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PubMed1985

Grace A. Goldsmith Award lecture. Trace element regulation of immunity and infection.

Protein-calorie malnutrition is associated with impaired immunocompetence and increased susceptibility to infection. Clinically evident nutritional deficiency syndromes, however, are composite of deficits of many essential nutrients, each of which may exert an important regulating effect on immunity. Among other nutrients, several trace elements have been shown to regulate immune responses, particularly cell-mediated immunity. Zinc undernutrition results in lymphoid atrophy and reduced capacity to respond to many T-cell-dependent antigens. Plaque forming cell response to heterologous erythrocytes is decreased, as is the function of B cells. In zinc deficient rodents, the generation of cytotoxic lymphocytes in the spleen is reduced. Antibody-dependent cell-mediated cytotoxicity is largely unchanged. In acrodermatitis enteropathica, lymphocyte proliferation response to mitogens is decreased and there are significant changes in delayed hypersensitivity responses and in the proportion of various T cell subsets. Neutrophil function is not changed by zinc deficiency. Iron deficiency results in a slight decrease in the number of rosette-forming T cells and a significant impairment of lymphocyte response to mitogens and antigens. Polymorphonuclear leukocytes are unable to kill ingested bacteria and fungi in an efficient manner. Copper deficiency impairs cell-mediated immunity, as does selenium deficiency when it is associated with vitamin E lack. Several pathogenetic mechanisms may underlie such alterations in immunity. Many heavy metals impair immune responses. These effects of trace elements on immunity may have important fundamental and practical implications.

Animals↗
PubMed1985

Clinical and biochemical manifestations of zinc deficiency in human subjects.

During the past two decades, essentiality of zinc for man has been established. Deficiency of zinc in man attributable to nutritional factors and several diseased states has been recognized. High phytate content of cereal proteins decreases availability of zinc; thus the prevalence of zinc deficiency is likely to be high in the population subsisting mainly on cereal proteins. Zinc deficiency has been noted to occur in patients with malabsorption syndrome, chronic renal disease, cirrhosis of the liver, sickle cell disease, AE (acrodermatitis enteropathica), and other chronically debilitating diseases. Growth retardation, male hypogonadism, skin changes, poor appetite, mental lethargy, and delayed wound healing are some of the manifestations of chronically zinc-deficient human subjects. In severely zinc-deficient patients, dermatological manifestations, diarrhea, alopecia, mental disturbances, and intercurrent infections predominate. If untreated, the condition becomes fatal. Zinc deficiency affects testicular functions adversely in man and animals. This effect of zinc is at the end-organ level. It appears that zinc is essential for spermatogenesis. Zinc is involved in many biochemical functions. Several zinc metalloenzymes have been recognized in the past decade. Zinc is required for each step of cell cycle in microorganisms and is essential for DNA synthesis. The effect of zinc on protein synthesis may be attributable to its vital role in nucleic acid metabolism. The activities of many zinc-dependent enzymes have been shown to be affected adversely in zinc-deficient tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Clinical zinc deficiency during adequate enteral nutrition.

Deficiency of zinc (Zn), resulting in characteristic skin changes resembling those seen in acrodermatitis enteropathica, has been reported in patients on total parenteral nutrition, but rarely in patients on long-term enteral feeding. Reported here is a patient who developed characteristic skin changes while he was receiving what was considered to be a balanced liquid enteral diet. The skin rash resolved with Zn supplementation.

Enteral Nutrition↗
PubMed2006

Zinc in skin pathology and care.

OBJECTIVES: To assess the significance of zinc in the etiology of various dermatological conditions and examine the role of zinc as a mode of treatment for a wide range of dermatoses. METHODS: Review of existing literature through searches using the PubMed site with zinc and the dermatosis in question as search words. RESULTS: Severe zinc deficiency states such as acrodermatitis enteropathica are associated with a variety of skin manifestations, such as perioral, acral and perineal dermatitis. These syndromes can be reversed with systemic zinc repletion. In addition to skin pathologies which are clearly zinc-dependent, many dermatological conditions (e.g. dandruff, acne and diaper rash) have been associated and treated with zinc. Success rates for treatment with zinc vary depending on the disease, mode of application and zinc salt used. Usually, alternative modes of treatment are superior to zinc. CONCLUSIONS: Generally, it seems that with the exception of systemic deficiency states, there is very little evidence to convincingly demonstrate the efficacy of zinc as a first-line treatment for any dermatological conditions. Further research is needed in order to establish the indications for zinc treatment in dermatology, optimal mode of delivery, type of compound and therapeutic indexes.

Humans↗
PubMed2000

Antigenic conservation of an immunodominant invariable region of the VlsE lipoprotein among European pathogenic genospecies of Borrelia burgdorferi SL.

Lyme disease is caused by genetically divergent spirochetes, including 3 pathogenic genospecies: Borrelia burgdorferi sensu stricto, B. garinii, and B. afzelii. Serodiagnosis is complicated by this genetic diversity. A synthetic peptide (C(6)), based on the 26-mer invariable region (IR(6)) of the variable surface antigen of B. burgdorferi (VlsE), was used as ELISA antigen, to test serum samples collected from mice experimentally infected with the 3 genospecies and from European patients with Lyme disease. Regardless of the infecting strains, mice produced a strong antibody response to C(6), which indicates that IR(6) is antigenically conserved among the pathogenic genospecies. Twenty of 23 patients with culture-confirmed erythema migrans had a detectable antibody response to C(6). A sensitivity of 95.2% was achieved, with serum samples collected from patients with well-defined acrodermatitis chronica atrophicans. Fourteen of 20 patients with symptoms of late Lyme disease also had a positive anti-IR(6) ELISA. Thus, it is possible that C(6) may be used to serodiagnose Lyme disease universally.

Amino Acid Sequence↗
PubMed1981

Plasma zinc, rate of weight gain, and the energy cost of tissue deposition in children recovering from severe malnutrition on a cow's milk or soya protein based diet.

Thirty-four malnourished children were rehabilitated on either a cow's milk or a soya protein based formula diet. The soya diet contained 25% less zinc than the cow's milk diet and 1.33 mmol/l phytic acid. When the marasmic children were given either of these diets they had a dramatic fall in their plasma zinc concentration. Children given the soya formula had an even more profound drop in plasma zinc, to levels associated with acrodermatitis enteropathica. Plasma zinc remained low throughout the phase of rapid weight gain, but rose when a mixed diet was given and the children ceased gaining weight. There was a negative correlation between the rate of weight gain and the plasma zinc concentration, the rate of new tissue synthesis being the predominant modulator of the plasma zinc concentration. The energy cost of tissue deposition was initially low on the cow's milk diet and relatively high on the soya diet. Later, the energy costs rose in the cow's milk fed children. The rate of weight gain was less on the soya diet; however, the appetite, as measured by the ad libitum dietary intakes, did not differ between the diets, or correlate with the plasma zinc concentration. This may be due to the relatively low protein content of the diets used. It is concluded that dietary zinc may limit the rate of weight gain during periods of recovery in body mass and may be a cause for the excessive deposition of adipose tissue.

Animals↗
PubMed1985

Serum alkaline phosphatase and serum zinc levels in the diagnosis and exclusion of zinc deficiency in man.

In the present study we monitored serum zinc (Zn) and serum alkaline phosphatase (AP) levels during Zn supplementation in (A) a young zinc depletion syndrome (ZDS) patient with severe Zn deficiency, (B) three acrodermatitis enteropathica (AEP) patients with mild Zn deficiency and (C) 7 elderly and 3 younger patients without Zn deficiency. In (A) serum Zn and serum AP values were low, but following parenteral Zn the parameters rose to normal levels (r = +0.79, p less than 0.001). In (B) serum Zn and serum AP levels decreased when oral Zn was stopped, but shortly returned to normal upon reinitiation of Zn. In (C) Zn therapy caused a rise in the serum Zn concentration whereas the serum AP activity decreased (r = -0.01, p greater than 0.1). The results suggest that serial determinations of serum Zn and serum AP during Zn supplementation may be a valid tool in the diagnosis of severe and mild Zn deficiency as well as in the exclusion of the diagnosis.

Adolescent↗
PubMedDate not supplied

Clinical pathologic correlations of Lyme disease.

The multisystem effects caused by Borrelia burgdorferi in Lyme disease are multiple, varied, and unpredictable. In some patients, the full extent of the infection consists of a stage I acute systemic viral-like illness. Stage II primarily involves the cardiovascular system (myocarditis) and/or the central nervous system (CNS) (meningoencephalitis, polyradiculitis). More inflammatory cells are found in the heart and nervous system structures during this intermediate stage than are found in any tissues involved during stage I. Stage III is characterized by peripheral neuropathy and CNS disorders such as dementia or transverse myelitis and arthritis and synovitis of large joints such as the knee. Chronic Lyme disease is also associated with multiple and seemingly unrelated cutaneous manifestations such as acrodermatitis chronica atrophicans, sclerodermoid-like reactions, lichen sclerosus et atrophicus, subcuticular fibrous nodules, eosinophilic fasciitis-like lesions of the extremities, and, possibly, granuloma annulare. With care, spirochetes can be recovered or demonstrated by silver staining in most of the above lesions. Spirochetes have yet to be seen in the tissues of autonomic ganglia or peripheral nerves.

Acute Disease↗
PubMed1984

Identification of copper- and zinc-binding ligands in human and bovine milk.

The object of this study was to identify copper and zinc ligands detected during modified gel chromatography ( MGC ) of bovine and human milk ultrafiltrates. Isolation by anion-exchange chromatography and subsequent proton nuclear magnetic resonance (NMR) spectroscopy analysis demonstrated that the sole major low-molecular-weight ligand binding copper and zinc in bovine milk is citrate. Human milk apparently also contains citrate as a major metal-binding ligand but also contains amino acids, of which primarily glutamate was purified by anion-exchange chromatography. The amino acids bind copper well but are weak zinc-binding ligands. An artifactual MGC peak was seen in the milks, which was shown to be caused by the calcium present in the milk samples. No major differences in zinc-binding capacity were demonstrated between the low-molecular-weight fractions of the two milks. Although citrate may play a role in zinc uptake, it is apparently not the difference between the milks crucial to the acrodermatitis enteropathica individual. The difference in zinc availability between the milks may lie in some other aspect such as binding by proteins, which were noted to bind metal during MGC of nonultrafiltered milks.

Amino Acids↗
PubMed2000

The dynamic link between the integrity of the immune system and zinc status.

The results of more than three decades of work indicate that zinc deficiency rapidly diminishes antibody- and cell-mediated responses in both humans and animals. The moderate deficiencies in zinc noted in sickle cell anemia, renal disease, chronic gastrointestinal disorders and acrodermatitis enteropathica; subjects with human immunodeficiency virus; children with diarrhea; and elderly persons can greatly alter host defense systems, leading to increases in opportunistic infections and mortality rates. Conversely, short periods of zinc supplementation substantially improve immune defense in individuals with these diseases. Mouse models demonstrate that 30 d of suboptimal intake of zinc can lead to 30-80% losses in defense capacity. Collectively, the data clearly demonstrate that immune integrity is tightly linked to zinc status. Lymphopenia and thymic atrophy, which were the early hallmarks of zinc deficiency, are now known to be due to high losses of precursor T and B cells in the bone marrow. This ultimately leads to lymphopenia or a failure to replenish the lymphocytic system. Glucocorticoid-mediated apoptosis induced by zinc deficiency causes down-regulation of lymphopoiesis. Indeed, zinc itself can modulate death processes in precursor lymphocytes. Finally, there is substantial evidence that zinc supplementation may well reduce the impact of many of the aforementioned diseases by preventing the dismantling of the immune system. The latter represents an important area for research.

Aged↗
PubMed1987

Histological evidence for spirochetal origin of morphea and lichen sclerosus et atrophicans.

In order to elucidate the possible spirochetal origin of morphea and lichen sclerosus et atrophicans (LSA), we investigated biopsy specimens from 13 patients with morphea and 13 patients with LSA. Four patients with acrodermatitis chronica atrophicans (ACA), three with erythema chronicum migrans (ECM), and 11 patients with other inflammatory dermatoses served as controls. Formalin-fixed, paraffin-embedded sections were stained by an avidin-biotin-immunoperoxidase method, using serum of a patient with ACA that contained IgG antibodies to Borrelia burgdorferi. As positive control substrate, formalin-fixed culture suspensions of B. burgdorferi strain B31 were used. They presented either as thin, mostly linear, but partially dotted, stained spirochetes or, in contrast, as thick, "swollen," heavily stained organisms. Identical structures could also be detected on histological sections of one patient with ECM, four patients with morphea, and six patients with LSA. These findings provide evidence for the spirochetal origin of both morphea and LSA.

Adult↗
PubMed1990

Spirochetal forms in the dermal lesions of morphea and lichen sclerosus et atrophicus.

Morphea and lichen sclerosus et atrophicus are cutaneous diseases that are manifest by an early edematous stage, followed later by sclerosis and atrophy. They share features with acrodermatitis chronica atrophicans and erythema chronicum migrans, diseases that have been linked to infection by the spirochete Borrelia burgdorferi. A modified silver stain was used to identify the presence of spirochetes in skin biopsy specimens of patients with morphea and lichen sclerosus et atrophicus. Spirochetal forms were identified in the lesional skin of 10 of 25 patients with morphea and in 10 of 21 cases of lichen sclerosus et atrophicus. These spiral forms of bacteria had a significant tendency to occur in early and fully developed lesions of morphea and in early lesions of lichen sclerosus et atrophicus, whereas they tended to be absent in lesions demonstrating late pathological changes.

Atrophy↗
PubMed1987

The surgical pathology of human Lyme disease. An enlarging picture.

Lyme disease is a multisystems infectious disorder caused by the spirochete, Borrelia burgdorferi. Infection occurs by ticks feeding on mammalian hosts, including humans. The distribution of the tick and spirochete is world-wide and is especially prevalent where there are large deer populations. The disease is seen in three stages. Stage I is a cutaneous rash (erythema chronicum migrans) consisting of lymphoplasmacytic infiltrates around dermal vessels. Stage II is characterized by varying forms of meningopolyradiculitis, with or without Bell's palsy or cardiac involvement (complete or incomplete heart block) and with interstitial endomyocarditis of lymphocytes and plasma cells. Lymphoplasmacellular infiltration is seen in the meninges, ganglia, and peripheral nerves. Chronic and intermittent oligoarthritis is the hallmark of stage III disease, characterized by hypertrophic synovitis, often with fibrinaceous deposits and synovial vascular occlusion. Stage III chronic dermatologic syndromes (lymphadenosis benigna cutis, acrodermatitis chronicum atrophicans) consist of cutaneous lymphoid hyperplasia and vascular changes. Neurologic demyelination syndromes also occur in stage III. Plasma cells occur in all stages, but are more prominent in stages II and III. Spirochetes can be demonstrated by silver impregnation stains in some cases.

Arachnid Vectors↗
PubMed1994

Primary cutaneous immunocytoma. A B-cell lymphoma that can easily be mistaken for cutaneous lymphoid hyperplasia.

It has been estimated that immunocytomas comprise roughly 2% of all cutaneous lymphomas. We studied five patients with primary cutaneous immunocytomas who presented with cutaneous nodules or plaques. Many of the infiltrates were "top-heavy" and polymorphous with admixed eosinophils, macrophages, lymphoid follicles, and non-neoplastic lymphocytes. Other potentially confusing findings were one case each of spongiotic dermatitis and leukocytoclastic vasculitis. The neoplastic cells were often situated at the peripheries of nodules and ranged from those with nuclei that resembled small lymphocytes to others that resembled immunoblasts. Most had eccentrically placed nuclei and fan-shaped cytoplasm. Monotypic kappa-light chain was found in all five cases, accompanied by gamma-heavy chain in two cases, and mu-heavy chain in one. In situ hybridization detected only kappa-mRNA in the four cases that yielded technically satisfactory results. The neoplastic cells did not express the B-cell antigen CD20; T-cells formed the centers of many nodules. Inappropriate staining for CD43 was evident in the neoplastic cells of one case. Because of reports of immunocytomas complicating acrodermatitis chronica atrophicans, we stained sections with an antiserum to Borrelia burgdorferi, which did not detect that organism. In situ hybridization did not detect EBER-1 RNA of the Epstein-Barr virus, which can be present in immunocytomas in immunocompromised patients. One patient died of disease after failing chemotherapy; another is alive with disseminated disease, and three are in remission following excision of lesions alone in two patients and chemotherapy in one patient who had relapsed following both excision and radiation therapy.

Adult↗
PubMed1976

A syndrome of acute zinc deficiency during total parenteral alimentation in man.

Changes in the plasma and urine levels of the trace metal zinc have been followed in a series of 37 adult patients totally supported by intravenous alimentation. Copper has also been determined in more recent cases. In such a seriously ill group, although urinary zinc loss may be very high at the height of catabolism, severe plasma depletion does not occur unless there is a subsequent phase of sustained anabolism and weight gain. In four patients plasma zinc fell to very low levels during this phase and three of this group developed a syndrome characterized by diarrhea, mental depression, para-nasal, oral and peri-oral dermatitis, and alopecia. The response to oral or intravenous zinc therapy is striking, except for hair regrowth which is delayed but eventually complete. The syndrome we have recognized in adult man has not been previously described. It resembles however the parakeratosis of zinc deficient swine and it is also very similar to Acrodermatitis enteropathica, a genetically determined disorder of infants very recently linked to zinc deficiency. Zinc is clearly essential to human metabolism and it should be included in all parenteral alimentation regimes particularly during the period of rapid, sustained, weight gain.

Adult↗
PubMed1994

Successful amplification of DNA specific for Finnish Borrelia burgdorferi isolates in erythema chronicum migrans but not in circumscribed scleroderma lesions.

Early diagnosis of Borrelia burgdorferi infection, hampered by the absence of detectable antibodies in most patients with erythema chronicum migrans is important to prevent late-stage neurologic, rheumatologic, and skin disorders. Furthermore, B. burgdorferi has been claimed to be the causative agent in localized scleroderma (morphea). We used PCR amplification to search for B. burgdorferi outer surface protein OspA-specific sequences in DNA obtained from lesional skin biopsies on Finnish patients with clinically suspect erythema chronicum migrans, lymphocytoma, morphea, or with diverse skin manifestations and persistent high antibodies to B. burgdorferi flagellar antigen. Seronegative patients with other skin lesions served as controls. The amplicons obtained with primers specific for B. burgdorferi type strain B31 ospA sequence did not hybridize to the corresponding probes, and thus the DNA amplified from a Finnish B. burgdorferi erythema chronicum migrans skin isolate was sequenced. This 98-nucleotide sequence of ospA (332-429) showed 11% to 14% nucleotide divergence compared with the North American type strain (B31), several European strains, and an East Siberian tick strain. The sequence was almost identical (99%) to a Swedish isolate from acrodermatitis chronica atrophicans. Using oligonucleotides specific for the Finnish strain, a positive polymerase chain reaction-based hybridization was obtained in six of seven untreated erythema chronicum migrans patients infected in Finland or in Estonia, and in the lymphocytoma patient. Only two of the erythema chronicum migrans patients had IgG or IgM antibodies to flagellin. However, all seven morphea lesions as well as the other lesions were polymerase chain reaction negative. Polymerase chain reaction-based hybridization of B. burgdorferi OspA gene from skin-derived DNA thus provides a sensitive and specific diagnostic tool. In conditions not unequivocally known to be caused by B. burgdorferi, like in morphea, this assay was negative. We also demonstrate that peri-Baltic B. burgdorferi isolates show homology in their OspA genes but differ from geographically more distant isolates.

Antibodies, Bacterial↗
PubMed2004

Cutaneous inflammatory pseudotumor--a spectrum of various diseases?

BACKGROUND: Inflammatory pseudotumor (IPT) also known as inflammatory myofibroblastic tumor (IMT) or plasma cell granuloma (PCG) has been rarely reported in the skin. METHODS: We describe five patients with cutaneous IPT and present clinicopathologic features along with detailed immunohistochemical analysis including anaplastic lymphoma kinase (ALK)-1. RESULTS: The patients age ranged from 15 to 89 years with a median of 56 years. All patients presented with solitary, firm, papules and nodules. There was no evidence of constitutional symptoms, local recurrence, or lymph node involvement. Histopathological examination revealed two distinct patterns; one type (n = 3) displayed dense, lymphoplasmacytoid infiltrates containing lymphoplasmacytoid cells and plasma cells with occasional germinal centers and hyalinized collagen bundles but was devoid of a myofibroblastic component. It showed features of tumors previously described as cutaneous PCG. Although an infectious etiology, including Borrelia burgdorferi-specific DNA, could not be demonstrated, we observed many features that overlapped with those of fibrous nodules of acrodermatitis chronica atrophicans. The other pattern (n = 2) revealed spindled myofibroblasts focally arranged in a fascicular pattern, an admixed lymphoplasmacytoid infiltrate set in a background of thickened collagen bundles, findings akin to the conventional type of IMT. The cases with a myofibroblastic component (n = 2) did not show any evidence of ALK-1 reactivity. CONCLUSIONS: We believe that the term cutaneous IPT subsumes lesions of diverse etiology. Tumors with detectable myofibroblasts represent true cases of IMT. Cutaneous PCG is a discrete disorder biologically distinct from conventional IMT representing a reaction pattern that is also found in disorders, such as spirochete-induced fibroid nodules and localized chronic fibrosing vasculitis.

Activin Receptors, Type I↗
PubMed1991

Lyme borreliosis--a review and present situation in Japan.

The skin diseases Erythema (chronicum) migrans (ECM, EM), Lymphadenosis benigna cutis (LABC), and Acrodermatitis chronica atrophicans (ACA) have long been described in northern Europe, and dermatologists are very familiar with these manifestations, which have been successfully treated with penicillin for about 40 years without the causative agent being known. Certain neurologic symptoms could be linked to tickbites during the 1920's and later also to EM. In 1977, Steere et al. reported a new form of inflammatory arthritis, mainly in school children in the community of Lyme, Connecticut, U.S.A., which they could also associate with preceding erythema and tickbites. Five years later, Burgdorfer was able to isolate Borrelia spirochetes from Ixodes ticks, which are known to be vectors of Lyme disease as well as of EM and ACA. The following year, Borrelia spirochetes were also isolated from Ixodes ticks and from skin lesions of patients in Sweden and Germany. These findings resulted in a large number of reports of new discoveries related to this infection, which is now known under the names of tick-borne or Lyme borreliosis and, in the U.S., also as Lyme disease or Lyme arthritis. It has proven to be a great imitator disease, mainly through its involvement of the neurological system, and to be far more widespread than previously thought. The full course of the disease is not yet known, however it is clinically, like another spirochetosis, syphilis, divided into early and late stages. Manifestations involve mainly the skin, the joints, the nervous system (Neuroborreliosis), and the heart. Antibiotic treatment is effective, especially in the early stages. Like syphilis, the disease can be self-healing without treatment. People who are exposed to ticks should be aware of the risk of contracting this disease, also in Japan where Ixodes ticks have been shown to be carriers of Borrelia spirochetes. Cases, particularly of EM, but also with neurological symptoms, have already been diagnosed in Hokkaido, Honshu, Shikoku, and Kyushu. As Lyme borreliosis is now proven to exist in Japan, it is beneficial for dermatologists to know about the various presentations of this disease. This paper will briefly summarize the historical background, the clinical stages, the diagnosis, and the treatment of Lyme borreliosis, with a summary of the present situation in Japan.

Animals↗