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Biomedical subjects

L E King

Publications and source records attributed to L E King.

At least 19 recordsLinked to original sources
PubMed2006

Radiographic joint damage in rheumatoid arthritis is associated with differences in cartilage turnover and can be predicted by serum biomarkers: an evaluation from 1 to 4 years after diagnosis.

INTRODUCTION: The objective of this study was to determine whether serum biomarkers for degradation and synthesis of the extracellular matrix of cartilage are associated with, and can predict, radiographic damage in patients with rheumatoid arthritis (RA). METHODS: Clinical and radiographic data of 87 RA patients were recorded 1 year after disease onset and then annually up to four years. Serum concentrations of four cartilage biomarkers were determined at these time points: a neoepitope formed by collagenase cleavage of type II collagen (C2C), a neoepitope formed by collagenase cleavage of type II collagen as well as type I collagen (C1,2C), a carboxy propeptide of type II procollagen formed during synthesis (CPII), and a cartilage proteoglycan aggrecan turnover epitope (CS846-epitope). Biomarker concentrations between patients with rapid radiographic progression (>7.3 Sharp/van der Heijde units per year) and those with slow radiographic progression (<2.3 units per year) were compared. In addition, we evaluated the long-term and short-term predictive value of each biomarker for progression of radiographic damage. RESULTS: Patients with rapid radiographic progression had higher C2C, higher C1,2C, and higher CS846-epitope levels than slow progressors. CPII levels showed no differences. Most importantly, the long-term radiographic progression for C2C, for C1,2C, and for CS846-epitope can be predicted by the biomarker value at year 1 after disease onset. C2C was also a predictor for joint space narrowing and annual radiographic damage during the subsequent year. CONCLUSION: This study shows that the concentration of serum biomarkers of cartilage collagen breakdown and proteoglycan turnover, but not of collagen synthesis, are related to joint destruction in RA. The use of these biomarkers may be of value when studying progression of joint damage in patients with RA.

Aged↗
PubMed2004

Detection of aggrecanase- and MMP-generated catabolic neoepitopes in the rat iodoacetate model of cartilage degeneration.

OBJECTIVE: To characterize the time course of aggrecan and type II collagen degradation in the rat iodoacetate model of cartilage degeneration in relationship to the temporal sequence that has been described in human osteoarthritis (OA). DESIGN: Rats were injected intra-articularly in one knee joint with iodoacetate and damage to the tibial plateau was assessed from digitized images captured using an image analyzer. The articular cartilage from the tibial plateau was harvested, extracted and glycosaminoglycan (GAG) content was measured using the dimethylmethylene blue (DMMB) assay. Cartilage aggrecan neoepitopes were detected in cartilage extracts by Western blotting using antibodies recognizing the aggrecanase-generated C-terminal neoepitope NITEGE (BC-13) and the MMP-generated C-terminal neoepitope DIPEN (BC-4). A type II collagen collagenase-generated neoepitope was detected in cartilage extracts by ELISA using the Col2-3/4Cshort antibody; denatured collagen was detected using the Col2-3/4m antibody. RESULTS: Degenerative joint changes and proteoglycan (GAG) loss progressed with time after iodoacetate injection. Western blotting of cartilage extracts of iodoacetate treated rats demonstrated an increase in both aggrecanase- and MMP-generated epitopes with the NITEGE aggrecanase neoepitope being significantly elevated on days 7, 14 and 21 while DIPEN the MMP neoepitope was significantly elevated on days 7 and 14. The type II collagen neoepitope recognized by Col2-3/4Cshort was significantly increased in cartilage extracts of rats at days 14 and 21 after iodoacetate injection. CONCLUSION: The proteoglycan fragments extracted from the knee cartilage of rats after the intra-articular injection of iodoacetate appeared to result from cleavage at both aggrecanase and MMP sites. Cleavage of type II collagen by collagenase was also detected after iodoacetate injection and occurred subsequent to the initiation of aggrecan loss. These observations serve to demonstrate similarities in the mechanisms of cartilage degeneration induced by iodoacetate to those seen in articular cartilage in OA.

Aggrecans↗
PubMed2003

Alopecia areata in C3H/HeJ mice involves leukocyte-mediated root sheath disruption in advance of overt hair loss.

Alopecia areata (AA) can be induced in C3H/HeJ mice by grafting full-thickness AA-affected skin. An 8- to 12-week delay between surgery and overt hair loss onset provides an opportunity to examine disease pathogenesis. Normal haired C3H/HeJ mice were sham-grafted or grafted with AA-affected skin. Mice were euthanatized 2, 4, 6, 8, 10, and 12 weeks after surgery along with chronic AA-affected mice as a positive control. Until 6 weeks after grafting, inflammation was only evident around anagen-stage hair follicles in host skin adjacent to but not distant from the AA-affected graft. From 8 weeks on, AA-grafted but not sham-grafted mice exhibited a diffuse dermal inflammation at distant sites that progressively focused on anagen-stage hair follicles at 10 and 12 weeks. Perifollicular inflammation was primarily composed of CD4+ and CD8+ cells associated with follicular epithelium intercellular adhesion molecule -1 expression. Only CD8+ cells penetrated intrafollicularly by 12 weeks after surgery, although both CD4+ and CD8+ intrafollicular cells were observed in chronic AA-affected mice. Under electron microscopy, intrafollicular lymphocyte and macrophage infiltration associated with hair follicle dystrophy was prominent 10 weeks after surgery, primarily within the differentiating outer and inner root sheaths. This study shows that focal follicular inflammation develops some time in advance of overt hair loss and focuses on the differentiating root sheaths in C3H/HeJ mice. The severity of inflammation and the degree of hair follicle dystrophy induced by the infiltrate appear to reach a threshold level before overt hair loss occurs.

Alopecia Areata↗
PubMed2002

What is the 'true' function of skin?

Conventional textbook wisdom portrays the skin as an organ that literally enwraps whatever each of us stands for as a more or less functional, individual member of the mammalian species, and has it that the skin primarily establishes, controls and transmits contacts with the external world. In addition, the skin has long been recognized to protect the organism from deleterious environmental impacts (physical, chemical,microbiological), and is well-known as crucial for the maintenance of temperature, electrolyte and fluid balance. Now, ever more studies are being published that show the skin to also operate as a huge and highly active biofactory for the synthesis,processing and/or metabolism of an astounding range of e.g. structural proteins, glycans, lipids and signaling molecules. Increasingly, it becomes appreciated that the skin, furthermore, is an integral component of the immune, nervous and endocrine systems, with numerous lines of cross-talk between these systems established intracutaneously (e.g. Ann NY Acad Sci Vol 885, 1999; Endocrine Rev 21:457-487, 2000; Physiol Rev 80:980-1020, 2001; Exp Dermatol 10: 349-367, 2001). All these emerging cutaneous functions beyond the classical image of the skin as a barrier and sensory organ are immediately relevant for many of the quandaries that clinical dermatology, dermatopathology, and dermatopharmacology are still struggling with to-date, and offer the practising dermatologist attractive new targets for therapeutic intervention. Yet, many of these skin functions are not even mentioned in dermatology textbooks and await systematic therapeutic targeting. Following a suggestion by Enno Christophers, the current 'Controversies' feature brings together an unusually diverse council of biologists and clinicians, who share their thought-provoking views with the readers and allow us to peek into the future of research in cutaneous biology, not the least by reminding us of the -- often ignored -- evolutionary and embryonal origins of our favorite organ. Hopefully, this unique discussion feature will foster an understanding of the 'true' skin functions that is both more comprehensive and more profound than conventional teaching on this topic, and will stimulate more than 'skin-deep' reflections on the full range of skin functions.

Aging↗
PubMed2002

Apoptosis plays a distinct role in the loss of precursor lymphocytes during zinc deficiency in mice.

Lymphopenia is a characteristic of zinc deficiency, which is associated with massive loss of pre-B and pre-T cells from the primary lymphoid organs of zinc-deficient mice that have elevated serum corticosterone (CS). We examined whether this naturally elevated glucocorticoid level is associated with increased apoptotic loss of pre-T cells in the thymus of A/J and CAF1/J mice. In three experiments, partially atrophied thymuses were removed from 20 marginally zinc-deficient (ZD) young adult mice and cultured for 6 h in parallel with thymocytes prepared from 17 adequately fed mice. Thymocyte immunophenotyping combined with flow cytometric cell cycle analysis was used to identify the degree of apoptotic cell death among thymocytes of the two dietary groups, which were compared in the absence of in vivo phagocytosis. Apoptosis was enhanced 50-300% among pre-T cells (CD4+CD8+) prepared from ZD mice. This resulted in a 38% shrinkage of the thymic pre-T cell compartment, which was associated with an 80% decrease in thymic cell number. Pro-T cells (CD4-CD8-) and mature T cells (CD4+CD8-, CD4-CD8+), which express higher levels of Bcl-2 protein, survived ZD to a greater extent and formed a greater proportion of the remaining thymocyte population in ZD mice. Collectively, these data show that heightened degrees of apoptotic cell death induced in vivo by CS-disrupted thymic T cell lymphopoiesis, identifies the means of disruption of marrow B cell lymphopoiesis and explains the appearance of lymphopenia.

Animals↗
PubMed2001

Amyopathic dermatomyositis.

Amyopathic dermatomyositis is a variant of dermatomyositis that is characterized by the typical skin rash but without the muscle abnormalities. It has been proposed that the amyopathic and myopathic forms of dermatomyositis exist on a continuum, a concept that is supported by family and genetic studies and the observation that a small proportion of amyopathic patients transform to a frankly myopathic state. The amyopathic state is defined by a lack of muscle weakness and through diagnostic tests, including serum muscle enzymes, electromyogram studies, and muscle biopsies, that are usually normal or show only minimal abnormalities. Despite the lack of weakness, many patients complain of debilitating fatigue. More sensitive measures of muscle function, such as P-31 magnetic resonance spectroscopy, suggest that muscle metabolism is abnormal in amyopathic patients. The amyopathic form is more commonly seen in adults than in children, although juvenile cases are reported. Some early series suggested no association with underlying malignancies, but recent reports indicate that malignancies occur. Determining whether a patient has amyopathic rather than myopathic disease may have prognostic implications.

Adult↗
PubMed2001

Melanocyte and gonad activity as potential severity modifying factors in C3H/HeJ mouse alopecia areata.

Circumstantial evidence has previously suggested gonad derived steroid hormones and melanogenesis related antigens may modify human alopecia areata (AA). AA-like hair loss can be induced in C3H/HeJ mice after skin allografts from spontaneous AA-affected mice. This inducible model was used to evaluate hormones and hair follicle melanocyte presence as disease-severity modifiers. Ten females and 9 males were gonadectomized and received AA-affected allografts. All gonadectomized mice had 2-4 weeks delay in AA onset relative to non-gonadectomized controls. Two females and 4 males failed to develop any AA by 25 weeks after grafting. The experiment was repeated with gonadectomized female and male mice plus non-gonadectomized mice subcutaneously implanted with silastic capsules containing 80 microg 17beta estradiol or 10 mg 5alpha dihydrotestosterone, respectively. Five of 11 ovariectomized and 9 of 11 non-ovariectomized, estradiol supplemented females developed AA with extremely rapid progression. Three of 8 castrated, but none of 11 non-castrated, dihydrotestosterone-supplemented males expressed AA. In a separate study, 14 mice were freeze-branded, producing white hair on the dorsal lumbar region, and later received full-thickness allografts. Thirteen mice developed patchy pigmented and non-pigmented hair loss. One mouse developed diffuse, pigmented hair loss, but with white hair survival persisting 25 weeks after grafting. The results suggest that gonadal steroid hormones can modulate C3H/HeJ mouse AA where estradiol promoted rapid progression of AA while dihydrotestosterone increased resistance to AA onset. In general, both pigmented and non-pigmented C3H/HeJ mouse hair is susceptible to AA. Murine AA susceptibility and severity clearly involves an interplay between genetic and epigenetic factors.

Alopecia Areata↗
PubMed2001

Chlamydia pneumoniae and chronic skin wounds: a focused review.

The genus, Chlamydophilia, as obligate intracellular pathogens, induce chronic scarring in humans. Chlamydia pneumoniae, a common cause of pneumonia, infects endothelial cells and circulating macrophages. Evidence that C. pneumoniae is an opportunistic pathogen in chronic skin ulcers and other inflammatory skin conditions analogous to its role in atherosclerosis is reviewed.

Chlamydophila Infections↗
PubMed2001

Nineteen documented cases of Loxosceles reclusa envenomation.

OBJECTIVE: Our purpose was to review documented Loxosceles reclusa (brown recluse spider) envenomations and to describe the natural history. METHODS: This article is a retrospective review of 19 documented cases seen in a university dermatology clinic. The study included the cases of 11 female and 8 male patients between the ages of 15 and 54 years with documented cases of brown recluse spider bite between 1987 and 1993. Rest, ice compresses, elevation, and prophylactic antibiotics were used in all cases. Fourteen patients received dapsone and 11 received nonsteroidal anti-inflammatory drugs. Two patients were hospitalized. A 3-point scale of cutaneous lesion severity was developed. Analysis of the association between maximum lesion severity (mild, moderate, severe) and time to complete healing or final evaluation was statistically significant (P < .001). RESULTS: All patients presented with localized erythema. Most bites were on the extremities (18/19; 95%). The most common presenting symptom was pain at the bite site (10/19; 53%). Eleven patients (58%) had skin necrosis; 32% of them had areas of necrosis larger than 1 cm(2). Time to healing ranged from 5 days to more than 17 weeks (mean, 5.6 weeks). Average time to healing for grade 3 (severe) lesions was 74 days, for grade 2 (moderate) lesions 22 days, and for grade 1 (mild) lesions 8 days (in patients seen more than once). CONCLUSIONS: Brown recluse spider bites frequently induce necrotic, slowly healing lesions. Maximum lesion severity is a predictor of time to complete healing.

Adolescent↗
PubMed2001

Necrotic arachnidism.

UNLABELLED: Necrotic arachnidism is the potential cutaneous reaction to spider bite venom. In the United States, members of 7 spider families may be responsible for envenomation sufficiently severe to warrant treatment. Characteristics of several spiders, in particular Loxosceles spiders, whose bite is toxic to humans are described, and diagnostic standards, preventive measures, and treatment options are reviewed. (J Am Acad Dermatol 2001;44:561-73.) LEARNING OBJECTIVE: After the completion of this learning activity, participants should be familiar with the characteristics of several different spider families endemic to the United States. Furthermore, this learning activity should aid in the prevention and diagnosis of spider bites as well as in the classification and treatment of specific bites.

Humans↗
PubMed2001

Histologic features of actinic keratoses in solid organ transplant recipients and healthy controls.

BACKGROUND: Squamoproliferative lesions are common in patients who are immunosuppressed, particularly in recipients of solid organ transplants. Histologic features in such biopsy specimens may differ from those of otherwise healthy patients. Actinic keratoses (AKs) in transplant recipients may possess pathologic characteristics that suggest that they arose in an immunosuppressed host. OBJECTIVE: We evaluated 30 randomly selected AKs from 25 recipients of solid organ transplants and compared their histologic features to those of 50 AKs from 45 patients who were not immunosuppressed. METHODS: Tissue samples were categorized by sex, patient age, and site of biopsy. Sixteen separate histologic criteria were evaluated in a blinded fashion in each specimen. Statistical analysis was performed between the two groups with and without controlling for the age of the patient. RESULTS: The transplant group was significantly younger (54.8 years) than the nontransplant group (70.0) and contained more men (88%) than women (51%). AKs from transplant recipients were statistically more likely to demonstrate bacterial colonization, confluent parakeratosis, hyperkeratosis, increased mitotic activity, and verrucous changes. After controlling for age only, hyperkeratosis failed to be more prevalent in the transplant group. CONCLUSION: Certain histopathologic features are more common in AKs of immunosuppressed transplant recipients and may be used to distinguish between those removed from otherwise healthy persons.

Adult↗
PubMed2001

A distinct role for apoptosis in the changes in lymphopoiesis and myelopoiesis created by deficiencies in zinc.

Reduced numbers of lymphocytes in the peripheral immune system appeared to be a significant cause of the loss in host defense capacity in humans and animals that are zinc deficient (ZD). A series of studies verified that ZD substantially reduced the lymphocyte compartment of both the marrow and thymus in young adult mice, with large losses noted among the pre-B and pre-T cells. Suboptimal nutriture along with chronic production of glucocorticoids generated during ZD had accelerated apoptosis among these precursor lymphocytes two- to threefold. Thus, the primary cause of the lymphopenia created by ZD was reduced production of lymphocytes and heightened cell death among precursor cells. The data will also show that myelopoiesis in the marrow was protected and enhanced numbers of myeloid progenitor cells were found in S and G2/M. Thus, as zinc became limiting the second line of defense appeared to be down-regulated via reduction of lymphopoiesis while cells of the myeloid lineage were protected to maintain the first line of defense that provides innate immunity. This may represent an important adaptation of the immune system to suboptimal nutriture that deserves further exploration.

Animals↗
PubMed2001

Middermal elastolysis in two patients with lupus erythematosus.

Despite lupus erythematosus (LE) being considered a "connective tissue disease," little has been written about the elastic fiber changes in the skin of affected patients. We report our histologic findings in two patients with unusual cutaneous lesions. Elastic fiber loss was noted, and scattered giant cells with elastic fiber phagocytosis were prominent in one patient. The findings are similar to those described for middermal elastolysis. Other authors have reported patients with LE and elastic fiber loss resembling anetoderma. We believe that a spectrum of elastic fiber changes can occur in patients with LE and may be induced by infiltrating lymphocytes and/or circulating antibodies.

Adult↗
PubMed2000

Pyoderma gangrenosum and Chlamydia pneumoniae infection in a diabetic man: pathogenic role or coincidence?

Chlamydia Pneumoniae is not a known cause of skin infections, but unusual pathogens cause chronic infections in diabetic patients. Multiple idiopathic pyoderma gangrenosum-like (PG-like) lesions were refractory to multiple therapeutic agents in a diabetic patient who had C pneumoniae identified by serologic tests and polymerase chain reaction. Based on complete resolution by prolonged anti-chlamydial antibiotic therapy and concomitant decrease in serologic and titers determined by polymerase chain reactions, the PG-like lesions were presumed to be due to C pneumoniae.

Aged↗
PubMed2000

Lanceolate hair-J (lahJ): a mouse model for human hair disorders.

Lanceolate hair-J (lahJ) arose spontaneously in 1994 on the DBA/1LacJ inbred background at The Jackson Laboratory. Mutant mice were runted, alopecic, and lacked vibrissae. As they aged, their skin wrinkled. Affected mice developed a noninflammatory, proliferative skin disease with follicular dystrophy. Hair fibers developed a number of abnormalities including periodic nodules along the shaft (trichorrhexis nodosa), compaction resembling trichorrhexis invaginata, spiral fractures, broken tips, and lance-shaped tips. This mutation exhibits some characteristics that resemble an autosomal recessive ichthyosiform disease that occurs in humans characterized in part by peculiar, invaginating, multinodal, hair shaft abnormalities known as Netherton's syndrome. Periodic nodules also resemble the human genetic based disease monilethrix. This autosomal recessive mouse mutation, allelic with lanceolate hair (lah), based on breeding studies, is located on mouse Chromosome 18, within a cluster of genes coding for adhesion molecules. Homozygotes for either of these allelic mouse mutations have elevated serum IgE levels, a feature also common with human Netherton's syndrome.

Alleles↗