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PubMed1992

Detection of mutations in the insulin receptor gene in patients with insulin resistance by analysis of single-stranded conformational polymorphisms.

We analyzed single-stranded conformational polymorphisms to screen for mutations and polymorphisms in the insulin receptor gene in subjects with or without insulin resistance. Using this new technique, we demonstrated the existence of mutations in the insulin receptor gene which we had identified previously. In addition, a new mutation was found in exon 20 of the insulin receptor gene in a patient with moderate insulin resistance associated with morbid obesity, acanthosis nigricans, and polycystic ovary syndrome. The patient was heterozygous for a mutation substituting Leu (CTG) for Pro (CCG) at codon 1178. Pro1178 is a part of a characteristic sequence motif (D1150 F1151 G1152---A1177 P1178 E1179) common to many protein kinases. Analysis of single-stranded conformational polymorphisms was also used to estimate the frequency of a polymorphism at codon 1058. The two codons CAC (1058 His) and CAT (1058 His) both had a prevalence of 50% in 30 Japanese subjects. These data demonstrate that analysis of single-stranded conformational polymorphisms is a simple and sensitive screening method for mutations and polymorphisms in the insulin receptor gene in subjects with or without insulin resistance. Identification of a mutation in the insulin receptor gene in a patient with a moderate degree of insulin resistance associated with morbid obesity suggests that insulin receptor mutations may exist in patients with Type 2 (non-insulin-dependent) diabetes mellitus associated with a moderate degree of insulin resistance.

Amino Acid Sequence↗
PubMed1991

Recombinant human insulin-like growth factor I (rhIGF I) reduces hyperglycaemia in patients with extreme insulin resistance.

The syndrome of type A insulin resistance is encountered in young women and is characterized by glucose intolerance or frank diabetes mellitus, endogenous hyperinsulinism, insensitivity to insulin administration, acanthosis nigricans and virilization. The insulin resistance is due to reduced cellular insulin binding because of a lack of or defective binding sites and/or because the interaction with the tyrosine kinase of the beta-subunit is hindered. This study was undertaken to find out whether hyperglycaemia in these patients may be influenced by the administration of recombinant human insulin-like growth factor I which exerts insulin-like effects through the insulin receptor as well as the type 1 insulin-like growth factor I receptor. Recombinant human insulin-like growth factor I was intravenously administered in two subsequent doses of 100 micrograms/kg body weight to three women with type A insulin resistance. An immediate but slow fall of blood glucose was observed. The glucose disappearance rate was 28.0 mumol/min, i.e. considerably lower than that seen in healthy subjects. The markedly elevated insulin and C-peptide levels fell in a parallel manner to blood glucose but not to normal levels. The results show that recombinant human insulin-like growth factor I, presumably by reacting with the type 1 insulin-like growth factor receptor, can normalize serum glucose levels in patients with severe insulin resistance at least for several hours. We suggest that the potential or recombinant human insulin-like growth factor I to control hyperglycaemia in type A insulin resistant patients should be explored in more depth.

Adolescent↗
PubMed1988

Relationship between macrophage infiltration and epidermopoiesis in delayed-type hypersensitivity.

The relationship between epidermopoiesis and macrophage infiltration was studied in delayed-type hypersensitivity (DTH) skin lesions in guinea pigs that had been sensitized with heat-killed tubercle bacilli or bovine serum albumin (BSA). Macrophages were identified with acid-phosphatase and nonspecific esterase stains, and the epidermal proliferative response was studied at DTH challenge sites by autoradiography. The number of macrophages in the sensitized animals was higher than that in the nonsensitized animals 48-72 h following challenge injections, when labelling indices were also elevated in the former group. Soluble factor(s) from cultured macrophages transiently enhanced the DNA synthesis of epidermal cells in cultures and in the sites injected with the factor(s). These results suggest that macrophages retained in the DTH lesion may play a role in an acceleration of epidermal proliferation, thus leading to acanthosis and lichenification.

Animals↗
PubMed1979

In vitro examination of cell proliferation in dermatofibroma and in the overlying epidermis.

In nine typical cases of dermatofibroma autoradiographic methods were used to examine the proliferative activity in the tumor and in the overlying epidermis. The number of DNA-synthesizing cells in the dermal nodular lesions was extremely low (0 -- 0.1%). In seven of nine skin lesions acanthosis was to be seen in the overlying epidermis. The quantity of DNA-synthesizing cells in the epidermis overlying the dermatofibroma was not related to the thickness of the epidermis and remained independent, whether the predominant element in the tumor is fibrillar or cellular. In this study we were able to demonstrate the existence of a direct relation between the degree of epidermal proliferation and the distance between the tumor and the epidermis. The duration of DNA-synthesis was constant.

Cell Division↗
PubMed1984

Dermatopathological studies on skin lesions of MRL mice.

The MRL-lpr/lpr(MRL/l) mouse is a new animal model for human systemic lupus erythematosus (SLE) and skin lesions with hair loss and scab formation are one of the characteristic manifestations in this mouse. We investigated the histopathology of the skin lesions in MRL/l mice and studied the related autoimmune phenomenon. Light microscopical observations revealed hyperkeratosis, acanthosis, hypergranulosis, liquefaction, vasodilation in the dermis and T-cell infiltration into the dermis at the age of 5 months (mo). Immunohistological studies showed the presence of immunoglobulins and/or complement depositions at the dermal-epidermal junction (DEJ). In some mice there was deposition of immunoglobulin at the DEJ at 2 mo and in 90%-100% of MRL/l mice at over 5 mo. Temporal relationship was present among cutaneous immunoglobulin depositions, the occurrence of anti-DNA antibodies and proteinuria. These findings suggest that MRL/l mice might provide a new aid for studying the biological mechanisms of the development of skin lesions in human SLE.

Age Factors↗
PubMed1987

Verrucous carcinoma of the larynx--a misnomer.

A serie of our observations of so-called "verrucous carcinomas" of the larynx show that these peculiar lesions do not develop true infiltrating growths or metastases, and do not fulfill the criteria of a true carcinoma. Our experiences indicate that these cases can be treated successfully by repeated endoscopic resections. We have found that no aggressive radical treatment - either by surgery or irradiation - is necessary in managing these lesions. Although the etiology of "Ackerman's tumor" of the larynx is still uncertain, we suggest that the lesions develop as the result of a virus infection and propose again the term "verrucous acanthosis" instead of verrucous carcinoma for this disease.

Carcinoma, Papillary↗
PubMed1982

Psoriatic leukotactic factor. Further physicochemical characterization and effect on the epidermal cells.

A leukocyte chemotactic factor with a molecular weight of around 12,500 daltons is found in large amounts in psoriatic scales. Except for complement-activated serum none of the extracts prepared from individual contaminants found in psoriatic scales showed an elution pattern similar to that of the psoriatic leukotactic factor (PLF) by Sephadex G-75 chromatography. Checkerboard experiments showed that PLF was highly chemotactic and mildly chemokinetic for polymorphonuclear leukocytes (PMNs). Purification of PLF yielded a cationic peptide fraction similar to that of anaphylatoxin. Intradermal injection of a potent PLF solution into guinea pigs produced degenerative changes in the epidermis within 24 h, particularly in the differentiated cells of the upper epidermis. It increased epidermopoiesis as assessed by incorporation of 3H-thymidine. Planimetric analysis of the epidermis revealed a marked increase in epidermal thickness after 5 days. Since PLF per se did not influence the proliferative capabilities of isolated basal cells or exert any damaging effect on differentiated epidermal cells in human epidermal cell culture, we speculated that PLF induced the advent of PMNs abound with hydrolytic enzymes and toxic substances, which were responsible for the damage of the upper epidermis resulting in the formation of parakeratosis and of acanthosis.

Animals↗
PubMed1983

Keratin polypeptide composition as a biochemical tool for the discrimination of benign and malignant epithelial lesions in man.

An investigation was undertaken of the keratin polypeptides of various benign and malignant tumors of the human skin and vaginal epithelium by one and two dimensional gel electrophoresis. The keratin patterns of benign tumors were found to be similar to the patterns of normal epithelium or stratum corneum. The relative proportion of stratum-corneum associated keratin polypeptides to those polypeptides characteristic for the living layers corresponds to morphological features (e.g., hyperkeratosis, acanthosis). In contrast to benign tumors, epithelial carcinomas totally lack the group of high-molecular-weight keratins. This finding may be helpful in the diagnostic discrimination between benign and malignant epithelial lesions.

Electrophoresis↗
PubMed1977

Disturbance of DNA-Synthesis in early psoriasis.

In earlier studies we have shown that there is a significant prolongation of DNA-synthesis time (ts) in the epidermal cells of fully developed psoriatic lesions. The present study shows that this prolongation is to be observed even in very early plaques. The prolongation of ts precedes the development of acanthosis. A dermal infiltrate with increased proliferative activity seems to be a stimulus, in the sense of a Koebner-phenomenon. There is no pronounced prolongation of ts in other acute or chronic inflammatory processes of the skin. The behaviour of the infiltrate in psoriasis is similar to that in allergic patch test reaction. However, the abnormal psoriatic epidermis, with disturbed DNA-synthesis, does not react to the above mentioned infiltrate with a limited hyperproliferation but with the development of a psoriatic plaque. There is obviously congenital disturbances of metabolism within the epidermal cells in psoriasis.

Acute Disease↗
PubMed1980

Epidermal changes induced by oral excess of aromatic retinoid in guinea pigs.

The effect of oral aromatic retinoid Ro 10-9359 in a high dosage (25 mg/kg/day) on guinea pig epidermis was investigated by light and electron microscopy. The induced morphological alterations showed two different stages: (a) In the injury stage, seen aftr one week of retinoid administraion, the epidermis was mainly characterized by lack of the horny layer and vacuolar cytoplasmic disintergration of the malpighian layer with intracellular edema and accumulation of some PAS-positive material. Tonofilaments and desmosomes were markedly reduced, keratinosomes were increased in number. (b) In the recovery stage, seen after 3 weeks of administration, the horny layer had reappeared, the edematous and vacuolar changes were diminished and the epidermis became slightly acanthotic. Hypergranulosis with numerous spongiform keratohyalin granules was a prominent feature. The number of tonofilaments, desmosomes, and keratinosomes showed a clear tendency to normalization. In conclusion, high systemic doses of aromatic retinoid initially exert a cytotoxic, keratolytic, and mucoplastic effect on the normal guinea pig epidermis. Nevertheless, the affected keratinocytes adapt themselves, despite the further administration of the drug, showing a gradual restoration of these changes and a stimulation of epidermal proliferation, leading to acanthosis.

Animals↗
PubMed1976

[Sebaceous filaments (author's transl)].

Sebaceous filaments are cylindrical tubes of whitish-yellowish color, which can be expressed from areas of the face rich in sebaceous follicles by pinching the skin or by the cyanoacrylat-technique. Sebaceous filaments are most commonly found in the centrofacial areas and the alae nasae in postpuberal individuals with large facial pores and seborrhea. Sebaceous filaments are composed of a skeleton of 10-30 horny cell layers which enclose a mixture of bacteria, sebaceous lipid, corneocyte fragments and one hair. Following the expression of the filament the follicle refills within 30 days. The various portions of sebaceous follicles (acro- and infrainfundibulum) and the follicular contents are presented at the light microscopial and ultrastructural level. Follicles containing sebaceous filaments have a conspicuous granular layer and no acanthosis. Sebaceous filaments should be differentiated from a microcomedo and trichostasis spinolosa. They are a common morphological variant of sebaceous follicles.

Acne Vulgaris↗
PubMed1977

The nature and frequency of the histological changes found in psoriasis vulgaris.

A total of 272 biopsies (from psoriatic lesions with a diameter of 2-10 cm) were performed on 178 psoriasis patients. Sections from these biopsies were stained with haematoxylin-eosin and by the PAS and trichrome techniques. Each section was investigated for the presence or absence of para- and hyperkeratosis, acanthosis, mitoses, intercellular edema and spongiosis of the epithelial ridges, edema at the top of the connective tissue-papillae, the number of leucocytes penetrating the epidermis at the top of these papillae, classical Munro abscesses, abscesses in the horny layer and Kogoj spongiform pustules, and the results were noted. It was found that the site of the biopsy in the psoriasis lesion, the location of the psoriasis lesion from which material for biopsy was taken and the moment of time during the course of the disease at which the biopsy was performed, had no influence on the histological signs observed in a given patient. In other words, the histological picture of psoriasis plaques from 2-10 cm found in a given patient exhibits a high degree of constancy. Some evidence was found indicating that signs of latent psoriasis may probably be present in the healthy skin of a psoriasis patient. It is generally assumed that the epidermis above the connective tissue-papillae in cases of psoriasis is thinner than normal. Our investigation showed that the reverse is the case: the thickness of the epidermis in the psoriasis efflorescences is significantly greater than in healthy skin nearby in the same patient.

Humans↗
PubMed1977

[Histopathology and histochemistry of psoriasis under photochemotherapy (author's transl)].

Fifty-two biopsies from involved and clinically normal looking skin of patients with psoriasis vulgaris and from normal control subjects, all being treated with 8-MOP-UVA (PUVA) were obtained between days 2 and 300. The following parameters were investigated: 1. initial PUVA effects; 2. initial regression of psoriasis under PUVA-therapy; 3. late effects of PUVA-therapy on regression of psoriatic lesions; 4. EFFects on melanocytes and pigmentation; and 5. long-term effects of PUVA-therapy. Paraffin embedded and cryostat sections were prepared with routine stains for light microscopy and enzyme histochemical special stains. The regression of psoriatic lesions following PUVA-therapy was separately assessed for epidermal and dermal components. The sequence of events was as follows: re-establishment of a continous stratum granulosum, re-establishment of a continuous normal appearing stratum corneum, regression of acanthosis and papillomatosis, and regression of inflammatory infiltration. During the initial phase of PUVA-therapy there is a sharp increase of melanocytes which leads to a foamy appearance of the basal cell area. Long term studies did not reveal actinic damage of the skin, neither in the epidermis (absence of actinic keratoses or squamous cell carcinomas) nor in the dermis (absence of actinic "solar" elastosis).

Histocytochemistry↗
PubMed1990

Inflammation of guinea pig dermis. Effects of leukotriene B4 receptor antagonist, SC-41930.

Neutrophil (PMNL) infiltration is a prominent feature of human psoriasis. Psoriatic skin lesions contain abnormally high amounts of leukotriene B4 (LTB4), itself a potent PMNL chemoattractant both in vivo and in vitro. SC-41930 (7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8- propyl-2H-1-benzopyran-2-carboxylic acid), an orally active LTB4 receptor antagonist, was tested topically in models of skin inflammation induced by 200 nmol of the calcium ionophore A23187 or 200 micrograms phorbol-12-myristate-13-acetate (PMA) applied topically to the guinea pig ear as assessed by ear weight, levels of the PMNL marker enzyme myeloperoxidase (MPO), and histological examination (PMA model) at 4 and 18 h respectively. When coapplied topically with A23187 or PMA, SC-41930 significantly inhibited epidermal inflammation with ED50 values of 0.6 and 4 mg, respectively. SC-41930 treatment also was associated with lowered dermal LTB4 levels in both models. The PMA-induced skin inflammation model also was assessed histologically and revealed acanthosis, edema, PMNL infiltration, and rete ridge prominence as long as 96 h after a single application that was completely inhibited by SC-41930 topical coapplication. Furthermore, oral treatment (40 mg/kg) significantly reduced edema and inflammatory cell infiltration in both models. These models possess many of the characteristics of human psoriasis, and agents such as SC-41930 that demonstrate activity in these models may well have therapeutic utility in the treatment of human psoriasis.

Administration, Cutaneous↗
PubMed1976

Leukoplakia of the anal canal.

Two cases of leukoplakia of the anal canal are presented, with illustrations of the typical gross and microscopic appearance. The lesions were asymptomatic, and were discovered by routine rectal examination. Histological findings included hyperkeratosis and acanthosis extending cephalad from the anal verge to the dentate line. Followup after 3 and 15 years revealed no evidence of dysplastic changes, and a review of the literature did not uncover any reported cases with dysplasia or with documented evolution to malignancy. There is little evidence that leukoplakia of the anal canal is premalignant but patients should be followed carefully, since the natural history of this rare lesion is unknown.

Adult↗
PubMed1995

Altered distribution of keratinization markers in epidermolytic hyperkeratosis.

Epidermolytic hyperkeratosis (EH) is a genetic disorder of keratins associated with epidermal differentiation. Affected individuals carry gene mutations for conserved sequences of keratins K1 or K10. The structural alterations of tonofilaments in EH seem to be a direct consequence of the keratin gene mutations. EH epidermis, however, shows many other unexplained abnormalities including acanthosis, hypergranulosis, and hyperkeratosis. To further elucidate the pathogenetic mechanism of EH, we studied distribution patterns of other keratinization-associated molecules including involucrin, small proline-rich protein (SPRR) 1, loricrin and trichohyalin in the skin of four patients by light and electron microscopic immunohistochemistry in conjunction with conventional transmission electron microscopy. The middle to upper epidermal cells showed moderate to strong immunoreactivities to involucrin, SPRR1 and loricrin antibodies. Both intracellular staining and cell peripheral staining was seen for involucrin and SPRR1 antibodies. Loricrin labelling was prematurely associated with the plasma membrane of granular cells, possibly relating to abnormal keratin filament aggregation and cellular vacuolization. Some loricrin labelling was localized on the keratin aggregates, suggesting intermolecular associations between keratin and loricrin. Trichohyalin, hardly detectable in normal epidermis, was present in some granular and cornified cells in EH in association with keratin filaments, suggesting that it may function as an intermediate filament-associated protein. While cornified cell envelopes were intensely labelled only with loricrin antibodies in normal skin, they were immunoreactive to involucrin, SPRR1 and loricrin antibodies in EH. Sequential change in electron density of the cornified cell envelopes, a constant feature in normal skin, was often absent in EH. These results suggest an altered assembly process of cornified cell envelopes in EH.

Adolescent↗
PubMed1981

Granular cell tumors of the gastrointestinal tract and perianal region: a study of 74 cases.

Seventy-four patients with 75 examples of granular cell tumors occurring in the gastrointestinal tract and perianal region were studied. Twenty-four were located in the esophagus, eight in the stomach, three in the small bowel, four in the appendix, twenty in the large bowel, and sixteen in the perianal region. Nine cases had multiple tumors either occurring in the same area of the bowel or in other organs, mostly the skin. Approximately 50% of the tumors occurring in the esophagus and perianal region showed varying degrees of acanthosis or pseudoepitheliomatous hyperplasia. In the perianal tumors the pseudoepitheliomatous hyperplasia was much more extensive and could be mistaken for squamous cell carcinoma. The world literature was reviewed and a total of 66 cases of granular cell tumors were reported in the area of study. In neither our 74 nor the other reported cases was there evidence of recurrence or malignant behavior of the tumors, thus confirming their benign biologic behavior.

Adolescent↗
PubMed1985

Significance of diffuse granularity and nodularity of the esophageal mucosa at double-contrast radiography.

Out of 5000 consecutive double-contrast examinations of the esophagus, 50 cases presented a diffuse finely granular or nodular appearance of the mucosa. Endoscopy was subsequently performed in 38 cases and biopsy in the majority of these. In 23 of the 38 verified cases the diagnosis was reflux esophagitis. In the other 15 cases the diagnoses were: candidal esophagitis (4), leukoplakia (2), glycogenic acanthosis (1), and diffuse leiomyomatosis (1). A normal mucosa was demonstrated in 7 cases. Our study indicates that a radiologically granular or nodular appearance of the esophageal mucosa often indicates reflux esophagitis and less commonly identifies diffuse lesions of variable origin.

Biopsy↗