Wound Healing

Question 1

Which of the following is FALSE regarding polymorphonuclear neutrophils (PMNs) and their role in wound healing?

A. PMNs release proteases that degrade ground substance within the wound site.

B. Neutrophils use fibrin clot generated at the wound site as scaffolding for migration into the wound.

C. Neutrophil migration is stimulated by local prostaglandins, complement factors, interleukin-1 (IL-1),
tumor necrosis factor-a (TNF-a), transforming growth
factor-ß (TGE-ß), platelet factor 4, or bacterial products.

D. PMNs are the first cells to infiltrate the wound, peaking at 24 to 48 hours.

E. Neutrophils release cytokines that later assist with collagen deposition and epithelial closure.

Answer 1

Answer: E

Polymorphonuclear neutrophils (PMNs) are the first infiltrating cells to enter the wound site, peaking at 24 to 48 hours.

Increased vascular permeability, local prostaglandin release, and the presence of chemotactic substances such as complement factors, interleukin-1 (IL-1), tumor necrosis factor-a (TNF-a), transforming growth factor-ß (TGF-ß), platelet factor 4, or bacterial products all stimulate neutrophil migration.

The postulated primary role of neutrophils is phagocytosis of bacteria and tissue debris. PMNs are also a major source of cytokines early during inflammation, especially TNF-a, which may have a significant influence on subsequent angiogenesis and collagen synthesis. PMNs also release proteases such as collagenases, which participate in matrix and ground
substance degradation in the early phase of wound healing.

Other than their role in limiting infections, these cells do not appear to play a role in collagen deposition or acquisition of mechanical wound strength. On the contrary, neutrophil factors have been implicated in delaying the epithelial closure of wounds. (See Schwartz 10th ed., p. 243.)

Question 2

The proliferative phase of wound healing occurs how long after the injury?

A. 1 day

B. 2 days

C. 7 days

D. 14 days

Answer 2

Answer: C

Normal wound healing follows a predictable pattern that
can be divided into overlapping phases defined by the cellular populations and biochemical activities:
(1) hemostasis and inflammation, (2) proliferation, and (3) maturation and remodeling.

The proliferative phase is the second phase of wound healing and roughly spans days 4 through 12. It is during this phase that tissue continuity is reestablished.

Fibroblasts and endothelial cells are the last cell populations to infiltrate the healing wound, and the strongest chemotactic factor for fibroblasts is platelet-derived growth factor (PDGF).

Upon entering the wound environment, recruited fibroblasts first need to proliferate, and then become activated, to carry out their primary function of matrix synthesis remodeling.

This activation is mediated mainly by the cytokines and growth factors released from wound macrophages. (See Schwartz
10th ed.,p. 241.)

Question 3

Which of the following is true regarding the fibroblastic
phase of wound healing?

A. Early during wound healing, the predominant composition of the matrix is fibronectin and type II
collagen.

B. After complete replacement of the scar with type III
collagen, the mechanical strength will equal that of uninjured tissue approximately 6 to 12 months post injury

C. Even though the tensile strength of a wound reaches a plateau after several weeks, the tensile strength will increase over another 6 to 12 months due to fibril formation and cross-linking.

D. As the scar matures, matrix metalloproteinases
(MMPs) break down type I collagen and replace it with
type III collagen.

Answer 3

Answer: C

The maturation and remodeling of the scar begins during the fibroblastic phase, and is characterized by a reorganization of previously synthesized collagen. Collagen is broken down by matrix metalloproteinases (MMPs), and the net wound collagen content is the result ol a balance between collagenolysis and collagen synthesis.

There is a net shift toward collagen synthesis and eventually the reestablishment of extracellular matrix composed of a relatively acellular collagen-rich scar.

Wound strength and mechanical integrity in the fresh
wound are determined by both the quantity and quality of the newly deposited collagen. The deposition of matrix at the wound site follows a characteristic pattern: fibronectin and collagen type III constitute the early matrix scaffolding; glycosaminoglycans and proteoglycans represent the next significant matrix components; and collagen type I is the final
matrix.

By several weeks postinjury the amount of collagen in the wound reaches a plateau, but the tensile strength continues to increase for several more months. Fibril formation and fibril cross-linking result in decreased collagen solubility, increased strength, and increased resistance to enzymatic degradation of the collagen matrix.

Fibrillin, a glycoprotein secreted by fibroblasts, is essential for the formation of elastic fibers found in connective tissue. Scar remodeling continues for many (6-12) months postinjury, gradually resulting in a mature, avascular, and acellular scar.

The mechanical strength of the scar never achieves that of the uninjured tissue.

(See Schwartz 10th ed.,p. 245.)

Question 4

Which of the following is commonly seen in Ehlers-Danlos syndrome (EDS)?

A. Small bowel obstructions.

B. Spontaneous thrombosis.

C. Direct or recurrent hernias in children.

D. Abnormal scarring of the hands with contractures.

Answer 4

Answer: C

Ehlers-Danlos syndrome (EDS) is a group of 10 disorders that present as a defect in collagen formation. Over half of the affected patients manifest genetic defects encoding alpha chains of collagen type V, causing it to be either quantitatively or structurally defective.

These changes lead to “classic” EDS with phenotypic findings that include thin, friable skin with prominent veins, easy bruising, poor wound healing, atrophic scar formation, recurrent hernias, and hyperextensible joints.

Gastrointestinal (GI) problems include bleeding, hiatal hernia, intestinal diverticula, and rectal prolapse.

Small blood vessels are fragile, making suturing difficult during surgery.

Large vessels may develop aneurysms, varicosities, arteriovenous fistulas, or may spontaneously rupture.

(See Schwartz 10th ed., p. 246.)

Question 5

Patients with Marfan syndrome are associated with what genetic decect?

A. MFN-1 gene deletion

B. Type I collagen gene mutation

C. COL7A1 gene mutation

D. FBN-1 gene mutation

Answer 5

Answer: D

Patients with Marfan’s syndrome have tall stature, arachnodactyly, lax ligaments, myopia, scoliosis, pectus excavatum, and aneurysm of the ascending aorta. Patients who suffer from this syndrome are also prone to hernias. Surgical repair of a dissecting aneurysm is difficult, as the soft connective tissue fails to hold sutures. Skin may be hyperextensible, but shows no delay in wound healing.

The genetic defect associated with Marfan’s syndrome is a mutation in the FBN-1 gene which encodes for fibrillin. Previously, it was thought that structural alteration of the microfibrillar system was responsible for the phenotypic changes seen with the disease. However, recent research indicates an intricate relationship that FBN-1 gene products play in TGF-ß signaling. (See Schwartz 10th ed., p. 246.)

Question 6

When a long bone fracture is repaired by internal fixation with plates and screws

A. Callus at the fracture site forms more rapidly.

B. Delayed union is prevented.

C. Direct bone-to-bone healing occurs without soft callus formation.

D. Endochondral ossification is more complete.

Answer 6

Answer: C

Precise fracture reduction and fixation allows the fracture to heal bone-to-bone without the soft callus formation and endochondral ossification, which are characteristic of closed fracture management.

However, internal reduction does not prevent delayed union, especially when infection or poor blood supply are present. (See Schwartz 1 Oth ed., p. 249.)

Question 7

Which of the following is FALSE regarding healing of full¬
thickness injuries of the GI tract?

A. Serosal healing is essential to form a water-tight barrier to the lumen of the bowel

B. Extraperitoneal segments of bowel that lack serosa
have higher rates of anastomotic failure.

C. There is an early decrease in marginal strength due to an imbalance of greater collagenolysis versus collagen synthesis.

D. Collagen synthesis is done by fibroblast and smooth
muscle cells.

E. The greatest tensile strength of the GI tract is provided by the serosa.

Answer 7

Answer: E

The submucosa lies radially and circumferentially outside of these layers, is composed of abundant collagenous and elastic fibers, and supports neural and vascular structures. The submucosa is the layer that imparts the greatest tensile strength and greatest suture-holding capacity, a characteristic that should be kept in mind during surgical repair of the GI tract.

Additionally, serosal healing is essential for quickly achieving a watertight seal from the luminal side of the bowel. The importance of the serosa is underscored by the significantly higher rates of anastomotic failure observed clinically in segments of bowel that are extraperitoneal and lack serosa (ie, the esophagus and rectum).

The early integrity of the anastomosis is dependent on
formation of a fibrin seal on the serosal side, which achieves watertightness, and on the suture-holding capacity of the intestinal wall, particularly the submucosal layer.

There is a significant decrease in marginal strength during the first week due to an early and marked collagenolysis.

The lysis of collagen is carried out by collagenase derived from neutrophils, macrophages, and intraluminal bacteria.

Collagenase activity occurs early in the healing process, and during the first 3 to 5 days collagen breakdown far exceeds collagen synthesis.

The integrity of the anastomosis represents equilibrium between collagen lysis, which occurs early, and collagen synthesis, which takes a few days to initiate.

Collagen synthesis in the GI tract is carried out by both fibroblasts and smooth muscle cells. (See Schwartz 10th ed., p. 249.)

Question 8

Steroids impair wound healing by

A. Decreasing angiogenesis and macrophage migration

B. Decreasing platelet plug integrity

C. Increasing release of lysosomal enzymes

D. Increasing fibrinolysis

Answer 8

Answer: A

The major effect of steroids is to inhibit the inflammatory
phase of wound healing (angiogenesis, neutrophil and macrophage migration, and fibroblast proliferation) and the release of lysosomal enzymes.

The stronger the anti-inflammatory effect of the steroid compound used, the greater the inhibitory effect on wound healing. Steroids used after the first 3 to 4 days postinjury do not affect wound healing as severely as
when they are used in the immediate postoperative period.

Therefore if possible, their use should be delayed or, alternatively, forms with lesser anti-inflammatory effects should be administered.

In addition to their effect on collagen synthesis, steroids
also inhibit cpithclialization and contraction and contribute to increased rates of wound infection, regardless of the time of administration. Steroid-delayed healing of cutaneous wounds can be stimulated to epithelialize by topical application of vitamin A. Collagen synthesis of steroid-treated wounds also can be stimulated by vitamin A. (See Schwartz
10th cd., p. 253.)

Question 9

What type of nerve injury involves disruption of axonal continuity with preserved Schwann cell basal lamina?

A. Neurapraxia

B. Axonotmesis

C. Neurotmesis

D. Axonolysis

Answer 9

Answer: B

There are three types of nerve injuries: neurapraxia (focal demyelination), axonotmesis (interruption of axonal continuity but preservation of Schwann cell basal lamina), and neurotmesis (complete transection).

Following all types of injury, the nerve ends progress through a predictable pattern of changes involving three crucial steps:

(1) survival of axonal cell bodies;
(2) regeneration of axons that grow across the
transected nerve to reach the distal stump; and
(3) migration and connection of the regenerating nerve ends to the appropriate nerve ends or organ targets.

Phagocytes remove the degenerating axons and myelin sheath from the distal stump (Wallerian degeneration).

Regenerating axonal sprouts extend from the proximal stump and probe the distal stump and the surrounding tissues.

Schwann cells ensheathe and help in remyelinating the regenerating axons. Functional units are formed when the regenerating axons connect with the appropriate end targets.
(See Schwartz 10th cd.,p. 251.)

Question 10

The major cause of impaired wound healing is

A. Anemia

B. Diabetes mellitus

C. Local tissue infection

D. Malnutrition

Answer 10

Answer: C

All the factors listed impair wound healing, but local infection is the major problem. The surgeon should make every effort to remove all devitalized tissue and leave a clean wound for closure. (Sec Schwartz 10th cd., p. 252.)

Question 11

How docs diabetes mellitus impair wound healing?

A. Local hypoxemia, reduced angiogenesis, and inf animation due to vascular disease.

B. Glycosylation of proteoglycans and collagen in
wound bed due to hyperglycemia.

C. Decreased collagen accretion noted in patients with
type II diabetes mellitus.

D. Increased bacterial load to due to hyperglycemia.

Answer 11

Answer: A

Uncontrolled diabetes results in reduced inflammation,
angiogenesis, and collagen synthesis. Additionally, the large and small vessel disease that is the hallmark of advanced diabetes contributes to local hypoxemia.

Defects in granulocyte function, capillary ingrowth, and fibroblast proliferation all have been described in diabetes. Obesity, insulin resistance, hyperglycemia, and diabetic renal failure contribute significantly and independently to the impaired wound healing
observed in diabetics. (See Schwartz 10th cd.,p. 253.)

Question 12

Supplementation of which of the following micronutri¬
ents improves wound healing in patients without micro¬
nutrient deficiency?

A. Vitamin C

B. Vitamin A

C. Selenium

D. Zinc

Answer 12

Answer: B

The vitamins most closely involved with wound healing are vitamin C and vitamin A. There is no evidence that excess vitamin C is toxic; however, there is no evidence that super-therapeutic doses of vitamin C are of any benefit.

Vitamin A deficiency impairs wound healing, while supplemental vitamin A benefits wound healing in nondeficient humans and animals. Vitamin A increases the inflammatory response in wound healing, probably by increasing the lability of lysosomal membranes. There is an increased influx of macrophages, with an increase in their activation and increased collagen synthesis.

Vitamin A directly increases collagen production and epidermal growth factor receptors when it is
added in vitro to cultured fibroblasts.

As mentioned before, supplemental vitamin A can reverse the inhibitory effects of corticosteroids on wound healing.

Vitamin A also can restore wound healing that has been impaired by diabetes, tumor formation, cyclophosphamide, and radiation. Serious injury or stress leads to increased vitamin A requirements.

In the severely injured patient, supplemental doses of vitamin A have been recommended. Doses ranging from 25,000 to 100,000 IU/day have been advocated.

Zinc is the most well-known element in wound healing and has been used empirically in dermatologic conditions for centuries.

To date, no study has shown improved wound healing
with zinc supplementation in patients who arc not zinc deficient. (See Schwartz 10th cd.,p. 255.)

Question 13

Which type of collagen is most important in wound healing?

A. Type III

B. Type V

C. Type VII

D. Type XI

Answer 13

Answer: A

Although there are at least 18 types of collagen described, the main ones of interest to wound repair are types I and III.

Type I collagen is the major component of extracellular matrix in skin.

Type III, which is also normally present in skin, becomes more prominent and important during the repair process.

(See Schwartz 10th cd., p. 244.)

Question 14

What is FALSE regarding healing of cartilage?

A. Cartilage is avascular and depends on diffusion of
nutrients.

B. Superficial cartilage wounds are not associated with
an inf ammatory response.

C. Cartilage injuries often heal slowly and result in per¬
manent structural defects.

D. A major source of nutrients to cartilage is from nearby
periosteum.

Answer 14

Answer: D

Cartilage consists of cells (chondrocytes) surrounded by an extracellular matrix made up of several proteoglycans, collagen fibers, and water.

Unlike bone, cartilage is very avascular and depends on diffusion for transmittal of nutrients across the matrix. Additionally, the hypcrvascular perichondrium contributes substantially to the nutrition of the cartilage.

Therefore, injuries to cartilage may be associated with permanent defects due to the meager and tenuous blood supply.

The healing response of cartilage depends on the depth of injury. In a superficial injury, there is disruption of the proteoglycan matrix and injury to the chondrocytes. There is no inflammatory response, but an increase in synthesis of proteoglycan and collagen dependent entirely on the chondrocyte.

Unfortunately, the healing power of cartilage is often
inadequate and overall regeneration is incomplete. Therefore, superficial cartilage injuries are slow to heal and often result in persistent structural defects. (Sec Schwartz 10th cd., p. 251.)

Question 15

Signs of malignant transformation in a chronic wound
include

A. Persistent granulation tissue with bleeding

B. Overturned wound edges

C. Nonhcaling after 2 weeks of therapy

D. Distal edema

Answer 15

Answer: B

Malignant transformation of chronic ulcers can occur in any long-standing wound (Marjolin ulcer). Any wound that does not heal for a prolonged period of time is prone to malignant transformation.

Malignant wounds are differentiated clinically from nonmalignant wounds by the presence of overturned wound edges.

In patients with suspected malignant transformations, biopsy of the wound edges must be performed to rule out malignancy.

Cancers arising de novo in chronic wounds include both squamous and basal cell carcinomas. (See Schwartz 10th cd., p. 259.)

Question 16

What is the difference between hypertrophic scars (HTS) and keloids?

A. Keloids are an overabundance of fibroplasia as a result of healing, hypertrophic scars are a failure of collagen remodeling.

B. Hypertrophic scars often regress over time, whereas keloids rarely regress.

C. Hypertrophic scars are more common in darker-pigmented ethnicities.

D. Hypertropic scars extend beyond the border of the original wound.

Answer 16

Answer: B

Hypertrophic scars (HTS) and keloids represent an overabundance of fibroplasia in the dermal healing process.

HTS rise above the skin level but stay within the confines of the original wound and often regress over time.

Keloids rise above the skin level as well, but extend beyond the border of the original wound and rarely regress spontaneously (Fig. 9-1).

Both HTS and keloids occur after trauma to the skin, and maybe tender, pruritic, and cause a burning sensation.

Keloids are 15 times more common in darker-pigmented ethnicities, with individuals of African, Spanish, and Asian ethnicities being especially susceptible.

Men and women are equally affected. Genetically, the predilection to keloid formation appears to be autosomal dominant with incomplete penetration and variable expression.

(See Schwartz 1 Oth cd., Figure 9-11, p. 261.)

Question 17

The treatment of choice for keloids is

A. Excision alone

B. Excision with adjuvant therapy (eg, radiation)

C. Pressure treatment

D. Intralesional injection of steroids

Answer 17

Answer: B

Excision alone of keloids is subject to a high recurrence rate, ranging from 45 to 100%. There are fewer recurrences when surgical excision is combined with other modalities such as intralesional corticosteroid injection, topical application of silicone sheets, or the use of radiation or pressure.

Surgery is recommended for debulking large lesions or as second-line therapy when other modalities have failed.

Silicone application is relatively painless and should be maintained for 24 hours a day for about 3 months to prevent rebound hypertrophy.

It may be secured with tape or worn beneath a pressure garment. The mechanism of action is not understood, but increased hydration of the skin, which decreases capillary activity, inflammation, hyperemia, and collagen deposition, may be involved.

Silicone is more effective than other occlusive dressings and is an especially good treatment for children and others who cannot tolerate the pain involved in other modalities.

(Sec Schwartz 10th cd., p. 262.)

Question 18

What is FALSE about peritoneal adhesions?

A. Most peritoneal adhesions are a result of intraabdominal surgery.

B. Intra-abdominal adhesions are the most common cause of small bowel obstruction.

C. Operations in the upper abdomen have a higher chance of causing adhesions that cause small bowel obstruction, especially involving the jejunum.

D. Adhesions are a leading cause of secondary infertility in women.

Answer 18

Answer: C

Peritoneal adhesions are fibrous bands of tissues formed between organs that are normally separated and/or between organs and the internal body wall.

Most intra-abdominal adhesions are a result of peritoneal injury, either by a prior surgical procedure or due to intra-abdominal infection.

Postmortem examinations demonstrate adhesions in 67% of patients with prior surgical procedures and in 28% with a history of intra-abdominal infection.

Intra-abdominal adhesions are the most common cause (65-75%) of small bowel obstruction, especially in the ileum.

Operations in the lower abdomen have a higher chance of producing small bowel obstruction.

Following rectal surgery, left colectomy, or total colectomy, there is an 11% chance of developing small bowel obstruction within 1 year, and this rate increases to 30% by 10 years.

Adhesions also are a leading cause of secondary infertility in women and can cause substantial abdominal and pelvic pain.

Adhesions account for 2% of all surgical admissions and 3% of all laparotomies in general surgery.

(See Schwartz 10th ed., p. 263.)

Question 19

Which growth factor has been formulated and approved for treatment of diabetic foot ulcers?

A. PDGF

B. IGF-1

C. IL-8

D. Keritinocyte growth factor

E. Laminin-5

Answer 19

Answer: A

At present, only platelet-derived growth factor BB (PDGF-BB) is currently approved by the FDA for treatment of diabetic foot ulcers.

Application of recombinant human PDGF-BB in a gel suspension to these wounds increases the incidence of total healing and decreases healing time.

Several other growth factors have been tested clinically and show some promise, but currently none are approved for use.

(See Schwartz 10th ed., p.267.)

Question 20

Which of the following statements regarding the role of collagen in wound healing is true?

A. Collagen synthesis in the initial phase of injury is the sole responsibility of endothelial cells.

B. Net collagen content increases for up to 2 years after injury.

C. At 3 weeks after injury, more than 50% of the tensile strength of the wound has been restored.

D. Tensile strength of the wound increases gradually for up to 2 years after injury; however, it generally reaches a level of only about 80% of that of uninjured tissue.

E. Tensile strength is the force necessary to reopen a wound.

Answer 20

ANSWER: D

COMMENTS: Synthesis of collagen by fibroblasts begins as early as 10 h after injury and increases rapidly; it peaks by day 6 or 7 and then continues more slowly until day 42. Collagen continues to mature and remodel for years.

Its solubility in saline solution and the thermal shrinkage temperature of collagen reflect the intermolecular cross-links, which are directly proportional to collagen age. After 6 weeks, there is no measurable increase in the net collagen content.

However, synthesis and turnover are ongoing for life. Historical accounts of sailors with scurvy (with impaired collagen production) who experienced reopening of previously healed wounds illustrate this fact.

Tensile strength correlates with the total collagen content for approximately the first 3 weeks of wound healing. At 3 weeks, the tensile strength of the skin is 30% of normal. After this time, there is a much slower increase in the content of collagen until it plateaus at about 6 weeks.

Nevertheless, tensile strength continues to increase because of intermolecular bonding in collagen and changes in the physical arrangement of collagen fibers.

Although the most rapid increase in tensile strength occurs during the first 6 weeks of healing, there is a slow gain for at least 2 years.

Its ultimate strength, however, never equals that of the unwounded tissue, with a level of just 80% of the original skin strength being reached.

Tensile strength is measured as the load capacity per unit area. It may be differentiated from burst strength, which is the force required to break a wound (independent of its area).

For example, in wounds of the face and back, burst strength is different because of differences in skin thickness, even though tensile strength may be similar.

Corticosteroids affect wound healing by inhibiting fibroblast proliferation and epithelialization.

The latter effect can be reversed by the administration of vitamin A.

Question 21

A 34-year-old man sustained a gunshot wound to his abdomen that necessitated exploratory laparotomy and small bowel resection. Two weeks after the initial operation, he was re-explored for a large intraabdominal abscess. Which of the following will result in the most rapid gain in strength of the new incision?

A. A separate transverse incision is made.

B. The midline scar is excised with a 1-cm margin.

C. The midline incision is reopened without excision of the scar.

D. The midline incision is left to heal by secondary intention.

E. The rate of gain in strength is not affected by the incision technique.

Answer 21

ANSWER: C

COMMENTS: When a normally healing wound is disrupted after approximately the fifth day and then reclosed, the return of wound strength is more rapid than that with primary healing.

This is termed the secondary healing effect and appears to be caused by the elimination of the lag phase present in normal primary healing.

If the skin edges more than about 7 mm around the initial wound are excised, the resulting incision is through essentially uninjured tissue, so accelerated secondary healing does not occur.

Question 22

A 29-year-old black woman is scheduled for incision and drainage of a breast abscess that has recurred three times despite ultrasound-guided needle drainage. The patient has a history of keloid formation and is concerned about an unsightly scar on her breast. Which of the following statements concerning wound healing is true?

A. Keloids contain an overabundance of fibroblasts.

B. A hypertrophic scar extends beyond the boundaries of the original wound.

C. Improvement is usually seen with keloid excision followed by intralesional steroid injection.

D. An incision placed perpendicular to the lines of natural skin tension will result in the least obvious scar.

E. Hypertrophic scars occur most commonly on the lower extremities.

Answer 22

ANSWER: C

COMMENTS: Keloids are caused by an imbalance between collagen production and degradation. The result is a scar that extends beyond the boundaries of the original wound. The absolute number of fibroblasts is not increased.

Treatment of keloids is difficult. There is often some improvement with excision and intralesional steroid injection. If this technique is not successful, excision and radiation treatment can be used.

Hypertrophic scars contain an overabundance of collagen, but the dimensions of the scar are confined to the boundaries of the original wound. Hypertrophic scars are often seen in the upper part of the torso and across flexor surfaces.

Scar formation is affected by multiple factors, including the patient’s genetic makeup, wound location, age, nutritional status, infection, tension, and surgical technique.

In planning for surgical incisions, an effort to parallel natural tension lines will promote improved wound healing.

Question 23

A 30-year-old man is scheduled for definitive management of his open wounds after undergoing embolectomy and fasciotomies on his left lower extremity. Which of the following statements is true regarding the use of split- and full-thickness skin grafts?

A. A split-thickness skin graft undergoes approximately 40% shrinkage of its surface area immediately after harvesting.

B. A full-thickness skin graft undergoes approximately 10% shrinkage of its surface area immediately after harvesting.

C. Secondary contraction is more likely to occur after adequate healing of a full-thickness skin graft than after adequate healing of a split-thickness skin graft.

D. Sensation usually returns to areas that have undergone skin grafting.

E. Skin grafts may be exposed to moderate amounts of sunlight without changing pigmentation.

Answer 23

ANSWER: D

COMMENTS: Skin grafts are considered to be full thickness when they are harvested at the dermal-subcutaneous junction.

Split-thickness skin grafts are those that contain epidermis and variable partial thicknesses of the underlying dermis. They are usually 0.018 to 0.060 inch in thickness.

Cells from epidermal appendages deep to the plane of graft harvest resurface on the donor site of a split-thickness skin graft in approximately 1 to 3 weeks, depending on the depth.

The donor site requires a moist environment to promote epithelialization, and such an environment is maintained by using polyurethane or hydrocolloid dressings.

Because a full-thickness graft removes all epidermal appendages, the defects must be closed primarily. When a skin graft is harvested, there is immediate shrinkage of the surface area of the graft.

This process, known as primary contraction, is due to recoil of the elastic fibers of the dermis.

The thicker the skin graft, the greater the immediate shrinkage, with full-thickness grafts shrinking by approximately 40% of their initial surface area and split-thickness grafts shrinking by approximately 10% of their initial surface area.

Shrinkage must be considered when planning the amount of skin to harvest for covering a given wound size.

Secondary contraction occurs when contractile myofibroblasts in the bed of a granulating wound interact with collagen fibers to cause a decrease in the wound’s surface area.

Secondary contraction is greater in wounds covered with split-thickness grafts than in those covered with full- thickness grafts.

The amount of secondary contracture is inversely proportional to the amount of dermis included in the graft rather than the absolute thickness of the graft.

Dermal elements hasten the displacement of myofibroblasts from the wound bed.

Sensation may return to areas that have been grafted if the bed is suitable and not significantly scarred. Although sensation is not completely normal, it is usually adequate for protection. This process begins at about 10 weeks and is maximal at 2 years.

Skin grafts appear to be more sensitive than the normal surrounding skin to melanocyte stimulation during exposure to ultraviolet sunlight.

Early exposure to sunlight after grafting may lead to permanently increased pigmentation of the graft and should be avoided.

Dermabrasion or the application of hydroquinones may be beneficial in reducing this pigmentation.

Question 24

A 21-year-old graduate student has a large hypertrophic scar on the lower part of her face. The patient had sustained a laceration on her face 2 years previously after hitting her face on the side of a swimming pool. Which of the following statements regarding scar revision is true?

A. Scar maturation refers to the change in size of the wound in the first 1 to 2 months.

B. Scar revision should have been performed in the first 3 months after injury to minimize fibrosis.

C. Revision should be performed earlier in children than in adults.

D. It corrects undesirable pigmentation.

E. Scar revision should be delayed for approximately 1 year to allow maturation.

Answer 24

ANSWER: E

COMMENTS: Changes in pliability, pigmentation, and configuration of a scar are known as scar maturation.

This process continues for many months after an incision; therefore it is generally recommended that revision not be carried out for approximately 12 to 18 months because natural improvement can be anticipated within this period.

In general, scar maturation occurs more rapidly in adults than in children.

Most erythematous scars show little improvement after revision; therefore scar revision should not be undertaken for correction of undesirable scar color alone.

Question 25

A 68-year-old diabetic man undergoes a below-knee amputation. The patient’s postoperative course is complicated by severe depression and anorexia. Before discharge, the patient is started on a multivitamin regimen. Which of the following statements regarding wound healing is true?

A. Vitamin A is needed for hydroxylation of lysine and proline in collagen synthesis.

B. High doses of vitamin C improve wound healing.

C. Vitamin E is involved in the stimulation of fibroplasia, collagen cross-linking, and epithelialization.

D. Zinc deficiency results in delayed early wound healing.

E. Iron deficiency has been linked to defects in long-term
wound remodeling.

Answer 25

ANSWER: D

COMMENTS: Vitamin A is involved in the stimulation of fibroplasia and epithelialization. Although there has been no conclusive evidence of its efficacy in humans, in animal studies vitamin A has been shown to reverse the inhibitory effects of glucocorticoids in the inflammatory phase of wound healing and epithelialization.

Vitamin C is a necessary cofactor in the hydroxylation and cross-linking of lysine and proline in collagen synthesis. Deficiencies in vitamin C (scurvy) can lead to the production of inadequately hydroxylated collagen, which either degrades rapidly or never forms proper cross-links. Doses higher than physiologic doses do not improve wound healing.

Vitamin E is applied to wounds and incisions by many patients, but there is no evidence to support the role of vitamin E in wound healing. Large doses of vitamin E have been found to inhibit wound healing.

Zinc is a necessary cofactor of RNA and DNA polymerase, and deficiencies have been linked to poor early wound healing.

Iron (specifically, the ferrous iron) is necessary for converting hydroxyproline to proline. However, chronic anemia and iron deficiency have not been linked to delayed or impaired wound healing.

Question 26

Which of the following statements regarding wound epithelialization is true?

A. Integrins act as a key modulator of the interaction between epithelial cells and the surrounding environment.

B. Structural support and attachment between the epidermis and dermis are provided by tight cell junctions.

C. Early tensile strength of the wound is a direct result of collagen deposition.

D. A reepithelialized wound develops hair follicles and sweat glands like those seen in the normal skin.

E. Contact inhibition can prevent collagen deposition and result in a chronic (nonhealing) wound.

Answer 26

ANSWER: A

COMMENTS: Migration of epithelial cells is one of the earliest events in wound healing. Shortly after injury and during the inflammatory phase, basal epithelial cells begin to multiply and migrate across the defect, with fibrin strands being used as the support structure.

Integrins are the main cellular receptors involved in epithelial migration; they act as sensors and integrators between the extracellular matrix and the epithelial cell cytoskeleton.

Tight junctions within the epithelium contribute to its impermeability, whereas the basement membrane contributes to structural support and attachment of the epidermis to the dermis.

Surgical incisions seal rather promptly and after 24h are protected from the external environment.

Early tensile strength is a result of blood vessel ingrowth, epithelialization, and protein aggregation. After covering the wound, the epithelial cells keratinize. The reepithelialized wound has no sweat glands or hair follicles, which distinguishes it from the normal skin.

Control of the cellular process during wound epithelialization is not completely understood, but it appears to be regulated in part by contact inhibition, with growth being arrested when two or more similar cells come into surface contact.

Derangements in the control of this process can result in epidermoid malignancy. Malignancy is more frequently observed in wounds resulting from ionizing radiation or chemical injury, but it can occur in any wound when the healing process has been chronically disrupted.

For example, squamous cell carcinoma may develop in patients with chronic burn wounds or osteomyelitis (Marjolin’s ulcer).

Question 27

In DNA replication, what type of mutation is specifically
associated with the generation of a stop codon?

A. Point mutation

B. Missense mutation

C. Nonsense mutation

D. Frameshift mutation

E. Neutral mutation

Answer 27

ANSWER: C

COMMENTS:

A change in a single base pair is known as a point mutation.

A single amino acid change resulting from a point mutation is known as a missense mutation.

A missense mutation may cause changes in the structure of the protein that lead to altered biologic activity.

Nonsense mutations occur if a point mutation results in the replacement of an amino acid codon with a stop codon. Nonsense mutations lead to premature termination of translation and often result in the loss of encoded protein.

Frameshift mutations occur when a few base pairs are added or deleted and lead to the introduction of unrelated amino acids or stop codons.

A neutral mutation occurs when the change results in the substitution of a different but chemically similar amino acid.

Frequently, the amino acids are similar enough that little or no change occurs in the resultant protein.

Question 28

Which of the following is correct regarding cell signaling?

A. Cytokines are exclusively peptide mediators.

B. Autocrine mediators are secreted by a cell and act on adjacent cells of a different type.

C. Cytokines are usually produced by cells specialized for only that purpose.

D. The effects of hormones are generally local rather than global.

E. Growth factors are frequently mediated by second messenger systems such as diacylglycerol (DAG) and cyclic adenosine monophosphate (cAMP).

Answer 28

ANSWER: E

COMMENTS: Cytokines are proteins, glycoproteins, or peptides that bind to target cell surface receptors to stimulate a cellular response. They are important mediators of wound healing.

Cytokines can reach target cells by paracrine, autocrine, or intracrine routes. Paracrine mediators are produced by one cell and act on an adjacent target cell. Autocrine mediators are secreted by a cell and act on cell surface receptors on the same cell. Intracrine mediators act within a single cell.

Hormones are released by cells and act on a distant target (endocrine route). Although the distinction between cytokines and hormones has blurred, in general, hormones are secreted from specialized glands (e.g., insulin, parathyroid hormone) and cytokines are secreted by a wide variety of cell types.

Hormones typically induce body-wide effects, whereas the effects of cytokines may be more localized (e.g., wound healing at the site of an injury). Generally, growth factors are named according to their tissue of origin or their originally discovered action.

Growth factors interact with specific membrane receptors to initiate a series of events that ultimately lead to stimulation of cell growth, proliferation, or differentiation.

The intermediate events activate a variety of second messenger systems mediated by agents such as inositol 1,4,5-triphosphate (IP3), DAG, and cAMP.

Question 29

A 25-year-old man presents to the office with complaints of contracture of his left index finger after a burn injury. Which of the following statements is true about growth factors?

A. Epidermal growth factor (EGF) stimulates the production of collagen.

B. Vascular endothelial growth factor (VEGF) and platelet- derived growth factor (PDGF) both stimulate angiogenesis by binding to a common receptor.

C. Fibroblast growth factor (FGF) stimulates wound contraction.

D. Transforming growth factor-β (TGF-β) is stored in endothelial cells.

E. Tumor necrosis factor-α (TNF-α) inhibits angiogenesis.

Answer 29

ANSWER: C

COMMENTS: EGF was the first cytokine described. It is a potent mitogen for epithelial cells, endothelial cells, and fibroblasts.

EGF stimulates the synthesis of fibronectin, angiogenesis, and collagenase activity.

PDGF is released from the alpha granules of platelets and is responsible for the stimulation of neutrophils and macrophages and for increasing the production of TGF-β.

PDGF is a mitogen and chemotactic agent for fibroblasts and smooth muscle cells and stimulates angiogenesis, collagen synthesis, and collagenase activity.

VEGF is similar to PDGF but does not bind to the same receptors. VEGF is mitogenic for endothelial cells. Its role in promoting angiogenesis has led to an interest in anti-VEGF therapies for cancer.

FGF has acidic and basic forms whose actions are identical but whose strengths differ (basic FGF is 10 times stronger than acidic FGF). FGF is mitogenic for endothelial cells, fibroblasts, keratinocytes, and myoblasts; stimulates wound contraction and epithelialization; and induces the production of collagen, fibronectin, and proteoglycans. It is an important mediator of angiogenesis.

TGF-β is released from the alpha granules of platelets and has been shown to regulate its own production in an autocrine manner. TGF-β stimulates fibroblast proliferation and the production of proteoglycans, collagen, and fibrin. It is an important mediator of fibrosis. Administration of TGF-β has been suggested as an approach to reduce scarring and reverse the inhibition of wound healing by glucocorticoids.

TNF-α is a mitogen for fibroblasts and is produced by macrophages. It stimulates angiogenesis and the synthesis of collagen and collagenase.

Question 30

An 85-year-old nursing home patient is found to have a worsening stage III sacral pressure ulcer. The ulcer is debrided and tissue for culture obtained. Tissue cultures reveal 108 organisms per gram of tissue after operative debridement. What is the next most appropriate step in the management of the patient’s wound?

A. Muscle flap coverage

B. Wound vacuum-assisted closure (VAC)

C. Intravenous antibiotics

D. Repeat debridement

E. Debridement with immediate application of a split-thickness skin graft

Answer 30

ANSWER: D

COMMENTS: The National Pressure Ulcer Advisory Panel has recommended a staging system for pressure sores that is useful in planning treatment.

Stage I is represented by the presence of non- blanching erythema of intact skin.

Stage II is characterized by partial-thickness skin loss involving the epidermis or dermis. Clinically, the ulcer is manifested as a blister, abrasion, or shallow crater.

Stage III is full-thickness skin loss with involvement of the underlying subcutaneous tissue. Stage III wounds may extend down to but not through the underlying fascia.

Stage IV represents full-thickness skin loss with extensive destruction or tissue necrosis of underlying structures, which may include muscle and bone.

Studies have shown that wounds with quantitative cultures revealing more than 106 organisms per gram of tissue that undergo reconstruction with skin or even muscle flaps have a significantly greater risk for complications, including infection, accumulation of fluid, and wound dehiscence.

Similarly, a skin graft is unlikely to survive in an environment with such a high bacterial inoculate.

Negative- pressure wound therapy, such as with the wound VAC system, involves the use of a sponge and an occlusive dressing connected to a suction apparatus in a closed system.

In patients with large wounds, a wound VAC may serve as a bridge to reduce the wound size for definitive reconstruction. It has been shown to be effective in reducing wound edema, controlling wound drainage, encouraging diminution of wound size, and facilitating the formation of granulation tissue.

Although studies have shown that wound VAC therapy may reduce bacterial counts over time, the most appropriate management of such patients is repeat debridement of the wound.

Intravenous antibiotics may be recommended to treat the underlying osteomyelitis.

Question 31

A 45-year-old woman undergoes bilateral transverse rectus abdominis muscle (TRAM) breast reconstruction after modified radical mastectomy. The patient is scheduled for postoperative radiation therapy and is concerned that this will affect her wound-healing ability. Which of the following statements regarding wound healing in this patient is true?

A. Denervation has a profound effect on wound contraction and epithelialization.

B. A bacterial count of 1000 organisms per square centimeter retards wound healing.

C. Chemotherapy beginning 10 to 14 days after primary wound closure has little effect on the final status of a wound.

D. Tissue ischemia is the main component of tissue damage after irradiation.

E. Postoperative radiation therapy should be delayed for at least 4 to 6 months after surgery to decrease the incidence of wound complications.

Answer 31

ANSWER: C

COMMENTS: Denervation has no effect on wound contraction or epithelialization. Flap wounds in paraplegics heal satisfactorily when other factors, such as nutrition and temperature, are controlled.

Subinfectious bacterial levels appear to accelerate wound healing and the formation of granulation tissue. However, when the level reaches 106 organisms per square centimeter of wound, healing is delayed because of decreased tissue oxygen pressure, increased collagenolysis, and a prolonged inflammatory phase.

Various chemotherapeutic agents affect wound healing. Most anti-metabolic agents (e.g., 5-fluorouracil) do not delay wound healing, although agents such as doxorubicin have been shown to delay wound healing.

When chemotherapy begins 10 to 14 days after wound closure, little effect is noted on its final status despite a demonstrable early retardation in the wound strength.

Tissue ischemia may not be the primary factor involved in chronic wound- healing problems associated with irradiation. Such problems are most likely related to changes within the nuclei and concomitant cytoplasmic malformation.

To decrease wound complications, it is usual to delay surgery until at least 3 to 4 weeks after full-dose irradiation and to avoid radiation therapy for at least 3 to 4 weeks after surgery.

Question 32

A 46-year-old man is evaluated shortly after undergoing radiation therapy and chemotherapy for primary laryngeal cancer. He also gives a history of long-term steroid use for rheumatoid arthritis. The patient complains of a chronic, nonhealing wound on his neck, just over his right clavicular head. Which statement regarding the treatment of this wound is true?

A. The wound should be treated with compression dressings.

B. The wound should be treated with injected steroids.

C. The patient should start taking vitamin A, and the wound should be covered with antimicrobial dressings.

D. The patient should start taking vitamin C, and the wound should be kept open to air.

E. The wound should be excised and a skin graft applied.

Answer 32

ANSWER: C

COMMENTS: Radiation results in progressive endarteritis obliterans and microvascular damage to the skin, which leads to skin ischemia and fibrotic interstitial changes. This leaves wounds in the skin particularly prone to infection.

The use of antimicrobial dressings capable of maintaining a moist environment is ideal for these wounds.

Research also supports the use of hyperbaric oxygen and growth factors to promote wound healing. Patients taking steroids should receive daily vitamin A supplements.

Wounds in these patients show decreased rates of angiogenesis, collagen deposition, and cellular proliferation.

Wounds should be kept free of bacterial contamination.

Question 33

A 25-year-old ballet dancer with a history of anorexia nervosa arrives at the emergency department with right lower quadrant pain. After an appendectomy, a wound infection at the surgical site requires debridement. The patient is placed on an antibiotic regimen, and the wound is packed with wet-to-dry dressings. Regarding wound healing and malnutrition, which of the following statements is true?

A. Hypoproteinemia leads to decreased levels of arginine and glutamine, which are essential in wound healing.

B. Cell membranes rapidly become dehydrated in the absence of vitamin E, resulting in delayed wound healing.

C. Zinc is essential to the fibroblast’s ability to cross-link collagen.

D. Vitamin D serves an immunomodulatory role in wound healing.

E. The patient should be treated with high-dose vitamin C, vitamin A, and zinc.

Answer 33

ANSWER: D

COMMENTS: Adequate amounts of protein, carbohydrates, fatty acids, and vitamins are essential for wound healing. Hypoproteinemia results in decreased delivery of the essential amino acids used in the synthesis of collagen.

Carbohydrates and fats provide energy for wound healing, and in their absence, proteins are rapidly broken down.

Fatty acids are vital components of cell membranes.

Vitamin C is a cofactor for hydroxylation of lysine and proline during collagen synthesis, and its deficiency leads to decreased collagen cross-linking by fibroblasts. Vitamin C is also effective in providing resistance to infection.

Vitamin A is essential for normal epithelialization, proteoglycan synthesis, and enhanced immune function.

Vitamin D is required for normal calcium metabolism, but it is also involved in promoting immune function in the skin.

Vitamin E has not been shown to play a role in wound healing.

Zinc deficiency leads to a deficient formation of granulation tissue and inhibition of cellular proliferation.

Increased administration of vitamins and minerals does not accelerate wound healing and often has a deleterious effect.

Question 34

Which of the following statements regarding second messenger systems is true?

A. Most receptor proteins (such as G proteins) are completely extracellular.

B. Both the “first messenger” and “second messenger” mediators of cell signaling function within the cell cytoplasm.

C. Adenylate cyclase stimulates the conversion of cAMP to adenosine triphosphate (ATP).

D. IP3 generally increases cytoplasmic calcium concentrations.

E. IP3 and DAG together lead to inactivation of protein kinase C.

Answer 34

ANSWER: D

COMMENTS: The thyrotropin (TSH) receptor is a Gαs receptor found mainly on the surface of thyroid follicular cells. When activated, it stimulates increased production of thyroxine (T4) and triiodothyronine (T3).

Several families of receptor proteins have been identified. The most common is the G protein (guanine nucleotide–binding protein) family, a subset of guanosine triphosphatase (GTPase) enzymes. All G protein–coupled receptors have characteristic seven transmembrane domains.

Binding of an extracellular ligand causes a conformational change in the receptor that allows it to exchange guanosine diphosphate (GDP) for guanosine triphosphate (GTP) on the intracellular portion of the G protein.

The intracellular portion of the “large” (heterotrimeric) G protein–coupled receptor consists of three subunits, Gα, Gβ, and Gγ. Other “small” (monomeric) G protein receptors have only a homologue of the Gα portion.

There are several important subsets of the “large” G protein receptors, and they are classified according to the specific intracellular pathway that is activated.

Gαs stimulates membrane-associated adenylate cyclase to produce cAMP from ATP. cAMP is a second messenger that activates protein kinase A, which results in the phosphorylation of downstream targets. Gαs ligands include adrenocorticotropic hormone (ACTH), calcitonin, glucagon, histamine (H2), TSH, and many others.

Gαi inhibits the production of cAMP from ATP. Gαi ligands include acetylcholine (M2 and M4), dopamine (D2, D3, and D4), and histamine (H3 and H4). Gαq activates phospholipase C, which cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into IP3 and DAG.

IP3 mediates the release of calcium from intracellular reservoirs, such as the endoplasmic reticulum (ER), sarcoplasmic reticulum (SR) in muscle, and mitochondria. IP3 and DAG together work to activate protein kinase C, which can modulate membrane permeability and activate gene transcription. Gαq ligands include histamine (H1), serotonin (5-HT2), and muscarinic receptors.

The most well-known “small” G protein receptors are the Ras family GTPases. The Ras receptors influence a wide variety of processes in the cell, including growth, cellular differentiation, and cell movement.

Question 35

Inflammatory breast cancer is diagnosed in a 36-year-old woman. A decision is made to treat the patient with radiation, along with paclitaxel and doxorubicin. Which of the following statements regarding cellular motility and contractility is true?

A. Actin fibers are found mainly in muscle cells.

B. The interactions between actin and myosin that underlie the contraction of skeletal muscle require calcium but not ATP.

C. Intermediate filaments extend from the centrosome to the nucleus.

D. The proteins kinesin and dynein are required for directional transport of cellular components along the microtubules.

E. The microtubules used to form the spindle apparatus are synthesized de novo before each mitosis.

Answer 35

ANSWER: D

COMMENTS: The cytoskeleton provides the structural framework for the cell. It is composed of three main types of protein polymers: actin filaments, intermediate filaments, and microtubules.

Actin filaments are found in nearly all types of cells. They form a cortical layer beneath the plasma membrane of most cells, the stress fibers of fibroblasts, and the cytoskeleton of microvilli of intestinal epithelial cells.

In muscle cells, the interaction between the heads of myosin (thick filaments) and actin (thin filaments) requires hydrolysis of ATP to separate the filaments at the end of the power stroke.

Calcium and troponin C (an actin-associated protein) are also required to expose the binding site for myosin on the actin filament. Intermediate filaments are a heterogeneous group of proteins that extend from the nucleus to the cell surface. They interact with other cytoskeletal filaments and binding proteins to produce their effects.

Microtubules arise from the centrosome, with the cell’s microtubule-organizing center being located near the nucleus. Microtubules are in a constant dynamic equilibrium between assembly and disassembly.

Movement of cellular components, such as vacuoles, along the microtubules requires ATP and either of two associated proteins: kinesin for movement away from the centrosome and dynein for movement toward it.

Cilia and flagella contain columns of doublet microtubules in a 9–2 arrangement (nine doublets in a circle surrounding two central doublets). Movement is accomplished when the doublets slide along each other in a process mediated by dynein and fueled by hydrolysis of ATP.

Microtubules also play an important role in cell division. Assembly of the mitotic spindle involves replication and splitting of the microtubule-organizing center into the two spindle poles and reorganization of the cytoskeletal microtubules to form the spindle apparatus.

Question 36

Regarding chemotherapeutic agents, which of the following statements is true?

A. Paclitaxel is a manmade taxane first manufactured in the polycarbon industry.

B. Taxanes unwind DNA thus preventing transcription.

C. Vinca alkaloids inhibit cell division by disrupting the mitotic spindle.

D. Doxirubicin intercalates between DNA base pairs thus disrupting transcription.

E. Taxanes impair the progression of topoisomerase ii.

Answer 36

ANSWER: C

COMMENTS: Taxanes function as mitotic inhibitors by inhibiting depolymerization of the mitotic spindle, which results in a “frozen” mitosis.

Paclitaxel is a natural taxane that prevents depolymerization of cellular microtubules.

The vinca alkaloids (e.g., vinblastine, vincristine) also inhibit cell division but by disrupting the mitotic spindle.

Doxorubicin (Adriamycin) intercalates between DNA base pairs and impairs the progression of topoisomerase ii, which unwinds DNA for transcription.

Question 37

A 27-year-old woman sustains an incomplete T10 spinal cord injury after falling off a horse. The patient is given 30 mg/kg of methylprednisolone. Which of the following is true regarding steroid hormones and their receptors?

A. Steroid hormones are synthesized from proteins.

B. In the bloodstream, steroid hormones often dimerize to facilitate transport.

C. Steroid hormone receptors are found only in the cytoplasm.

D. Heat shock proteins (HSPs) are usually associated with cytosolic steroid hormone receptors.

E. Binding of the steroid hormone to a receptor induces a second messenger cascade to alter cellular metabolism.

Answer 37

ANSWER: D

COMMENTS: Steroid hormones are synthesized from cholesterol. Their lipophilic nature allows them to cross cell membranes easily.

Steroid hormones can be divided into five groups based on their receptors: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestogens.

In the bloodstream, steroid hormones are generally bound to specific carrier proteins such as sex hormone–binding globulin or corticosteroid-binding globulin.

Receptors for steroid hormones are most commonly located in the cytosol, although they are also found in the nucleus and on the cell membrane.

After binding to the steroid hormone, steroid receptors often dimerize.

For many cytosolic steroid receptors, binding of the ligand induces a conformational change and releases HSPs.

Nuclear steroid receptors are not generally associated with HSPs.

HSPs themselves have several roles, including functioning as intracellular chaperones for other proteins, serving as transcription factors, and facilitating antigen binding.

They may also serve as targets for therapeutics.

Ultimately, the activated steroid receptor must enter the nucleus to serve as a transcription factor for augmentation or suppression of the expression of particular genes.

The resulting messenger RNA leaves the nucleus for the ribosomes, where it is translated to produce specific proteins.

Question 38

A 55-year-old man with a history of hepatitis C cirrhosis has complaints of nausea, fever, and progressive lethargy. Part of his evaluation includes an assessment of his hepatitis C viral load. Which of the following tests would be most useful in assessing his hepatitis C viral load?

A. Western blot

B. Gel electrophoresis

C. Fluorescence microscopy

D. Polymerase chain reaction (PCR)

E. Expression cloning

Answer 38

ANSWER: D

COMMENTS: Western blot is a technique used to detect specific proteins in a sample. An antibody to the protein of interest is used as a probe.

Gel electrophoresis is a method for separating proteins or nucleic acids according to their size, mass, or composition.

It is based on the differential rate of movement of the molecules of interest through a gel when an electric field is applied.

PCR is a technique by which DNA may be massively amplified.

Primers or oligonucleotides are synthesized to complement one strand of the DNA to be amplified.

Amplification involves three temperature-cycled steps:

(1) heating for separation (denaturation) of the double-helix structure into two single strands,
(2) cooling for hybridization of each single strand with its primer (annealing), and
(3) heating for DNA synthesis (elongation).

The steps are repeated with exponential amplification of the DNA of interest.

When RNA is used, reverse transcriptase is employed initially to transcribe the RNA to DNA before amplifica- tion. Quantitative PCR can be used in real time to measure the starting concentration of DNA or RNA in a sample, for example, the amount of hepatitis C RNA in a blood sample.

With expression cloning, DNA coding for a protein of interest is cloned into a plasmid (extrachromosomal DNA molecule) that can be inserted into a bacterial or animal cell.

The cell expresses the protein, which allows the production of sufficient amounts for study.

Fluorescence microscopy is performed by labeling a component of interest in a sample with a molecule that absorbs light at one wavelength and emits at another (fluorescence).

Question 39

A 56-year-old man underwent total thyroidectomy for papillary cancer. On the first postoperative day, the patient complains of circumoral tingling and muscle weakness. Which of the following statements regarding the electrical properties of cell membranes is not true?

A. Ions flow through hydrophilic channels formed by specific transmembrane proteins.

B. Lipids provide the ability to store electric charge (capacitance).

C. Active pumps maintain the ionic gradients necessary for a resting membrane potential.

D. Initiation of an action potential depends on voltage-gated channels.

E. Large numbers of sodium ions rush in during the initial phase of a nerve action potential.

Answer 39

ANSWER: E

COMMENTS: This patient has clinical findings associated with hypocalcemia.

Specific transmembrane proteins provide hydrophilic paths for the ions (primarily Na+, K+, Ca2+, and Cl−) involved in electrical signaling.

The amino acid sequence in specific regions of these proteins determines the selectivity for ions.

The lipid component of the plasma membrane provides the capability of storing electric charge (capacitance), and the protein component provides the capability of resisting electric charge (resistance).

Establishment and maintenance of a resting cell membrane potential require the separation of charge maintained by membrane capacitance, selective permeability of the plasma membrane, concentration gradients (intracellular versus extracellular) of the permeant ions, and impermeant intracellular anions.

Active pumping by the sodium [sodium- potassium adenosine triphosphatase (Na+, K+-ATPase)] or calcium pumps generally maintains the ionic concentration gradients.

Action potentials are regenerative (self-sustaining) transient depolarizations caused by the activation of voltage-sensitive sodium and potassium channels.

Only a small volume of Na+ is necessary to initiate an action potential.

In fact, the amount of Na+ that flows into a typical nerve cell during an action potential would change the intracellular Na+ concentration by only a few parts per million.

Question 40

Which cell junction acts as a transmembrane linkage without an intracellular communication function?

A. Tight junction
B. Gap junction
C. Desmosome
D. Connexon
E. All of the above junctions have an intracellular communication function

Answer 40

ANSWER: C

COMMENTS: Any patient undergoing abdominal surgery will sustain a certain amount of capillary leakage.

A proposed mechanism involves increased release of nitric oxide (NO), which causes vasodilation in precapillary cells and vasoconstriction in postcapillary cells, ultimately resulting in increased third-spacing of fluids.

There are three major types of cell junctions: gap junctions, desmosomes, and tight junctions.

Gap junctions are the most common and function primarily in intercellular communication and cellular adhesion. The connection between cells maintained by a gap junction is not particularly stable; it depends on a variety of complexes on each cell but not on connecting proteins (hence the term gap). Gap junctions serve as a pathway of permeability between cells for many different molecules weighing up to 1000 daltons.

Connexons are protein assemblies formed by six identical protein subunits. They span the intercellular gap of the lipid bilayer to form an aqueous channel connecting the bilayers.

Desmosomes function as cellular adhesion points but do not provide a pathway of communication. They are linked by filaments that function as transmembrane linkers, but desmosomes are not points of true cell fusion.

Tight junctions, in contrast, are true points of cell fusion and are impermeable barriers. They prevent leakage of molecules across the epithelium in either direction. They also limit the movement of membrane proteins within the lipid bilayer of the plasma membrane and therefore maintain cells in a differentiated polar state.

Question 41

A 42-year-old woman with a history of end-stage renal disease is being evaluated for cadaveric renal transplantation. Which of the following statements regarding cell surface antigens is true?

A. Cell surface antigens are generally glycoproteins or glycolipids.

B. Histocompatibility antigens are not cell surface antigens.

C. ABO antigens are glycoproteins.

D. ABO antibodies are present at birth.

E. Human leukocyte antigen (HLA) has an extracellular hydrophobic region and an intracellular hydrophilic region.

Answer 41

ANSWER: A

COMMENTS: Cell surface antigens are generally glycoproteins or glycolipids that are anchored to either a protein or a lipid. Common examples include the ABO blood group antigens and the histocompatibility antigens.

Antigens of the ABO system are glycolipids whose oligosaccharide portions are responsible for the antigenic properties.

The structures of the blood group oligosaccharides occur commonly in nature and lead to the stimulation needed to produce anti-A or anti-B antibodies after a few months of life.

HLA antigens are two-chain glycoproteins that are anchored in the cell membrane at the carboxyl terminal. These antigens contain an extracellular hydrophilic region, a transmembrane hydrophobic region, and an intracellular hydrophilicregion. This transmembrane structure allows extracellular signals to be transmitted to the interior of the cell.

Question 42

Regarding chemical messengers, which statement is true?

A. They depend on cell surface–bound proteins to exert their effect.

B. They are limited to intracellular receptors to exert their effect.

C. First messengers bind directly to DNA to begin the protein synthesis process.

D. Extracellular ligands are termed the “second messengers.”

E. Extracellular ligands are termed the “first messengers.”

Answer 42

ANSWER: E

COMMENTS: Chemical messengers can influence intracellular physiology via several mechanisms.

Some ligands, such as acetylcholine (binding to the nicotinic cholinergic receptor) or norepinephrine (binding to the potassium channel in cardiac muscle), directly bind to ion channels in the cell membrane to alter their conductance.

Some lipid-soluble messengers, such as steroid and thyroid hormones, enter the cell and bind to nuclear or cytoplasmic receptors, which then bind to DNA to increase transcription of selected mRNA.

Many other extracellular messengers bind to the extracellular portion of transmembrane receptor proteins to trigger the release of intracellular mediators.

The extracellular ligands are termed as the “first messenger,” whereas the intracellular mediators are “second messengers.” Examples of second messengers include IP3, DAG, calcium, and cAMP.

Question 43

A 67-year-old man undergoes revascularization of his right lower extremity after sustaining thrombosis secondary to a popliteal artery aneurysm. Shortly after surgery, a compartment syndrome of the affected limb develops and is attributed to reperfusion injury. Research suggests that ER stress may be responsible for apoptosis after ischemia. Which of the following statements regarding the ER is not true?

A. Rough ER is a primary site of lipid synthesis.

B. Smooth ER plays an important role in the metabolism of drugs.

C. Ribosomes attached to the rough ER manufacture proteins for use within the cell.

D. SR is found mainly in epithelial cells.

E. SR plays an important role in gluconeogenesis.

Answer 43

ANSWER: B

COMMENTS: The ER is part of a network that includes mitochondria, lysosomes, microbodies, the Golgi complex, and the nuclear envelope.

This network forms an intracellular circulatory system that allows vital substrates to reach the interior of the cell for transportation and assembly.

There are two types of ER. Rough ER is coated with ribosomes and functions as the site of synthesis of membrane and secreted proteins.

Other ribosomes that circulate freely in the cytoplasm synthesize proteins destined to remain within the cell.

Smooth ER plays a major role in metabolic processes, including the synthesis of lipids and steroids, metabolism of carbohydrates (especially gluconeogenesis), drug detoxification, and molecular conjugation.

Smooth ER contains the enzyme glucose-6-phosphatase, which converts glucose-6-phosphate to glucose during gluconeogenesis.

Cells that synthesize large amounts of protein for export have abundant rough ER, whereas cells that produce steroids (e.g., those in the adrenal cortex) generally have smoother ER.

The smooth ER is continuous with the nuclear envelope. The SR is a distinct type of smooth ER found in striated and smooth muscles. The SR contains large stores of calcium, which it sequesters and then releases when the cell is stimulated.

The release of calcium from the SR plays a major role in excitation–contraction coupling, which allows muscle cells to convert an electric stimulus to a mechanical response.

Question 44

Which of the following statements regarding lysosomes is true?

A. Primary lysosomes usually contain extracellular material targeted for digestion.

B. Lysosomal enzymes work effectively in the acidic pH of the cytoplasm.

C. Serum levels of lysosomal acid phosphatases may have prognostic value in diseases such as prostate cancer.

D. Lysosomal storage diseases such as Tay-Sachs result from unregulated activity of lysosomal enzymes.

E. To better isolate their hydrolytic enzymes, lysosomes are resistant to fusion with other cell membranes.

Answer 44

ANSWER: C

COMMENTS: Lysosomes are membrane-bound organelles that contain acid hydrolases.

Heterolysosomes are involved in the endocytosis and digestion of extracellular material, whereas autolysosomes are involved in digestion of the cell’s own intracellular material.

Primary lysosomes are formed by the addition of hydrolytic enzymes (from the rough ER) to endosomes from the Golgi complex.

Combining a primary lysosome with a phagosome creates a phagolysosome. Lysosomal enzymes are hydrolases that are resistant to autolysis.

They function best in the acidic milieu of the lysosome; the slightly alkaline pH of the surrounding cytosol helps protect the cell from injury if the lysosome leaks.

Acid phosphatase is a marker enzyme for lysosomes. Different forms of acid phosphatases are found in lysosomes from various organs, and serum levels may be indicative of specific diseases (for example, prostatic acid phosphatase may have prognostic significance in prostate cancer).

One of the distinguishing characteristics of lysosomal membranes is their ability to fuse with other cell membranes.

Lysosomal membranes have a high proportion of lipids in a micellar configuration, primarily because of the presence of the phospholipid lysolecithin. This increased micellar configuration facilitates fusion of the lysosome membrane with the phagosome membrane for digestion and with the plasma membrane for secretion.

Steroids are thought to work partially by stabilizing lysosomal membranes, thereby inhibiting membrane fusion and enzyme release.

Lysosomes may engage in autophagocytosis, which is thought to be important for cell turnover, cell remodeling, and tissue changes.

Several lysosomal storage diseases, such as Tay-Sachs, Gaucher, and Pompe disease, are caused by inactive or missing lysosomal digestive proteins. These genetic diseases lead to the accumulation of normally degraded substrates within the cell.

Question 45

A 56-year-old man is transferred from the county jail with complaints of hemoptysis, fever, and chills. The patient had undergone left lower lobectomy 6 years ago for an isolated lung nodule. Chest radiography on admission shows a lesion in the left upper lobe that is concerning for tuberculosis. The cell wall of Mycobacterium tuberculosis prevents lysosomes from fusing with phagosomes, which contributes to its tendency to lead to granuloma formation. Which of the following statements regarding endocytosis is not true?

A. Phagocytosis refers to engulfment of particulate matter.

B. Pinocytosis refers to the engulfment of soluble material.

C. Only specialized cells of the immune system are capable of endocytosis.

D. Opsonins increase the likelihood of phagocytosis by binding to the antigen.

E. Antibodies and complement fragments can serve as opsonins

Answer 45

ANSWER: C
COMMENTS: All cells are capable of endocytosis, which is the process of internalizing extracellular molecules by engulfing the molecule within the cell membrane.

Pinocytosis (cell drinking) is the engulfment of soluble material. Phagocytosis (cell eating) is the process by which cells ingest solids. For cells of the immune system, such as macrophages, dendritic cells, and polymorphonuclear leukocytes, phagocytosis is particularly important in recognizing and com- bating pathogens.

In phagocytosis the cell membrane surrounding the engulfed material pinches off and forms a vesicle called phagosome.

The phagosome maintains the material separate from the cytosol of the cell. The phagosome fuses with a lysosome, which leads to degradation of the engulfed material. Degradation can be oxygen dependent (by the production of reactive oxygen species) or oxygen independent (generally by proteolytic enzymes and cationic proteins).

Typically, both the target (antigen) and the phagocyte are negatively charged. This limits their ability to come into close proximity.

Opsonins are molecules that act to enhance phagocytosis. Opsonization occurs when antigens are bound by antibody or complement molecules (or both).

Phagocytic cells express recep- tors (Fc, CR1) that bind opsonin molecules (antibody, C3b), which greatly increases the affinity of the phagocyte for the antigen. Phagocytosis is an unlikely event if the antigen is not opsonized.

Question 46

For tumors with a high mitotic index indicative of active growth, which portion of the cell cycle in the actively dividing cells is most sensitive to ionizing radiation?

A. S phase 
B. M phase 
C. G1 phase
D. G2 phase
E. All phases are equally radiosensitive.

Answer 46

ANSWER: B

COMMENTS: The primary mechanism by which ionizing radiation induces cell death is direct or indirect injury to DNA. Ionizing radiation can cause lethal damage (damage that cannot be repaired; for example, most double-strand DNA breaks) or sublethal damage (damage that can be repaired if conditions are correct; for example, most single-strand DNA breaks).

Factors that increase the cell’s ability to repair damage make it less sensitive to ionizing radiation.

The cell division cycle is divided into four distinct phases.

Replication of DNA occurs in the synthesis (S) phase, whereas nuclear division and cell fission occur in the mitotic (M) phase.

The intervals between these two phases are called the gap (G) phases.

Cells in the M phase (mitosis) have the least capability to repair sublethal damage and hence are the most radiation sensitive.

Cells in the S phase have the most capability of repairing damage and consequently are the most radiation resistant.

Resting cells (G0) are less sensitive to radiation injury than cells that are actively dividing (and proceeding through the cell cycle).

Cancer cells are generally less differentiated (with less ability to repair DNA damage) and more rapidly dividing than normal tissue.

The fact that tumor cells are usually more sensitive to radiation than the surrounding normal tissue is an important determinant of the utility of radiation therapy.

Question 47

Which of the following statements regarding oxidative phosphorylation and mitochondria is true?

A. Glycoproteins are transported into the mitochondrial matrix to facilitate oxidative phosphorylation.

B. The citric acid cycle takes place within the inner mitochondrial membrane.

C. Oxidative phosphorylation via ATP synthase converts adenosine diphosphate (ADP) to ATP.

D. Electrochemical (proton) gradients provide the energy to power chemosmotic production of ATP.

E. Mitochondrial DNA is almost exclusively paternally derived.

Answer 47

ANSWER: D

COMMENTS: Metabolic substrates such as fats, proteins, and glycoproteins are converted to fatty acids and pyruvate and transported into mitochondria.

Within the mitochondrial matrix, they are metabolized by the citric acid (Krebs) cycle to produce the reduced forms of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2).

The reducing power of these substrates fuels transfer of electrons from electron donors to receptors as oxidative phosphorylation.

The resultant high-energy electrons pass along the electron transport chain and release the energy used to move protons across the inner mitochondrial membrane to generate potential energy in the form of electrical and pH gradients.

ATP synthase uses the energy obtained from allowing protons to flow down this gradient to synthesize ATP from ADP. This process is called chemosmosis.

Three ATP molecules are generated for each mole of oxygen consumed.

Mitochondrial DNA is transmitted only from the mother because sperm contains few mitochondria.

During sepsis, inhibited mitochondrial function as a result of hypoxia or other mediators of sepsis has been postulated to contribute to organ injury through accelerated oxidant production and thus promotion of cell death.

Question 48

A 26-year-old with a history of type 2 neurofibromatosis is scheduled to undergo resection of an acoustic neuroma. The NF2 gene is located on the long arm of chromosome 22. Which of the following statements regarding chromosomes is not true?

A. The nucleus contains the entire cellular DNA.

B. Histones compact and organize the DNA strands.

C. Interactions between DNA and proteins expose specific genes and control their expression.

D. During mitosis, the spindle apparatus attaches to the chromosome at the centromere.

E. Telomeres maintain chromosomal length through the replication cycles.

Answer 48

ANSWER: A

COMMENTS: Chromosomes are formed by the combination of double-stranded helical DNA with histones and other proteins.

The interactions between DNA and proteins stabilize the chromosomal structure. Most cellular DNA is located in the nucleus, although a small portion is found in the mitochondria.

Each chromosomal double helix contains approximately 108 base pairs.

There are several levels of organizational restructuring, from DNA and histones binding to form chromatin all the way to the complex folded structure of the chromosome itself.

To express a gene, that portion of the chromosome must be unfolded and unwrapped to expose the DNA double helix.

Gene expression is regulated by the binding of nonchromosomal proteins, called transcription factors, to specific regions of the DNA (enhancer and promoter sequences).

Several distinct regions of chromosomes are identifiable: the origins of replication (sites of initiation of DNA synthesis), the centromere (site of spindle attachment during mitosis), and telomeres (specialized end structures that maintain the length of the chromosome through replication cycles).

Question 49

Which enzyme is responsible for the catalysis of deoxynucleoside triphosphates into DNA?

A. DNA helicase

B. DNA ligase

C. DNA polymerase

D. DNA primase

E. All of the above

Answer 49

ANSWER: C

COMMENTS: DNA polymerases are enzymes that catalyze the assembly of deoxynucleoside triphosphates into DNA.

There are several types of DNA polymerases.

DNA polymerase III promotes DNA elongation by nucleotide linkage, whereas

DNA polymerase I functions to fill gaps and repair DNA.

DNA helicase is the enzyme involved in unwinding the double-stranded DNA into individual strands before replication, transcription, or repair.

DNA primase catalyzes the formation of RNA primers used to initiate DNA synthesis.

DNA ligase joins the DNA fragments generated by the degradation of RNA primers.

Question 50

Which of the ff regarding protein synthesis is not true?

A. Transcription of messenger RNA occurs in the nucleus.

B. Messenger RNA moves from the nucleus to the cyto- plasm and attaches to free ribosomes in the cytoplasm.

C. The enzyme RNA polymerase catalyzes the transcription of messenger RNA from DNA.

D. Introns are placed into the DNA transcript by splicing.

E. Posttranslational processing includes glycosylation and enzymatic cleavage.

Answer 50

ANSWER: D

COMMENTS: The sequence of nucleotides in DNA determines the amino acid sequence of the protein. Protein synthesis involves

(1) transcription of messenger RNA from the gene that codes for the protein,
(2) translation of the messenger RNA into a protein, and
(3) posttranslational processing of the protein, which may involve enzymatic cleavage or glycosylation of the protein.

Transcription takes place in the nucleus, whereas translation and post- translational processing occur in the rough ER, Golgi complex, or free ribosomes in the cytoplasm.

Transcription of messenger RNA from DNA occurs by the assembly of complementary base pairs on the DNA template one nucleotide at a time. This step is catalyzed by the enzyme RNA polymerase.

Eukaryotic genes are interrupted by noncoding regions called introns. Introns are removed from the RNA transcript by splicing.

The resulting messenger RNA is moved to the cytoplasm in which it binds to ribosomes to begin translation.

The initial step in protein synthesis is attachment of the messenger RNA to a ribosome that is preloaded with transfer RNA that recognizes the start codon (three bases) AUG and thus sets the reading frame for the translation.

Subsequent binding of aminoacyl–transfer RNA to the ribosomes that match the three-nucleotide codons specifying each amino acid results in peptide synthesis as the ribosome moves along the messenger RNA molecule.

The first portion of the protein that is synthesized is an amino-terminal leader called the signal peptide. At this stage, the ribosome becomes attached to the rough ER.

As translation continues, the signal peptide is inserted into the rough ER membrane by another transmembrane protein and later cleaved as the peptide elongates.

Question 51

Which of the following methods is most useful for determining the RNA content of a sample?

A. Southern blotting
B. Northern blotting
C. Western blotting
D. PCR
E. None of the above

Answer 51

ANSWER: B

COMMENTS: Blotting is a method used to study macromolecules (DNA, RNA, or proteins) separated by gel electrophoresis (usually by size) and transferred onto a carrier (technically, the transfer is the “blot”).

The macromolecules can then be visualized by specific probes or staining methods. A Southern blot is used for detection of specific DNA sequences. A Northern blot performs the same function but for RNA or mRNA samples.

A Western blot is used to detect specific proteins in a sample, with an antibody to the protein of interest being used as a probe.

An Eastern blot is a modification of the Western blot technique that is used to detect posttranslational modification of proteins.

There are several other modifications of the technique; for example, Southwestern blotting is used to detect DNA-binding proteins.

The origin of the nomenclature is derived from the Southern blot, which is named after its inventor biologist Edwin Southern.

Question 52

The three phases of wound healing, in order, are:

A. Inflammation, proliferation, and maturation
B. Inflammation, proliferation, and contraction
C. Eschar formation, inflammation, and maturation
D. Fibrous exudate, granulation, and epithelialization
E. Coagulation, granulation, and epithelialization

Answer 52

ANSWER: A

COMMENTS: Wound healing is broken down into three phases: inflammation, proliferation, and maturation.

There are many events associated with these phases, and taken together, they describe a continuous process where many events occur simultaneously.

The inflammatory phase starts immediately after the injury occurs and lasts up to 72 h. After the injury, there is a transient period (about 10 min) of vasoconstriction followed by active vasodilation.

These events are mediated by substances released secondary to the local tissue injury.

Vasoactive components such as histamine cause brief periods of vasodilation and increased vascular permeability.

The kinins (bradykinin and kallidin) are released by the enzymatic action of kallikrein, which is formed after activation of the coagulation cascade.

These components, in addition to those of the complement system, stimulate the release of prostaglandins (particularly PGE1 and PGE2), which work in concert to maintain more prolonged vessel permeability not only of capillaries but also of larger vessels.

In addition, these substances, particularly the complement component C5a and platelet-derived factors such as PDGF, act as chemotactic stimuli for neutrophils to enter the wound.

Although neutrophils can phagocytize bacteria from a wound, the results of studies involving clean wound healing show that healing can proceed normally without them.

Monocytes, however, must be present for normal wound healing because in addition to their role in phagocytosis, they are required to trigger a normal fibroblast response.

The later phases of wound healing include the prolifera- tive or regenerative phase and the remodeling phase. The proliferative phase is marked by the appearance of fibroblasts in the wound, which leads to the formation of granulation tissue.

The remodeling (maturation) phase involves an increase in wound strength secondary to collagen remodeling and lasts up to 1 year after the initial injury. The three main phases of wound healing may occur sequentially or simultaneously.

Question 53

Which of the following statements regarding wound healing is true?

A. Granulation tissue results from the cross-linking of coagulation debris.

B. Fibroblasts migrate to the acute wound after the appear- ance of granulation tissue.

C. Myoepithelial cell–derived growth factors cause fibroblast differentiation.

D. It is during the proliferative phase that the scaffolding for tissue repair is laid.

E. Mucopolysaccharide levels peak 6 weeks after injury.

Answer 53

ANSWER: D

COMMENTS: After the acute effects of inflammation begin to resolve, the proliferative phase of healing begins. It is during this phase of wound healing that the scaffolding for tissue repair is created because of angiogenesis, fibroplasia, and epithelialization.

The formation of granulation tissue characterizes this phase. Granulation tissue is composed of a capillary bed; fibroblasts; macro- phages; and loosely arranged hyaluronic acid, collagen, and fibronectin.

The collagen in the granulation tissue is produced by fibroblasts. The fibroblasts themselves dedifferentiate from nearby mesenchymal cells.

The time taken by these cells to become collagen-producing fibroblasts is 3–5 days. This period is known as the lag phase.

Tensile strength correlates with the total collagen content for approximately the first 3 weeks of wound healing.

At 3 weeks, the tensile strength of the skin is 30% of the normal. It plateaus at about 6 weeks.

Simultaneously, macrophages and platelets produce cytokines and growth factors that stimulate fibroblast production.

Collagen synthesis peaks at 4 weeks and then enters a phase of collagen maturation that can continue for months.

During the maturation phase, glycoprotein and mucopolysaccharide levels decrease and new capillaries regress and disappear.

Question 54

How does von Willebrand factor VIII affect coagulation
during the inflammatory phase of wound healing?

A. Von Willebrand factor causes platelets to adhere to intact endothelium.

B. Integrin receptors require von Willebrand factor as a coenzyme.

C. Von Willebrand factor stimulates megakaryocytes to produce platelets.

D. Platelet-collagen contact requires von Willebrand factor VIII.

E. Von Willebrand factor VIII facilitates collagen cross-linking.

Answer 54

ANSWER: D

COMMENTS: Platelets delivered to the wound perform several acts that result in platelet plug formation. The first act is adherence to damaged endothelium. This is mediated by a number of platelet and integrin receptors. Platelet activation requires contact with exposed type IV and V collagen from the damaged capillary endothelium. This initial contact requires von Willebrand factor VIII. The factor is synthesized in megakaryocytes and endothelial cells.

Question 55

Regarding polymorphonucleocytes (PMN) and macrophages, which statement is true?

A. PMNs are essential for wound healing.

B. Macrophages are essential for wound healing.

C. Both PMNs and macrophages are essential for wound healing.

D. M1 macrophages predominate in the proliferative phase.

E. Macrophages are phenotypically stable.

Answer 55

ANSWER: B

COMMENTS: PMNs mediate wound inflammation but are not essential for wound healing. Macrophages are able to replace their antimicrobial role. Sterile wounds heal normally without PMNs. However, macrophages are crucial to wound healing. They appear 24 to 48 h after injury and are derived from migrating monocytes initially attracted to the wound.

The macrophage exhibits two different phenotypes, and they are differentiated by their method of activation.

A macrophage stimulated by lipopolysaccharide INF gamma becomes an M1 macrophage. These macrophages release TMF-alpha, NO, and interleu- kin (IL)-6.

M2 macrophages are activated by IL-4 and IL-13; they suppress inflammatory reactions and play a role in wound healing and angiogenesis.

In the inflammatory phase of wound healing, M1 macrophages predominate.

In the proliferative phase, M2 macrophages predominate.

Question 56

Acute vs. chronic wounds?

Answer 56

Acute: 3-4 weeks
Chronic: beyond 4-6 weeks

Question 57

Tetanus prone vs. non-tetanus prone wounds?

Answer 57

Tetanus prone:
>6h
Stellate wounds, avulsion, abrasion
>1cm
Missile, crush, burn, frostbite
\+signs of infection
\+devitalized tissue
\+contaminants

Non-tetanus prone:
6h or less
Linear
1cm or less
Sharp surface
No signs of infection
No devitalized tissue
No contaminants

Question 58

Class I (Clean) wounds?

Answer 58

Uninfected operative wound in which no inflammation is encountered and the respiratory, alimentary, genital or uninfected urinary tract is not entered.

Closed primarily and drained as necessary with closed drainage.

Hernia repair, breast biopsy
1-2% infection rate

Question 59

Class II (Clean-contaminated) wounds?

Answer 59

An operative wound in which the respiratory, alimentary, genital or urinary tracts are entered under controlled conditions and without unusual contamination.

Cholecystectomy, elective GI surgery (not colon), colorectal surgery
2.1 - 1.4%

Question 60

Class III (contaminated) wounds?

Answer 60

Open fresh accidental wounds. Operations with major breaks in sterile technique (eg open cardiac massage) or gross spillage from the GI tract and incisions in which acute nonpurulent inflammation is encountered are included in this category.

Penetrating abdominal trauma
Large tissue injury
Enterotomy during bowel obstruction

15-30% infection rate

Question 61

Class IV (dirty, infected) wounds?

Answer 61

Old traumatic wounds with retained devitalized tissue and those that involve existing clinical infection or perforated viscera

Perforated diverticulitis
Necrotizing soft tissue infections

> 30%

Question 62

Normal phases of Wound healing?

Answer 62

1) Hemostasis and Inflammation
- Release of chemotactic factors from wound site

2) Proliferation (Days 4-12)
- Tissue continuity is reestablished
- Fibroblasts and endothelial cells are the last cell populations to infiltrate the healing wound
- Strongest chemotactic factor for fibroblasts: PDGF
- Upon entering the wound environment, recruited fibroblasts first need to proliferate, and then become activated to carry out their primary function of matrix synthesis remodeling

3) Maturation and Remodeling
- Begins during the fibroblastic phase
- Reorganization of previously synthesized collagen
- Collagen is broken down by matrix metalloproteases, and net wound collagen content is the result of a balance between collagenolysis and collagen synthesis.

4) Epithelialization
- Proliferation and migration of epithelial cells adjacent to the wound
- Process begins within 1 day of injury and is seen as thickening of the epidermis at the Wound edge.

Question 63

First infiltrating cells to enter the wound site?

Answer 63

PMNs (peak at 24-48h)

Question 64

Achieve significant numbers by 48-96h post injury and remain present until wound healing is complete?

Answer 64

Macrophages

Question 65

Peak at 1 week post injury, and bridge the transition from the inflammatory to the proliferative stage of wound healing?

Answer 65

T lymphocytes

Also exert a downregulating effect on fibroblast collagen synthesis by cell-associated interferon-gamma, TNF-alpha and IL-1