Denice S. Feig MD, MSc, FRCPC

• Associate Professor
• Department of Medicine
• University of Toronto
• Head, Diabetes in Pregnancy Program
• Division of Endocrinology
• Mount Sinai Hospital
• Toronto, Ontario, Canada

All of the latter patients had neurocutaneous melanosis and large/giant congenital melanocytic nevi in a posterior axial location; the median age at diagnosis was 3 years (range: 1 month to 50 years; average age: 11 hiv infection essay 200mg molnupiravir with visa. An additional 10 patients presented with metastatic melanoma with an unknown primary hiv infection rates in the us molnupiravir 200mg otc. A study based on a database of 1008 patients with large/giant congenital melanocytic nevi or multiple medium-sized congenital melanocytic nevi found a significantly lower risk than in previous publications: 2 hiv infection and aids an overview purchase molnupiravir online now. More recently hiv infection wbc count order 200mg molnupiravir mastercard, a comprehensive review of 14 studies that examined the development of melanoma in patients with congenital melanocytic nevi reported an overall risk of melanoma of 0 hiv infection means purchase discount molnupiravir line. When a cutaneous melanoma develops in a relatively small congenital melanocytic nevus, it appears most commonly at the dermal­ epidermal junction in a fashion similar to that of other conventional melanomas. However, cutaneous melanomas arising in larger congenital melanocytic nevi can develop within the dermis, subcutaneous fat, or even deeper, as a distinct nodule84. Rarely, other malignant tumors may arise in these lesions, including rhabdomyosarcomas, malignant peripheral nerve sheath tumors, fibrosarcomas, leiomyosarcomas, osteogenic sarcomas, and liposarcomas. Leptomeningeal melanomas can arise in patients with neurocutaneous melanosis and most commonly involve the frontal and temporal lobes. It is characteristic to observe nevus cells in a single-cell array throughout the middle or lower reticular dermis and even extending into the septa of the subcutis. Especially helpful is the presence of nevus cells surrounding (cuffing) and within the walls of blood vessels, within adnexal structures such as hair follicles and sweat glands, and within cutaneous nerves, particularly when in the lower half of the reticular dermis. Specifically, nevus cells may be found in the papillae and epithelium of hair follicles, in the sebaceous glands, in arrector pili muscles, and in the eccrine ducts of the lower dermis. There is often maturation and diminished cellularity with increasing depth within the dermis. Uncommonly, congenital melanocytic nevi may show striking neural differentiation suggesting a peripheral nerve sheath tumor such as a neurofibroma. Structures resembling Meissner corpuscles, Verocay bodies, or neuroid tubules may be observed. Neurocutaneous melanosis is defined by the proliferation of benign "melanotic cells" (a term used to avoid a more precise designation such as melanocyte or melanoblast) in the meninges. This melanosis may involve the convexities and base of the brain, the ventral surfaces of the pons and medulla, and the upper cervical and lumbosacral spinal cord. Differential Diagnosis Although large/giant congenital melanocytic nevi are quite distinctive, occasionally they are confused with plexiform neurofibromas, as the latter can have both hyperpigmentation and hypertrichosis. The differential diagnosis of small congenital nevi includes congenital smooth muscle hamartoma, atypical nevus, and melanoma. For medium-sized congenital nevi, an additional entity to consider is Becker melanosis. Of course, the possibility of melanoma exists for any clinically atypical area. The distinction between melanoma and a proliferating nodule can be difficult, but the latter tends to blend with the associated congenital nevus and has only mild atypia and occasional mitoses. Neurocutaneous melanosis and meningeal melanocytomas can also be seen in association with nevus of Ota and phakomatosis pigmentovascularis. Additional associated abnormalities Patients with large/giant congenital nevi can also have urinary tract anomalies, obstruction of orifices by the nevus. The decision to remove a congenital nevus is individualized and based on melanoma risk, age of the individual, anatomic location (especially proximity to vital structures), presence or absence of neurocutaneous melanosis, anticipated cosmetic outcome, and complexity of removal. The routine excision of uniform-appearing small and medium-sized congenital nevi no longer seems justified due to the low melanoma risk. An acceptable alternative to surgical excision is baseline photography, education, and yearly examination. The treatment of large/giant congenital nevi is more problematic, since melanoma risk is present from birth. If such large/giant nevi are to be excised, most authorities recommend delaying the procedure for at least 6 months so as to decrease the risk from general anesthesia (see Table 112. Since the prognosis of patients with symptomatic neurocutaneous melanosis is so poor, initial staged excisions of large/ giant congenital melanocytic nevi should be delayed in such individuals. In the past, dermabrasion was sometimes performed, resulting in a more lightly pigmented and less elevated congenital nevus. More recently, especially in Europe, repeat curettage performed during the first few weeks of life (when there is a cleavage plane in the upper dermis) has led to similar results. Q-switched ruby, Q-switched alexandrite) have also been used to treat congenital nevi, but recurrence of pigmentation is an issue as is persistence of nevus cells85. As mentioned previously, when melanoma supervenes in a large congenital nevus, it may involve the dermal or subcutaneous component and be difficult to detect early. Cutaneous melanoma arising in the smaller types of congenital melanocytic nevi usually begins in the epidermis and can be detected more readily. There are several lines of evidence to suggest that nevus spilus is a type of congenital melanocytic nevus86. Pathogenesis A nevus spilus often has an oval shape, but it may have a block-like configuration or follow the lines of Blaschko (see Ch. This type of nevus is thought to represent a localized "field defect" and has been likened to a garden of melanocytes in which any type of nevus can develop, simultaneously or sequentially86. A nevus spilus persists indefinitely and increased degrees of speckling over time have been documented by serial photography. There are reports of cutaneous melanoma arising within a nevus spilus88 and on occasion melanocytic dysplasia has been noted in the nevus spilus adjacent to the site of melanoma development. As with conventional congenital melanocytic nevi, the risk of melanoma may be related to size88, but it may also be related to the type of "speckles". The latter patients also have organoid nevi, which combine features of epidermal nevi and sebaceous nevi. Patients with speckled lentiginous nevi may have ipsilateral dysesthesia, muscular weakness or hyperhidrosis, a combination referred to as the "speckled lentiginous nevus syndrome". Pathology the tan macule or patch of nevus spilus is characterized by lentiginous melanocytic hyperplasia associated with elongated epidermal rete ridges. The hyperpigmented macular foci are also characterized by lentiginous melanocytic hyperplasia or junctional nevi, whereas the papular foci represent compound, dermal, blue, Spitz, and/or atypical nevi. The first hypothesis holds that all halo nevi are atypical, but this has not been supported by histologic evaluations. The second theory holds that halo nevi are the result of a host response directed against nonspecifically altered nevomelanocytes in response to a physical, chemical or other insult or perhaps result from an autoimmune pathogenesis, as in vitiligo. The basis for nevus cell destruction in halo nevi is poorly understood, but both humoral and cellular immunologic factors have been implicated. Individuals with regressing halo nevi (but not other types of conventional nevi) have antibodies directed against melanoma cells, and lymphocytes isolated from patients with halo nevi and from melanoma patients are cytotoxic to melanoma cells in culture. However, it is not known whether the preceding observations are important in the pathogenesis of halo nevi or are merely epiphenomena. While the central nevus component of an active halo nevus is usually associated with a dense mononuclear cell infiltrate, the peripheral white halo has little or no such infiltrate. Perhaps destruction of melanocytes within the depigmented zone is secondary to the diffusion of a cytotoxic factor. Erythema occasionally precedes the development of the depigmented halo, which is thought to appear over a period of weeks to months. In typical halo nevi, the central nevus often measures 3­6 mm in diameter, has smooth and well-defined borders, and has a homogeneous color. By dermoscopy, globular and/or homogeneous patterns that typify benign nevi in children and young adults are usually observed90. The development of circumscribed poliosis involving scalp hairs, eyebrows or eyelashes can be a clue to the presence of a halo nevus in these locations. Halo nevi are most typically located on the upper back, but may be found in any location. Rarely, the central nevus persists indefinitely (and the halo repigments); usually the nevus regresses over months to years, leaving a white macule. Complete repigmentation of the skin is seen in the vast majority of patients, but the process may take years to decades. A new onset of multiple halo nevi may be a sign of an ocular or cutaneous melanoma elsewhere, especially in older adults. Occasionally, halo nevi appear following immunotherapy for melanoma or administration of other medications. However, neither has an associated tan patch as a background, and agminated nevi have less variation in the types of nevi present. Treatment Because of reports of cutaneous melanoma developing within a nevus spilus, it seems advisable that patients be followed on a periodic basis (photography may be helpful). Individual pigmented lesions with atypical features or suspicious change should be evaluated histologically. Although the mean age is ~15 years, these nevi have been noted to appear from the first to the fifth decade of life89. There is no gender predilection, but those patients who develop halo nevi in general have an overall increased number of melanocytic nevi. Approximately 20% of individuals with halo nevi have vitiligo and their nevi are less often associated with atypical features. In the fully evolved stages, the central nevus is associated with a well-circumscribed, dense, somewhat band-like infiltrate of mononuclear cells, almost exclusively lymphocytes and histiocytes, which occupies the papillary dermis and penetrates the nests of nevus cells. The latter change can be so prominent that nevus cells are difficult to distinguish from surrounding lymphoid cells without special stains. While any combination of conventional nevus, blue nevus, or Spitz nevus may potentially be observed, a common combination is a conventional compound nevus plus a blue nevus. Sometimes within the dermis of a conventional nevus there is a very discrete population of enlarged, pigmented, polygonal/epithelioid melanocytes and/ or spindled melanocytes, in association with melanophages. The incidence of combined nevi has been estimated to be ~1% of all melanocytic nevi sampled for histopathologic examination. The clinical characteristics of the central melanocytic lesions determine whether a biopsy is performed, but halo nevi are exceedingly more common than halo primary melanomas, especially in adolescents. Clinical Features the clinical features are directly related to the types of nevus components present. Combined nevi may arise at any site, but they have a predilection for the head and neck region (especially those with a blue nevus component), followed by the trunk. Treatment the approach to patients with halo nevi is individualized and depends upon the clinical setting. All persons with halo nevi should be questioned regarding a personal or family history of cutaneous melanoma, atypical nevi, and vitiligo. Each halo nevus should be inspected carefully for features of an atypical melanocytic nevus or melanoma. The patient also should undergo a comprehensive skin examination for evidence of other halo nevi, atypical nevi, melanoma, or vitiligo. If no atypical features are observed, the patient should be followed with periodic skin examinations. Individuals beyond 40 years of age with new-onset halo nevi should be examined carefully for melanoma (ocular and cutaneous). Pathology the histologic features also vary depending on the types of nevi present. Recurrent nevi are most commonly observed on the trunk, followed by the head and neck region. Most of the recurrences have followed a shave excision, at an estimated rate of 10­30%. In one series, ~50% of the recurrences were noted within 6 months of the surgical procedure96. Pathogenesis the recurrence of melanocytic nevi reflects an intraepidermal proliferation of residual melanocytes, possibly originating from nearby sweat ducts, hair follicles, or intraepidermal melanocytes. Trophic factors stimulating melanocyte migration, melanocyte proliferation, or both, may be related to mechanisms of wound healing or scar formation. The dermoscopic features of persistent nevi are sometimes difficult to distinguish from melanoma. Clinical features that point to the need for a repeat biopsy include progressive enlargement, extension beyond the confines of the surgical scar, and a longer time interval before recurrence (>6 months)97. Differential Diagnosis the differential diagnosis of recurrent nevi includes the lentiginous melanocytic proliferations and the pigmented streaks due to basilar hyperpigmentation that can both develop in surgical excision scars (including those for melanoma). Additional entities to consider are traumatized nevi, recurrent atypical melanocytic nevi, and recurrent melanoma. In general, a recurrent melanocytic nevus is confined to the area of the surgical scar, appears within 6 months of surgery, and exhibits a banal histologic picture. Recurrent atypical nevi may have more disordered intraepidermal melanocytic proliferation (even a pagetoid pattern) and greater cytologic atypia than conventional recurrent nevi. Clinical features suggesting melanoma include irregular pigmentation, progressive enlargement, extension beyond the confines of the surgical scar, and a longer time interval before recurrence (>6 months). The presence of intraepidermal melanocytes extending beyond the dermal scar should be considered highly suspicious for melanoma. The epidermis usually exhibits effacement of the rete pattern and variable lentiginous or nested proliferation of melanocytes. Treatment Establishing that a previous surgical procedure has occurred is integral to the diagnosis. Review of the previous biopsy specimen is mandatory if any atypicality is noted histologically. Clinical features that point to the need for a repeat biopsy are outlined above and histopathologic findings guide the need for further re-excision. P9 Atypical melanocytic nevi with dermoscopic patterns commonly seen in benign melanocytic nevi. Additional contributing factors include genetic predisposition, mutagenic environmental events, and antitumor host response.

A multiple (10 to >300) secondary lesions hiv infection lymphadenopathy buy molnupiravir 200 mg on line, either in proximity to or distant from the primary site hiv infection rates 2015 order molnupiravir now. Up to 25% of affected individuals have concomitant mucosal disease hiv infection unprotected molnupiravir 200mg on line, and patients may have systemic symptoms such as fever and malaise hiv infection rates africa cheap 200 mg molnupiravir with mastercard. Diffuse cutaneous leishmaniasis is a rare presentation that develops in the setting of reduced cell-mediated immunity hiv transmission statistics condom 200 mg molnupiravir visa, analogous to lepromatous leprosy. Nasal infiltration and mucosal ulceration may develop due to spread from nearby skin lesions, but destruction of the nasal septum is rare. Mucocutaneous/mucosal leishmaniasis After a variable time period ranging from a few months to more than 20 years, mucocutaneous/mucosal disease develops in some patients infected with Leishmania spp. Mucosal lesions range from edema of the lips and nose to perforation of the nasal septum or (less often) the laryngeal cartilage or palate. In some patients, there is extensive loss of tissue in both the mouth and nose, causing a characteristic "tapir face" known as espundia. Anthroponotic or, less frequently, zoonotic cutaneous leishmaniasis occasionally develops into chronic lupoid leishmaniasis, which clinically and histologically (epithelioid granulomas surrounded by lymphocytes) resembles the lupus vulgaris form of cutaneous tuberculosis. The amastigotes are few in number and difficult to find in lupoid leishmaniasis, making establishment of the diagnosis more challenging. New World cutaneous leishmaniasis has a wide clinical spectrum, including plaque-like, sporotrichoid, pustular, impetigo-like, eczematoid, sarcoid-like, lupoid, erysipeloid, papulotuberous, verrucous14, disseminated, and diffuse presentations. Fever, wasting, cough, lymphadenopathy, and hepatosplenomegaly are the most common systemic findings (Table 83. There may be an abrupt onset or slow progression, and fever may be continuous or intermittent. Additional complications include enteritis, oronasal or gastrointestinal hemorrhage, pneumonia, and nephritis, which may lead to death14. Co-infection often results in an atypical clinical presentation, reduced therapeutic response, and increased mortality. Laboratory findings Globulin >30 g/l Albumin <30 g/l Anemia Leukopenia Thrombocytopenia Elevated bilirubin Elevated liver transaminases Elevated alkaline phosphatase Positive Leishmania serology Parasitologically proven Pathology Histologically, cutaneous lesions typically show ulceration, pseudoepitheliomatous hyperplasia, and a mixed inflammatory infiltrate composed of histiocytes, lymphocytes, plasma cells, and neutrophils. Over time, lesions develop an increasing number of giant cells and fewer parasites; in longstanding cutaneous leishmaniasis, tuberculoid granulomas with caseation necrosis may be observed. In the cicatricial stage, the epidermis becomes flattened and hyperpigmented in areas with dermal fibrosis. In diffuse cutaneous leishmaniasis, numerous amastigotes are present within foamy histiocytes; in contrast, the disseminated form features a primarily lymphoplasmacytic infiltrate with few amastigotes. The parasite can be detected in the lymph nodes, bone marrow, and spleen in patients with visceral leishmaniasis. This form of cutaneous leishmaniasis is most commonly seen in Sudan and India, where it occurs in 50% and 10% of patients cured of visceral leishmaniasis, respectively17. Skin findings include hypopigmented macules, malar erythema, skin-colored nodules, and verrucous papules18. Diagnosis the diagnosis of cutaneous leishmaniasis can be confirmed by demonstrating the presence of amastigotes in dermal macrophages within skin biopsy specimens, tissue impression smears (touch preparations), and smears obtained by dermal scraping or needle aspiration of skin lesions2,14,20. The histologic differential diagnosis includes other infections characterized by parasitized macrophages (see Table 77. The morphology and distribution of diffuse cutaneous leishmaniasis can mimic lepromatous leprosy; however, in the former the eyebrows are spared and the lesions are usually less infiltrative14. Treatment Factors to consider in the treatment of leishmaniasis include the region of the world in which the infection was acquired, the species of Leishmania, the site(s) and severity of the infection, and host factors such as immune status and age. The benefit of therapy needs to be balanced with the goal of minimizing drug toxicity. Without treatment, Old World cutaneous leishmaniasis typically resolves within 2­4 months (L. Indications for systemic treatment of Old World cutaneous leishmaniasis include (1) an immunocompromised host; (2) >4 lesions of substantial size. Local therapy or, if the lesions are healing spontaneously within 6 months, observation are options for patients who do not meet these criteria. Parenteral pentavalent antimonials and miltefosine are first-line systemic treatments for cutaneous and mucocutaneous/mucosal leishmaniasis, whereas liposomal amphotericin B is the treatment of choice for visceral leishmaniasis22,24. Additional interventions that have shown some efficacy for cutaneous and (in combination with other agents) mucocutaneous/mucosal leishmaniasis include heat therapy31, cryotherapy, photodynamic therapy, and oral allopurinol. Drugs or vaccines that completely prevent leishmanial infection have not yet been developed. The best form of protection is to avoid the bite of the sandfly and eliminate animal reservoirs. In this context, the delayed skin reaction test (Montenegro skin test or Leishman reaction), which uses leishmanial antigens to induce a cellmediated response, has traditionally been an important diagnostic tool. A phenolated suspension of killed promastigotes is injected intradermally, usually on the volar aspect of the forearm. The test is usually negative during the febrile phase of visceral leishmaniasis, but it often becomes positive after cure. Serologic testing is most useful for visceral and occasionally mucocutaneous disease, although it is not specific due to cross-reactivity. Organisms in this group that can produce cutaneous disease include enteric pathogens. DifferentialDiagnosis the differential diagnosis of cutaneous leishmaniasis includes persistent arthropod bite reaction, basal cell carcinoma, tuberculosis, nontuberculous mycobacterial infections, and subcutaneous mycoses; other infectious causes of lesions in a lymphocutaneous pattern are listed in Table 77. Mucocutaneous leishmaniasis can resemble paracoccidioidomycosis and tertiary syphilis. Contraception is required during administration and for 2 months after the drug is discontinued. However, there can be extraintestinal manifestations, including cutaneous involvement32. Infection is associated with poor sanitation, crowded living facilities, and lower socio-economic status. In high-income countries, risk factors include a history of travel to or residence in high-prevalence areas, institutionalization, immunosuppression, and sexual behavior (especially men having sex with men). Humans are the reservoir for the disease, and an asymptomatic carrier may excrete up to 45 million cysts a day in the stool. Transmission of amebiasis is fecal­oral via contaminated hands, water, or food and oral­anal sex. Limited evidence of efficacy; other azole antifungals that have been utilized (with variable (Pentostam), 85 mg/ml for meglumine antimonate (Glucantime). Pathogenesis Once the cyst is ingested, it makes its way to the colon, where it becomes a trophozoite. Although trophozoites can be excreted, cysts represent the primary excreted form32,33. Infection of intestinal mucosa depends upon interaction of lectins on the surface of the ameba with mucin glycoproteins on the intestinal epithelium34. The trophozoites kill target cells upon direct contact, due in part to the release of proteolytic enzymes. The trophozoites also have the capacity to destroy neutrophils, resulting in release of their intracellular contents, which further contribute to the destruction of host tissues. Multiple largeulcersontheleg ofapatientwith amebiasis Notethe extensivetissue destructionand resemblanceto pyoderma gangrenosum Courtesy, Treatment Oral metronidazole is the drug of choice for amebiasis due to E. Other medications that have been used include diloxanide, tinidazole, pentamidine, and iodoquinol23. Epidemiology At least three genera of free-living amebas cause disease in humans, including Naegleria, Acanthamoeba, and Balamuthia37. These amebas are found worldwide in the soil and (especially for the former two organisms) fresh water. Such infections may be acquired from exposure of microabrasions or open wounds in the skin to soil and water sources; encephalitis can also result from infection of the nasal/respiratory mucosa via inhalation. Naegleria fowleri infection can cause acute, fatal encephalitis but is not known to have skin manifestations. Unlike Acanthamoeba infections, which only affect immunocompromised patients, most B. Extraintestinal complications, which can occur from hematogenous spread via invasion through the gastrointestinal epithelium, include hepatic abscesses, empyema and pericardial effusions32,34. Skin involvement occurs as a result of extension of rectal amebiasis to the anus, perianal skin, or vulva; spread to the abdominal wall from a colostomy or after surgical drainage of a liver abscess; or inoculation of the penis during anal intercourse. Primary cutaneous amebiasis via external inoculation is exceedingly rare but has been reported on the face35,36. Ulcerative lesions are usually painful and somewhat oval in shape, with irregular borders and intervening areas of unaffected skin. Pathology and diagnosis Histologically, ulcerated lesions have central necrosis with adjacent pseudoepitheliomatous hyperplasia. Mixed inflammatory infiltrates are present in the dermis and can extend into the subcutaneous tissue. Within the ulcerated and necrotic areas, it is possible to identify the trophozoites of E. They have ample, finely granular eosinophilic cytoplasm, eccentric nuclei, and prominent nucleoli, and some may contain phagocytized red cells. Chronic lesions show prominent irregular epidermal hyperplasia and inflammatory infiltrates, with few organisms present. Touch and wet drop preparations from the pus may also be utilized to identify the trophozoites3. Examination of fresh stool has a low yield for demonstrating the trophozoite, and multiple stool samples must be obtained32. Once the diagnosis is established, evaluation of other body sites for involvement is recommended. However, clinically unaffected individuals have been shown to have antibodies against B. The presence of predisposing factors such as local disruption of the skin or mucosal barrier is likely required for infection. Although there is usually a single skin lesion, local "satellite" lesions or involvement of multiple sites can occur. Neurologic manifestations are similar to those in other forms of meningoencephalitis and include headache, altered mental status, cranial nerve dysfunction, and seizures; however, the symptoms may have an insidious onset and chronic course. Differential diagnosis A diagnosis of amebiasis should be considered in patients with painful anogenital ulcers. In high-income countries, a patient with colitis and necrotic cutaneous ulcers would more likely have inflammatory bowel disease-associated pyoderma gangrenosum. Verrucous lesions in the anogenital region may be confused with condylomata acuminata and squamous cell carcinoma. In the dermis of affected skin, there is a mixed granulomatous infiltrate with many giant cells, but usually few identifiable trophozoites45a. Brain imaging in patients with advanced disease reveals calcified, mass-like lesions47. Reduviid bugs feed mainly on human, animal or avian blood, but they sometimes engage in cannibalism or coprophagia, which may result in vector-to-vector transmission of T. A favorite habitat for these bugs is cracks in the walls of mud huts in poor rural areas, and they are known as kissing bugs because of their habit of biting the face of humans. Chagas disease kills approximately 10 000 people per year52, mostly in rural areas of Latin America; it represents the leading cause of parasitic death in Latin America and the third leading cause in the world. The acute form of the disease (see below) is seen more commonly in children, and, in some areas, 85% of children under the age of 10 years are infected. Chagas­Mazzadisease Africantrypanosomiasis:Africansleeping sickness Although the genus Trypanosoma consists of at least 20 species of protozoa, only two are known to cause human disease. The parasites penetrate the skin (generally via the bite wound) or mucosa (usually the conjunctiva). The latter are released when the cells rupture and then can either infect other cells or enter the bloodstream, where they become the source of infection for new vectors. The autonomic nervous system that innervates the heart and gastrointestinal tract appears to be a primary target of T. The visceral involvement seen in the chronic stage (see below) is thought to reflect neuronal damage during the acute phase. A role for autoimmunity in the chronic phase of the disease has also been hypothesized. In addition, trypomastigotes have the ability to penetrate the smooth muscle of the heart and the wall of the gastrointestinal tract53. Then, many years or even decades after the initial infection, 30% of patients develop symptoms of chronic Chagas disease55. The heart is the organ most commonly affected and the clinical manifestations include congestive heart failure, arrhythmias, and heart block53. The gastrointestinal tract is also frequently involved, leading to megacolon and megaesophagus. When this happens, the disease is often more severe than in typical cases of Chagas disease and patients may develop nodules and plaques favoring the lower extremities49,54a. Pathology Histologically, at the site of parasite entry (chagoma), there is interstitial edema and a mononuclear cell infiltrate. Within cells in the subcutaneous tissue and muscle, aggregates of amastigotes may be seen. Enlarged lymph nodes are hyperplastic and intracellular amastigotes can be observed. Because the concentration of parasites is low even in the acute stage, hemoconcentration techniques are used to enhance the yield. Xenodiagnosis represents a specific and fairly sensitive (50%) method, and it can be used to confirm a serologic diagnosis49; however, this technique is expensive and is only available in large laboratories in endemic areas.

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Pathogenesis While the pathogenesis of necrobiotic xanthogranuloma is as yet unknown hiv infection symptoms in hindi order molnupiravir 200mg without prescription, its strong association with monoclonal gammopathies has led to several hypotheses antivirus scan order molnupiravir discount. The paraprotein may act either as a primary inciting agent or as a cofactor in eliciting a giant cell granulomatous reaction antiviral therapy order molnupiravir online pills. In a review of 17 cases antiviral classification order 200 mg molnupiravir visa, there was no evidence of a monoclonal proliferation of plasma cells within the inflammatory infiltrate of skin lesions45 anti viral hand gel uk purchase molnupiravir cheap online. It has been suggested that necrobiotic xanthogranuloma and normolipemic plane xanthoma exist along a spectrum, given their shared relationship to paraproteinemia46. Pathology Classic, non-ulcerated lesions have a normal epidermis and superficial dermis. The granulomas consist of histiocytes, foam cells, lymphoid follicles, plasma cells and giant cells with zones of necrobiosis. Cholesterol clefts are found in areas of "necrobiosis" (altered collagen, in which there appears to be necrosis, loss of collagen bundle integrity, and nuclear debris). A prominent feature is the presence of both Touton giant cells and large, bizarre foreign body giant cells. These cells are found scattered within the granuloma and often at the margins of areas of necrobiosis. Clinical features Cutaneous lesions, typically multiple, have appeared in all cases. Other reported features include telangiectasias, atrophy, ulceration and scarring, with scars being common sites for the development of new lesions. The trunk, remainder of the face, and proximal extremities are also frequently involved. Approximately 50% of patients have ophthalmic manifestations, which include orbital masses, ectropion, ptosis, conjunctival lesions, keratitis and scleritis, episcleritis, anterior uveitis, and proptosis47. A hallmark feature of necrobiotic xanthogranuloma is the associated paraproteinemia, an IgG monoclonal gammopathy, which is found in at least 70% of cases. The paraproteinemia can be detected by serum protein electrophoresis and/or the more sensitive immunofixation electrophoresis. Less commonly, cryoglobulinemia and/or an underlying lymphoproliferative disorder are observed. Of the 48 patients described by Mehregan and Winkelmann44, a plasma cell dyscrasia was found in 17 patients (with eight fulfilling the criteria for multiple myeloma) and lymphoproliferative disorders in two patients. In a more recent retrospective study from the same institution, a higher percentage of patients (12 of 17 [71%]) had a monoclonal gammopathy, with three fulfilling the criteria for multiple myeloma45. Postmortem examination has demonstrated involvement of multiple organ systems, with endocardial necrobiotic xanthogranuloma found in most cases. In one series, when patients with necrobiotic xanthogranuloma developed a plasma cell dyscrasia or a lymphoproliferative disorder (10 of 26 patients), these disorders often arose after the onset of cutaneous manifestations and did not tend to be aggressive48. Subcutaneous nodules also need to be distinguished from the nodules of rheumatoid arthritis and subcutaneous granuloma annulare. However, most of these disorders can be excluded on the basis of morphology, distribution pattern, histologic features, and associated systemic manifestations (if any). Treatment No controlled clinical studies are available regarding the treatment of necrobiotic xanthogranuloma. In a retrospective study of 17 patients, low-dose corticosteroids plus chlorambucil was found to be the most effective treatment regimen45. With rare exceptions, topical and locally injected corticosteroids have been tried with minimal or no benefit; in case series, systemic corticosteroids (including pulsed high-dose dexamethasone) have resulted in improvement in some patients. A recurrence rate of ~40% was observed in one series following surgical excision of lesions48. Responses to newer therapies for multiple myeloma, including pomalidomide, bortezomib, carfilzomib and autologous hematopoietic stem cell transplant, await future studies. The clinical spectrum of disease ranges from a solitary cutaneous form to multicentric reticulohistiocytosis, a disease with both cutaneous and systemic features. Well-developed lesions demonstrate a classic histopathology consisting of mononucleated and multinucleated giant cells with a "ground glass" appearance. History Giant cell reticulohistiocytoma, an isolated cutaneous tumor sometimes referred to as a solitary reticulohistiocytoma, was first reported in 1950 by Zac51. The term multicentric reticulohistiocytosis was introduced by Goltz and Laymon52 in 1954 to define those cases with both cutaneous and systemic manifestations. Familial histiocytic dermatoarthritis, described in 1973, is a very rare variant of multicentric reticulohistiocytosis, characterized by a familial occurrence and associated glaucoma, uveitis and cataracts53. Multicentric reticulohistiocytosis is a disease characterized primarily by cutaneous and mucous membrane reticulohistiocytomas and severe arthropathy, although histiocytic infiltrates can be found in multiple organs (see below). There is an association with hyperlipidemia, a positive tuberculin skin test, systemic vasculitis, and autoimmune disease. Up to 25­30% of multicentric reticulohistiocytosis patients have reportedly had an associated malignancy, with a range of solid and hematologic malignancies55a. Cutaneous lesions range from a few millimeters to 2 cm and are skin-colored to pink, red­brown or yellow. Small papules aligned along the proximal and lateral nail folds result in a characteristic "coral bead" appearance. Approximately one-half of patients develop papules and nodules of the oral, pharyngeal, and/or nasal mucosae. Less common findings include a "leonine facies" secondary to severe facial involvement, periarticular rheumatoid-like nodules, an initial photodistribution, and secondary nail changes. A 6­8-year course of symmetric, erosive arthritis of multiple joints is common, and there is progression to arthritis mutilans in ~45% of patients. The joints of the fingers and hands, as well as the knees and wrists, are most commonly involved, although any joint may be affected. Rarely, there is histiocytic involvement of the heart, eye, lungs, thyroid, liver, kidney, muscle, salivary gland, and/or bone marrow. For most, the disease spontaneously remits within 5­10 years, although patients are often left with significant disability. Fatal disease has been rarely reported in patients with widespread systemic involvement. Well-developed lesions demonstrate a dermal infiltrate of lymphocytes and histiocytes, with occasional plasma cells and eosinophils. The multinucleated cells have nuclei arranged haphazardly, aligned at the periphery, or clustered in the center. Histopathologic findings that are more frequently observed in solitary reticulohistiocytoma, as compared to multicentric reticulohistiocytosis, include neutrophils within the infiltrate, spindle cells admixed with the polygonal cells, and a greater frequency of xanthomatous changes within the histiocytic infiltrate56. Epidemiology All forms of reticulohistiocytoses occur predominantly in Caucasian adults, with pediatric cases being exceptionally rare. Multicentric reticulohistiocytosis is uncommon, occurring most frequently in women during their fourth decade of life. Giant cell reticulohistiocytoma occurs in young adults and has no gender predilection. In one study from the 1960s, 56% of multicentric reticulohistiocytosis patients had a positive tuberculin skin test54, leading to the suggestion that mycobacteria could be a possible trigger. In addition, multicentric reticulohistiocytosis has been reported to respond to antituberculosis treatment. Others have proposed that the histiocytic response in multicentric reticulohistiocytosis is an immunologic process related to an underlying neoplastic or autoimmune disorder. Some authors view giant cell reticulohistiocytoma as synonymous with the solitary or eruptive adult form of xanthogranuloma42. Differential diagnosis the nodule of giant cell reticulohistiocytoma is not distinctive, and the clinical differential diagnosis is broad. Some examples of adult xanthogranuloma have been reported to have a similar clinical presentation, histology and immunophenotype to giant cell reticulohistiocytoma42. While the constellation of clinical and histopathologic findings will eventually lead to the correct diagnosis, several biopsies over time may be required in some patients. Clinical features Giant cell reticulohistiocytoma presents as a single, asymptomatic, yellow to red nodule. Rarely, multiple cutaneous lesions develop without any evidence of systemic disease. Systemic therapies for multicentric reticulohistiocytosis often focus on treating the symptoms of disease, and in general have not been effective in achieving remission or in altering the course of the disease. Cutaneous lesions 1628 occur in a minority of patients with systemic disease, are usually multiple, and are clinically nonspecific. Sinus histiocytosis with massive lymphadenopathy was described as a distinct entity by Rosai and Dorfman58 in 1969. However, the eponymous designation "Rosai­Dorfman disease" is more appropriate as some patients have extranodal lesions as the sole manifestation of the condition59. Epidemiology For a time, there was a repository for cases of Rosai­Dorfman disease, rather than a registry in the true sense. In 1990, the repository contained 423 patients, and by 1995, almost 600 cases had been reported60,61. Rosai­Dorfman disease has a widespread geographic distribution, although there is a higher incidence in the West Indies. The systemic form occurs most commonly in children and young adults and is more frequently seen in male patients. In 1990, an equal percentage of white and black patients, 44% of each, were in the repository60. On the other hand, the skin-limited form occurs primarily in adults and favors women. Pathogenesis the etiology of Rosai­Dorfman disease has not been identified, though a viral pathogenesis has been postulated. It has also been suggested that Rosai­Dorfman disease may be closely related to autoimmune lymphoproliferative syndrome, an inherited disorder associated with defects in Fas-mediated apoptosis (see Table 60. Mutations in this same gene also lead to the autosomal recessive disorders H syndrome (see Table 70. Pathology Rosai­Dorfman disease is a disorder whose characterization was based upon specific findings in affected lymph nodes. However, consistent and unique histopathologic and immunohistochemical findings in the skin make diagnosis possible, even in cases without lymph node involvement. Affected lymph nodes demonstrate dilated sinuses containing neutrophils, lymphocytes, plasma cells, and histiocytes with large vesicular nuclei and abundant cytoplasm. A characteristic, although not unique, feature is emperipolesis, or the taking up of intact lymphocytes and plasma cells by the histiocytes. Cutaneous lesions demonstrate a dense dermal infiltrate of histiocytes with scattered lymphocytes, plasma cells and neutrophils. Occasional findings include foamy histiocytes within dilated lymphatics, thick-walled venules with surrounding plasma cells, lymphoid aggregates, fibrosis, and multinucleate histiocytes. In Asian patients with Rosai­Dorfman disease, cutaneous lesions often demonstrate IgG4 expression within plasma cells, suggesting a link with IgG4-related disease (see Ch. Clinical features While Rosai­Dorfman disease is often an indolent, self-limited disease, a protracted course marked by remissions and exacerbations occurs in a number of patients. The characteristic clinical feature is massive, painless, bilateral cervical lymphadenopathy. However, any nodal site may be involved, unilateral involvement may occur, and an absence of lymph node involvement has been reported in multiple patients. There are multiple reports of Hodgkin and non-Hodgkin lymphomas occurring in association with, or prior to , Rosai­Dorfman disease. Of note, development of histiocytic sarcoma in a patient with autoimmune lymphoproliferative syndrome and associated Rosai­Dorfman disease was recently reported66. Immune disorders occur in approximately 15% of patients with Rosai­Dorfman disease. Anti-red blood cell autoantibodies and joint disease are the most common findings. In one analysis, 10 of 14 fatal cases were noted to have some form of immune dysfunction67. Other unfavorable prognostic signs include disseminated nodal disease or involvement of the liver, kidney or lower respiratory tract. Over 40% of patients with Rosai­Dorfman disease have at least one extranodal site of involvement. Cutaneous involvement occurs in approximately 10% of patients with the systemic form. The skin may be the only organ involved, with skin-limited disease increasingly being recognized. The diagnosis of cutaneous Rosai­Dorfman disease is based upon the combination of characteristic histologic and immunohistochemical findings. The differential diagnosis of massive lymphadenopathy includes Hodgkin lymphoma, non-Hodgkin lymphoma, chronic lymphocytic leukemia, metastases, infectious lymphadenopathies, and Kikuchi disease (a histiocytic necrotizing lymphadenitis that often affects young Asian women). Rosai­Dorfman disease is differentiated by a typical combination of clinical and laboratory findings plus confirmatory histology and immunohistochemistry. Treatment Many lesions are asymptomatic and heal spontaneously, thus not requiring treatment. Based upon case reports, improvement has been observed with thalidomide, imatinib, 2-chlorodeoxyadenosine, and clofarabine71. A review and characterization of the disorder was provided by Altman and Winkelmann73 in 1962. Mucous membrane lesions are found in 40­60% of patients, with the upper airway and oral mucosa being commonly involved. Rarer associations include monoclonal gammopathies due to plasma cell dyscrasias and thyroid disorders.

For example hiv infection rate with condom cheap 200mg molnupiravir with amex, 25% of newborn girls have a white line (linea vestibularis) in the posterior vestibule that could be confused with scar tissue produced by sexual abuse hiv infection statistics in kenya cheap 200 mg molnupiravir visa. Other conditions that are occasionally misdiagnosed as sexual abuse are listed in Table 90 hiv infection cd4 count buy molnupiravir 200 mg with amex. A summary of recommended steps in the evaluation and management of suspected child abuse is provided in Table 90 antiviral foods list buy molnupiravir in india. Legal protection is generally given to healthcare providers who make such reports in good faith antiviral drug for hiv cheap molnupiravir 200 mg with amex. When a child gives a history of sexual abuse or has physical findings highly suggestive of abuse, an immediate referral should be made to a child protective services agency. If the history and physical findings are less certain, it may be most appropriate for experienced medical personnel to make the decision of whether sexual abuse is likely and referral to child protective services is warranted, since the potential negative impact of misdiagnosis on the family structure is substantial19. Whenever feasible, any child suspected of being sexually abused should be examined by a pediatrician or gynecologist experienced in evaluating children for signs of abuse. Anogenital examination by multiple physicians should be avoided if possible, given the potential trauma this may impose on the child. Lastly, because physical signs of sexual abuse may resolve within a few days, children should be evaluated by an experienced provider as soon as possible13. When the history and/or physical findings suggest the possibility of oral, genital, or rectal contact, cultures and serologic tests to evaluate for sexually transmitted diseases are indicated. If the abuse occurred within 24 hours of the examination, samples should also be collected for forensic evidence13. Some children withdraw and develop feelings of worthlessness, helplessness, hopelessness, and depression. Others exhibit aggressive and impulsive behavior and are at risk for delinquency, substance abuse, absenteeism from school or work, adolescent pregnancy, sexual promiscuity, and prostitution. Abused children are more likely as adults to abuse their own children and spouses. In summary, the dermatologist may be the first physician to encounter the abused child, so it is important to be alert for signs of abuse, perform the appropriate documentation and testing, and report it to the proper authorities. It is often necessary to enlist the help of a primary care physician or gynecologist experienced in the evaluation of abuse. An atlas by Hobbs and Wynne20 provides additional information and color illustrations. Introduction In 1997, the International Network for the Prevention of Elder Abuse was established to address elder abuse around the world21. In most countries, both the healthcare system and legal statutes recognize the types of elder abuse listed in Table 90. Approximately one in four 1610 elders is at risk of abuse, and ~6% have experienced significant abuse in the past month21,22. Abuse also occurs in residential and nursing care facilities, and nearly one-third of such facilities have been cited for an abuse violation24. Elderly individuals living alone are more likely to be victims of financial abuse, but they are at lower risk for other forms of abuse25. Physical abuse is reported to occur more frequently in elders with dementia, especially those with a history of aggressive behavior. Social isolation has also been identified as a risk factor, with victims more likely to be isolated from friends and family other than the person with whom they are living than are non-victims21. Pathologic characteristics of perpetrators of elder abuse include mental illness, particularly depression, and alcohol abuse. Tools such as the Elder Abuse Suspicion Index have also been developed to improve physician identification of elder abuse28,28a. Unfortunately, abused elders may not always have findings clearly attributable to abuse. Conversely, older individuals may have findings that mimic abuse but which are actually a result of accidental injuries or chronic disease21,29,29a. Although direct questions about abuse are appropriate, the interviewer may prefer to begin with general questions about safety issues and the home environment. Attempts to elicit details about the nature, frequency, and provoking factors of abuse are recommended21. The physician must use considerable caution in interacting with a suspected abuser. One of the risks of confronting an alleged abuser is that access to the elderly person may be lost. If the physician deems it necessary to interview a suspected abuser, an empathetic nonjudgmental approach may be helpful21. Elder self-neglect is a related entity that occurs three times more commonly than abuse by others and is associated with a 16-fold increase in risk of death during the first year after diagnosis30. Elder self-neglect typically reflects impaired coping and decision making because of cognitive and/or functional impairments30. Management Because elder abuse is multifactorial, potential interventions are based on the context of abuse. A multidisciplinary team involving physicians, nurses, social workers, elder care attorneys, adult protection agencies and, when appropriate, law enforcement officials is helpful when dealing with elder abuse. If the abused person is competent to make medical decisions and willing to accept intervention, education regarding elder abuse can be provided, a safety plan implemented, and the patient as well as family members referred to appropriate services. In summary, dermatologists should remain vigilant in looking for physical signs of abuse in elderly patients, especially those who are dependent on caregivers. Dermatologists who encounter signs of elder abuse are responsible for initiating the evaluation process that protects these fragile members of society. A comprehensive assessment should be done, preferably by a provider who has substantial experience with the clinical and psychosocial aspects of elder abuse. Disease expression ranges from mild, sometimes asymptomatic, single-organ involvement to severe, progressive multisystem disease. Type 1 dermal dendrocytes may be involved in phagocytosis, antigen presentation, inflammation, collagen production and wound healing, while the function of type 2 dermal dendrocytes is less certain. These two types represent myeloid dendritic cells and are distinct from plasmacytoid dendritic cells. Dysfunction of these various histiocytes has led to a group of wellknown, but poorly understood, disorders. For years, many of the histiocytoses were known by numerous names, reflecting the lack of understanding and agreement regarding their origin. Electron microscopy and the development of immunohistochemical stains have since provided insight into these conditions. Of note, each group represents a spectrum of disease, with overlap between entities. This article covers the most common and several of the rarer histiocytic disorders in detail (Table 91. In addition, the rare malignant histiocytic disorders and the even rarer dendritic cell hamartomas are reviewed. In 1953, Lichtenstein1 grouped the three disorders into a single entity which he called histiocytosis X. Twenty years later, Hashimoto and Pritzker2 described the entity congenital self-healing reticulohistiocytosis. Immunologic and ultrastructural studies confirmed the relationship of the pathologic cells in histiocytosis X and congenital self-healing reticulohistiocytosis to Langerhans cells, providing a basis for the Writing Group of the Histiocyte Society, in 1987, to reclassify them as "Langerhans cell histiocytoses"3. However, an annual incidence of at least five per million children is often quoted, with the adult incidence suspected to be less than one-third that of children. Additionally, in two families with affected non-twin siblings, parental consanguinity was known in one and possible in the other. Although viral and immunologic etiologies had long been considered, it is more likely that the latter. Whether the cell of origin is an immature myeloid dendritic cell or a mature tissue-based dendritic cell remains to be determined. For historical context, the three classically described variants and the more recently recognized congenital self-healing reticulohistiocytosis are discussed here. Both groups represent a spectrum of disease, from self-resolving and skin limited to severe multi-organ involvement with significant morbidity. The major features of the rare malignant histiocytic disorders and even rarer dendritic cell hamartomas are also reviewed. It is a multisystem disease that nearly always develops prior to age 2 years, and commonly presents in children less than 1 year of age. However, only if the key functions of the organ are affected is such involvement of prognostic significance. Lung, liver, lymph node, and bone involvement commonly occur at some point during the illness. Osteolytic bone lesions are painful, usually multiple, and most frequently involve the cranium. Occasionally, the hematopoietic system can be affected, with thrombocytopenia and anemia portending a poor prognosis. Classically, Hand­Schüller­Christian disease represents the triad of diabetes insipidus, bone lesions, and exophthalmos. Typically, Hand­Schüller­ Christian disease begins between the ages of 2 and 6 years. Patients with the complete triad are rare, as exophthalmos is uncommon and often a late finding. While early cutaneous lesions are similar to those seen in Letterer­Siwe disease, older lesions can become xanthomatous. Ulcerative nodules may develop in the oral and genital areas, with premature loss of teeth possible secondary to gingival lesions. At least 80% of patients with Hand­Schüller­Christian disease develop bone lesions, the cranium being preferentially involved. The chances of reversing the diabetes insipidus with radiation or chemotherapy are remote once symptoms develop. Skin and mucous membrane lesions are rare, with a single asymptomatic granulomatous lesion of the bone the most common manifestation. The cranium is most frequently affected, though lesions can also develop within the ribs, vertebrae, pelvis, scapulae, and long bones. It presents at birth or in the first few days of life with a characteristic eruption of widespread red to purplish-brown papulonodules, which may have a vascular appearance or resemble a "blueberry muffin" rash (see Ch. Solitary papules or nodules (often eroded or ulcerated) and disseminated vesicular eruptions have also been observed. Mucous membrane lesions and systemic involvement occasionally occur, including later-onset diabetes insipidus. Diabetes insipidus can also develop and, as in children, is more likely when bony involvement of the skull is present. Severe multisystem disease, classically referred to as Letterer­Siwe disease, is rare in adults. Pulmonary involvement can be isolated or be a component of multisystem disease and it favors men who smoke cigarettes8a. Involvement of "risk organs" - hematopoietic system, liver, lungs and/or spleen substantially increases the risk of disease-related mortality. However, in individuals with single-system disease or multisystem disease that does not involve risk organs, mortality rates are very low. These cells are large, 10­15 microns in diameter, with a reniform (kidney-shaped) nucleus. Older lesions that are no longer proliferative may appear granulomatous, xanthomatous or fibrous. Older bone lesions, on the other hand, may show only xanthomatous or fibrous changes. Langerin, a transmembrane C-type lectin that serves as an endocytic receptor, is a highly specific Langerhans cell marker. Because Langerin is the major protein of Birbeck granules, Langerin immunostaining can be used as a substitute for demonstration of Birbeck granules by electron microscopy. For more extensive cutaneous disease, based upon case reports, thalidomide, azathioprine or methotrexate may be effective. However, this drug is not viewed as first-line therapy for skin-limited disease14. For those with risk organ involvement, an extended treatment regimen (12 vs 6 months) led to a lower risk of disease reactivation. Epidemiology Benign cephalic histiocytosis is rare, with ~60 cases having been described to date. The disorder typically begins by the age of 1 year and always within the first 3 years of life. Occasionally, lesions may develop on the trunk and arms, with infrequent involvement of the buttocks and thighs. The papules eventually flatten, often leaving residual hyperpigmentation that fades over time. Most children are otherwise healthy without involvement of the mucous membranes or internal organs. However, diabetes insipidus has been reported in a young girl with benign cephalic histiocytosis18. In one study, the most typical finding was a well circumscribed infiltrate of histiocytes in the superficial to mid reticular dermis16. The histiocytes can be pleomorphic or round and regular, and they are often admixed with scattered lymphocytes and sometimes a few eosinophils. Treatment Benign cephalic histiocytosis is generally a self-limiting disorder and no treatment is usually needed. However, regular examinations of all patients with benign cephalic histiocytosis is recommended, as both exacerbations of the disease and diabetes insipidus can occur. Generalized Eruptive Histiocytoma Synonyms: Eruptivehistiocytoma Generalizederuptive histiocytosis Clinical features the eruption is characterized by recurrent crops of red to brown papules. The papules are usually arranged symmetrically, and mucosal surfaces are occasionally involved.

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