multiplication leads to plasma cell, polymorph and macrophage infiltration, with later endarteritis.
4. What are the three stages of syphilis?
Primary, secondary, and tertiary syphilis.

HOwever, not all pts go thru all three stages; a substantial amt remain permanently free of disease after suffering the primary or secondary stages of infection.

The secondary stage may be followed by a latent period of 3-30 years, after which the disease may occur - the tertiary stage.
5. How does T. pallidum survive in the body?

How does it evade host immune responses?
Unlike most bacterial pathogens, T. pallidum can survive in the body for many years despite a vigorous immune response.

It has been suggested that the healthy treponeme evades recognition and elimination by the host by maintaining a cell surface rich in lipid. This layer is antigenically unreactive and the antigens are only uncovered in dead and dying organisms when the host is then able to respond.

*Tissue damage is mostly due to the host response.
6. What are the symptoms of syphilis at the inoculating stage and then primary stage?
There may be a primary chancre at site of infection. Infection takes 2-10 weeks depending on inoculum size.

Primary syphilis is characterized by enlarged inguinal nodes with spontaneous healing. This is due to the proliferation of treponemas in regional lymph nodes.
7. What are the symptoms of secondary syphilis?
Flu-like illness; myalgia, headache, fever, mucocutaneous rash, spontaneous resolution.

This is due to the multiplication and production of lesions in lymph nodes, liver, joints, muscles, skin, and mucous membrane.
8. What are the symptoms of tertiary syphilis?
1. Neurosyphilis; general paralysis of the insane, tabes dorsalis
2. Cardiovascular syphilis; aortic lesions, heart failure
3. Progressive destructive disease

These are the result of further dissemination and invasion and host response (cell-mediate hypersensitivity).
9. Can an infected woman transmit T. pallidum to her baby in utero?
Yes, the disease may manifest as:
1. Serious infeciton resulting in intrauterine death
2. Congenital abnormalities, which may be obvious at birth
3. Silent infection, which may not be apparent until about 2 years of age (facial and tooth deformities)
10. How is T. pallidum diagnosed under microscopy?
Under microscopy, the organisms have tightly wound, slender coils w/pointed ends and are sluggishly motile in unstained preparations.

T. pallidum is very thin (about 0.2 mm diameter), and cannot be seen Gram-stain preparations. Silver impregnation stains can be used to demonstrate the organisms in biopsy material.
11. What is the mainstay of Dx for syphilis?
Serologic tests. These are divided into non-specific tests and specific tests.

Nonspecific tests are teh VDRL and RPR test.

Specific tests are the treponemal antibody test, FTA-ABS test, and MHA-TP.
12. What are the VDRL and RPR tests?
Cardiolipin, from beef heart, allows detection of anti-lipid IgG and IgM formed in the patient in response to lipoidal material released from cells damaged by the infection, as well as to lipids in the surface of T. pallidum.

VDRL= Veneral disease Research Laboratory test

RPR = Rapid plasma reagin test

*However, these tests are nonspecific and may be false positives. These tests can, however, provide an indication of therapeutic efficacy of treatment.
13. What are the treponemal antibody test, FTA-ABs test, and MHA-TP test?
These tests use recombinant proteins or treponemal antigens extracted from T. pallidum.

These tests are:
1. Enzyme-linked immunosorbent assays which detect IgM and IgG
2. The fluorescent treponemal antibody absorption test (FTA-ABS) in which the pt's serum is first absorbed with non-pathogenic treponemes to remove cross-reacting antibodies before reactions w/T. pallidum antigens
3. The microhemagglutination assay (MHA-TP)
14. Are these specific tests confirmatory?
Yes, these tests should be used to confirm that a positive result w/a non-specific test is truly due to syphilis.

They tend to remain positive for many years and may be the only positive test in pts w/late syphilis. However, they remain positive after appropriate antibiotic treatment and cannot be used as indicators of therapeutic response.
15. How can one confirm a Dx of syphilis in babies?
One can test for IgM and retesting at 6 months of age, by which time maternal antibody levels have waned. Antibody titers remain elevated in babies w/congenital syphilis
16. What is the treatment for syphilis?
Penicillin is the DOC for treating people w/syphilis and their contacts. Pts allergic to penicillin can be given tetracycline or doxycycline. Only penicillin can reliably treat the fetus when administered to a pregnant mother.
17. What is gonorrhea?
Gonorrhea is caused by the Gram-negative coccus Neisseria gonorrhoeae. Its reservoir is human and transmission is direct, usually thru sexual contact, from person to person.

The organism is sensitive to drying and does not survive outside well.
18. How does gonorrhea invade?
The gonococcus has special mechanisms to attach itself to mucosal cells. The usual site of entry into the body is via the vagina or urethral mucosa of the penis, but other sexual practices may result in the deposition of organisms in the throat or on the rectal mucosa.

Special adhesive mechanisms prevent the bacteria from being washed away by urine or vaginal discharges. Following attachment, the gonococci rapdily multiply and spread thru the cervix in women, and up the urethra in men.
19. What are the seven virulence factors for gonorrhea?
1. Pilus aids attachment to mucosa
2. Por proteins form pores thru outer membrane
3. Opa proteins assist binding to epithelial cells
4. LOS (endotoxin activity)
5. Rmp proteins inhibit 'cidal' activity of serum
6. IgA protease core contains enzyme; released by cell to destroy IgA1
7. Capsule resists phagocytosis, unless antibody present
20. How is the host damaged in gonorrheal infection?
Host damage in gonorrhea results from gonococcal induced inflammatory responses.

Infection is usually localized, but in some cases bacteria isolates can invade the blood stream and spread to other parts of the body.
21. What are the symptoms of gonorrhea?
Gonorrhea is initially asymptomatic in many women, but can later cause infertility. Sypmtoms develop w/in 2-7 days of infection and are characterized:

-in the male by urethral discharge and pain on passing urine
-in the female by vaginal discharge
22. Are all pts with gonorrhea infections symptomatic?
At least 50% of all infected women have only mild sypmmtoms or are completely asymptomatic. Asymptomatic infection, however, is not the usual course of events in men.

Women may not be alerted to their infection unless or until complications arise such as PID, chronic pelvic pain, or infertility resulting from damage to the fallopian tubes.
23. What is ophthalmia neonatorum?
Ophthalmia neonatorum is characterized by a sticky discharge in the eye socket.
24. Does disseminated infection occur with gonorrhea?
Disseminated infection occurs in 1-3% of women, but is less common in men. It is a function of the strain and also of host factors.

About 5% of people w/disseminated infection have deficiencies in complements (C5-C8).
25. How is gonorrhea diagnosed?
A Dx is made from microscopy and culture of appropriate specimens.

Although a purulent discharge is a characteristic of local gonococcal infection, it is not possible to distinguish reliably.

The finding of Gram-negative intracellular diplococci in a smear of urethral discharge from a symptomatic male is a highly sensitive and specific test for gonorrhea.
26. Why is culturing essential in the investigation of infection in women and asymptomatic men?
1. It's used to confirm identity of the isolate; misinterpretation of microscopy results can cause severe distress
2. It's used to perform antibiotic susceptibility tests
3. It's used to aid in the distinction between treatment failure and re-infection.
27. What is the treatment for gonorrhea?
Antibacterials used to treat gonorrhea are ceftriaxone and fluoroquinolones such as ciprofloxacin, but resistance is increasing.
28. What causes chlamydial infection?
Chlamydiae trachomatis serotypes D-K cause sexually transmitted genital infections.

The chlamydiae are very small bacteria that are obligate intracellular parasites. They have a more complicated life cycle than free living bacteria b/c they can exist in different forms.
29. What are the two forms of chlamydiae?
1. The elementary body (EB) is adapted for extracellular survival and for initiation of infection

2. The reticulate body (RB) is adapted for intracellular multiplication
30. What are the three groups of serotypes of Chlamydia trachomatis?
1. Serotypes A, B, and C are the causes of the serious eye infection trachoma.
2. Serotypes D-K are the cause of genital infections and associated ocular and respiratory infections.
3. Serotypes L1, L2, and L3 cause the systemic disease lymphogranuloma venereum (LFV).
31. How is chlamydia spread?
The majority of infections are genital and are acquired during sexual intercourse. Asymptomatic infection is common, especially in women.
32. How do chlamydiae enter the host?
Chlamydiae enter the host thru minute abrasions in the mucosal surface. They bind to specific receptors on the host cells and enter the cells via parasite-induced endocytosis.

Once in the cell, fusion of the chlamydia-containing vesicle w/lysosomes is inhibited and the EB begins its developmental cycle.

Within 9-10 hr or cell invasion, the EBs differentiate into metabolically active RBs, which divide via binary fission and produce fresh Eb progeny. These are then released into the EC environment.
33. What are the clinical effects of C. trachomatis infection?
The clincical affects appear to result from cell destruction and the host's inflammatory response.

The released EBs invade adjacent cells or cells distant from teh site of infection if carried in lymph or blood.

Growth of C. trachomatis D-K seems to be restricted to columnar and transitional epithelial cells.

Genital tract infection with serotypes D-K is locally asymptomatic in most women, but usually symptomatic in men.
34. What are the symptoms of C. trachomatis D-K in men and women and children?

What are the possible complications?
MEN: Urethritis, epididymitis, proctitis, conjunctivitis; (Reiter's syndrome and systemic spread are complications)

Women: Urethritis, cervicitis, bartholinitis, salpingitis, conjunctivitis; (ectopic pregnancy, infertility, perihepatitis arthritis dermatitis are complications)

NEONATES: conjunctivitis (interstitial pneumonitis is a complication)
35. How is chlamydial urethritis and cervicitis Dx via culture?
As chlamydia are obligate intracellular parasites, traditional identification by isolation must be performed by growth in all cultures. The specimen is suspended in fluid and centrifuged on to a monolayer of tissue culture (McCoy) cells pretreated with cycloheximide, which enhances uptake of chlamydiae.

After 48-72 h, C. trachomatis forms characteristic cytoplasmic inclusions, which stain with iodine b/c they contain glycogen.
36. How is C. trachomatis detected on microscopy?
Can be detected in smears of clinical specimens using slides stained with fluorescein conjugated monoclonal antibodies and viewed by UV microscopy.

Can also be detected with ELISA
37. How is chlamydia treated?
Chlamydial infection is treated or prevented w/doxycycline or tetracycline.

It is recommended that pts receiving treatment for gonorrhea also be treated w/doxycycline for possible concurrent chlamydial infection.

Erythromycin should be used for babies.
38. What is lyphogranuloma venereum (LGV)?
LGV is caused by C. trachomatis serotypes L1, L2, and L3.

LGV is a serious disease especially common in Africa, Asia, and South America.

LGV is a systemic infection involving lymphoid tissue and is treated with doxycline or erythromycin.
39. What does LGV infection look like?
The primary lesion is an ulcerating papule at the site of inoculation and may be accompanied by fever, headache, and myalgia. The lesion heals rapidly, but the chlamydiae proceed to infect the draining lymph nodes, causing characteristic inguinal buboes which gradually enlarge.

The infection may disseminate from the lymph nodes to cause proctitis.
40. What are the complications of LGV infection?
Systemic complications include fever, hepatitis, pneumonitis, and menigo-encephalitis.

The infection may:
-cause abscesses to form in lymph nodes, which suppurate and discharge thru the skin
-cause chronic granulomatous reactions in lymphatics and give rise to fistula in ano or genital elephantiasis.
41. What is a chancroid (soft chancre)? What causes it?
Chancroid is caused by the Gram-negative Haemophilus ducreyi and is characterized by painful genital ulcers.

Symptoms are painful non-indurated genital ulcers and local lymphadenitis.

In Africa and Asia, chancroid is the commonest cause of genital ulcers.
42. How is chancroid Dx and Tx?
Chancroid is Dx via microscopy and culture and treated with azithromycin, ceftriaxone, erythromycin or ciprofloxacin.

Gram-stained smears show large # of short Gram-negative rods and chains, often described as having a 'school of fish' appearance.
43. What is donovanosis?
Donovanosis is caused by Calymmatobacterium granulomatis and is characterized by genital noduels and ulcers.

It is rare in temperate climates, but common in tropical and subtropical regions.

The nodules erode to form granulomatous ulcers that bleed readily on contact.
44. How is donovanosis Dx and Tx?
Donovanosis is Dx by microscopy and treated w/tetracycline.

The stain used is Wright's or Giemsa stain. 'Donovan bodies' appear as clusters of blue or black stained organisms w/in the cytoplasm of mononuclear cells.
45. What is mycoplasmas and non-gonococcal urethritis?
Mycloplasma hominis, genitalium, and Ureaplasma urelyticum may be causes of genital tract infection.

These organissm freq colonize the genital tracts of healthy sexually active men and women.

M. genitalium may cause non-gonococcal urethritis, M. Hominis may cuase PID, postabortal and postpartum fevers, and pyelonephritis. U. urealyticum has also been associated w/non-gonococcal urethritis and prostatitis.

Treated with tetracyclines or erythromycin (for Ureaplasmas)
46. What is candida infection?
Candida albicans cause a range of genital tract diseases, which are treated w/oral or topical antifungals.

The yeast is a normal inhabitant of the vagina, but in some women the candidal load increases and causes an intensely irritant vaginitis w/a cheesy vaginal discharge. This may be accompanied by urethritis and dysuria and may present as a UTI.
47. How is candida infection Dx and Tx?
Dx is confirmed by microscopy and culture of the discharge.

Treatment w/an oral antifungal such as fluconazole or a topical such as nystatin is recommended.
48. What is trichomonas infection?
Trichomonas vaginalis is a protozoan parasite and causes vaginitis w/copious discharge. T. vaginalis inhabits the vagina in women and the urethra (sometimes prostate) in men.
49. How is trichomonas transmitted and what are the symptoms?
It is transmitted during sexual intercourse.

In women, heavy infections cause vaginitis w/a characteristic copious foul-smelling discharge. There is an associated increase in the vaginal pH. The infection should be distinguished from bacterial vaginosis.

In men, T. vaginalis is rarely symptomatic but sometimes cause a mild urethritis.
50. How is trichomonas Dx and Tx?
Microscopy shows actively motile trophozoites.

Metronidazole is recommended for symptomatic T. vaginalis infections.
51. WHat is bacterial vaginosis?
Bacterial vaginosis is associated w/Gardnerella vaginalis plus anaerobic infection and a fishy-smelling vaginal discharge.
52. What are the four clinical signs of non-specific bacterial vaginosis?
1. Excessive malodorous vaginal discharge
2. Vaginal pH > 4.5
3. Present of clue cells (vaginal epithelial cells coated w/bacteria)
4. A fishy amine-like odor

*3 of the 4 criteria are needed for Dx.
53. What is the Tx for bacterial vaginosis?
Treated with oral metronidazole.
54. What is genital herpes?
Herpes simplex virus (HSV-2) is the most common cause of genital herpes, but HSV-1 is being detected more frequently.

Genital herpes is characterized by ulcerating vesicles that can take up to 2 weeks to heal.
55. What do the lesions in HSV-2 look like?
The primary genital lesion on the penis or vulva is seen 3-7 days after infection. It consists of vesicles that soon break down to form painful shallow ulcers.
56. Besides the ulcerating vesicles, what are the symptoms of genital herpes?
Local lymph nodes are swollen, and there may be constitutional symptoms including fever, headache, and malaise. Occasionally the lesions are on the urethra, causing dysuria.

Healing takes up to 2 weeks, but the virus travels up sensory nerve endings to establish latent infections in dorsal root ganglion neurones where it can reestablish infection.
57. How is genital herpes Dx and Tx?
HSV can be isolated from vesicle fluid or ulcer swabs and the isolate types by immunofluoresence. The cytopathic effect is characteristic and is seen within 1-2 days post inoculation, with ballooning degenerating cells and multinucleate giant cells.

Tx is with oral aciclovir, valaciclovir, or famciclovir.
58. What is HPV infection?
Many papillomavirus types are transmitted sexually and cause genital warts.

Warts (condylomata acuminata) appear on the penis, vulva, and perianal regions after an incubation period of 1-6 mos. They may not regress for many months and can be treated w/podophyllin.
59. What does HPV infection on the cervix look like?
The lesion on the cervix is a flat area of dysplasia visible by colposcopy as a white plaque after the local application of 5% acetic acid. B/c of their association w/cervical CA types 16 and 18, cervical lesions are best removed by laser or loop excision.
60. What is HIV?
HIV is a retrovirus, so called b/c this single stranded RNA virus contains a pol gene that codes for a reverse transcriptase.
61. How is virus replication regulated in HIV?
HIV virus replication is regulated by at least six genes. The replication cycle is often halted after integration fo the provirus so that the infection remains latent in the cell.

The tat and rev genes function as transactivating factors, and can increase the production of viral RNAs and proteins when latently infected cells are stimulated to differentiate or stimulated by infection with HSV or CMV.
62. What are the three groups of HIV-1?
HIV-1 groups:

M (Main - subgroups A to J)
N (New)*
O (Outlier)*

*Western central Africa.

Subtype B is the most common in US and Europe
63. What cells does HIV infect?
HIV mainly infects cells bearing the CD4 cell surface antigen and also requires chemokine receptor.

The CD4 cells include Th cells, monocytes, dendritic cells, and microglia. The CD4 molecule acts as a high affinity binding site for the viral gp120 envelope glycoprotein. Productive replication and cell destruction does not occur until the Th cell is activated.

*Langerhans' cells (dendritic cells in the skin and genital mucosa) may be the first cells infected. Later in the disease, there is a disruption of histologic pattern in lymphoid follicles as a result of breakdown of follicular dendritic cells.
64. How does HIV-1 enter host cells?
HIV-1 enters host cells by binding the viral gp120 to CD4 receptors and a chemokine co-receptor on the host cell surface.
65. What is the importance of CCR5?
***The CCR5 beta-chemokine receptor is important in establishing infection. Those people with CCR5 gene deletions are resistant to infection.

On the other hand, disease progression has been associated with HIV variant using the CxCR4 alpha-chemokine receptor.
66. What is the course of HIV infection?
1. Initial good Tc resposne which reduces viremia with enutralizing antibodies
2. The the immune system begins to suffer gradual damage, and the number of circulating CD4-positive T cells steadily falls and the HIV load rises
3. Eventually the pt loses the battle to replace lost T cells and the number falls more rapidly (reduced NK and cytotoxic T cells, and functional changes in T lymphs with reduced responses to mitogens, reduced IL-2 and IFN gamma.)
67. How is the host response diminished in HIV infection?
The host response is further handicapped by the high rate of viral evolution assisted by the lack of a reverse transcriptase proofreading function.

The virus exists as a quasispecies, in other words the infection comprises a number of heterogeneous strains and some are immune escape variants.
68. What is HIV-2 infection?
HIV-2 appears to be transmitted less easily than HIV-1, probably b/c the viral load is lower, and the progression to AIDS is slower.

HIV-2 is endemic in W. Africa, and has spread to Portugal and parts of India.
69. What increases the risk of HIV infection?
Genital ulcers are associated with a 4x increase in the risk of infection.

Also, viral strains from Asia and sub-Saharan Africa have been sown to infect Langerhans' cells in genital mucosa more easily than do other strains.
70. Can HIV be transmitted vertically from mother to offspring?
HIV can also be transmitted vertically from infected mother to offspring, but the infant is not infected in 55-85% of pregnancies, the upper limit being associated with avoiding breast-feeding. Overall, the infant is infected in about 20% of pregnancies in utero and intrapartum. The transmission rate peri- and postnatally is around 11-16%, the higher end of the range depending on whether the child has been breast-fed for up to 24 months.

In resource-poor countries it has been shown that giving one dose of one antiretroviral drug to both mother and child reduced HIV transmission by 47%.
71. What is the risk of a health-care worker getting infected by HIV?
Healthcare workers are at risk of HIV infection after sustaining needlestick or mucous membrane splash injuries involving an HIV-infected source.

The risk of infection is approximately 1 in 400 and is dependent on a number of factors, including depth of the injury and amount of blood to which the recipient has been exposed.

Wearing protective clothing such as gloves and goggles is part of universal precautions to avoid exposure.
72. What are the symptoms of primary HIV infection?
Primary HIV infection may be accompanied by a mild mononucleosis-type illness.

Signs and symptoms of the mild mononucleosis-type illness associated with HIV infection include fever, malaise and lymphadenopathy. A maculopapular rash may occur.
73. How soon after primary HIV infection can an antibody response be detected?
Antibody responses can be detected in a few weeks, and Tc cells are formed.

The acute infection and rapid, widespread viral dissemination is followed by a chronic asymptomatic stage.

Infected cells are, however, still present, and at a later stage the infected individual may develop weight loss, fever, persistent lymphadenopathy, oral candidiasis and diarrhea.
74. How does HIV progress to AIDS?

What is the most common neurologic manifestation?
Further viral replication takes place until finally, some years after initial infection, full-blown AIDS develops.

Viral invasion of the CNS, with self-limiting aseptic meningoencephalitis as the most common neurological picture, occurs in early infection.

It is characterized by multiple small nodules of inflammatory cells; most of the infected cells appear to be microglia or infiltrating macrophages. These cells express the CD4 antigen, and it has been suggested that infected monocytes carry the virus into the brain
75. What viruses can cause HIV-associated encephalopathy?
These include infections by HSV, varicella-zoster virus (VZV), Toxoplasma gondii, JC virus (progressive multifocal leukoencephalopathy, PML) and Cryptococcus neoformans.
76. What is slim disease?
Some patients, especially in Africa, develop a wasting disease ('slim' disease), possibly due to unknown intestinal infections or infestations, and perhaps also to the direct effects of the virus infecting cells of the intestinal wall.
77. What is AIDS?
AIDS, symptomatic disease, consists of a large spectrum of microbial diseases acquired or reactivated as a result of the underlying immunosuppression due to HIV. The disease picture of AIDS is therefore an indirect result of infection with HIV.
78. What is the treatment for HIV/AIDS?
Antiretroviral therapy results in a dramatic improvement in disease prognosis.

In combination with two NRTIs, the NNRTI or PI drugs have had a dramatic effect on progression to AIDS and led to the term highly active antiretroviral therapy (HAART).
79. What is a drawback of HAART therapy?
One drawback has been a number of important side-effects of the drugs, including mitochondrial toxicity and altered fat distribution known as lipodystrophy.

Treatment compliance with certain drugs is a problem because of the side-effects and the number and frequency of pills taken each day. This is important, as missing any doses can lead to the development of drug resistance, thus limiting treatment options.
80. Can HAART help genital and CSF infections?
Not always, HIV is found in various compartments of the body including the CSF and genital tract.

Antiretroviral drugs may not penetrate these sites, resulting in a high viral load detectable in semen despite suppression of the plasma HIV load.
81. What is a good indicator to viral replication in HIV?
Plasma HIV-1 RNA load is a good indicator of viral replication, and failure of antiretroviral therapy is seen by a rise in viral load.
82. In addition to HAART, what else is used to treat AIDS?
Treatment of AIDS involves prophylaxis and treatment of opportunist infections as well as using antiretrovirals.

When opportunist infections are diagnosed, they are treated appropriately, for example co-trimoxazole or pentamidine with or without steroids for P. jiroveci, ganciclovir for CMV, and fluconazole or amphotericin for C. neoformans infection.
83. How is HIV Dx?
Initially, an HIV-1 and -2 antibody or combination assay which includes antibody and p24 antigen is carried out. The latter have been developed to reduce the diagnostic window period.

Assay reactivity is confirmed using an alternative HIV test format on the original unseparated sample stored in the laboratory. This is to ensure that a specimen separation error has not occurred.

HIV type differentiation may be carried out using an immuno-blot, where the antigens are coated on nitrocellulose strips. A positive result is confirmed on a further blood sample, to ensure that the original sample had not been mislabeled at collection.
84. How is HIV Dx in a newborn?
Diagnosis of HIV infection in newborn infants is a problem. If IgG antibodies are present they are presumably of maternal origin, but commercial tests for virus-specific IgM and IgA antibodies, which would signify in utero infection, are not yet available.

Samples from infants are tested at various time intervals up to 12-24 months for p24 antigen, HIV-1 RNA and/or HIV-1 proviral DNA, and HIV antibody to assess their HIV status.
85. What is done to Factor VII for hemophiliacs to prevent the spread of HIV?
Heat treatment of Factor VIII is carried out as a further precaution before this product is used to treat hemophiliac patients.

HIV has a delicate outer envelope and is highly susceptible to heat and chemical agents.

HIV is inactivated under pasteurization conditions and also by hypochlorites, even at concentrations as low as 1 in 10 000 ppm; 2.5% glutaraldehyde and ethyl alcohol are also effective against the virus.
86. What is teh most likely type of vaccine to be created for HIV to prevent sexual transmission?
To prevent sexual transmission, mucosal immunity is needed, and this is likely to come from a mucosally administered vaccine.
87. What are the opportunist STDs?
Opportunist STDs include salmonellae, shigellae, hepatitis A, Giardia intestinalis and Entamoeba histolytica infections.

They are less common in modern times, but Entamoeba histolytica/dispar was the major pathogen in the so-called 'gay bowel syndrome'.

Together with chronic infections such as CMV and cryptosporidiosis, they contribute to intestinal symptoms and diarrhea in AIDS patients.
88. How is HBV tranmitted?
The virus and its surface antigen, HBsAg, are detectable in semen, saliva and vaginal secretions. Titers in blood are higher and, like HIV, transmission is more likely when genital areas are ulcerated or contaminated with blood (e.g. menstrual blood).

Hepatitis B transmission among male homosexuals parallels the transmission of HIV, with passive anal intercourse as a high risk factor. Hepatitis D transmission is similar to that of hepatitis B.

Hepatitis C is less commonly transmitted sexually; <5% of long-term sexual partners are infected.
89. What causes crabs?

What is the Tx?
The 'crab louse', Phthirus pubis, is distinct from the other human lice. They are well adapted for life in the genital region, clinging tightly to the pubic hairs.

It takes up to 10 blood feeds a day and this causes itching at the site of the bites. Eggs called 'nits' are seen attached to the pubic hairs, and the characteristic lice, up to 2 mm long, are visible (often at the base of a hair) under a hand lens or by microscopy. Infestation is common.

Tx is with 1% permethrin shampoo.
90. What causes genital scabies?

How is it Tx?
Sarcoptes scabiei may cause local lesions on the genitalia, and can thus be sexually transmitted.

Patients may have evidence of scabies elsewhere on the body, with burrows between the fingers or toes.

Genital scabies is treated with 5% permethrin cream.
91. What is oxidative phosphorylation?

What are the components?

What regulates it?
Generation of ATP from oxidative phosphorylation requires an electron donor (NADH or FAD(2H)), an electron acceptor (O₂), an intact inner mitochondrial membrane that is impermeable to protons, all the components of the ETC, and ATP synthase.

It is regulated by the rate of ATP utilization.
92. Why is oxidative phosphorylation important for ATP homeostasis?
Most cells are dependent on oxidative phosphorylation for ATP homeostasis. During oxygen deprivation from ischemia, an inability to generate energy from the ETC results in increased permeability of this membrane and mitochondrial swelling.

*Mitochondrial swelling is a key element in the pathogenesis of irreversible cell injury leading to cell lysis and death.
93. What is the chemiosmotic hypothesis?

What is the final electron acceptor?
The energy for ATP synthesis is provided by an electrochemical gradient across the inner mitochondrial membrane. This electrochemical gradient is generated by the components of the ETC, which pump protons across the inner mitochondrial membrane as they sequentially accept and donate electrons.

The final acceptor is O₂, which is reduced to H₂O.
94. What is the electron transport chain?

What are the five components?
In the ETC, electrons are donated by NADH or FAD(2H) and are passed sequentially thru a series of electron carriers embedded in the inner mitochondrial membrane.

Froma NADH, electrons are transferred sequentially thru:
1. NADH dehdyrogenase (complex I)
2. Coenzyme Q
3. Cytochrome b-c₁ complex (complex III)
4. Cytochrome c
5. Cytochrome c oxidase (complex IV)
95. What is the electrochemical potential gradient?

Why is it necessary?
The transmembrane movement of protons generates an electrochemical gradient with two components; the membrane potential, and the proton gradient.

The electrochemical potential (proton motive force)
drives protons back into the mitochondrial matrix.

The protons are attracted to the more negatively charged matrix side of the membrane, where the pH is more alkaline.
96. What is ATP synthase?
ATP synthase, (F₀F₁ATPase), the enzyme that generates ATP, is a multisubunit enzyme that contains an inner membrane portion (F₀) and a stalk and headpiece (F₁) that project into the matrix. The headpiece is composed of three alpha-beta subunit pairs. Each beta-subunit contains a catalytic site for ATP synthesis.

The headpiece is held stationary by a delta-subunit attached to a long b-subunit connected to a subunit a in the membrane.
97. How does ATP synthase operate?
The influx of protons thru the proton channel turns the rotor. The rotation exposes a different proton-containing c-subunit to the portion of the channel that is open directly to the matrix side. Each c-subunit contains a glutamyl carboxyl group. B/c the matrix has a lower proton concentration, the glutamyl carboxylic acid group releases a proton into the matrix portion fo the channel.

Rotation is completed by an attraction btwn the negatively charged glutamyl residue and a positively charged arginyl group on the a-subunit.
98. What is the binding-change mechanism for ATP synthase?

How many protons does it take to complete one turn of the rotor?
As the asymmetric shaft rotates to a new position, it forms three different conformations depending on the position of the gamma-stalk subunit.

The new position of the shaft alters the conformation of one B-subunit so that it releases a molecule of ATP and another subunit spontaneously catalyzes synthesis of ATP from inorganic phosphate, one proton, and ADP.

12 c-subunits are hypothesized, and it takes 12 protons to complete one turn of the rotor and synthesize 3 ATP.
99. What are the oxidation-reduction components of the ETC?
1. Flavin mononucleotide (FMN)
2. Fe-S centers
3. CoQ
4. Fe in cytochromes b, c₁, a, and a₃

The reduction potential of each complex of the chain is at a lower energy level than the previous complex, so energy is released as electrons pass thru each complex. This energy is used to move protons against their concentration gradient so they become concentrated on the cytosolic side of the inner membrane.
100. What is NADH dehydrogenase?
NADH dehydrogenase is an enormous complex that contains a binding site for NADH, several FMN and Fe-S center binding proteins, and binding sites for CoQ.

An FMN accepts 2 electrons from NADH and is able to pass single electrons to the Fe-S centers.

Fe-S centers, which are able to delocalize single electrons into large orbitals, transfer electrons to and from CoQ.
101. What are succinate dehydrogenase and the other flavoproteins?
In addition to NADH dehydrogenase, succinate dehydrogenase and other flavoproteins in the inner mitochondrial membrane also pass electrons to CoQ.

Succinate dehydrogenase is part of the TCA cycle and also a component of complex II of the ETC.

ETF-CoQ oxidoreductase accepts electrons from ETF (electron-transferring flavoprotein), which acquires them from fatty acid oxidation and other pathways.

Glycerol 3-phosphate dehydrogenase is a flavoprotein that is part of a shuttle for reoxidizing cytosolic NADH.
102. What is CoQ?
CoQ is the only component of the ETC that is not protein bound. The large hydrophobic side chain confers lipid solubility, and CoQ is able to diffuse thru the lipids of the inner mitochondrial membrane.

When the oxidize quinone form accepts a single electron, it forms a free radical.

*The transfer of single electrons makes it the major site for generation of toxic oxygen ROS.
103. What is the function of the semiquinone form of CoQ?
The semiquinone can accept a second electron and two protons from the matrix side of the membrane to form the fully reduced quinone.

The mobility of CoQ in the membrane, its ability to accept 1-2 electrons, and its ability to accept and donate protons enable it to participate in the proton pumps for both complexes I and III as it shuttles electrons between them.
104. What are the remaining components of the ETC?
Cytochromes. Each cytochrome is a protein that contains a bound heme. B/c of differences in the protein component of the cytochromes and small differences in the heme structure, each heme has a different reduction potential.

The cytochromes of the b-c₁ complex have a higher energy level than those of cytochrome oxidase (a and a₃). Thus, energy is released by electron transfer btwn complexes III and IV.
105. The iron in the cytochromes is in what state?
The iron atoms in the cytochromes are in the Fe3+ state. As they accept an electron, they are reduced to Fe2+. As they are reoxidized to Fe3+, the electrons pass to the next component of the ETC.
106. The iron in heme in Hgb, unlike the iron in cytochromes, never changes its oxidation state (it is Fe2+ in Hgb).

What accounts for this difference in iron oxidation states btwn Hgb and cytochromes?
Normally, the protein structures binding the heme either protect the iron from oxidation or allow oxidation to occur.
107. What is hemoglobin M?
In hemoglobin M, a rare hemoglobin variant found in the human population, a tyrosine is substituted for the histidine at position F8 in the nromal Hgb A.

This tyrosine stabilizes the Fe3+ form of heme, and these subunits cannot bind oxygen.

This is a lethal condition if it is homozygous.
108. What is the last cytochrome complex?

What ions in this cytochrome complex facilitate the collection of electrons?
Cytochrome oxidase, which passes electrons from cytochrome c to O₂.

It contains cytochromes a and a₃ and the oxygen binding site.

A whole O₂ molecule must accept 4 electrons to be reduced to 2 H₂O molecules.

Bound copper (Cu+) ions in the cytochrome oxidase complex facilitate the collection of the 4 electrons and the reduction of O₂.
109. What is the Km for O₂ in cytochrome oxidase?

How does it compare to that of myoglobin and hemoglobin?
Cytochrome oxidase has a much lower Km for O₂ than myoglobin or hemoglobin.

Thus, O₂ is pulled from the RBC to myoglobin, and from myoglobin to cytochrome oxidase, where it is reduced to H₂O.
110. What causes the proton pumping into the intermembranous space?
This proton pumping is generally facilitated by the vectorial arrangement of the membrane-spanning complexes. Their structure allows them to pick up electrons and protons on one side of the membrane and release protons on the other side as they transfer an electron to the next component of the chain.
111. What is the Q cycle?
The Q cycle invovles a double cycle of CoQ reduction and oxidation. CoQ accepts 2 protons at the matrix side together with 2 electrons. It then releases protons into the intermembrane space while donating one electron back to another component of the cytochrome b-c₁ complex and one to cytochrome c.
112. What is the significance of the direct link between the electron transfer and proton movement?
One cannot occur w/o the other.

Thus, when protons are not being used for ATP synthesis, the proton gradient and the membrane potential build up.

This "proton backpressure" controls the rate of proton pumping, which controls electron transport and O₂ consumption.
113. What is the overall energy yield from the ETC?
4 x H⁺ transferred out for each ATP synthesized

NADH oxidation produces 2.5 ATP molecules

FAD(2H) oxidation produces 1.5 ATP molecules

Only 30% of the available energy used for ATP synthesis

The remaining energy is used for ion transport into the mitochondrion and for thermogenesis
114. What is the effect of lack of O₂ on the ETC?

What about respiratory chain inhibitors?
In the absence of O₂, no ATP is generated from oxidative phosphorylation, b/c electrons back up in the chain.

The action of the respiratory chain inhibitor cyanide, which binds to cytochrome oxidase, is similar to that of anoxia; it prevents proton pumping by the complexes.

Although complete inhibition of any one complex inhibits proton pumping at all of the complexes, partial inhibition of proton pumping can occur when only a fraction of the molecules of a complex contains bound inhibitor. The partial inhibition results in a partial decrease of the max rate of ATP synthesis.
115. What are mitochondrial OXPHOS diseases?
Any illness resulting from deficiency of a mitochondrially
located protein which is involved in energy metabolism. Many due to defects in mitochondrial DNA

Mt DNA encodes:
-13 polypeptides involved in oxidative phosphorylation
-22 mitochondrial tRNAs
-2 rRNAs

(Mt DNA repair mechanisms less effective than genomic mechanisms, more ROS damage and deleterious mutations more frequent)
116. What is Leber’s Hereditary Optic Neuropathy (LHON)
LHON causes sudden blindness in young males.

Less common symptoms – mild dementia, ataxia, peripheral neuropathy.

It is inherited maternally and caused by various mutations in complexes I, II and IV polypeptides encoded by mitochondrial DNA

90% caused by mutations in NADH dehydrogenase
117. What is Myotonic Epilepsy and Ragged Red Fiber Disease (MERRF)?
Myoclonus, ataxia, muscle weakness, deafness and progressive dementia - primarily CNS and muscle systems are affected.

Caused by mutations in mitochondrial RNAs (most commonly mtRNAlys)

The mitochondria, obtained by muscle biopsy, are enlarged and show abnormal patterns of cristae. The muscle tissue also shows ragged red fibers.
118. What is Mitochondrial Myopathy, Encephalomyopathy, Lactic Acidosis and Stroke-like episodes (MELAS)?
MELAS is a progressive neurodegenerative disease characterized by strokelike episodes between 5 -15 years of age. The typical presentation of patients with MELAS syndrome includes mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes.

Other features, such as seizures, DM, hearing loss, cardiac disease, short stature, endocrinopathies, exercise intolerance, and neuropsychiatric dysfunction are clearly part of the disorder.

Caused by mutations in tRNAleu
119. What is Kearns-Sayre syndrome?
Onset prior to 20 years of age; characterized by ophthamoplegia, atypical retinitis pigmentosa, mitochondrial myopathy, and one of the following: cardiac conduction defect, cerebellar syndrome, or elevated CSF proteins.

It is caused by deletion of contiguous segments of tRNA and OXPHOS polypeptides, or caused by mutations of tandemly arranged normal mtDNA and an mtDNA with a deletion mutation.
120. What is Pearson syndrome?
Pearson syndrome is a systemic disorder of oxidative phosphorylation that predominantly affects bone marrow.

IT is caused by deletion of contiguous segments of tRNA and OXPHOS polypeptides, or duplication mutations consisting of tandemly arranged normal mtDNA and an mtDNA with a deletion mutation.
121. What is Leigh disease (subacute necrotizing encephalopathy)?
Leigh disease is characterized by a mean age of onset at 1.5-5 years; clinical manifestations include optic atrophy, ophthalmoplegia, nystagmus, respiratory abnormalities, ataxia, hypotonia, spasticity, and developmental delay or regression.

7-20% of cases have mutations in F₀ subunits of ATP synthase.
122. What are the roles of NRF-1 and NRF-2?
THe nuclear respiratory factors NRF-1 and NRF-2 are nuclear transcription factors that bind to and activate promoter regiosn of the nuclear genes that encode subunits of the respiratory chain complexes, including cytochrome c.

They also activate the transcription of the nuclear gene for the mitochondrial transcription factor (mTF)-A. The protein product of this gene translocates into the mitochondrial matrix, where it stimulates transcription and replication of the mitochondrial genome.
123. How do nuclear DNA mutations differ from mtDNA mutations?
They differ in several ways.

These mutations do not show a pattern of maternal inheritance but are usually autosomal recessive. The mutations are uniformly distributed to daughter cells and, therefore, are expressed in all tissues that contain the allele for a particular tissue-specific isoform. However, phenotypic expression will still be the most apparent in tissues w/high ATP requirements.
124. What is coupling of electron transport and ATP synthesis?
The electrochemical gradient couples the rate of the ETC to the rate of ATP synthesis.

B/c electron flow requires proton pumping, electron flow cannot occur faster than protons are used for ATP synthesis (coupled oxidative phosphorylation) or returned to the matrix by a mechanism that short-circuits the ATP synthase pore.
125. What is the relationship between ATP and ADP in coupling?
The more ADP is present to bind to the ATP synthase, the greater will be proton flow thru the ATP synthase pore, from the intermembrane space to the matrix. Thus, as ADP levels rise, proton influx increases, and the electrochemical gradient decreases. The proton pumps of the ETC respond with increased pumping and electron flow to maintain the electrochemical gradient.

The result is increased O₂ consumption.

The increased oxidation of NADH in the ETC and the increased concentration of ADP stimulate the pathways of fuel oxidation, such as the TCA cycle, to supply more NADH and FAD(2H) to the ETC.
126. What are the ATP requirements in the body tissues, skeletal muscles, and heart?
In most tissues, the rate of ATP utilization is nearly constant over time. However, in skeletal muscles, the rates of ATP hydrolysis change dramatically as the muscle goes from rest to rapid contraction.

In the heart, Ca2+ activation of TCA cycle enzymes provides an extra push to NADH generation, so that neither ATP nor NADH levels fall as ATP demand is increased.
127. What is uncoupling?
Uncoupling ATP synthesis from electron transport - dissipation of proton gradient by protons “leaking” back into the matrix without passing through the ATP synthase channels “uncouples” oxidation from ATP production. Eventually, mitochondrial integrity and function are lost.

The energy of oxidation is dissipated as heat. Chemical uncouplers are poisons (e.g. dinitrophenol).

Uncoupling is also a physiological mechanism of thermogenesis
128. What are uncoupling proteins (UCPs)?
UPCs form channels thru the inner mitochondrial membrane that are able to conduct protons from the intermembrane space to the matrix, thereby short-circuiting ATP synthase.
129. What is UCP1 (thermogenin)?
UCP1 (thermogenin) is associated with heat production in brown adipose tissue.

Brown adipose tissue contains many mitochondria (hence color). Inner mitochondrial membrane of brown adipose tissue contains UCP1 to produce HEAT instead of ATP.
130. Where is UCP 2-5 found?
UCP2 is found in most cells, UCP3 is found principally in skeletal muscle.

UCP4 and 5 are found in the brain.

*It has been hypothesized that UCP3 acts as a transport protein to remove FA anions and lipid peroxides from the mitochondria, thereby reducing the risk of forming oxygen free radicals and thus decreasing the occurrence of mitochondrial and cell injury.
131. What about proton leaking and resting metabolic rate?
A low level of proton leak across the inner mitochondrial membrane occurs in our mitochondria all the time, and our mitochondria are normally partially uncoupled.

About 20% of our resting metabolic rate is the energy expended to maintain the electrochemical gradient dissipated by our basal proton leak.
132. How is transport thru the inner mitochondrial membrane accomplished?
The inner membrane forms a tight permeability barrier to all polar molecules. Translocases are needed for transport.

The electrochemical potential gradient drives the transport of ions across the inner mitochondrial membrane on specific translocases (ATP-ADP translocase AKA ANT).

Each translocase is composed of specific membrane-spanning helices that bind only specific compounds.
133. How is transport thru the outer membrane accomplished?
In contrast, the out membrane contains relatively large unspecific pores called VDACs (voltage-dependent anion channels) thru which a wide range of ions diffuse. These bind cytosolic proteins such as hexokinase, which enables hexokinase to have access to newly exported ATP.
134. What is the mitochondrial permeability transition pore?
The mitochondrial permeability transition invovles the opening of a large nonspecific pore called MPTP thru the inner mitochondrial membrane and outer membranes at sites where they form a junction.

The basic components of the mitochondrial permeability transition pore are adenine nucleotide translocase (ANT), the VDAC, and cyclophilin D (which is a cis-trans isomerase for the proline peptide bond).
135. How is the MPTP opened/closed?
Normally, ANT is a closed pore that functions in exchange of ATP for ADP in the intermembrane space. However, increased mitochondrial matrix calcium, excess phosphate, or ROS/RNOS, can activate opening of the pore.

Conversely, ATP on the cytosolic side of the pore and an acidic pH and a membrane potential across the inner membrane protect against pore opening.

A lack of ATP for maintaining the low intracellular calcium can contribute to pore opening.
136. What happens when MPTP is opened?
When the MPTP opens, protons flood in, and maintaining a proton gradient becomes impossible.

Anions and cations enter the matrix, mitochondrial swelling ensues, and the mitochondria become irreversibly damaged. The result is cell lysis and death.
137. How is the loss of mitochondrial activity a major route for initiating apoptosis?
The intermembrane space contains procaspases 2, 3, and 9, which are proteolytic enzymes that are in the zymogen form (they must be proteolytically cleaved to be active).

It also contains apoptosis initiating factor (AIF) and caspase-activated DNAase (CAD). AIF initiates chromatin condensation and degradation. Cytochrome c, which is loosely bound to the inner mitochondrial membrane, may also enter the intermembrane space when the electrochemical potential gradient is lost.

The release of cytochrome c and the other proteins in the cytosol initiated apoptosis.
138. How are cytochrome c and the other proteins released to cause apoptosis?

Three theories...
One theory is that Bax (a member of the Bcl-2 family of proteins that forms an ion channel in the outer mitochondrial membrane) allows the entry of ions into the intermembrane space, causing swelling of this space and rupture of the outer mitochondrial membrane.

Another theory is that Bax and VDAC (which is known to bind Bax and other Bcl-2 family members) combine to form a large pore.

Finally, it is possible that the MPTP or ANT participate in rupture of the outer membrane, but they close in a way that still provides the energy for apoptosis.
139. Ischemia and hypoxia in heart muscle result in ...?
Inadequate generation of ATP for the maintenance of low intracellular sodium and calcium levels.

As a consequence, the myocardial cells in that location of the infarct have become swollen and the cytosolic proteins creatine kinase (MB-isoform) and troponin (heart isoform) leak into the blood.
140. What is a side effect of doxorubicin?
Its clinical use is limited by a specific, cumulative, dose-dependent cardiotoxicity. Impairment of mitochondrial activity may play a role in this toxicity.

Doxorubicin binds to cardiolipin, a lipid component of the inner mitochondrial membrane, where it might directly affect components of oxidative phosphorylation.

Doxorubicin inhibits succinate oxidation, inactivates cytochrome oxidase, interacts w/ CoQ, adversely affects ion pumps, and inhibits ATP synthase.

It also decreases the ability of the mitochondria to sequester calcium and increases ROS leading to damage.
141. Why does fatigue occur in iron deficiency anemia?
Fatigue results in part from the lack of electron transport for ATP production.

This is b/c iron deficiency anemia is characterized by decreased levels of Hgb and other iron-containing proteins in the blood, including iron containing cytochromes and Fe-S centers of the ETC.
142. What is nitroprusside converted to that is potentially toxic?
During prolonged infusions of 24-48 hours or more, nitroprusside is converted to cyanide, an inhibitor of the cytochrome c oxidase complex.

B/c small amts of cyanide are detoxed in the liver by conversion to thiocyanate, which is excreted in the urine, the conversion of nitroprusside to cyanide can be monitored by following blood thiocyanate leves.
143. Why does an impairment of the ETC result in lactic acidosis?
The effect of inhibition of ETC is an impaired oxidation of pyruvate, fatty acids, and other fuels.

This results in higher-than-normal levels of lactate and pyruvate in the blood and an increased lactate:pyruvate ratio.

Also it leads to an increase in NADH/NAD⁺ ratio, which inhibits pyruvate dehydrogenase and causes the accumulation of pyruvate. It also increases the conversion of pyruvate to lactate.
144. What an effect of salicylate on ATP concentrations?
High concentrations of salicylate partially uncouple mitochondria.

[ATP]↓ and [AMP]↑ stimulate glycolysis

Blood [lactate]↑ causing metabolic acidosis
145. Antibodies against cardiac ATP-ADP translocase result in death - why?
As ATP is hydrolyzed during muscular contraction, ADP is formed. This ADP must exchange into the mitochondria on ATP-ADP translocase to be converted back to ATP.

Inhibition of ATP-ADP translocase results in rapid depletion of the cytosol ATP levels and loss of cardiac contractility.
146. How do thyroid hormones affect levels of UCP2 and UCP3?
In hyperthyroidism, the efficiency with which energy is derived from the oxidation of fuels is significantly less than normal.

Hyperthyroidism leads to increased heat production, and increased levels of UCP2 and UCP3.