Generalized lupus panniculitis and antiphospholipid syndrome in a patient without complement deficiency.

Generalized chronic cutaneous lupus including lupus panniculitis in childhood is rare and usually occurs in the setting of genetic complement deficiencies. The association with antiphospholipid syndrome is even more rare. We report a 13-year-old girl with extensive lupus panniculitis since the age of 8 months and no evidence of complement deficiency. She recently developed antiphospholipid syndrome characterized by anticardiolipin antibodies and digital necrosis.

"Centripetal flagellate erythema": a cutaneous manifestation associated with dermatomyositis.

We describe 3 patients with dermatomyositis who presented with flagellate erythema. This cutaneous eruption is characterized by erythematous linear lesions on the trunk and proximal extremities. Histologic examination of this eruption in one of our cases revealed an interface dermatitis. Review of the literature and records of 183 patients with connective tissue diseases from our institution has shown that this peculiar eruption has been reported only in dermatomyositis. Because of the location of this eruption, we encourage the use of the term "centripetal flagellate erythema" to distinguish this entity from other linear eruptions seen in patients with connective tissue diseases.

Alternative medicine. Is it all in your mind?

Therapeutic interventions may trigger nonspecific mechanisms whose effects are not attributable to the specific properties of a given treatment. Recent investigations on the placebo effect as well as other mind-body interactions are helping us to understand some of the underlying mechanisms, as well as beginning to provide us with potentially effective adjuvant treatment strategies for a variety of human diseases.

Rapid increases in peptide processing enzyme expression in hippocampal neurons.

Recent studies have demonstrated that seizure activity causes a dramatic increase in neuropeptide expression in specific regions of the rat hippocampus. In this study we investigated the effect of electroconvulsive treatment (ECT) on the expression of three posttranslational processing enzymes involved in the production of many bioactive peptides from their inactive precursors. Peptidylglycine alpha-amidating monooxygenase (PAM) converts peptidylglycine substrates into alpha-amidated products and prohormone convertases 1 and 2 perform the tissue-specific endoproteolytic cleavage of many prohormones. After a single ECT, in situ hybridization demonstrated a rapid increase in the level of PAM mRNA in the dentate granule cells of the hippocampus, reaching peak levels between 1 and 4 h and then returning to near baseline levels within 24 h. Northern blot analysis confirmed the changes in PAM mRNA expression seen by using in situ hybridization. Similar rapid changes in PAM mRNA expression were seen after repeated ECT, suggesting that chronic ECT did not affect the regulation of PAM expression in the hippocampus. Immunohistochemical staining demonstrated an increase in PAM protein in the molecular layer of the dentate gyrus at 4 and 8 h after a single ECT. Based on in situ hybridization, levels of mRNA for the prohormone convertases 1 and 2 were also increased in dentate granule cells after a single ECT. Prohormone convertase 2 mRNA levels exhibited a slower response to ECT, not reaching maximal levels until 8 h after ECT. The response of the dentate granule cells of the hippocampus to ECT provides a model system for studying the rapid, coordinate regulation of peptide-processing enzymes.

Use of endoproteases to identify catalytic domains, linker regions, and functional interactions in soluble peptidylglycine alpha-amidating monooxygenase.

The production of alpha-amidated peptides is accomplished through the sequential action of two enzymes, peptidylglycine alpha-hydroxylating monooxygenase (PHM) and peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL), that are contained within the bifunctional peptidylglycine alpha-amidating monooxygenase (PAM) protein. Tissue-specific alternative splicing and endoproteolysis are known to generate both soluble and integral membrane mono- and bifunctional PAM proteins. In order to investigate the functional consequences of these differences we purified PAM-3, a soluble 95-kDa bifunctional form of the enzyme, from the spent medium of stably transfected hEK-293 cells. Using NH2-terminal sequence analysis of products of limited endoproteolysis and antibody cross-reactivity we identified protease-sensitive regions at the NH2 terminus, between the 35-kDa PHM and 42-kDa PAL domains and at the COOH terminus of the protein. Endoproteolytic removal of the COOH-terminal region from the bifunctional PAM-3 protein shifted the pH optimum of PHM to a more alkaline pH, increased the turnover number (kappa(cat)) of PHM and decreased its KM for alpha-N-acetyl-Tyr-Val-Gly; the catalytic properties of PAL were not altered. Since peptide amidation can be a rate-limiting step in the biosynthesis of neuropeptides, similar increases in PHM activity in vivo may play an important role in regulating the extent of peptide alpha-amidation.

Expression of a peptide processing enzyme in cultured cells: truncation mutants reveal a routing domain.

Peptidylglycine alpha-amidating monooxygenase (PAM) is a bifunctional enzyme responsible for the alpha-amidation of peptides in secretory granules of neuroendocrine cells. The single gene encoding PAM undergoes tissue-specific alternative splicing and endoproteolytic processing to generate bifunctional membrane proteins with a single transmembrane domain as well as soluble proteins that are mono- or bifunctional. In order to examine the endoproteolytic processing and subcellular localization of the various forms of PAM in cells lacking regulated secretory granules, we established stably transfected hEK-293 cell lines expressing naturally occurring and mutant forms of PAM. As expected, newly synthesized soluble PAM proteins were rapidly secreted into the medium. Integral membrane protein forms of PAM were largely localized in the perinuclear region with punctate staining visible throughout the cell and 2-5% of the enzyme activity detectable on the cell surface. Bifunctional PAM proteins were slowly released into the medium after expression of integral membrane protein forms of PAM. Deletion of 77 amino acids from the COOH-terminus of the integral membrane forms of PAM resulted in a membrane-bound protein which retained both enzymatic activities but accumulated on the cell surface. Rapid internalization of full-length PAM proteins was observed by incubating live cells with antiserum to PAM; deletion of the COOH-terminal domain eliminated the ability of cells to internalize PAM. Thus the cytoplasmic domain of integral membrane PAM contains a routing determinant recognized by cells lacking the regulated secretory pathway.

Differential expression of Langerhans cells in the epidermis of patients with leprosy.

Eighteen patients with lepromatous leprosy (LL) showed a significant reduction (P less than 0.001) of Langerhans cells (LC) irrespective of whether the biopsies were obtained from involved (398 +/- 186) or healthy skin (304 +/- 98). The cells showed morphological changes consisting mainly of loss of dendritic processes. Twenty-four controls (age, sex and race matched) had a mean number of LC of 632 +/- 138. In tuberculoid patients (TT) significant differences were observed, depending on the site of biopsy. Nine biopsies from involved skin had 993 +/- 206 LC, whereas 11 from healthy skin had 448 +/- 96 (P less than 0.001). This difference was confirmed in six additional borderline tuberculoid (BT) and TT patients in whom biopsies were simultaneously obtained from involved (973 +/- 179) and uninvolved skin (498 +/- 99). In 10 patients with indeterminate leprosy the LC density did not differ from the control population (630 +/- 261). The expression of LC numbers in BT and TT patients may represent migration of these cells from healthy skin to involved areas or mobilization of a central pool. The low density found in LL patients could interfere with adequate presentation of mycobacterial antigens leading to tolerance. Alternatively the presence of T helper cells in TT infiltrates may produce factors that recruit LC; their absence in LL lesions may account for the decrease in LC expression.

Altered erythrocyte C3b receptor expression, immune complexes, and complement activation in homosexual men in varying risk groups for acquired immune deficiency syndrome.

We studied levels of erythrocyte C3b receptors (E-CR1) and correlated them to the level of circulating immune complexes (CIC) and complement activation in patients with or at risk for acquired immunodeficiency syndrome (AIDS). A significant reduction was found in patients with AIDS (185 +/- 93 CR1/cell), AIDS-related complex, and generalized lymphadenopathy, whereas healthy male homosexuals or normal controls had 434 +/- 193 and 509 +/- 140 CR1/cell, respectively (P less than 0.001). Family studies indicate that this defect is acquired. Reduction in E-CR1 was associated with increased levels of CIC when assayed by binding to Raji cells, but not when tested by C1q binding. Complement activation was assessed by levels of C3bi/C3d-g in plasma, measured with a monoclonal antibody specific for a neoantigen in C3d. AIDS patients had increased C3 activation (2.68 +/- 1.67%) when compared with normal controls (0.9 +/- 0.22%) (P less than 0.01). The decreased E-CR1, the presence of CIC, and C3 activation suggest that complement activation by immune complexes may play a role in the clinical expression of the disease.

Deficiency of erythrocyte C3b receptor (CR1) in AIDS and AIDS-related syndromes.

The expression of C3b receptors (CR1) on erythrocytes of gay men at various levels of risk for AIDS was studied. Fourty-nine heterosexual male controls had a mean (X) +/- standard deviation of 516 +/- 136 CR1 per erythrocyte (CR1-3); 17 asymptomatic gay men had X = 423 +/- 156, 16 gay men with one AIDS-related complex (ARC) symptom or sign had X = 342 +/- 154, 9 patients with ARC had X = 252 +/- 76, and 14 gay men with AIDS had X = 173 +/- 76 CR1-E. The patients with ARC and AIDS had a highly significant decrease in CR1-E when compared with normal individuals (p = less than 0.001) and studies of families of 4 AIDS patients suggest that this defect is acquired.

Dermatitis ampollar mucosinequiante y atrofiante. Hallazgos clinicos, histopatologicos e inmunologicos. / Mucous and atrophying bullous dermatitis. Clinical histopathological and immunological findings

Se comunican dos casos de dermatitis ampollar mucosinequiante y atrofiante (penfigoide cicatrizal). Una de las pacientes estudiadas comienza y evoluciona durante 1 ano con lesiones exclusivamente cutaneas que conducen al diagnostico de penfigoide ampollar. Posteriormente aparece el tipico compromiso mucoso. En el segundo caso, el comienzo fue cutaneo-mucoso. La histologia y la inmunofluorescencia directa e indirecta, corresponden al diagnostico de penfigoide cicatrizal. Los hallazgos en estos casos y la bibliografia consultada, muestran al penfigoide cicatrizal y al ampollar como un mismo proceso patologico, con diferencias clinicas, evolutivas y pronosticas. Se actualiza, ademas, la frecuencia y evolucion de las localizaciones en piel y mucosas, las observaciones al microscopio electronico, los diagnosticos diferenciales mas destacados y las diferentes terapeuticas propuestas, para el control de esta entidad cronica, rebelde y recidivante

Dermatitis ampollar mucosinequiante y atrofiante. Hallazgos clinicos, histopatologicos e inmunologicos. / Mucous and atrophying bullous dermatitis. Clinical histopathological and immunological findings

Se comunican dos casos de dermatitis ampollar mucosinequiante y atrofiante (penfigoide cicatrizal). Una de las pacientes estudiadas comienza y evoluciona durante 1 ano con lesiones exclusivamente cutaneas que conducen al diagnostico de penfigoide ampollar. Posteriormente aparece el tipico compromiso mucoso. En el segundo caso, el comienzo fue cutaneo-mucoso. La histologia y la inmunofluorescencia directa e indirecta, corresponden al diagnostico de penfigoide cicatrizal. Los hallazgos en estos casos y la bibliografia consultada, muestran al penfigoide cicatrizal y al ampollar como un mismo proceso patologico, con diferencias clinicas, evolutivas y pronosticas. Se actualiza, ademas, la frecuencia y evolucion de las localizaciones en piel y mucosas, las observaciones al microscopio electronico, los diagnosticos diferenciales mas destacados y las diferentes terapeuticas propuestas, para el control de esta entidad cronica, rebelde y recidivante