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1. Cutaneous Manifestations of Internal Disease Residents Conference
Hallie McDonald, MD
August 16, 2005
2. Diabetes Mellitus According to Perez et al (3) ,approximately 30% of patients with DM develop skin lesions at some point
Overall prevalence of cutaneous disorders does not differ between type I and type II diabetics
Type I patients get more autoimmune-type lesions
Type II patients get more cutaneous infections
3. Diabetes Mellitus Cutaneous lesions usually appear after the development of DM, but may be the first presenting sign
Four major groups of skin findings
Skin diseases associated with DM (necrobiosis lipoidica and diabetic bullae)
Cutaneous manifestions of diabetic complications (neuropathic ulcers)
Skin reactions to diabetic treatment
4. Necrobiosis Lipoidica (NL) NL appears in 0.3-1.6% of diabetics (2,4)
Anywhere from 11-65% of patients with NL have DM at the time of skin dx (2,7,8)
If they do not have DM at time of dx, about 90% will develop diabetes, have abnormal glucose tolerance, or report parents with DM (2, 4)
Diabetic control has no effect on the course of NL.
5. Necrobiosis Lipoidica (NL) NL is 3x more common in women.
According to Jelinek, (9) NL appears earlier (mean age 22) in Type I diabetics than Type II (mean age 49.)
Begins as an oval, violaceous patch and expands slowly.
Advancing border is red.
Central area turns yellowish brown.
Central area atrophies and telangiectasia become evident.
13% of cases progress to ulceration
6. Necrobiosis Lipoidica (NL) Classically, NL occurs bilaterally on the pretibial or medial malleolar areas.
Spontaneous resolution occurs in 13-19% with residual scarring.
Treatment: potent topical steroids, intralesional steroids at the active border, or rarely systemic steroids
7. Necrobiosis Lipoidica (NL)
8. Necrobiosis Lipoidica (NL)
9. Necrobiosis Lipoidica (NL)
10. Necrobiosis Lipoidica (NL)
11. Necrobiosis Lipoidica (NL)
12. Granuloma Annulare (GA) Controversy surrounds the association between GA and DM.
A case-control study by Nebesio et al. (5) failed to reveal a statistically significant correlation between the two.
A retrospective study by Studer et al. (6) suggested that up to 12% of patients presenting with GA had DM.
Despite conflicting studies, it is reasonable to screen patients presenting with GA for DM.
13. Granuloma Annulare (GA) Appearance
Ring of small, firm, flesh-colored or red papules
If localized, most frequently found on lateral and dorsal surfaces of hands and feet
Disease begins with an asymptomatic, flesh-colored papule that undergoes central involution
Over months, a ring of papules grows
Can spontaneously regress without scarring
Focal degeneration of collagen in the upper and mid-dermis, palisaded histiocytes around collagen bundles, and abundant dermal mucin
14. Granuloma Annulare (GA) Treatment
If localized, best left untreated.
Can treat with intralesional steroids, if needed
If generalized, can also use dapsone, isotretinoin, freezing, cyclosporin, or PUVA.
15. Granuloma Annulare (GA)
16. Granuloma Annulare (GA)
17. Granuloma Annulare (GA)
18. Granuloma Annulare (GA)
19. Granuloma Annulare (GA)
20. Granuloma Annulare (GA)
21. Granuloma Annulare (GA)
22. Diabetic Bullae Approximately 0.5% of diabetics (2)
More common in men with long-standing DM and neuropathy
Two types have been described
More frequent, non-scarring lesions with a histologic intraepidermal split without acantholysis
Less common, occasionally hemorrhagic bullae that heal with scarring, slight atrophy, and have a histologic subepidermal split
Pathogenesis not well-understood
Could be related to trauma with reduced threshold for blister formation
Other theories include immunologic factors, disturbed catabolism of calcium, magnesium, or carbohydrates, microangiopathy, and vascular insufficiency
Painless bullae on non-inflamed base that appear suddenly
Most common on the dorsa and sides of lower legs and feet, sometimes with similar lesions on the hands and forearms
Bullae contain clear, sterile fluid
23. Diabetic Bullae Bullae tend to heal spontaneously in 2-5 weeks
Bullosis diabeticorum remains a diagnosis of exclusion with negative immunofluorescence studies, porphyrin levels, and cultures
DDx: bullous pemphigoid, epidermolysis bullosa acquisita, porphyria cutanea tarda, bullous impetigo, erythema multiforme, and coma blisters
May recur in the same or new locations
If large and symptomatic, can aspirate the fluid leaving an intact blister roof as a wound covering
24. Diabetic Bullae
25. Diabetic Bullae
26. Diabetic Bullae Histology showing a noninflammatory blister with a subepidermal and focally intraepidermal separation
27. Acanthosis Nigricans Seen in situations of insulin resistance
Besides in DM, also seen in the following:
Carcinomas, especially of the stomach
Secondary to meds (nicotinic acid, estrogen, or corticosteroids)
Other endocrine syndromes (PCOS, acromegaly, Cushings disease, hypothyroidism)
According to Cruz (12) , it may be related to insulin binding insulin-like growth factor receptors on keratinocytes and dermal fibroblasts, thus stimulating growth.
28. Acanthosis Nigricans Appearance
Hyperpigmented, velvety plaques in body folds, mostly axillae and neck
Can also present on groin, umbilicus, areolae, submammary areas, and on the hands (tripe hands)
Treatment- usually asymptomatic
Retinoic acid and salicylic acid
29. Acanthosis Nigricans
30. Acanthosis Nigricans
31. Acanthosis Nigricans
32. Skin Infections in DM Occur in 20-50% of poorly controlled diabetics (2, 4)
More common in Type II
May be related to abnormal microcirculation, hypohidrosis, PVD, neuropathy, decreased phagocytosis and killing activity, impaired leukocyte adherence, and delayed chemotaxis all seen in diabetics (2, 9, 10, 11)
33. Skin Infections in DM Fungal infections- most common
Psedudohyphae and spores on KOH prep support dx of Candida
Purulent drainage may indicate secondary bacterial infection
Because maceration and skin breaks can serve as portals of infection, tinea pedis should be treated aggressively in diabetics
Treatment includes drainage of any abscesses, keeping the digits dry, and topical antifungals (clotrimazole)
34. Candidiasis in Diabetics White, curdlike material adherent to erythematous, fissured oral commisure; angular stomatitis
35. Candidiasis in Diabetics Initial pustules on erythematous base that become eroded and confluent
36. Candidiasis in Diabetics
37. Candidiasis in Diabetics
38. Candidiasis in Diabetics
39. Candidiasis in Diabetics
40. Skin Infections in DM Bacterial Infections- can be more severe and widespread in diabetics
Malignant otitis externa
Fatal in over 50% patients (13)
Can progress to chondritis, osteomyelitis, and bacterial meningitis
Treat up to 3 months with oral quinolones but may need IV antibiotics
41. Malignant Otitis Externa in Diabetics
42. Skin Infections in DM Bacterial infections in DM
Reddish tan scaling patches of the upper inner thighs, axillae, toe web spaces, and inframammary creases
Gram positive Corynebacterium minutissimum
Identified with Woods light coral fluorescence
Treat with oral erythromycin for 5 days
43. Erythrasma in Diabetics
44. Erythrasma in Diabetics
45. Erythrasma in Diabetics
46. Woods Lamp in the Diagnosis of Erythrasma
47. Cutaneous Manifestations of Diabetic Complications: Foot Ulcers Responsible for 70% of annual lower limb amputations in the U.S.(2)
Large economic impact from medical and surgical therapy, rehab, loss of work, and mortality
Prevention is key
Daily foot inspections, appropriate footwear
Causes for ulcer formation:
Peripheral neuropathy (60-70%)
Treatment: aggressive debridement and offloading or with a contact cast
Vascular disease (15-20%)
Treatment: surgical re-vascularization
Combination of peripheral neuropathy and vascular disease (15-20%)
48. Cutaneous Reactions to Diabetic Treatment Insulin
Allergy may be local or systemic and usually occurs within the first month of therapy
Erythematous or urticarial pruritic nodules at the site of injection
Lipoatrophy can also occur
Circumscribed depressed areas of skin at the insulin injection site 6-24 months after starting insulin
More common in women and children
Pathogenesis unknown but may be related to lipolytic components of the insulin preparation, an immune complex-mediated inflammatory process with lysosomal enzyme release, cryotrauma from refrigerated insulin, or mechanical trauma from injection
Lipohypertrophy can also occur
Soft dermal nodules that resemble lipomas at sites of frequent injection
May be a response to the lipogenic action of insulin
Treat and prevent by rotating sites of injection
49. Cutaneous Reactions to Diabetic Treatment: Lipoatrophy
50. Cutaneous Reactions to Diabetic Treatment- Insulin Highly purified or recombinant insulins have a reduced allergy prevalence (0.1-0.2%) (4)
Observe the patients technique to make sure it isnt intradermal
Treatment includes substitution of a more purified insulin, discontinuation or desensitization for severe systemic rxns
51. Cutaneous Reactions to Diabetic Treatment-Oral Hypoglycemics Most rxns are associated with the first-generation sulfonylureas (chlorpropamide and tolbutamide)
1-5% of patients on these drugs will develop skin rxns during the first 2 months of treatment (2,4)
Most commonly, they present with maculopapular eruptions that resolve despite continuation of the drug
For patients of chlorpropamide, 10-30% will develop a disulfiram-like rxn of flushing, headache, tachycardia, and shortness of break after ingesting alcohol. This seems to be autosomal dominant. (2,3)
Second-generation sulfonylureas can also be associated with cutaneous rxns.
52. Hyperthyroidism and the Skin Thyroid hormone plays a pivotal role in the growth and formation of hair and sebum production.
Thyroid hormone stimulates epidermal oxygen consumption, protein synthesis, mitosis, and determination of epidermal thickness.
There is increased cutaneous blood flow and peripheral vasodilation.
53. Hyperthyroidism and the Skin Skin is usually warm, moist, and smooth
Hyperpigmentation, esp. creases of palms and soles, gingiva, and buccal mucosa
Hyperhydrosis, particularly of palms and soles
Scalp hair can be soft, fine and sometimes accompanied by non-scarring alopecia
5% of patients with hyperthyroidism have nail findings (14)
54. Plummers Nail in Hyperthyroidism
55. Scleromyxedema in Hyperthyroidism Numerous firm white, yellow, or pink papules on face, trunk, axillae, and extremities
Lesions result from accumulation of hyaluronic acid in the dermis, accompanied by large fibrocytes (14, 15)
Can be accompanied by weight loss, esophageal dysmotility, vascular dz, Raynauds phenomenon, monoclonal gammopathy, neurologic manifestations, joint dz, and myopathy (14)
Treatment of hyperthyroid state with radioactive iodine does not improve skin findings (14, 16)
56. Scleromyxedema in Hyperthyroidism
57. Scleromyxedema in Hyperthyroidism
58. Graves Disease These patients can have all of the other previously mentioned cutaneous manifestations of hyperthyroidism in addition to several unique entities
Pretibial myxedema (0.5-4% of patients)
Presentation varies from peau dorange appearance to extensive infiltration that mimics elephantitis vurrucosa nostra
Most often, bilateral, asymmetric, raised, firm plaques or nodules varying from pink to brown, sometimes with woody induration
Can appear anywhere (arms, shoulders, head)
Can treat with topical steroids, intralesional steroids, IV pulse steroids, or IVIG
Pathogenesis remains unknown, but one theory suggests pretibial fibroblasts are the target for antithyroid antibodies(14)
In support of this theory, Wu et al. (16) reported the presence of TSH and TSH receptor antibody binding in fibroblasts as well as the presence of RNA encoding the extracellular domain of the TSH receptor.
59. Pretibial Myxedema in Graves Disease Bilateral, asymmetric, raised, firm plaques or nodules varying from pink to brown, sometimes with woody induration
60. Pretibial Myxedema in Graves Disease
61. Pretibial Myxedema in Graves Disease
62. Thyroid Acropachy in Graves Disease
63. Graves Disease and Thyroid Acropachy AP radiograph of the hand demonstrates feathery periosteal bone proliferation of the diaphyses of the metacarpals and proximal phalanges
64. Hypothyroidism and the Skin Skin changes in hypothyroidism reflect a hypometabolic state and subsequent reduced core body temperature results in cutaneous vasoconstriction. (14)
Skin is cool, dry, and pale.
Pallor results from cutaneous vasoconstriction and increased deposition of water and mucopolysaccharides in the dermis, which alter the refraction of light
Hypohydrosis may lead to palmoplantar keratoderma
Carotenemia (from decreased hepatic conversion of beta carotene to Vit A) gives skin yellowish hue (14, 17)
Hair: dry, brittle, coarse; partial alopecia
Loss of hair from lateral 1/3 of eyebrows
65. Hypothyroidism Facies with Generalized Myxedema Generalized myxedema
Occurs as a result of deposition of dermal acid mucopolysaccharides (esp. hyaluronic acid and chondroitin sulfate) in the skin
Skin is non-pitting
Face: swollen lips, broad nose, macroglossia, and puffy eyelids
66. Thyroid Disease and Other Cutaneous Disease Associations Autoimmune thyroid disease has been associated with other cutaneous diseases
Alopecia areata (18)
Pemphigus vulgaris (19)
Derived from the Greek vitelius, signifying a calf's white patches
Fairly symmetric pattern of white macules with well-defined borders
Connective tissue diseases
Dermatomyositis (21) , SLE (22) , scleroderma(23)
67. Alopecia Areata Associated with Autoimmune Thyroid Disease Rapid onset of total hair loss in a sharply defined, usually round, area
Regrowth begins in 1 to 3 months and may be followed by loss in the same or other areas
68. Pemphigus foliaceus Associated with Autoimmune Thyroid Disease Pemphigus foliaceus: recurrent shallow erosions, erythema, scaling, and crusting
69. Pemphigus vulgaris Associated with Autoimmune Thyroid Disease Painful oral erosions usually precede the onset of skin blisters by weeks or months
70. Pemphigus vulgaris Associated with Autoimmune Thyroid Disease
71. Cutaneous Paraneoplastic Syndromes In 1976, Helen Ollendorff Curth set criteria that should be met before a skin disease can be called a paraneoplastic dermatosis (24,25) :
Both conditions start approximately the same time
Both conditions follow a parallel course
Neither the onset nor the course of either condition is dependent on the other
A specific tumor occurs with a specific skin manifestation
The dermatosis is not common in the general population
A high percentage of association between the two conditions is noted
Currently, only the first two criteria should be met to call a skin disease a paraneoplastic process (24, 25) .
72. Cutaneous Paraneoplastic Syndromes May be initial clue to underlying neoplasm
Can herald the recurrence of a malignancy
Necrolytic migratory erythema
Sign of Leser-Trelat
Hypertichosis lanuginosa acquisita
73. Necrolytic Migratory Erythema Glucagonoma syndrome includes glucose intolerance, weight loss, anemia, hair and nail changes, hypoaminoaciduria, psychiatric disturbances, and thromboembolic disease (24, 26)
Skin manifestation of the glucagonoma syndrome
Erythematous macules and papules, often annular or arciform, on central face, lower abdomen, perineum, groin, buttocks, and thighs
Progress to erosions secondary to epidermal necrosis
Skin disease has waxing and waning course that does not seem to follow the course of the glucagonoma
Pathophysiology is not known, but it is probably related to catabolism from increased levels of glucagon
When physician suspects this, be aggressive
75% glucagonomas are metastatic at time of diagnosis(27)
Gold standard for treatment is surgery
74. Necrolytic migratory erythema Erythematous macules and papules, often annular or arciform than can progress to erosions
75. Sign of Leser-Trelat First described in 1890 as an increase in the number of cherry angiomas in patients with cancer (28)
Now refers to an increase in number or size of seborrheic keratoses in patients with internal malignancy (24)
Most often found in patients with adenocarcinoma of the stomach or colon (28) , but also reported with hematopoietic, breast, lung, ovarian, and uterine cancers (24, 29, 30)
Can appear as early as 5 months before the dx of cancer or as late as 9.8 months after (29)
76. Sign of Leser-Trelat Pathogenesis could be due to elevated levels of growth factors, disrupted epidermal cell turnover regulation, and impeded host defense (30)
Treatment of the underlying malignancy results in involution of the SKs in about of cases (24,31)
77. Hypertrichosis lanuginosa acquisita Sudden appearance of downy, soft, nonpigmented hair on the body
Most common associated malignancy is lung followed by colorectal cancer (32)
Also has been associated with bladder, ovarian, uterine, and pancreatic cancer (24, 33)
Typically occurs on face, but also on trunk, limbs, and ears
Palms, soles, and genitals are spared
Can be associated with other signs and symptoms, including glossitis, glossodynia, diarrhea, adeopathy, and acanthosis nigricans
In some cases, the hypertrichosis resolves with treatment of the tumor (24)
78. Bazexs Syndrome Violaceous, symmetric papulosquamous plaques on the acral surfaces of ears, nose, hands, and feet
75% have nail changes including longitudinal or horizontal ridging, thickening, subungal debris, and discoloration (24)
Mostly male (93% in one study) (34)
Associated with squamous cell carcinoma of the oropharynx, larynx, lung, or esophagus
In one review, cutaneous changes preceded the diagnosis of malignancy by an average of 11 months in over 60% of patients with Bazexs syndrome (35)
79. Bazexs Syndrome Violaceous, symmetric papulosquamous plaques on the acral surfaces of ears, nose, hands, and feet
The dermatosis improves with cancer treatment and worsens as the cancer progresses (24)
Nail changes tend to persist after effective cancer treatment and resolution of other skin manifestations
80. Dermatomyositis Proximal muscle weakness, elevated CK and aldolase
Heliotrope rash, Gottrons papules, and others
Poikiloderma, periungual telangiectasia, scalp pruritis and erythema
Some factors associated with higher incidence of paraneoplastic dermatomyositis
Older age, male gender, patients that are difficult to control
Perform age-appropriate cancer screening for dermatomyositis patients
25% will develop malignancy (24, 35) , most commonly
Genital neoplasms in women (24, 36)
Respiratory tract neoplasms in men (24, 36)
81. Heliotrope Rash in Dermatomyositis Heliotrope rash (violaceous erythema) of periorbital skin
82. Gottrons papules in Dermatomyositis Flat-topped, violaceous or erythematous papules on extensor surfaces
83. Erythroderma Exfoliative dermatitis with a dramatic presentation characterized by widespread erythema and scaling of skin
Often have lymphadenopathy, headaches, malaise, photosensitivity, and chills
Pathogenesis is unknown, but may have to do with elevated cytokines and adhesion molecules causing increased epidermal turnover and exfoliation
Many potential causes, including pre-existing dermatoses, drug rxns, and malignancy.
Skin changes most commonly present before the diagnosis of malignancy is made.
According to a study by Nicolis (37) , 20 out of 24 patients with erythroderma and mycosis fungoides, Hodgkins, or other lymphomas or leukemias had skin changes up to 25 years before the dx of cancer was made.
Most often associated with lymphomas and leukemias (24, 37, 38, 39)
Also been reported with liver, lung, thyroid, and prostate cancer (38)
84. Erythroderma May begin as scattered erythematous pruritic patches that generalize with time
Palms and soles usually spared
Treat the underlying malignancy and use topical steroids.
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88. References Photo references:
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