PubMed Health⌕ Search

Biomedical subjects

Mary L Williams

Publications and source records attributed to Mary L Williams.

18 recordsLinked to original sources
PubMed2006

Barrier dysfunction and pathogenesis of neutral lipid storage disease with ichthyosis (Chanarin-Dorfman syndrome).

Neutral lipid storage disease with ichthyosis (NLSDI; Chanarin-Dorfman syndrome) is an ichthyosiform syndrome, often associated with mutations in a lipid hydrolase, CGI-58. The presence of oil red O-positive, neutral lipid droplets in tissue biopsies, and/or in leukocytes on blood smears, coupled with a constellation of multisystem abnormalities and a pruritic ichthyosiform erythroderma, are together diagnostic of NLSDI. We investigated the pathogenesis of the ichthyosiform erythroderma in patients from three unrelated kindreds with a clinical diagnosis of NLSDI. Basal permeability barrier function and stratum corneum (SC) integrity were abnormal, but barrier recovery rates were faster than normal, as in atopic dermatitis. The basal barrier abnormality was linked to the secretion of lipid micro-inclusions, first segregated within lamellar bodies (LB), which then form a non-lamellar phase within the SC interstices, shown by combined ruthenium tetroxide post-fixation and lipid-retaining resin-white embedding. With colloidal lanthanum nitrate perfusion, excess water/solute movement was restricted to the SC interstices, and further localized to non-lamellar domains. Phase separation of excess stored lipid provides a unifying pathogenic mechanism not only for NLSDI, but also in several other inherited ichthyosiform disorders of lipid metabolism, such as recessive X-linked ichthyosis and type 2 Gaucher's disease.

1-Acylglycerol-3-Phosphate O-Acyltransferase↗
PubMed2006

Serine protease activity and residual LEKTI expression determine phenotype in Netherton syndrome.

Mutations in the SPINK5 gene encoding the serine protease (SP) inhibitor, lymphoepithelial-Kazal-type 5 inhibitor (LEKTI), cause Netherton syndrome (NS), a life-threatening disease, owing to proteolysis of the stratum corneum (SC). We assessed here the basis for phenotypic variations in nine patients with "mild", "moderate", and "severe" NS. The magnitude of SP activation correlated with both the barrier defect and clinical severity, and inversely with residual LEKTI expression. LEKTI co-localizes within the SC with kallikreins 5 and 7 and inhibits both SP. The permeability barrier abnormality in NS was further linked to SC thinning and proteolysis of two lipid hydrolases (beta-glucocerebrosidase and acidic sphingomyelinase), with resultant disorganization of extracellular lamellar membranes. SC attenuation correlated with phenotype-dependent, SP activation, and loss of corneodesmosomes, owing to desmoglein (DSG)1 and desmocollin (DSC)1 degradation. Although excess SP activity extended into the nucleated layers in NS, degrading desmosomal mid-line structures with loss of DSG1/DSC1, the integrity of the nucleated epidermis appears to be maintained by compensatory upregulation of DSG3/DSC3. Maintenance of sufficient permeability barrier function for survival correlated with a compensatory acceleration of lamellar body secretion, providing a partial permeability barrier in NS. These studies provide a mechanistic basis for phenotypic variations in NS, and describe compensatory mechanisms that permit survival of NS patients in the face of unrelenting SP attack.

Abnormalities, Multiple↗
PubMed2005

The price of pruritus: sleep disturbance and cosleeping in atopic dermatitis.

BACKGROUND: Atopic dermatitis is a common skin disorder that most often begins in infancy. Sleep disturbances in children with atopic dermatitis are likely due to itching and scratching and not only impact the afflicted child but may also affect the entire family. Sleep characteristics in young children with atopic dermatitis and their families have not been thoroughly investigated. OBJECTIVE: To evaluate sleep disturbance and cosleeping in young children with atopic dermatitis and evaluate the association between sleep characteristics and features of the disease. DESIGN AND METHODS: Parents of 300 children ranging in age from birth to 6 years with atopic dermatitis responded to 4 questions about sleep characteristics of their child and family. Analyses determined the prevalence of reported sleep disturbance and cosleeping, and their association with features of the patients and disease severity. RESULTS: Sleep disturbance attributed to atopic dermatitis was common; most parents (> 60%) reported that the dermatitis affected how well they or their child slept. Cosleeping because of the skin condition was reported by 30% of families, and most of these parents (66%) were bothered by the cosleeping. Sleep disturbance and cosleeping were directly associated with severity of atopic dermatitis and with the degree to which parents reported that the atopic dermatitis affected the child and family's happiness. CONCLUSIONS: Sleep disturbances were more common in children with atopic dermatitis than have been reported in children overall. These results demonstrate important sequelae of a very common childhood condition that warrant further investigation and the development of intervention strategies.

Adult↗
PubMed2005

Development of the Childhood Atopic Dermatitis Impact Scale: initial validation of a quality-of-life measure for young children with atopic dermatitis and their families.

To measure the effects of atopic dermatitis (AD) on the quality of life of affected young children and their families, we developed a prototype 62-item instrument, the Childhood Atopic Dermatitis Impact Scale (CADIS). The prototype CADIS was developed from a comprehensive conceptual framework based on data from parents and clinicians. The instrument had eight subscales (four each for child and parent): physical health, emotional health, physical functioning, and social functioning. The goal of this work was to test the validity of and to refine the prototype of CADIS. Two hundred seventy parents of children under the age of 6 y with AD responded to the instrument. Content validity was demonstrated by expert and parent reviews of the drafted and refined instrument, and by analyzing parents' responses to open-ended questions about their children's skin disease. Construct validity was assessed in exploratory factor analyses which supported a refinement in the conceptual framework to consist of two dimensions with five domains: child dimensions (symptoms and activity limitation/behavior), and parent dimensions (family/social function, sleep, and emotions). Seventeen items were eliminated, yielding a 45-item refined version of CADIS (score 0-180) with evidence of content and construct validity and suggested use in clinical research.

Adolescent↗
PubMed2004

Functional reprogramming of the primary immune response by T cell receptor antagonism.

The T cell receptor must translate modest, quantitative differences in ligand binding kinetics into the qualitatively distinct signals used to determine cell fate. Here, we use mice that express an endogenous T cell receptor (TCR) antagonist and an adoptive transfer system to examine the influence of TCR signal quality on the development of effector function. We show that activation of antigen-specific T cells in the presence of an antagonist results in a functional reprogramming of the primary immune response, marked by altered T cell homing, a failure to develop effector function, and ultimately clonal elimination by apoptosis. Importantly, antagonism does not block cell division, implying that the signals promoting clonal expansion and effector differentiation are distinct.

Adoptive Transfer↗
PubMed2004

Pathophysiologic basis for growth failure in children with ichthyosis: an evaluation of cutaneous ultrastructure, epidermal permeability barrier function, and energy expenditure.

OBJECTIVE: Because an impaired epidermal permeability barrier is present in many of the ichthyoses, we examined the contribution of barrier failure to caloric requirements in children with ichthyosis and growth failure. STUDY DESIGN: Transepidermal water loss (TEWL) and ultrastructural parameters of the permeability barrier were evaluated in 10 hospitalized children with ichthyosis and growth failure. Nutritional intake, resting energy expenditure, and calories lost as heat of evaporation were determined. RESULTS: Mean basal TEWL rates were markedly elevated in all study patients in comparison to the expected upper limit of normal (39.6+/-20.6 vs 8.7 mL/m(2) per hour). The severity of abnormalities in the ultrastructure of permeability barrier-related structures, assessed semiquantitatively, correlated significantly to mean basal TEWL rates (P <.001). Total body daily TEWL was elevated (746 +/- 468 vs 209 mL/d), resulting in a caloric drain of 433 +/- 272 kcal/d (21 +/- 9.8 kcal/kg per day) through heat of evaporation. Nutrient intake exceeded requirements in all, but resting energy expenditure exceeded predicted in 5 of 6 patients and correlated significantly with mean basal TEWL rates (P <.005). CONCLUSIONS: A defective permeability barrier in children with ichthyosis can result in ample chronic losses of water and calories to impair growth.

Adolescent↗
PubMed2004

Basis for abnormal desquamation and permeability barrier dysfunction in RXLI.

Mutations in the gene for steroid sulfatase (SSase), are responsible for recessive x-linked ichthyosis (RXLI). As a consequence of SSase deficiency, its substrate, cholesterol sulfate (CSO4), accumulates in the epidermis. Accumulation of this amphipathic lipid in the outer epidermis provokes both a typical scaling phenotype and permeability barrier dysfunction. Research on RXLI has illuminated several, potentially overlapping pathogenic mechanisms and provided insights about the role of SSase and CSO4 in normal differentiation, barrier maintenance, and desquamation. We now show here that SSase is concentrated in lamellar bodies (LB), and secreted into the SC interstices, along with other LB-derived lipid hydrolases. There, it degrades CSO4, generating some cholesterol for the barrier, while the progressive decline in CSO4 (a serine protease (SP) inhibitor) permits corneodesmosome (CD) degradation leading to normal desquamation. Two molecular pathways contribute to disease pathogenesis in RXLI: 1) excess CSO4 produces nonlamellar phase separation in the stratum corneum (SC) interstices, explaining the barrier abnormality. 2) The increased CSO4 in the SC interstices inhibit activity sufficiently to delay CD degradation, leading to corneocyte retention. We also show here that increased Ca++ in the SC interstices in RXLI could contribute to corneocyte retention, by increasing CD and interlamellar cohesion. RXLI represents one of the best understood diseases in dermatology--from the gene to the SC interstices, its etiology and pathogenesis are becoming clear, and assessment of disease mechanisms in RXLI led to new insights about the role of SSase and CSO4 in epidermis terminal differentiation.

Animals↗
PubMed2004

Nutritional status and gastrointestinal structure and function in children with ichthyosis and growth failure.

UNLABELLED: Growth failure occurs in several of the ichthyoses, a heterogeneous group of inherited disorders characterized by thickened or scaly skin. This suggests that there may be common pathogenic mechanisms causing failure to thrive. Previous studies have proposed that a hypermetabolic state induced by epidermal inflammation and hyperproliferation or enteropathy leading to malabsorption and nutritional deficiencies might account for the growth failure in icthyosis. OBJECTIVE: The purpose of this study was to examine the extent of enteropathy and nutritional deficiency in children with severe ichthyosis and growth failure. METHODS: Ten children with different types of ichthyoses and growth failure were studied. RESULTS: Evaluation of gastrointestinal structure and function revealed few abnormalities other than mild fat malabsorption in two patients. Total caloric intake exceeded established requirements for age, height, and weight in all patients. Deficiencies of fat-soluble vitamins were identified in a few subjects. Mild elevations in total calcium and magnesium blood level, elevated hematocrit levels, and constipation were observed in many patients. CONCLUSIONS: Nutritional deficiencies and gastrointestinal abnormalities are uncommon in children with ichthyosis and failure to thrive. Chronic hypovolemia caused by impaired epidermal permeability barrier may be common in this population.

Calcium↗
PubMed2004

Effects of atopic dermatitis on young American children and their families.

OBJECTIVE: The psychologic, physical, and social impact of atopic dermatitis is complex and varies among children of different ages, and the effects of atopic dermatitis on the quality of life of very young American children and their families are not well understood. This study was conducted to document these effects of atopic dermatitis on young children and their families. METHODS: Directed focus sessions were performed with parents of 26 young children with atopic dermatitis and 6 expert clinicians. Specific mentions of the ways in which atopic dermatitis affected the children and parents were reviewed, rank ordered, and categorized according to similarity in content. The categories were examined to determine the domains represented, and the domains were used to compose a conceptual framework of all of the ways that atopic dermatitis affects children and their families. RESULTS: Parents and experts mentioned a total of 181 specific quality-of-life effects. A conceptual framework, developed from the 181 effects, contains the domains of physical health, emotional health, physical functioning, and social functioning; each domain includes effects on both the child and the parents. CONCLUSIONS: Atopic dermatitis greatly affects the quality of life of afflicted children and their families. The comprehensive conceptual framework summarizes the ways in which atopic dermatitis affects the quality of life in young American children. This conceptual framework forms the basis from which quality-of-life instruments can be developed.

Child, Preschool↗
PubMed2003

The objective severity assessment of atopic dermatitis score: an objective measure using permeability barrier function and stratum corneum hydration with computer-assisted estimates for extent of disease.

OBJECTIVES: Clinical scores used to assess the severity of atopic dermatitis (AD) rely entirely on subjective criteria to evaluate the severity of lesions and the extent of involvement. The aim of this study was to develop an objective measure of AD severity by measuring stratum corneum (SC) functions and by using computer-assisted estimates of involved body surface areas (BSAs). DESIGN: Barrier function of the SC was assessed by measuring transepidermal water loss, and SC hydration was assessed by measuring capacitance. The extent of disease was assessed using a computer-assisted algorithm. PATIENTS: A total of 38 sequential volunteers aged 4 months to 18 years (25 girls, 13 boys) with mild to severe AD at a university outpatient pediatric dermatology clinic. MAIN OUTCOME MEASURES: The computer-assisted method for estimating BSA was compared with estimates using the "rule of nines." The Objective Severity Assessment of Atopic Dermatitis (OSAAD) score, derived from measurements of SC barrier function and SC hydration and normalized for extent of disease was compared with the Scoring Atopic Dermatitis (SCORAD) index. RESULTS: Measurements of epidermal permeability barrier function and SC hydration correlated with clinical estimates of disease severity. The computer-assisted measurements of the extent of disease correlated with estimates derived from the rule of nines. The OSAAD scores correlated with the currently used instrument for AD severity, the SCORAD index. CONCLUSION: The OSAAD is a new AD severity score that avoids the pitfalls of currently used subjective scoring systems by using objective measures.

Adolescent↗
PubMed2002

Extrafacial and generalized granulomatous periorificial dermatitis.

BACKGROUND: Granulomatous periorificial dermatitis is a well-recognized entity presenting most commonly in prepubertal children as yellow-brown papules limited to the perioral, perinasal, and periocular regions. The condition is self-limiting and is not associated with systemic involvement. OBSERVATIONS: We reviewed the medical charts of 5 healthy children presenting with extrafacial granulomatous papules in addition to the typical periorificial papules. These extrafacial lesions were clinically and histologically identical to the facial lesions, were self-limiting, and were not associated with systemic involvement. Resolution seemed to be hastened with the use of systemic antibiotic therapy in 4 of the 5 patients. CONCLUSIONS: Extrafacial lesions can occur in granulomatous periorificial dermatitis and do not appear to adversely affect the duration, response to therapy, or risk of extracutaneous manifestations. Overly aggressive evaluation and inappropriate systemic therapy should be avoided.

Administration, Oral↗
PubMed2002

Genetic changes in neoplasms arising in congenital melanocytic nevi: differences between nodular proliferations and melanomas.

Large congenital melanocytic nevi (CMN) are at an increased risk of developing melanoma. Several forms of secondary proliferations can arise in congenital nevi on rare occasions. Although some of these closely resemble melanoma both clinically and histologically, metastasis is rare. We used comparative genomic hybridization to analyze chromosomal aberrations in different types of proliferations arising in CMN and compared them to typical congenital nevi, clear-cut melanomas arising in congenital nevi, as well as primary cutaneous melanomas that were not associated with a CMN. Cases of CMN and CMN with secondary proliferations were assigned to six groups according to the predominant histological pattern: group I, bland congenital nevi (n = 6); group II, congenital nevi with foci of increased cellularity (n = 4); group III, CMN with a proliferation simulating superficial spreading melanoma in situ (n = 3); group IV, CMN with a proliferation simulating nodular melanoma (n = 9); group V, proliferating neurocristic hamartoma (n = 1); and group VI, melanoma arising in congenital nevus (n = 6). No aberrations were found in groups I to III, whereas seven of nine cases of group IV, and one of one case of group V, showed aberrations. In group IV six of seven cases with aberrations (86%) showed numerical aberrations of whole chromosomes exclusively. This pattern differed significantly from the findings in melanoma that arose within CMN (n = 6), group VI, or independent of CMN (n = 122) in which only 5% showed numerical changes only. The single case in group V showed aberrations similar to melanoma. The finding of frequent numerical chromosomal aberrations in atypical nodular proliferations arising in CMN identifies these as clonal neoplasms with a genomic instability consistent with a mitotic spindle checkpoint defect. This difference compared to the aberration pattern found in melanoma might explain their more benign clinical behavior and may be of diagnostic value in ambiguous cases.

Adolescent↗
PubMed2002

Oxysterol stimulation of epidermal differentiation is mediated by liver X receptor-beta in murine epidermis.

Liver X receptor-alpha and -beta are members of the nuclear hormone receptor superfamily that heterodimerize with retinoid X receptor and are activated by oxysterols. In recent studies we found that treatment of cultured human keratinocytes with oxysterolstimulated differentiation, as demonstrated by increased expression of involucrin and transglutaminase, and inhibited proliferation. The aims of this study were to determine: (i) whether oxysterols applied topically to the skin of mice induce differentiation in normal epidermis; (ii) whether this effect is mediated via liver X receptor-alpha and/or liver X receptor-beta; and (iii) whether oxysterols normalize epidermal morphology in an animal model of epidermal hyperplasia. Topical treatment of normal hairless mice with 22(R)-hydroxycholesterol or 24(S),25-epoxycholesterol resulted in a decrease in epidermal thickness and a decrease in keratinocyte proliferation assayed by proliferating cell nuclear antigen staining. Moreover, oxysterol treatment increased the levels of involucrin, loricrin, and profilaggrin protein and mRNA in the epidermis, indicating that oxysterols stimulate epidermal differentiation. Additionally, topical oxysterol pretreatment improved permeability barrier homeostasis. Whereas liver X receptor-alpha-/- mice revealed no alterations in epidermal differentiation, the epidermis was thinner in liver X receptor-beta-/- mice than in wild-type mice, with a reduced number of proliferating cell nuclear antigen positive cells and a modest reduction in the expression of differentiation markers. Topical oxysterol treatment induced differentiation in liver X receptor-alpha-/- mice whereas in liver X receptor-beta-/- mice there was no increase in the expression of differentiation markers. Whereas both liver X receptor-alpha and liver X receptor-beta are expressed in cultured human keratinocytes and in fetal rat skin, only liver X receptor-beta was observed on northern blotting in adult mouse epidermis. Finally, treatment of hyperproliferative epidermis with oxysterols restored epidermal homeostasis. These studies demonstrate that epidermal differentiation is regulated by liver X receptor-beta and that oxysterols, acting via liver X receptor-beta, can induce differentiation and inhibit proliferation in vivo. The ability of oxysterols to reverse epidermal hyperplasia suggests that these agents could be beneficial for the treatment of skin disorders associated with hyperproliferation and/or altered differentiation.

Animals↗
PubMed2002

Ceramide-dominant barrier repair lipids alleviate childhood atopic dermatitis: changes in barrier function provide a sensitive indicator of disease activity.

BACKGROUND: It is currently fashionable to consider atopic dermatitis (AD), like other inflammatory dermatoses, as immunologic in pathogenesis ("inside-outside" hypothesis). Accordingly, topical glucocorticoids and other immunosuppressive agents are mainstays of therapy, but the risk of toxicity from these agents is not insignificant, particularly in children. Alternatively, because stratum corneum (SC) permeability barrier function is also abnormal in AD, it has been hypothesized that the barrier abnormality could drive disease activity. Yet commonly used emollients and moisturizers do not correct the SC ceramide deficiency, the putative cause of the barrier abnormality. OBJECTIVES: We assessed the efficacy of a newly developed, ceramide-dominant, physiologic lipid-based emollient, when substituted for currently used moisturizers, in 24 children who were also receiving standard therapy for stubborn-to-recalcitrant AD. METHODS: All subjects continued prior therapy (eg, topical tacrolimus or corticosteroids), only substituting the barrier repair emollient for their prior moisturizer. Follow-up evaluations, which included severity scoring of atopic dermatitis (SCORAD) values and several biophysical measures of SC function, were performed every 3 weeks for 20 to 21 weeks. RESULTS: SCORAD values improved significantly in 22 of 24 patients by 3 weeks, with further progressive improvement in all patients between 6 and 20 or 21 weeks. Transepidermal water loss levels (TEWL), which were elevated over involved and uninvolved areas at entry, decreased in parallel with SCORAD scores and continued to decline even after SCORAD scores plateaued. Both SC integrity (cohesion) and hydration also improved slowly but significantly during therapy. Finally, the ultrastructure of the SC, treated with ceramide-dominant emollient, revealed extracellular lamellar membranes, which were largely absent in baseline SC samples. CONCLUSION: These studies suggest that (1) a ceramide-dominant, barrier repair emollient represents a safe, useful adjunct to the treatment of childhood AD and (2) TEWL is at least as sensitive an indicator of fluctuations in AD disease activity as are SCORAD values. These studies support the outside-inside hypothesis as a component of pathogenesis in AD and other inflammatory dermatoses that are accompanied by a barrier abnormality.

Adolescent↗
PubMedDate not supplied

Fatal septicemia in an infant with keratitis, ichthyosis, and deafness (KID) syndrome.

Keratitis, ichthyosis, and deafness (KID) syndrome is a rare congenital disorder of unknown etiology in which increased susceptibility to viral, bacterial, and mycotic infections has been observed. We report an infant with KID syndrome who died from overwhelming systemic infection. To date, investigations into the immune function of patients with this syndrome have not revealed a common underlying systemic immune deficit. However, the severity of infections and multiplicity of organisms observed in this syndrome suggest that a primary immunodeficiency is present in addition to an impaired cutaneous barrier to microorganisms.

Deafness↗
PubMedDate not supplied

Treatment of chronic lymphocytic leukemia with alemtuzumab: a review for nurses.

PURPOSE/OBJECTIVES: To review the use of the monoclonal antibody alemtuzumab in patients with advanced refractory B cell chronic lymphocytic leukemia (B-CLL) and nursing management during treatment. DATA SOURCES: Published articles, abstracts, book chapters, Web sites, and training material. DATA SYNTHESIS: Alemtuzumab can achieve disease remission in patients with chemorefractory B-CLL; however, management of high-risk patients presents certain challenges. Infusion-related events can be minimized by stepwise administration and appropriate prophylaxis. Cytopenia can be minimized by drug postponement and cytokine support or red blood cell or platelet transfusions. Patients also are at risk for infection because of lymphopenia, and anti-infective prophylaxis is mandatory at initiation of therapy until at least two months post-treatment. CONCLUSIONS: With satisfactory supportive measures in place, patients with chemorefractory B-CLL can experience the benefits of alemtuzumab therapy without excessive toxicity. IMPLICATIONS FOR NURSING: Nurses should be familiar with treatment and prophylactic protocols, be ready to offer supportive therapy to control side effects, and invest time in patient education.

Alemtuzumab↗