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Ethylmalonic encephalopathy (EE) is a severe intoxication disorder caused by mutations in the ETHE1 gene that encodes a mitochondrial sulfur dioxygenase involved in the catabolism of hydrogen sulfide. It is biochemically characterized by tissue accumulation of hydrogen sulfide and its by-product thiosulfate, as well as of ethylmalonic acid due to hydrogen sulfide-induced inhibition of short-chain acyl-CoA dehydrogenase. Patients usually present with early onset severe brain damage associated to encephalopathy, chronic hemorrhagic diarrhea and vascular lesions with petechial purpura and orthostatic acrocyanosis whose pathophysiology is poorly known. Current treatment aims to reduce hydrogen sulfide accumulation, but does not significantly prevent encephalopathy and most fatalities. In this review, we will summarize the present knowledge obtained from human and animal studies showing that disruption of mitochondrial and redox homeostasis may represent relevant pathomechanisms of tissue damage in EE. Mounting evidence show that hydrogen sulfide and ethylmalonic acid markedly disturb critical mitochondrial functions and induce oxidative stress. Novel therapeutic strategies using promising candidate drugs for this devastating disease are also discussed., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Ethylmalonic encephalopathy (MIM #602473) is a rare autosomal recessive metabolic condition caused by biallelic variants in ETHE1 (MIM #608451), characterized by global developmental delay, infantile hypotonia, seizures, and microvascular damage. The microvascular changes result in a pattern of relapsing spontaneous diffuse petechiae and purpura, positional acrocyanosis, and pedal edema, hemorrhagic suffusions of mucous membranes, and chronic diarrhea. Here, we describe an instructive case in which ethylmalonic encephalopathy masqueraded as meningococcal septicemia and shock. Ultrarapid whole-genome testing (time to result 60 h) and prompt biochemical analysis facilitated accurate diagnosis and counseling with rapid implementation of precision treatment for the metabolic crisis related to this condition. This case provides a timely reminder to consider rare genetic diagnoses when atypical features of more common conditions are present, with an early referral to ensure prompt biochemical and genomic diagnosis., (© 2022 Horton et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Bateman purpura is characterized by diffuse senile skin atrophy, senile purpura and spontaneous stellar pseudocicatrices. Cutaneous changes in the course of ageing have been related to lower levels of ascorbic acid into the dermis of elderly people., Objective: In this study, we postulate that senile purpura could be linked to dermal vitamin C deficiency and could be corrected by topical administration of this vitamin., Methods: A 12-weeks, hemi-member (forearm or leg), randomized double-blind comparative study was conducted in 18 patients with Bateman purpura aged over than 60 years. At each visit, clinical assessment and biometrological measurements were performed. Clinical examination and scoring by experts showed a significant improvement on the vitamin C-treated side compared with the control, with reduction of haemorrhage areas, increase of dermal thickness., Results: Twice-daily application of 5% topical vitamin C led to a clinically apparent improvement of the skin symptoms and allows beneficial effects on skin elasticity and thickness. Bateman purpura, a classical sign of photoaging whose origin has not clearly been recognized could be improved by vitamin C applied on to the skin., Conclusion: These results confirm the hypothesis of the underlying role of vitamin C deficiency in the determinism of Bateman purpura., (© 2017 European Academy of Dermatology and Venereology.)

Hydrogen sulfide (sulfide) accumulates at high levels in brain of patients with ethylmalonic encephalopathy (EE). In the present study, we evaluated whether sulfide could disturb energy and redox homeostasis, and induce mitochondrial permeability transition (mPT) pore opening in rat brain aiming to better clarify the neuropathophysiology of EE. Sulfide decreased the activities of citrate synthase and aconitase in rat cerebral cortex mitochondria, and of creatine kinase (CK) in rat cerebral cortex, striatum and hippocampus supernatants. Glutathione prevented sulfide-induced CK activity decrease in the cerebral cortex. Sulfide also diminished mitochondrial respiration in cerebral cortex homogenates, and dissipated mitochondrial membrane potential (ΔΨm) and induced swelling in the presence of calcium in brain mitochondria. Alterations in ΔΨm and swelling caused by sulfide were prevented by the combination of ADP and cyclosporine A, and by ruthenium red, indicating the involvement of mPT in these effects. Furthermore, sulfide increased the levels of malondialdehyde in cerebral cortex supernatants, which was prevented by resveratrol and attenuated by glutathione, and of thiol groups in a medium devoid of brain samples. Finally, we verified that sulfide did not alter cell viability and DCFH oxidation in cerebral cortex slices, primary cortical astrocyte cultures and SH-SY5Y cells. Our data provide evidence that bioenergetics disturbance and lipid peroxidation along with mPT pore opening are involved in the pathophysiology of brain damage observed in EE., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Ethylmalonic encephalopathy (EE) is an autosomal recessive devastating metabolic disorder affecting the brain, gastrointestinal tract, peripheral vessels and rarely the other vascular organs. We report a 10-month-old girl who presented as a meningococcemia clinic but later diagnosed ethylmalonic encephalopathy. Molecular analyses revealed a homozygous c.554 T > G; p. L185R mutation in ETHE1 gene. She was only partially benefited from riboflavine, coenzyme Q10, metronidazole, N-acetylcysteine and symptomatic treatment and discharged from hospital with the sequela of oxygene dependance and developmental delay. We observed N-acetylcysteine 100 mg/kg/day intravenous infusion theraphy may be the most important drug especially in comatous EE patients.

Defects in the gene encoding the persulfide dioxygenase ETHE1 are known to cause the severe inherited metabolic disorder ethylmalonic encephalopathy (EE). In spite of known clinical characteristics, the molecular mechanisms underlying the ETHE1 deficiency are still obscure. Herein, to further analyze the molecular phenotype of the disease, we applied an untargeted metabolomics approach on cultivated fibroblasts of EE patients for pinpointing alterations in metabolite levels. Metabolites, as direct signatures of biochemical functions, can decipher biochemical pathways involved in the cellular phenotype of patient cells. Using liquid chromatography-mass spectrometry-based untargeted metabolomics, we identified 18 metabolites that have altered levels in fibroblasts from EE patients. Our data demonstrate disrupted redox state in EE patient cells, which is reflected by significantly decreased level of reduced glutathione. Furthermore, the down-regulation of several intermediate metabolites such as the redox cofactors NAD(+) and NADH as well as Krebs cycle intermediates revealed clear alteration in metabolic regulation. Pantothenic acid and several amino acids exhibited decreased levels, whereas the β-citrylglutamate with a putative role in brain development had an increased level in the EE patient cells. These observations indicate the severe impact of ETHE1 deficiency on cellular physiology and redox state, meanwhile suggesting targets for experimental studies on novel treatment options for the devastating metabolic disorder.

Deficiency of mitochondrial sulfur dioxygenase (ETHE1) causes the severe metabolic disorder ethylmalonic encephalopathy, which is characterized by early-onset encephalopathy and defective cytochrome C oxidase because of hydrogen sulfide accumulation. Although the severe systemic consequences of the disorder are becoming clear, the molecular effects are not well defined. Therefore, for further elucidating the effects of ETHE1-deficiency, we performed a large scale quantitative proteomics study on liver tissue from ETHE1-deficient mice. Our results demonstrated a clear link between ETHE1-deficiency and redox active proteins, as reflected by downregulation of several proteins related to oxidation-reduction, such as different dehydrogenases and cytochrome P450 (CYP450) members. Furthermore, the protein data indicated impact of the ETHE1-deficiency on metabolic reprogramming through upregulation of glycolytic enzymes and by altering several heterogeneous ribonucleoproteins, indicating novel link between ETHE1 and gene expression regulation. We also found increase in total protein acetylation level, pointing out the link between ETHE1 and acetylation, which is likely controlled by both redox state and cellular metabolites. These findings are relevant for understanding the complexity of the disease and may shed light on important functions influenced by ETHE1 deficiency and by the concomitant increase in the gaseous mediator hydrogen sulfide. All MS data have been deposited in the ProteomeXchange with the dataset identifiers PXD002741 (http://proteomecentral.proteomexchange.org/dataset/PXD002741) and PXD002742 (http://proteomecentral.proteomexchange.org/dataset/PXD002741)., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The ethylmalonic encephalopathy protein 1 (ETHE1) catalyses the oxygen-dependent oxidation of glutathione persulfide (GSSH) to give persulfite and glutathione. Mutations to the hETHE1 gene compromise sulfide metabolism leading to the genetic disease ethylmalonic encephalopathy. hETHE1 is a mono-iron binding member of the metallo-β-lactamase (MBL) fold superfamily. We report crystallographic analysis of hETHE1 in complex with iron to 2.6 Å resolution. hETHE1 contains an αββα MBL-fold, which supports metal-binding by the side chains of an aspartate and two histidine residues; three water molecules complete octahedral coordination of the iron. The iron binding hETHE1 enzyme is related to the 'classical' di-zinc binding MBL hydrolases involved in antibiotic resistance, but has distinctive features. The histidine and aspartate residues involved in iron-binding in ETHE1, occupy similar positions to those observed across both the zinc 1 and zinc 2 binding sites in classical MBLs. The active site of hETHE1 is very similar to an ETHE1-like enzyme from Arabidopsis thaliana (60% sequence identity). A channel leading to the active site is sufficiently large to accommodate a GSSH substrate. Some of the observed hETHE1 clinical mutations cluster in the active site region. The structure will serve as a basis for detailed functional and mechanistic studies on ETHE1 and will be useful in the development of selective MBL inhibitors., (© The Author 2015. Published by Oxford University Press.)

Cocaine-associated retiform purpura is a recently described entity characterized by striking hemorrhagic necrosis involving areas of skin associated with administration of cocaine. Levamisole, an adulterant in cocaine, has been suggested as the main culprit pathogenetically. Four cases of cocaine-associated retiform purpura were encountered in the dermatopathology practice of C. M. Magro. The light microscopic findings were correlated with immunohistochemical and immunofluorescence studies. All 4 cases showed a very striking thrombotic diathesis associated with intravascular macrophage accumulation. Necrotizing vasculitis was noted in 1 case. Striking intercellular adhesion molecule-1 (ICAM-1)/CD54 expression in vessel wall along with endothelial expression of caspase 3 and extensive vascular C5b-9 deposition was observed in all biopsies examined. Cocaine-induced retiform purpura is a C5b-9-mediated microvascular injury associated with enhanced apoptosis and prominent vascular expression of ICAM-1, all of which have been shown in prior in vitro and in vivo murine models to be a direct effect of cocaine metabolic products. Antineutrophilic cytoplasmic antibody and antiphospholipid antibodies are likely the direct sequelae of the proapoptotic microenvironment. The inflammatory vasculitic lesion could reflect the downstream end point reflective of enhanced ICAM-1 expression and the development of antineutrophilic cytoplasmic antibody. Levamisole likely works synergistically with cocaine in the propagation of this syndromic complex.

Inherited defects of oxidative phosphorylation lead to heterogeneous, often multisystem, mitochondrial diseases. This review highlights those mitochondrial syndromes with prominent gastrointestinal and hepatic symptoms, categorised according to underlying disease mechanism. Mitochondrial encephalopathies with major gastrointestinal involvement include mitochondrial neurogastrointestinal encephalopathy and ethylmalonic encephalopathy, which are each associated with highly specific clinical and metabolic profiles. Mitochondrial hepatopathies are most frequently caused by defects of mitochondrial DNA maintenance and expression. Although mitochondrial disorders are notorious for extreme clinical, biochemical and genetic heterogeneity, there are some pathognomonic clinical and metabolic clues that suggest a specific diagnosis, and these are highlighted. An approach to diagnosis of these complex disorders is presented, together with a genetic classification, including mitochondrial DNA disorders and nuclear-encoded defects of mitochondrial DNA maintenance and translation, OXPHOS complex assembly and mitochondrial membrane lipids. Finally, supportive and experimental therapeutic options for these currently incurable diseases are reviewed, including liver transplantation, allogeneic haematopoietic stem cell transplantation and gene therapy.

Hydrogen sulfide (sulfide, H(2)S) is a colorless, water-soluble gas with a typical smell of rotten eggs. In the past, it has been investigated for its role as a potent toxic gas emanating from sewers and swamps or as a by-product of industrial processes. At high concentrations, H(2)S is a powerful inhibitor of cytochrome c oxidase; in trace amounts, it is an important signaling molecule, like nitric oxide (NO) and carbon monoxide (CO), together termed "gasotransmitters." This review will cover the physiological role and the pathogenic effects of H(2)S, focusing on ethylmalonic encephalopathy, a human mitochondrial disorder caused by genetic abnormalities of sulfide metabolism. We will also discuss the options that are now conceivable for preventing genetically driven chronic H(2)S toxicity, taking into account that a complete understanding of the physiopathology of H(2)S has still to be achieved.

Hydrogen sulfide (H(2)S) is a recently described endogenously produced gaseous signaling molecule that influences various cellular processes in the central nervous system, cardiovascular system, and gastrointestinal tract. The biogenesis of H(2)S involves the cytoplasmic transsulfuration enzymes, cystathionine β-synthase and γ-cystathionase, whereas its catabolism occurs in the mitochondrion and couples to the energy-yielding electron transfer chain. Low steady-state levels of H(2)S appear to be controlled primarily by efficient oxygen-dependent catabolism via sulfide quinone oxidoreductase, persulfide dioxygenase (ETHE1), rhodanese, and sulfite oxidase. Mutations in the persulfide dioxgenase, i.e. ETHE1, result in ethylmalonic encephalopathy, an inborn error of metabolism. In this study, we report the biochemical characterization and kinetic properties of human persulfide dioxygenase and describe the biochemical penalties associated with two patient mutations, T152I and D196N. Steady-state kinetic analysis reveals that the T152I mutation results in a 3-fold lower activity, which is correlated with a 3-fold lower iron content compared with the wild-type enzyme. The D196N mutation results in a 2-fold higher K(m) for the substrate, glutathione persulfide.

Ethylmalonic encephalopathy (EE) is a rare autosomal recessive disorder caused by mutations in the ETHE1 gene and characterized by chronic diarrhea, encephalopathy, relapsing petechiae and acrocyanosis. Nephrotic syndrome has been described in an infant with EE but the renal histology findings were not described in previous reports. We report a Palestinian girl with EE who presented with chronic diarrhea, encephalopathy, petechial rash and acrocyanosis. Subsequently, she developed progressive deterioration of renal function caused by rapidly progressive glomerulonephritis resulting in death within few days. This is, to our knowledge, the first reported occurrence of rapidly progressive glomerulonephritis in a child with ethylmalonic encephalopathy. Its presence is a serious complication associated with poor prognosis and may be explained by the diffuse vascular damage.

The pigmented purpuric dermatoses (PPD) are a group of diseases characterized by petechiae and bronze discoloration of the skin on the lower extremities. Histopathologically, extravasation of erythrocytes with hemosiderin deposition, a perivascular lymphocytic infiltrate centered on the superficial capillaries and endothelial cell swelling are seen. The granulomatous variant of PPD (GPPD) was described in 1996 and only 10 cases have been reported since in the literature, almost exclusively in patients of East Asian descent only involving the extremities. We present a case of GPPD in a Caucasian, North American Ashkenazi Jewish woman involving the thighs, back, forearms and wrists with concomitant non-granulomatous PPD of the shins. She presented with an asymptomatic, spreading, cayenne pepper-like rash. This rash intermittently involved the lower extremities and back for 15 years, but now involves the thighs with accompanying pink papules on the back, wrists and forearms. Histopathology of the thigh and back lesions revealed superficial lichenoid granulomatous dermatitis with palisading lymphocytes and focal interface changes. Extravasated erythrocytes were seen, but vasculitis was absent. No lymphocytic atypicality was noted and T-cell gene rearrangement studies were non-clonal. This is the second reported case of GPPD in a non-Asian patient and the first case involving sites other than the extremities., (Copyright © 2011 John Wiley & Sons A/S.)

The persistent pigmented purpuric dermatitides (PPPD) are a spectrum of dermatologic disorders characterized by petechial and pigmented macules usually confined to the lower limbs. Their etiology is unknown and several clinical variants are recognized. At the microscopic level they are characterized by angiocentric lymphocytic inflammation, red blood cell extravasation and hemosiderin deposition. A granulomatous variant of the PPPD has recently been described and to date eleven cases have been reported in the literature. In contrast to the conventional type, this variant is characterized histopathologically by ill-defined, non-necrotizing granulomata admixed with the lymphocytic inflammatory background. Although initially the granulomatous variant of the PPPD was thought to occur only in Asian patients, this sole racial predilection has not been substantiated. A tenuous association with hyperlipidemia has been noted but this requires further study. The principal importance of recognizing this entity lies in the need to include it in the histopathological differential diagnosis of granulomatous dermal infiltrates. We report here an additional patient with the granulomatous variant of PPPD and elaborate on this entity in the context of existing information in the literature., (Copyright © 2011 John Wiley & Sons A/S.)

Deficiency of the sulfide metabolizing protein ETHE1 is the cause of ethylmalonic encephalopathy (EE), an inherited and severe metabolic disorder. To study the molecular effects of EE, we performed a proteomics study on mitochondria from cultured patient fibroblast cells. Samples from six patients were analyzed and revealed seven differentially regulated proteins compared with healthy controls. Two proteins involved in pathways of detoxification and oxidative/reductive stress were underrepresented in EE patient samples: mitochondrial superoxide dismutase (SOD2) and aldehyde dehydrogenase X (ALDH1B). Sulfide:quinone oxidoreductase (SQRDL), which takes part in the same sulfide pathway as ETHE1, was also underrepresented in EE patients. The other differentially regulated proteins were apoptosis inducing factor (AIFM1), lactate dehydrogenase (LDHB), chloride intracellular channel (CLIC4) and dimethylarginine dimethylaminohydrolase 1 (DDAH1). These proteins have been reported to be involved in encephalopathy, energy metabolism, ion transport, and nitric oxide regulation, respectively. Interestingly, oxidoreductase activity was overrepresented among the regulated proteins indicating that redox perturbation plays an important role in the molecular mechanism of EE. This observation may explain the wide range of symptoms associated with the disease, and highlights the potency of the novel gaseous mediator sulfide.

Background: The primary function of regulatory T cells (Treg cells) is to regulate the function and proliferation of immunologically responsive T cells; the transcription factor Foxp3 is expressed by this cell populace and is held to be the standard marker for Treg cells., Design: A variety of cutaneous T-cell lymphocytic infiltrates were evaluated for Foxp3 expression., Results: Of the 95 cases, 33 (35%) were reactive, 40 (42%) were prelymphomatous cutaneous T-cell dyscrasia and 22 were (23%) T-cell lymphoma. The reactive category included dermatomyositis, lupus erythematosus, hypersensitivity reactions and graft-vs.-host disease. The prelymphomatous dyscrasia category was represented chiefly by pityriasis lichenoides chronica (PLC) and pigmented purpuric dermatosis (PPD). The Foxp3 reactivity was less than 10% for cases of dermatomyositis and lupus erythematosus, 23% for hypersensitivity cases, 0% for graft-vs.-host disease, 16% for the dyscrasias and 11% for the lymphomas. Intermediate grade and aggressive lymphomas had very few Foxp3+ cells (< 5%). There were fewer numbers of Foxp3+ T cells in the monoclonal variants of PLC and PPD., Conclusions: T-reg cells may play a role in controlling the extent of T-cell proliferations in the skin with a lack of T-regulatory function permissive to the development of various T-cell disorders.

Confocal laser scanning microscopy (CLSM) results in displaying multiple ruptures of capillaries and venules define conjunctival petechiae as a rhexis haemorrhage. In order to distinguish between petechiae which have arisen before death as opposed to post-mortem artefacts and the establishment of the age of the vessel's damage, we carried out an investigation on a collection of samples from medico-legal cases (positive petechiae: n=65; post-mortem artefacts: n=12; control: n=19) to establish whether the expression of the endothelial adhesion molecule P-selectin as demonstrated by immunohistochemical methods is influenced by trauma before death and possibly by time. Except for cases with massive congestion in those cases where the victim had survived for around minutes, CLSM examination revealed a strong endothelial reaction at the site where the vessel had ruptured. It was impossible to detect a strong P-selectin expression signal in both those vessels which had not suffered any mechanical insult and those which had experienced post-mortem rupture. Therefore, the elevated expression of P-selectin can be used as a criterion to distinguish between those lesions which have occurred in life and those which are post-mortem artefacts.

While some unequivocally benign infiltrates are easy to distinguish from cutaneous T-cell lymphoma (CTCL), drug-associated lymphomatoid hypersensitivity reaction and cutaneous lesions of collagen vascular disease can show cytologic atypia, clonality and an immunophenotypic profile that closely simulates CTCL and cause diagnostics difficulties. Similar immunophenotypic and molecular abnormalities to those of malignant lymphoma can also be observed in pityriasis lichenoides chronica (PLC), large plaque parapsoriasis (LPP), pigmented purpuric dermatosis (PPD) and atypical lymphocytic lobular panniculitis leading one to consider these entities as forms of cutaneous lymphoid dyscrasia. The purpose of our study was to evaluate the distinction of these various subcategories of cutaneous T-cell infiltrates by assessment of T-cell receptor (TCR)-beta gene rearrangement. Formalin-fixed paraffin-embedded skin biopsies from 80 patients containing a T-cell dominant lymphocytic infiltrate were analyzed for TCR-beta gene rearrangement. Our findings indicate that monoclonality is a reliable characteristic of CTCL with polyclonality being very infrequent. However, some cases of drug associated lymphomatoid hypersensitivity, collagen vascular disease and the various cutaneous lymphoid dyscrasias (i.e. PLC, PPD and atypical lymphocytic lobular panniculitis) could manifest restricted molecular profiles in the context of an oligoclonal process or frank monoclonality.

In order to investigate the importance of timing in the immunophenotypical characteristics of the inflammatory infiltrate and in the adhesion molecules expression in cutaneous necrotizing vasculitis (CNV) we carried on an immunohistopathologic study. An avidin-biotin-streptavidin peroxidase technique was performed on 21 lesional skin biopsy specimens obtained sequentially at 0 to 24, 72 and 120 hours from seven patients with a CNV presenting as palpable purpura. A panel of monoclonal antibodies specific for inflammatory cells (T lymphocytes, polymorphonuclear leukocytes, macrophages, dendritic cells) and different adhesion molecules (E-selectin, ICAM-1, VCAM-1, LFA-1, VLA-4) was used. Moreover, HECA-450 monoclonal antibody was used to identify cutaneous lymphocyte antigen (CLA) in the inflammatory infiltrate. In all cases, polymorphonuclear leukocytes predominated in the early phase of CNV and their number decreased significantly with time (p = 0.0001). The T lymphocytes were present from the beginning and their number remained stable or increased slightly in time (p = 0.1), thus becoming predominant in the perivascular infiltrate in older lesions. Macrophages were scattered on interstitium since the early phase and they showed a time-dependent increase (p = 0.0003). E-selectin (ELAM-1) expression was detected at the first biopsy and it decreased depending on the age of the evolving vasculitis (p = 0.0033). The expression of CLA decreased also with time in 5 of the 7 cases (p = 0.0001). Our study supports the existence of an unique histopathologic pattern in CNV, in which the inflammatory infiltrate varies with time at the expense of the number of polymorphonuclear cells and macrophages.

A case of pigmented purpuric dermatitis (PPD) in a Japanese man aged 59 years is reported with an interesting ultrastructural finding. Clinically, the lesions, which consisted of telangiectatic puncta and pigmentation, were irregular in shape and occurred predominantly on the lower legs without pruritus. Histologically, lymphocytic perivascular infiltrates and extravasation of red blood cells were observed in the papillary dermis. Ultrastructurally, endothelial cells with ovoid nuclei showed swelling and the lumen of the capillary became narrowed. Several banded structures, so-called fibrous long-spacing collagen (FLSC), were observed in the cytoplasm. They were spindle shaped, about 5 microm in length, and showed crossbands of 300-nm-wide intervals with fine intraperiodic bands. These structures were not observed in dermal connective tissue and fibroblasts. These results suggested that FLSC was synthesized in endothelial cells rather than being phagocytosed by endothelial cells, which might be helpful in investigating the etiology of PPD.

We report a 79-year-old female with anaphylactoid purpura on her legs and unusual large annular purpura on the trunk. Histopathological characteristics of leukocytoclastic vasculitis were observed in the upper and middle dermis of both types of skin lesions. She was complicated by Sjögren's syndrome and advanced cervical cancer. The annular purpura spontaneously resolved in a week and did not recur. However, the anaphylactoid purpura relapsed more frequently and spread more widely following the elevation of her serum SCC antigen levels from the onset of purpura until her death. We consider that the characteristic annular configuration was caused by the complication of Sjögren's syndrome and that the recurrent anaphylactoid purpura indicated paraneoplastic vasculitis primarily caused by the tumor specific protein immune complexes. Complication by Sjögren's syndrome many also play a role in the development of allergic vasculitis.

The aim of this study was to stain lung and thymus gland sections that had been taken from infants who had died of sudden infant death syndrome (SIDS) for interstitial hemosiderin and to compare the results with those obtained for controls. There were two groups of SIDS infants, one with, and a second group without, histories of apparent life-threatening events (ALTEs). No significant difference in numbers of cases with interstitial hemosiderin deposition was found between SIDS infants with histories of ALTEs (n = 4 of 12, 33.3%), SIDS infants without histories of ALTEs (n = 4 of 22, 18.2%), and controls (n = 4 of 24, 16.7%). However, if four of the control cases with histories of previous chest trauma were excluded, there was a significantly greater number of cases with pulmonary interstitial hemosiderin in the SIDS infants with histories of ALTEs compared with the subgroup of control infants with no previous chest trauma (n = 1 of 20, 5%) (P < .05). No relationship could be established between the timing of the ALTEs, the type of resuscitation or age of the infant at death, and the presence of hemosiderin. None of the sections of thymus gland stained positively for hemosiderin. Positive staining for pulmonary interstitial hemosiderin, therefore, differentiated a group of SIDS infants with histories of previous ALTEs from a subgroup of control infants with no histories of previous chest trauma. However, pulmonary interstitial hemosiderin staining could not be used with certainly to confirm or exclude previous ALTEs in individual SIDS cases as not every SIDS case with a history of an ALTE stained for pulmonary interstitial hemosiderin. In addition, positive staining occurred for SIDS infants without histories of ALTEs and also for control infants who died of other causes.

We report the genetic abnormalities in the protein C genes of a Spanish child with neonatal purpura fulminans and disseminated intravascular coagulation, associated with undetectable protein C levels. Direct sequencing of the nine protein C gene exons and their splice junctions indicated that the proband is a compound heterozygote with two mutant protein C gene alleles, Y124C and Q132X, that do not express protein C in plasma. The Y124C mutation was inherited from the mother and is due to a novel A to G transition at nucleotide 3416, which results in the substitution of cysteine for tyrosine 124, a highly conserved amino acid in EGF-like domains. The paternal inherited mutation (Q132X) is a C to T transition at nucleotide 3439, which replaces glutamine 132 with a Stop codon signal. This mutation, if expressed, should result in the synthesis of a truncated protein of 131 amino acids. Y124C or Q132X are present in the heterozygous state in the asymptomatic parents and siblings of the proband, all of which have half the normal plasma levels of protein C. Q123X has also been identified in families where type I PC deficiency is inherited as a clinically dominant trait. Therefore, the presence of the same mutation in a family showing a clinically recessive pattern of inheritance indicates that other factors, apart from the type of protein C gene mutation, are responsible for the clinical expression of protein C deficiency.

Background: Purpura pigmentosa chronica is an inflammatory skin disorder probably caused by an allergic reaction. Delayed-type hypersensitivity or immunocomplex vasculitis has been considered as a possible mechanism., Objective: Detailed analysis of cell adhesion molecule (CAM) modulation may give further insights into the pathogenesis and underlying immune reaction of this disease., Methods: By immunohistochemical techniques we investigated the in situ expression of integrins, selectins, and CAMs of the immunoglobulin superfamily., Results: Infiltrating lymphocytes expressed LFA-1, LFA-2, VLA-4, and VLA-5, whereas some of the macrophages were also positive for p150/95 and MAC-1. VLA-1 was found on lymphocytes near the basement membrane of the epidermis. Compared with uninvolved or healthy skin endothelial cells showed upregulation of ICAM-1, VCAM-1, and, focally, E-selectin. Some fibroblasts were positive for ICAM-1. ICAM-1 was also upregulated on lesional keratinocytes that also expressed alpha 2, alpha 3, and alpha 6 integrin chains on basal and suprabasal epidermal layers., Conclusion: Our findings demonstrate characteristic modifications in the expression of CAMs in purpura pigmentosa chronica and indicate the involvement of the epidermis in this disease. This modulation shows close parallels to those described for chronic delayed-type immune reactions of the skin.

Brazilian purpuric fever (BPF) is a newly described pediatric syndrome that results in significant morbidity and mortality. BPF is caused by specific phenotypic strains of Haemophilus influenzae biogroup aegyptius that are capable of intravascular survival. Immunoblotting of outer membrane proteins of H. influenzae biogroup aegyptius with normal human serum showed that most virulent strains of H. influenzae biogroup aegyptius associated with BPF expressed an immunologically prominent protein at 72 kDa. A corresponding protein in avirulent isolates migrated at 79 kDa. Although a minor component on SDS-PAGE analysis of the outer membrane, specific antibody against this protein is present in high concentrations in normal human serum.

1) The serum ASO and AH assays were performed and compared in a series of 90 healthy children and 7 pediatric patients with rheumatic fever and other disorders related to hemolytic streptococcus infection. 2) The upper physiological limit of serum AH titer was estimated to be 256X for children. 3) In rheumatic fever, sometimes the serum AH level rises earlier than elevation of serum ASO and remains to be high over a long period even after the serum ASO has returned to normal level. 4) The results suggest importance of the serum AH determination in the serologic diagnosis of rheumatic fever and other conditions of hemolytic streptococcus infection.

Biopsy of renal tissue from four patients with idiopathic focal nephritis and three patients with Henoch-Schönlein syndrome showed that C3 and properdin were deposited with IgA in the glomerular mesangium, C1q could not be detected. These observations suggest that glomerular injury in disorders characterized by mesangial deposits of IgA and C3 is mediated via the properdin system.