Treatment of the Erythema and Flushing of Rosacea

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Ataxia Telangiectasia Mutated

Individuals homozygous for germline mutations in ataxia telangiectasia mutated (ATM) have ataxia telangiectasia (AT), an autosomal recessive disorder characterized by cerebellar ataxia, oculocutaneous telangiectasias, radiation hypersensitivity, and an increased incidence of malignancy (29). AT homozygotes have cancer risks 60 to 180 times greater than the general population including non-Hodgkins lymphoma (nearly 100 lifetime risk) and breast and ovarian cancer (30). Heterozygosity for germline mutations in ATM was initially hypothesized by Swift et al. to confer an increased breast cancer risk and that screening mammography, a source of ionizing radiation, could theoretically increase the penetrance of such mutations (31). An initial study supporting the hypothesis was criticized due to the exceptionally low rate of breast cancer among the controls. In addition, subsequent studies did not consistently support a link between ATM mutation heterozygosity and breast cancer...

Hereditary haemorrhagic telangiectasia

Epistaxis requiring surgery in most patients arises from arterial bleeding. However, in the case of hereditary haemorrhagic telangiectasia epistaxis is due to both arterial and capillary bleeding. Results of any form of therapy, including arterial ligation are poor. These patients usually require a combination of arterial ligation (or embolization) together with local control. It is important to cause as little mucosal damage as possible as there is always need for repeated local therapy. A proactive approach is advisable, it is much more effective to treat and cauterize potential bleeding points regularly than to tackle major epistaxis once in a while. Both the carbon dioxide (CO2) and potassium titanyl phosphate (KTP) lasers have proved useful in the management of this condition.

FIGURE 1 Linear gingival erythema Source Courtesy of the International AIDS SocietyUSA From Refs 3 4

Also known as HIV gingivitis, a fiery red linear discoloration of the gingival margin can be seen in HIV disease, even without significant plaque formation (Fig. 1). Patients complain of spontaneous bleeding or are asymptomatic. Referral to an HIV dental specialist is recommended and usually involves debridement, local care, and systemic antibiotics.

Erythema Multiforme

EM is an acute, widely distributed hypersensitivity reaction associated with circulating immune complexes that are deposited in the basement membranes of the superficial vessels of the skin and mucosa. Subsequent complement activation produces vasculitis and thrombosis, leading to tissue ischemia and necrosis of the adjacent epithelium. The intensity of the skin and mucosal reaction varies from a localized minimal erythematous FIGURE 40 Erythema multiforme. Young adult male with rapid onset of generalized oral ulceration accompanied by typical target lesions of the skin. Note the hemor-rhagic, encrusted lips, a feature frequently seen in erythema multiforme. FIGURE 40 Erythema multiforme. Young adult male with rapid onset of generalized oral ulceration accompanied by typical target lesions of the skin. Note the hemor-rhagic, encrusted lips, a feature frequently seen in erythema multiforme. response to frank epithelial necrosis. Commonly identified precipitating factors include...

DNA repair and repair fidelity in metastatic variants

The recognition and repair of DNA damage occurs before the cells enter the S-phase of the cell cycle and cells are held in the G phase until the repair process is completed. This checkpoint control is exercised by the nuclear phosphoprotein p53 whose levels increase when any damage to the DNA is sustained (see page 28). Defects in DNA damage repair are often encountered, e.g. as seen in the human autosomal recessive disorder xeroderma pigmentosum (XP), which are defective in their ability to repair u.v.-induced DNA damage (Lehmann and Nortis, 1989). Ataxia telangiectasia (AT) is another example of an autosomal recessive syndrome comprising progressive cerebellar degeneration, oculocutaneous telangiectasias and immune deficiencies. AT patients show high cancer incidence (Swift et al., 1991). Cell lines isolated from AT patients show hypersensitivity to ionising radiation and to radiomimetic agents this is believed to be due to defective DNA repair (Painter and Young, 1980). All the...

GADD genes and their regulation by p53

Zhan et al. (1995) compared the response of GADD45, wafl cipl and mdm2 to ionising radiation (IR) in a panel of human cell lines. All three genes showed similar levels of transcriptional response to IR and the response was p53-dependent radiosensitisers enhanced and caffeine inhibited GADD45 and wafl cipl induction by IR. GADD45 and wafl cipl also showed similar growth suppressive effects. In ataxia telangiectasia cells, where p53 induction by exposure to radiation is delayed, the transcription of GADD45 and wafl cipl is also delayed (Artuso et al., 1995). Wild-type p53 may also modify the expression of other negative growth regulators. The mitogenic signal provided by insulin-like growth factor-1 (IGF-1) is inhibited by IGF-binding protein 3 0GF-BP3) and it would appear that wild-type, but not mutant, p53 can induce the expression of IGF-BP3 (Buckbinder et al., 1995).

Regulation of mdm2 by p53

The oncogenic properties of mdm2 have also been attributed to p53 inactivation (Momand et al., 1992 Oliner et al., 1992 Barak et al., 1993 Finlay, 1993). mdm2 expression is itself up-regulated by p53 (Barak et al., 1993 Otto and Deppert 1993 Wu et al., 1993). The mouse mdm2 contains two promoters one of these, P,, is located upstream of the gene and the second promoter P2 occurs within the first intron. Transcription from P2 has been shown to be strongly p53-dependent, but the up-stream promoter Pi is only mildly responsive (Barak et al., 1994). The human mdm2 also contains the highly p53-responsive intronic promoter (Zauber-man et al., 1995). This activation pattern results in two distinct transcripts which translate into mdm2 proteins with different p53 binding ability (Barak et al, 1994). When there is a suboptimal induction of p53, as in ataxia telangiectasia (AT) cells, there is also a suboptimal induction of mdm2 and other proteins such as Gadd45 and p21 (wafl cipl) (Canman et...

Classic Coumarinlnduced Skin Necrosis

Classic coumarin-induced skin necrosis (CISN) is a very rare complication of oral anticoagulant therapy (Cole et al., 1988). In its classic form, it is characterized by dermal necrosis, usually in a central (nonacral) location, such as breast, abdomen, thigh, or leg, that begins 3-6 days after starting therapy with warfarin or other coumarin anticoagulants (Fig. 9). Initially, there is localized pain, induration, and erythema that progresses over hours to central purplish-black skin discoloration and blistering, ultimately evolving to well-demarcated, full-thickness necrosis involving skin and subdermal tissues. Some patients require surgical debridement. Case reports suggest that congenital deficiency of natural anticoagulant proteins, especially protein C, is sometimes a pathogenic factor (Broekmans et al., 1983 Comp, 1993).

Differential Diagnosis

Multiple diseases can present with findings similar to those seen with Adamantiades-Behget's disease and should be considered when a patient presents with recurrent oral or genital ulcers, inflammatory eye disease, or other manifestations of vasculitis. Included in the differential diagnosis are systemic lupus erythematosus (Chapter 1), seronegative spondyloarthropathies, inflammatory bowel disease (Crohn's or ulcerative colitis) (Chapter 20), herpes or other viral infections (Chapter 10), other forms of vasculitis (Chapter 8), and inflammatory skin diseases such as pemphigus vulgaris or pemphigoid lesions (Chapter 37). All patients presenting with oral and genital ulcerations should undergo testing for herpes simplex virus using culture or polymerase chain reaction methods, to ensure that viral infection is not present. Erythema nodosum observed by a physician or patient, pseudofolliculitis, or papulopustular lesions aFindings applicable only in the absence of other clinical...

Low Risk Breast Cancer Genes

A growing list of genes is associated with more moderate risks of breast cancer. The first such gene to be identified was ATM. Mutations in this gene cause the recessive condition Ataxia-Telangiectasia (A-T) (62). Studies dating back over 30 years have suggested that relatives of A-T patients were at increased risk of breast (and perhaps other) cancer (63). This was long regarded as controversial because the studies were small. However, more recent national cohort studies, and direct studies of ATM mutations in breast cancer families and controls, have confirmed that ATM mutations confer an approximately twofold risk of breast cancer (with perhaps a higher relative risk at young ages) (64-67).

Complications And Prognosis

While sarcoidosis frequently pursues an unpredictable clinical course, its prognosis may correlate with specific types of disease onset and patterns of clinical manifestations. For example, acute onset of erythema nodosum with symptomatic bilateral hilar adenopathy usually has a self-limited course, while insidious onset of disease and extrapulmonary lesions are often followed by inexorable progression of pulmonary fibrosis (30). In the head and neck, complications of sarcoidosis include hearing loss, vestibular dysfunction, chronic sinusitis, infection, decreased visual acuity and blindness, hoarseness, upper respiratory obstruction, stridor, cranial nerve palsies, and pituitary dysfunction. The complications of the persistent ocular inflammation are described above, but it should be emphasized that sarcoidosis is a significant cause of blindness in the United States.

Specific side effects Enfuvirtide T20

The typical side effect of enfuvirtide is an injection site reaction (ISR) with erythema, induration, nodules, pruritus, ecchymosis, pain and discomfort. Almost every patient is affected, most of them, however, only mildly. ISR, therefore, rarely limits treatment, and only 3 to 7 of patients discontinue therapy ( Lazzarin 2003). The practitioner and the patient have to get used to the injection technique and the management of ISR. Good injection technique (including aseptic conditions) in conjunction with rotating injection sites (see Table 1), may be most effective in minimizing the incidence and severity, as well as the incidence of associated events, including infections. The appropriate management of ISR can lessen the reaction (see Table 1, Clotet 2004, Buhk 2004). Avoid indurated or erythematous areas

Classification of Tumor Suppressor Genes

The adenomatous polyposis coli (APC) gatekeeper gene are key molecular events in the development of FAP mutations of p53 or K-ras alone are not sufficient to lead to tumorigenesis if the APC gene product is functionally normal. Other gatekeeper genes besides APC are PTEN, p53, p73, Fhit, Rb, von Hippel-Lindau, and neurofibromatosis type 1. In contrast, caretakers suppress cell growth by ensuring the fidelity of DNA through the repair of DNA damage or the prevention of genomic instability. The caretaker genes include ATM (ataxia telangiectasia mutated), ATR (ATM and Rad3-related), BRCA1, BRCA2, and mismatch-repair genes. The inactivation of caretaker genes leads to genetic instabilities that promote the mutation of all genes, including gatekeepers. Landscaper genes are genes that lead to the abnormal proliferation of normal cells. For example, mutation of a landscaper gene in patients with juvenile polyposis syndromes leads to the abnormal proliferation of stromal cells instead of...

Venous Thromboembolism

Venous thromboembolism (VTE) has long been known as a complication ofcancer. Venous thromboembolisms are usually divided into deep venous thrombosis (DVT) and pulmonary embolism (PE). When DVTs affect the proximal veins of the lower extremities they are usually treated as a PE. We discuss VTE with all brain tumor patients at the initial consultation. Mechanism of action for VTE includes, venous stasis (immobility), intimal injury, and alterations in coagulation. In brain tumor patients, Sawaya et al. (46) has shown alterations in the fibrinolytic system and an underlying coagulopathy as causes of VTE. Other associations include age, prior DVT, smoking, oral contraceptives, and obesity. During surgery, brain tumor patients often have induced dehydration and hyperosmolality that increase the VTE risk. Malignant brain tumor patients have also been shown to display an increased risk of VTE with reports of upward of 28 of patients having symptomatic events (47). At our institution we have...

Clinical Manifestations

Initially, there is cellulitis which leads to invasion of the deeper tissues. Clinically, at this stage, skin changes of erythema and edema are seen. Redness, pain, and edema progress to central patches or dusky blue discoloration within 24 to 48 hours, and these areas become gangrenous by the fourth or fifth day. Anesthesia of the involved skin is very characteristic. Progressive tissue necrosis causes an invasion by the normal flora. Continuous

Head and Neck Manifestations

Tuberculous Lymphadenitis (Scrofula). This represents the most common form of extrapulmonary TB (13), and in 80 to 90 of cases, it is the only site of infection. In HIVnegative patients, it is usually bilateral and posterior cervical in location, presenting as an erythematous, painless mass along the anterior border of the sternocleidomastoid, typically without systemic symptoms (11). The tuberculin skin test (TST) is positive in more than 75 of patients. In HIV-positive patients, multiple sites may be involved, often with mediastinal and intra-abdominal lymphadenopathy, pulmonary or other organ involvement, and systemic symptoms. The TST is often negative in these patients. Of the patients, 10 Ocular TB. TB produces various ocular syndromes, including choroidal tubercles, uveitis (Chapter 6), iritis, and episcleritis. In suspected cases, a prompt referral to an ophthalmologist should be made. TB laryngitis is highly contagious, due to the effective aerosolization of bacilli-laden...

Systemic Manifestations

Facial lesions due to conditions associated with TB have been described these include erythema induratum of Bazin, papulonecrotic tuberculids, and others. M. tuberculosis DNA has been detected in erythema induratum skin lesions by PCR, and erythema nodosum has been attributed to primary TB. Skin involvement may result from exogenous inoculation, spread from an adjacent focus to the overlying skin, or hematogenous spread, often seen in patients with AIDS and tuberculous bacteremia. Any unexplained skin lesion, particularly one with nodular or ulcerative components, may be due to TB, especially in AIDS patients and biopsy and cultures are warranted.

Side Effects Of Radiotherapy Acute Reactions

Desquamation and some degree of erythema, which are managed with local ointments. Temporary alopecia within the radiation field is a common sequela. Fatigue may be observed with radiation therapy, but is often a function of several other variables such as age, performance status, underlying medical status, and extent of brain being irradiated.

Signs and symptoms

There are often prodromal signs with headache, malaise and photophobia, accompanied only rarely by fever. The affected areas are initially hypersensitive, and then become pruritic and or painful within hours or days. Pain can precede lesions by several days. Lesions often show segmental (always unilateral ) erythema with her-petiform blisters within one or more dermatomes. Lesions ulcerate, are often hemorrhagic, and gradually dry up. They should be kept dry and clean to avoid bacterial superinfection.

Posttranslational regulation signaling of DNA damage

The main regulator of p53 protein activity is Mdm-2, a protein that binds p53 in the N-terminus (residues 17-29), conceals its transcription activation domain, redirects p53 from nucleus to cytoplasm and acts as an ubiquitin ligase to target p53 for degradation by the proteasome. The MDM2 gene is a transcriptional target of p53, thus defining a feedback loop in which p53 controls its own stability (Moll and Petrenko, 2003). The p53 Mdm-2 complex is regulated by p14Arf (Alternative Reading Frame), a 14 kD protein encoded by an alternative reading frame of CDKN2A, the gene that encodes the tumor suppressor p16 (Moore et al., 2003). The kinetics, extent and consequences of p53 activation vary according to the nature and intensity of the inducing signals. In response to ionizing radiation, activation of p53 proceeds through phosphorylation of p53 in the N-terminus by kinases involved in DNA-damage sensing, such as Atm (the product of the Ataxia Telangiectasia mutated gene) and Chk2 (a...

Signs symptoms and diagnosis

In contrast to the classical KS found in older men, in whom the tumors usually occur on the lower legs and feet, HIV-associated KS does not have a preferential pattern of localization. It can begin on any area of the skin, but may also appear on oral, genital, or ocular mucous membranes. Typical findings are initially solitary, or a few asymptomatic purple macules or nodules, which have a predilection for distribution along relaxed skin tension lines. Disease progression is variable the macules or tumors can remain unchanged for months to years, or grow rapidly within a few weeks and disseminate. Rapid growth can lead to localized pain and a yellow-green discoloration of the area around the tumor as a result of hemorrhage. Further progression of the tumor can lead to central necrosis and ulceration. The tumors may bleed easily. Plaque-like and nodular KS lesions, often become confluent and can be accompanied by massive edema. In the oral cavity, the hard palate is frequently affected....

The Evidence For Lowpenetrance Genes

Some of the familial clustering of breast cancer occur as part of specific inherited breast cancer syndromes, where disease results from single genes conferring a high risk. Several genes associated with these syndromes have been identified including BRCA1, BRCA2, PTEN, and TP53. However, the susceptibility alleles in these genes are rare in the population and they account for a small minority of the inherited component of cancer. Highly penetrant variants in the breast cancer susceptibility genes BRCA1 and BRCA2 account for less than 20 of the genetic risk of breast cancer with other rarer high-penetrance genes such as TP53, ataxia telangiectasia-mutated (ATM), and PTEN counting for less than 5 (10). Other BRCA1 2-like genes are unlikely to exist as the majority of multiple case families can be accounted for by BRCA1 or BRCA2 (11) and, despite extensive research efforts, attempts to identify similar highly penetrant cancer susceptibility genes, using family based linkage studies,...

Clinical features

The majority of women present with a breast lump, which is confirmed on examination. In two-thirds of patients it is in the upper outer quadrant of the breast and characteristically is well defined, hard and with an irregular surface. The lump may be fixed to the skin or to the underlying chest wall and retraction or dimpling of the skin may be seen. The skin of the breast must be carefully examined for the presence of erythema which may indicate an inflammatory cancer (see The nipple should also be carefully examined for the presence of distortion or inversion. A nipple discharge may be present. This often contains blood and emanates from one duct. However, a variety of other nipple discharges (clear, coloured) may be present (see section on Nipple discharge). The presence of a scaly, erythematous nipple should raise the suspicion of Paget's disease of the nipple (see later).

Validity of Accelerated Aging Phenotypes

HGPS is caused by a defect in the gene LMNA, which through alternative splicing encodes both nuclear lamins A and C (Eriksson et al., 2003). Nuclear lamins play a role in maintaining chromatin organization. Less striking segmental progeroid syndromes include ataxia telangiectasia, caused by a heritable mutation of the gene ATM (ataxia telangiectasia mutated), a relay system conveying DNA damage signals to effectors (Shiloh, 2003), Cockayne syndrome and trichothiodystrophy, diseases based on defects in DNA repair and transcription (Lehmann, 2003), and Rothmund Thomson syndrome, like Werner syndrome, based on a heritable mutation in a RecQ gene (Lindor et al., 2000). There is evidence that each of these genes when defective can also lead to aging symptoms in the mouse, sometimes in combination with other gene defects (see later, and Hasty et al., 2003).

Stevensjohnson syndrome

SJS is one clinical presentation of a severe cutaneous drug reaction. Experts in the field utilize a classification in which erythema multiforme (EM), SJS, and toxic epidermal necrolysis (TEN) represent severity variants of the same process (28,29). EM-minor is usually self-limited and caused by infections. Drug-induced EM, termed EM-major, can progress into SJS or, when very severe, TEN. SJS is a bullous disorder, with ulceration, purpura, fever, and involvement of mucous membranes in more than two locations, as well as the skin. TEN is used to describe more severe SJS-like disease, with sloughing of the skin resembling a third-degree burn.

Bcl2 in p53induced apoptosis

The bcl2 and related genes are subject to regulation by the cell proliferation-related p53, which is one of the interacting pathways in the control of apoptosis. The wild-type p53 protein has a wide-ranging function, including regulation of cell cycle arrest, in a transient or sustained way, and regulation of apoptosis and cell senescence. DNA damage induces p53. Two kinases phosphorylate the suppressor protein. One of these is ATM, a 370 kDa protein, which is a member of the PI-3 kinase family. The importance of the ATM pathway is underlined by the fact that ATM is itself a suppressor protein of considerable significance in the pathogenesis of cancer being involved closely in DNA damage response and in the activation of the apoptotic process. ATM is mutated in ataxia-telangiectasia (AT) patients. AT characteristically involves progressive neuronal degeneration, enhanced radiation sensitivity and immunodeficiency. Furthermore, AT patients are predisposed to develop lymphoid tumours....

Germ Cell Tumors with Embryonal Neoplasia or Somatic Differentiated Malignancy

Are increasingly recognized.38 They may be bilateral39 and may be associated with androgen secretion and ataxia-telangiectasia. Microscopically, they are characterized by discrete aggregates of germ cells and immature cells reminiscent of Sertoli's cells and granulosa cells as cords or Call-Exner formations, defined by connective-tissue stroma. There are frequent calcifications (Figure 22-15). The most common malignancy arising in gonadoblastomas is germinoma, but teratoma, EST, and all other germ cell malignancies have been described.39,40

Vascular Disorders Leading To Platelet Dysfunction

Skin, collagen, and blood vessels are essential elements in the hemostatic system. Any abnormality, inherited or acquired, in any one of these components of the vascular system will lead to mucosal bleeding such as purpura, petechia, ecchymoses, or telangiectasia (Fig. 16.3). Tests of platelet function and numbers in these individuals will be normal. Senile purpura is a condition of aging in which skin loses its elasticity. Oftentimes, older individuals will bruise more easily and more prominently. Allergic purpura is seen in rare childhood disorders such as Henoch-Schonlein purpura, an immune complex disease that involves the skin, gastrointestinal tract, heart, and central nervous system. The purpura is often seen in the lower extremities. Purpura may occur due to infectious agents such as meningococcemia, Rocky Mountain spotted fever, staphylococci, or streptococcal infections.23 Conditions such as amyloidosis, vitamin C deficiency (scurvy), or Cushing syndrome may result in...

Overview of PIKK Family Members

Members of the PIKK family are involved in a diverse set of biological functions. The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a crucial role in site-specific V(D)J recombination in the developing immune system and in the nonhomologous end-joining (NHEJ) pathway of DNA repair 4 . The protein product of the gene mutated in ataxia-telangiectasia (ATM) and the ATM Rad3-related (ATR) protein have key roles in the signaling of DNA damage 5-7 . SMG-1, originally identified in a Caenorhabditis elegans screen as a suppressor of mor-phogen gradient, is involved in the process of nonsensemediated RNA decay (NMD) 8 , while the mammalian target of rapamycin (mTOR also termed FRAP or RAFT) is involved in controlling cellular growth in response to nutrients and amino acids by playing a pivotal role in controlling the translational machinery 9,10 . Another member of the PIKK family, TRRAP (transformation transcription associated protein), is an essential cofactor for

ATM and ATR Signalers of Genome Damage

A homozygous deficiency of ATM in humans leads to ataxia-telangiectasia (A-T), a debilitating disorder in which progressive loss of motor coordination (ataxia) is brought about by the gradual loss of Purkinje cells in the cerebellum 33 . In addition, A-T patients have an increased cancer incidence, and cells derived from these individuals are hypersensitive to ionizing radiation and to chemical agents that induce DNA double-strand breaks 33 . Notably, whereas normal cells delay progression through the cell cycle after treatment with such agents, A-T cells are defective in these checkpoint responses 5,6 . Indeed, A-T cells are deficient in the Gj S, G2 M, and S phase checkpoints. Over the past few years, a large number of research papers have addressed these checkpoint defects and it is now clearly established that ATM phosphorylates, and therefore appears to modulate the activities of, the key cell-cycle control proteins p53, BRCA1, NBS1, MDM2, RAD17, and CHK2. Recent review articles...

Genetic Factors Predisposing to Precursor Lymphoblastic Leukemia Lymphoma

While several genetic disorders are well known to predispose to lymphoblastic leukemia, including Down syndrome, Bloom syndrome, neurofibromatosis, and ataxia telangiectasia 62-66 , patients with these disorders collectively account for fewer than 5 of cases of ALL. Consequently, the existence and identity of predisposing genetic factors in the preponderance of patients with ALL remains largely undefined. The analysis of twins to gain insight into whether there exists a genetic propensity for the development of ALL is complicated by the fact that a significant subset of pediatric ALLs develops in utero with the attendant risk for transplacental leukemic metastasis 67 . Recent whole-genome association analyses have provided some initial insights 68, 69 . Using high-density single-nucleotide polymorphism (SNP)-based analysis, several germline polymorphisms have been identified which appear to confer an increased risk for the development of ALL. In two independent studies, SNPs located...

Human Heterogeneity

Individuals differ in susceptibility to cancer because of genetic, environmental, occupational, and lifestyle factors. A variety of genetic disorders have been identified as conferring substantially greater risk for certain types of cancer (1, 103). Examples include inherited cancer syndromes (such as familial retinoblastoma 103 ), genetically determined immunodeficiency diseases (such as ataxia telangiectasia 104 ), and recessive syndromes of DNA-deficient repair (such as xero-derma pigmentosum 105 ). Taken together, though, these syndromes explain only a small fraction of human cancer.

Vector DNA Metabolism

Evidence that DNA repair and recombination are directly involved in circularization or concatamerization of AAV vector genomes is supported by recent insights into possible biochemical mechanisms of their formation (178,180). In fibro-blasts from a patient with ataxia telangiectasia (ATM), there is greatly enhanced formation of AAV vector circular forms and enhanced integration of the head-to-tail concatemers as proviral genomes (181). The ATM gene is a PI-3 kinase that regulates the p53-dependent cell-cycle checkpoint and apop-totic pathways, and in these ATM cells the DNA double-strand break (DSB) repair systems that normally can be activated by UV irradiation appear to be already activated maximally.

Infectious Diseases Mycobacterial Infection

In contrast, patients with atypical cervical mycobacterial infection present with isolated lymphadenitis involving submandibular and submental groups (Fig. 1). These patients almost never present with constitutional symptoms. Affected nodes may become densely adherent to the subcutaneous and cutaneous tissues, resulting in skin necrosis manifested by erythema and fluctuance (Fig. 2).

Conventional treatment

Laser (Nd-YAG or Argon) can be used to destruct telangiectasia. An important trial included 47 patients with rectal bleeding after a median of 2 procedures, bleeding was controlled in 37 of them, with a median follow-up of 14 months157.The efficiency of Nd-Yag laser has been confirmed by retrospective trials158-161. Rectal ulceration, stricture, ileus or fistulae may occur157,158,161. Argon laser has been studied in non controlled trials. In one of the most important trial, a median of three procedures was performed bleeding stopped in all 14 patients, but recurrent bleeding occurred in 10 patients, requiring maintenance therapy162. Coagulation of telangiectasia can be realized by bipolar electrocoagulation, heater probe or more recently by argon plasma. Heater probe and bipolar coagulation seem to be equivalent 12 and 9 patients with bleeding resistant to steroid enema were cured, after a median of 4 procedures163. Argon plasma obtains same results, in non controlled trials164-167.

Diagnosis And Treatment

FIGURE 6 Matted telangiectasias on the lip of a patient with hereditary hemorrhagic telangiectasia. Courtesy of Dr. Terence O'Grady, University of California San Diego. FIGURE 6 Matted telangiectasias on the lip of a patient with hereditary hemorrhagic telangiectasia. Courtesy of Dr. Terence O'Grady, University of California San Diego.

The Gmcsf Antagonist E21R

E21R was well tolerated with, the most severe toxicities being World Health Organization grade 3 injection site erythema (n 1), grade 2 lethargy (n 3), grade 2 muscle aches and soreness (n 1), grade 2 joint pains (n 1), and grade 2 thirst (n 1). Dose-dependent transient mild eosinophilia was noted from d 3. Serum from patients treated at 600 g kg d or higher antagonized GM-CSF-mediated TF-1 cell proliferation in vitro. No evidence of pulmonary toxicity was seen based on symptoms, examination findings, or changes in circulating surfactant concentrations. In 10 of these patients with solid tumors, stable disease was the best response. A further hint of activity was observed in two of the four patients with prostate cancer, one at the initial and one at the final dose level who had decreases in their prostate-specific antigen concentration and received a second cycle of E21R. This study confirmed that E21R could be administered safely for 10 d. It further confirmed that levels of up to 1...

Breast and chest wall

HBO has been used in the management of breast and chest wall injury ' - . Carl prospectively reported outcome in 44 patients presenting with pain, oedema, erythema, fibrosis and telangiectasia after lumpectomy and radiotherapy for early breast cancers. Complications were scored using modified LENT-SOMA criteria. Only patients with at least grade 3 pain or a summed LENT-SOMA score of 8 were studied. Thirty-two patients received a median of 25 sessions with 100 oxygen at 2.4 ata for 90 min. Patients who received HBO had a significant reduction of pain, erythema and oedema compared to those who refused HBO however fibrosis and telangiectasia were not significantly reduced. Gothard245 reported a phase II trial in patients with chronic arm lymphoedema. The twenty-one patients received 30 sessions with 100 oxygen at 2.4 ata for 100 min over a period of 6 weeks. Arm volumes were measured in an operator-independent method. There was a statistically significant but clinically modest reduction...

Mucous Membrane Pemphigoid

FIGURE 30 Lichenoid stomatitis in chronic hepatitis C. This red and white lesion at a high-risk site like the lateral border of the tongue was sensitive to spicy food and was highly suspicious for a premalignancy. A biopsy showed a liche-noid mucositis without dysplasia. Note the central erythematous area surrounded by white, radiating striae, the typical lichenoid clinical appearance. Source Courtesy of Stacy Mullins, DDS. FIGURE 30 Lichenoid stomatitis in chronic hepatitis C. This red and white lesion at a high-risk site like the lateral border of the tongue was sensitive to spicy food and was highly suspicious for a premalignancy. A biopsy showed a liche-noid mucositis without dysplasia. Note the central erythematous area surrounded by white, radiating striae, the typical lichenoid clinical appearance. Source Courtesy of Stacy Mullins, DDS. FIGURE 32 Desquamative gingivitis in mucous membrane pemphigoid. Note the gingival erythema and erosion. Desquamative gingivitis is a clinical...

Effects of Oxidative Stress and Genotoxic Stress on Zebrafish Aging and Senescence

Oxidation, lipid peroxidation, and the extent of oxidized DNA. The effects of ROS on telomeres seem to be mediated through the susceptibility of the telomeric GGG sites to DNA damage. ROS actively attack these telomeric regions, predisposing to DNA strand breaks and damage leading to increased telomere shortening. Importantly, fibroblasts from donors of several premature aging syndromes, such as ataxia-telengiectasia (A-T) with mutations in the ataxia telangiectasia mutated (ATM) gene and Hutchinson-Gilford progeria syndrome (HGPS) with mutations in the lamin AC gene (lmna), have short telomeres (Allsopp et al., 1992 Metcalfe et al., 1996 Smilenov et al., 1997), consistent with reduced cell division potential in vitro. Recently, it has been suggested that ATM functions in the cellular response to oxidative damage (Ito et al., 2004 Reliene et al., 2004 Rotman and Shiloh, 1997 Watters, 2003). Support for this hypothesis comes from observations that ATM-deficient cells are very sensitive...

Diagnosis And Treatment The Infectious Etiologies

Infections in Immunocompromised Individuals. A special type of external otitis is termed malignant otitis externa. This is a bacterial otitis externa present in diabetic or immunocompromised patients in whom there is osteomyelitis of the skull base. The disorder is caused by Pseudomonas aeruginosa infection and may be recognized by granulation tissue in the external ear. The ear also may present with significant inflammation and erythema (12). A culture of the ear positive for Pseudomonas does not make the diagnosis, since Pseudomonas is part of the flora of a normal ear and can also be positive in simple otitis externa. The best diagnostic test is a bone scan looking for evidence of the osteomyelitis. It is important for clinicians to keep a high index of suspicion for this disorder, since, if not treated appropriately, the disorder can progress to lateral sinus thrombosis, involvement of the temporal mandibular joint (TMJ), multiple cranial nerve involvement, and meningitis (13,14).

Altered Notch Signaling in TALL

McCormick MK, Schinzel A, Petersen MB, et al. Molecular genetic approach to the characterization of the Down syndrome region of chromosome 21. Genomics. 1989 5 325-331. Stiller CA, Chessells JM, Fitchett M. Neurofibromatosis and childhood leukaemia lymphoma a population-based UKCCSG study. Br J Cancer. 1994 70 969-972. Passarge E. Bloom's syndrome the German experience. Ann Genet. 1991 34 179-197. Taylor AM, Metcalfe JA, Thick J, Mak YF. Leukemia and lymphoma in ataxia telangiectasia. Blood. 1996 87 423-438.

Rhinocerebral Mucormycosis

Schwartz noted that these nerve abnormalities are often consistent with orbital apex syndrome (unilateral ptosis, proptosis, visual loss, complete ophthalmoplegia, and ophthalmic and maxillary nerve anesthesia and anhidrosis) (11). Most cases of orbital apex syndrome are due to mucormycosis or Aspergillus, and visual loss is usually irreversible. In contrast with typical bacterial orbital cellulitis, patients with RCM may have minimal preseptal lid erythema, more pain in the forehead or temple than in the eye, and early onset of decreased sensation in the first and second divisions of cranial nerve V. The facial edema associated with RCM may be confused with periorbital cellulitis. The periorbital edema described for RCM is soft, cool, and nontender, differentiating it from the warm, tender, taut edema of cellulitis (9). Mucormycosis can be further distinguished from cellulitis by examining the character of the ptosis, if present RCM produces a paralytic ptosis in which the eyelid can...

Allergic rhinosinusitis

The diagnosis of allergic rhinosinusitis is based first upon clinical presentation. Thus, the presence of itchy watery eyes, sneezing, palatal itching, clear watery rhinorrhea, and sinus facial pressure suggest this disorder. In addition, the presence of other allergic manifestations such as asthma, eczema, or urticaria angioedema, and a family history of atopic disorders, provide further support. Exacerbation of symptoms during specific seasons of the year (spring trees, late spring to early summer grasses, and fall weeds and molds), or with certain exposures (e.g., cat), is additional evidence of an allergic etiology. Physical examination may be relatively unremarkable or may reveal pale and swollen nasal mucosa, sometimes described as a bluish discoloration, enlarged turbinates, and copious nasal secretions. Profound erythema of the mucosa and or the presence of purulent nasal discharge should suggest other diagnoses or the presence of complications of underlying allergic disease....

Pharmacological Toxicological Effects

John's wort, and more specifically hyperforin, has an inhibitory effect on epidermal langerhan cells, there was speculation that it may treat atopic dermatitis. A 4-week trial was conducted in which 21 patients with mild to moderate atopic dermatitis were treated twice daily with a cream standardized to 1.5 hyperforin on one side of their body and placebo on the other side. The primary end point of the study was severity scoring of atopic dermatitis (SCORAD) index, based on extent and intensity of erythema, papulation, crust, excoriation, lichenification, and scaling. Among the 18 participants that completed the study, the SCORAD index fell from a baseline score of 44.9 to 23.9 in the hyperforin group. The SCORAD index also fell from 43.9 to 33.6 in the placebo group. These results show statistically significant superiority of hyperforin cream over placebo, with no difference in skin tolerance to the two treatments. Of note, a secondary end point of the...

Histopathologic Characteristics

In HIV+ patients, neutrophils appear to be a rare finding in oral candidiasis lesions and are only encountered in a limited number of erythematous forms. The inflammatory cell infiltrate is primarily mononuclear in both pseudomembranous and erythema-tous cases of HIV-associated infection (Romagnoli et al., 1997). Few Candida hyphae are associated with the atrophic epithelium in erythematous candidiasis, whereas numerous organisms are found invading into the prickle cell layer of oral epithelium in pseudomembranous candidia-sis. In HIV+ patients the inflammatory infiltrate is heavier in erythematous candidiasis and consists of CD8+ lymphocytes and CD1a+ Langerhans cells (Romagnoli et al., 1997). In fact, in this study CD1a+ dendritic cells were the only cell type to be significantly increased in HIV+ oral candidiasis as compared to HIV+ or HIV- controls. These cells were almost exclusively restricted to the basal layer of the oral epithelium. Overall a change in localization of...

Inflammatory Autoimmune

Pemphigus is a rare disease that affects mucosal membranes. Although the term pemphigus may be erroneously used interchangeably with the condition bullous pemphigoid, it is a separate entity warranting a separate discussion. Pemphigus is characterized by vesicular lesions and bulla. There are multiple subtypes, with pemphigus vulgaris and pemphigus foliaceus being the most common (7). Other subtypes include pemphigus vegetans, pemphigus erythematosus, pemphigus herpetiformis, paraneoplastic pemphigus, drug-induced pemphigus, and IgA pemphigus. Although it is a disease of all ages, it typically occurs between the ages of 30 and 60. Pemphigus affects males and females equally. There is no known ethnic predilection. Its pathogenesis stems from an autoimmune mechanism in which circulating antibodies target keratinocyte cell surfaces. Cell-to-cell adhesion is disrupted and antibody complexes activate the complement cascade, creating local tissue damage. The cause of this...


Lymphocyte infiltration of the upper and middermis that can extend into the epidermis characterizes the erythematous plaque (Bircher et al., 1990). Dermal and epidermal edema (spongiosis) is observed in lesions that appear eczematous. The T lymphocytes of helper-suppressor (CD4+) phenotype predominate, together with FIGURE 14 (See color insert) Heparin-induced skin lesions. (A) Heparin-induced erythematous plaques UFH injections into the lower abdomen resulted in painful erythematous plaques beginning on day 7 of sc UFH treatment at this time, the platelet count fell only by 9 from 340 to 311 x 109 L. HIT antibody seroconversion from a negative baseline was shown using the serotonin release assay (from 0 to 84 serotonin release). (B) Heparin-induced skin necrosis UFH injections into the right anterior thigh led to skin necrosis a large black eschar with irregular borders is surrounded by a narrow band of erythema. The platelet count fell to 32 x 109 L despite stopping heparin, the...


Although AFP functions as a tumor marker, it is important to recognize other potential sources of serum elevation. AFP was first shown to be elevated in hepatocellular carcinomas.3 Other malignancies that have been associated with elevated AFP levels include pancreatic, gastric, and pulmonary malig-nancies.4 However, elevated serum levels of AFP do not necessarily denote malignancy. Certain benign processes, including benign liver disease, pregnancy, ataxia telangiectasia, and tyrosinemia, have


Jaundiced patients are often presented to surgeons with a diagnosis of obstructive, post-hepatic jaundice, already made. It is important though to consider other causes of jaundice in the history and examination, and questions should cover recent foreign travel, alcohol intake, drug history, blood transfusions, and sexually transmitted diseases. Examination may reveal signs of chronic liver disease such as finger clubbing, palmar erythema, spider naevi, and caput medusa.

Irritant Gases

The site of pulmonary injury is most dependent on the water solubility of the gas. High-solubility gases (e.g., ammonia, sulfur dioxide, formaldehyde, or methyl iso-cyanate) can affect all exposed mucous membranes, including ocular (irritation, erythema, and conjunctivitis, and with heavy exposure delayed-onset of cataracts), nasal (irritation, congestion, rhinorrhea, and erythema), facial burns (skin and lip), pharyn-geal (throat and tongue irritation, burns and edema), and laryngeal (burns, edema, and obstruction) injuries. Intermediate-solubility gases such as chlorine may produce upper-airway irritation, but the mucous membrane irritation is not as intense as for highly soluble gases. Because of its intermediate solubility, chlorine's effect extends more distal, producing both upper- and lower-airway injury, and pulmonary edema. Low-solubility gases, like phosgene or oxides of nitrogen, produce little in the way of upper-airway irritation, but produce intense damage to the lower...

Smoke Inhalation

The most common clinical problems associated with smoke inhalation are (1) upper and or lower-airway inflammation and (2) carbon monoxide toxicity, although hydrogen cyanide toxicity has gained recent attention. Fiberoptic bronchoscopy is very useful in evaluation of burn patients for airway injury by demonstrating carbonaceous material, airway edema, erythema, ulcerations, hemorrhage, blisters, or ischemia. During bronchoscopy, intubation should be considered, preferably over the

Mild DI

Cutis Marmorata or marbling is thought to result from bubble-related cutaneous venous obstruction. It usually presents as an area of erythema, frequently affecting the upper back and chest. Lesions may migrate spontaneously or with palpation and prominent linear purple markings are frequently observed. These manifestations are considered to be an overt manifestation of DI and should be promptly treated . Recompression often, although not always, leads to prompt resolution.


Cooley et al. (2007) confirmed a clinical benefit of pegylated liposomal doxorubi-cin in 80 of all patients treated and a tumour response rate in 55 . The most important side effects of anthracyclines are neutropenia (30 ), nausea, asthenia and anemia. This usually occurs after 8-10 cycles. The cardiotoxicity associated with anthracyclines should also be considered. However, usually it only occurs with long-term administration (cumulative doses of 450 mg doxorubicin and higher). Macular and painful erythema of the palms and soles (palmoplantar erythrodyses-thesia) is another notable side effect which can limit treatment. Paclitaxel is also a very effective drug for the treatment of KS (Tulpule 2002). The recommended dose is 100 mg m2 body surface area administered intravenously over 3-4 hours every 2 weeks. Partial remission is achieved in up to 60 of all treated patients. Paclitaxel is myelotoxic and almost always leads to alopecia, often after just one dose. Whether paclitaxel has...

Topical Reactions

Pected aseptic meningitis, applied crushed garlic cloves by adhesive band to the wrists for 6 hours (99). After 1 week, a round ulceration 1 cm in diameter surrounded by a slightly raised, erythematous border was noted on the left wrist. A similar, more superficial lesion was also seen on the right wrist. When questioned, the parents explained that these ulcerations were the residual blisters that had formed after garlic application. The author of this case report described this reaction as a second-degree chemical burn. An allergic mechanism was ruled out because the infant had not previously been exposed to garlic or onions. A patch test was not done for ethical reasons. Although Garty hypothesized that the infants' delicate skin predisposed them to garlic burns, such reactions have also been reported in older children and adults. For example, a 6-year-old child developed a necrotic ulcer on her foot after her grandmother applied crushed garlic under a bandage as a remedy for a...


During primary infection the bacilli multiply within the lung and form a Ghon focus. The primary complex is the Ghon focus along with the hilar lymphadenopathy that occurs. In the normal immunocompetent individual, the body mounts a significant hypersensitivity cellular reaction against the primary complex to kill the bacilli and contain the infection. This usually occurs within 4 to 6 weeks of infection. However, a few dormant bacilli may persist, with the only evidence being a positive tuberculin skin test. In some individuals the primary complex is not contained and they may develop tuberculous pneumonia that may be complicated by pleural effusions and collapse of the lung tissue. Cervical lymphadenopathy, meningitis, pericarditis, hypersensitivity reactions (e.g., erythema nodosum) and miliary spread may also occur in uncontained primary infection.

Preseptal cellulitis

This infection involves tissues anterior to the orbital septum and is sometimes preceded by trauma or sinusitis. Staphylococcus aureus, streptococci and Haemophilus influenzae are the common pathogens. Examination reveals eyelid erythema, swelling, warmth and tenderness, but there is neither proptosis nor restriction in ocular motility. Radiographs or CT scans may show signs of sinusitis or evidence of trauma. Systemic ampicillin combined with penicillinase-resistant antibiotics is the treatment of choice. Surgical treatment is indicated in unresponsive cases or for the treatment of associated sinusitis. While this condition in adults is relatively simple to treat, in infants and young children, this can constitute an emergency. The definition of the orbital septum in these cases is poor and it is not difficult for the infection to track through the septum into the tissues of the orbit. Since the orbit contains many vital structures, infection in this region can cause serious visual...

Siterelated aspects

From a clinical point of view, the perineal area is covered in a widespread and painful erythema. Cutaneous necrosis quickly develops. The infection spreads - more frequently in the case of secondary fasciitis -towards the abdomen, groin, buttocks and thighs. Systemic manifestations are also more common in the case of secondary fasciitis. From a clinical point of view, the initial disorder (e.g., tooth or throat pain, sub mandibular swelling, etc.) quickly makes way to a rapidly-spreading erythematous swelling involving the whole sub mandibular area ultimately encroaching the other side and providing the well-known clinical picture of Ludwig's Angina68. The infection then spreads to the face, the lower part of the neck, the supraclavicular area and the thorax.

Clinical aspects

Clinically, the lesion is revealed by pain, both spontaneous and when pressure is applied. Locally, an indurated dark red central zone can be observed, surrounded by erythema,. The cellulitis spreads and is typically made up of 3 zones (1) the peripheral erythematous zone (2) a dark red and painful intermediate zone (3) and a gangrenous and necrotic central zone

Burn Assessment

First-degree burns involve the epidermis layer of the skin, but not the dermal layer. These injuries are characterized by pain, erythema, and lack of blisters. These burns heal without scar formation. First-degree burns are not considered in calculation of the TBSA burned.


The adverse event profile associated with r-metHuSCF was first defined in two small phase 1 clinical trials investigating its utility in patients with cancer receiving chemotherapy (29,30). When administered to 17 patients with nonsmall-cell lung cancer in incremental doses of 10, 25, and 50 pg kg d before the administration of chemotherapy, a specific pattern of adverse events emerged. At the lowest dose level, adverse events were limited to the injection site. At dose levels 10 pg kg d, adverse events occurred as multisystem systemic reactions. Dose-related mild-to-moderate reactions occurred in all patients at all dose levels and included edema, urticaria, erythema, and pruritus. These reactions, mild to severe, as well as angioedema and der-matographia, occurred at distant cutaneous sites. Cough, throat tightness, sore throat, dyspepsia, and hypotension were transient and did not result in patient withdrawal from the study (29). In another phase 1 trial of identical design, rHuSCF...


During radiotherapy, inflammatory changes are prominent and consist in migration of leucocytes through the crypt wall, crypt abscesses, inflammatory cell infiltration in the surface epithelium and lamina propria, and a striking accumulation of eosinophilic granulocytes. These histologic changes are maximal 2 weeks after the beginning of the treatment90. Later radiotherapy induces swelling of the fibroblasts, a subendothelial deposition of hyaline material, an endothelial proliferation with endarteritis of the arterioles. The most marked changes are noted in the submucosa, contrary to the acute radiation injury which is most prominent in the mucosa91. Superficial neovascularization (telangiectasia) can be observed even in asymptomatic patients92. These pathological changes can result in rectal tissue ischemia and fibrosis, leading to bleeding, ulceration, stricture or fistulae93.


Endothelium continues several months after the treatment. Obliterative endarteritis with perivascular fibrosis result in ischemia185. Telangiectasia can be observed. Smooth muscle fibrosis, with collagen deposition, is responsible for the reduction of bladder capacity (urinary frequency, urgency)186-188. Cystitis is a syndrome characterized by irritative symptoms such frequency and dysuria hematuria may or may not be a part of cystitis (RTOG definition)98. The SOMA LENT score for bladder and urethral complications includes dysuria, frequency, hematuria, incontinence and decreased stream103.


See Hereditary hemorrhagic telangiectasia Hemosiderin, 66 Hemostasis basis of, 230 fibrin in, 271-272, 272f fibrinogen in, 270 normal, 282 variants of, 101t Hereditary hemochromatosis (HH), 72 laboratory diagnosis, 73 symptoms of, 73, 73t treatment, 73-74 Hereditary hemorrhagic telangiectasia, 252, 252f Hereditary pyropoikilocytosis, 101-102, 102f Hereditary spherocytosis (HS) clinical presentation, 98-100 genetics of, 98 laboratory diagnosis of, 100 pathophysiology of, 98 Hereditary stomatocytosis, 102 Hereditary xerocytosis, 102 Hermansky-Pudlak syndrome, 251 Herrick, James B., 117 Hewson, William, 230 Hexosaminidase A, 153 Hexose monophosphate shunt in myelofibrosis with myeloid metaplasia, 195f Telangiectasia, 252, 252f Terminal deoxynucleotidyl transferase, 165-166 TFPI. See Tissue factor pathway inhibitor Thalassemia gene alpha, 75 beta, 75

Pernicious Anemia

Pernicious Anemia Parietal Cells

A similar clinical appearance of the tongue mucosa may be seen in Vitamin B complex deficiencies and iron deficiency anemia (Fig. 44), which are also frequently associated with angular cheilitis. Since both Vitamin B12 and folate deficiencies exhibit macrocytic hyperchromic anemia, it is necessary to perform serum folate and B12 determinations in order to distinguish between them. Atrophic candidiasis (Fig. 45) may also produce a sensitive, erythematous, depapillated lingual mucosal surface. FIGURE 46 Central papillary atrophy. Also referred to as median rhomboid glossitis, this was long believed to be a developmental condition. It is now recognized as a form of erythematous candidiasis appearing as a well-demarcated zone of erythema in the midline of the dorsal tongue with a smooth or lobulated surface. The lesion is typically asymptomatic and frequently resolves with antifungal therapy.



Stomatitis refers to an inflammatory process involving the mucous membrane of the mouth that may manifest itself through a variety of signs and symptoms including erythema, vesiculation, bulla formation, desquamation, sloughing, ulceration, pseudomembrane formation, and associated discomfort. Stomatitis may arise due to factors that may be of either local, isolated conditions or of systemic origin. For example, a solitary oral ulcer with a history of a recurrent pattern may be classified as recurrent aphthous stomatitis, a purely local phenomenon. Another clinically-similar-appearing lesion, on the other hand, may represent an oral mucosal manifestation of a more generalized disease process such as Crohn's disease. Stomatitis may involve any site in the oral cavity, including the vermillion of the lips, labial buccal mucosa, dorsal ventral tongue, floor of mouth and hard soft palate, and gingivae. The differential diagnosis of stomatitis is challenging because the inflammatory...


Angioedema (Fig. 1) is the abrupt and transient swelling of the skin, mucous membranes, or both, including the upper respiratory and intestinal epithelial linings (11). In some cases, angioedema and urticaria should be viewed as varying manifestations of the same pathologic process, and they are common components of anaphylactic reactions. Angioedema involves the reticular dermis and subcutaneous or submucosal tissue, particularly of acral areas, while urticaria involves the papillary dermis and mid-dermis throughout the body. The depth of involvement will result in different clinical presentations. Urticarial lesions are erythema-tous, short lived (

How To Deal With Rosacea and Eczema

How To Deal With Rosacea and Eczema

Rosacea and Eczema are two skin conditions that are fairly commonly found throughout the world. Each of them is characterized by different features, and can be both discomfiting as well as result in undesirable appearance features. In a nutshell, theyre problems that many would want to deal with.

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