Reacciones granulomatosas a los tatuajes rojos: presentación de 5 lesiones / Granulomatous Reactions to Red Tattoo Pigments: A Description of 5 Cases

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Pulmonary computed tomography scan findings in chronic granulomatous disease

BACKGROUND: Chronic granulomatous disease is a phagocyte defect, characterised by recurrent infections in different organs due to a defect in NADPH oxidase complex. This study was performed to investigate pulmonary problems of CGD in a group of patients who underwent computed tomography (CT) scan. METHODS: Computed tomography scan was performed in 24 patients with CGD. The findings of the CT scan were documented in all of these patients. RESULTS: Areas of consolidation and scan formation were the most common findings, which were detected in 79% of the patients. Other abnormalities in order of frequencies were as follows: small pulmonary nodules (58%); mediastinal lymphadenopathy (38%); pleural thickening (25%); unilateral hilar lymphadenopathy (25%); axillary lymphadenopathy (21%); bronchiectasis (17%); abscess formation (17%); pulmonary large nodules or masses (8%); and free pleural effusion (8%). CONCLUSION: The pulmonary CT scans of the patients with CGD demonstrated a variety of respiratory abnormalities in the majority of the patients. While recurrent respiratory infections and abscesses are considered as prominent features of CGD, early diagnosis and precise check-up of the respiratory systems are needed to prevent further pulmonary complications

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Agrupación estacional de tres casos de síndrome de Löfgren / No disponible

El síndrome de Löfgren es una entidad definida por lapresencia de eritema nudoso, adenopatías hiliares bilaterales,poliartralgias, fiebre y, ocasionalmente, iritis. Se trata deuna forma habitual de presentación aguda de la sarcoidosis,enfermedad sistémica de etiología desconocida caracterizadapor la presencia de granulomas no caseificantes en los órganosafectados. Clásicamente se ha descrito su apariciónpreferente en primavera e invierno. Aunque para el diagnósticode sarcoidosis se requiere, además de un cuadro clínicoy una evolución compatibles, la presencia de granulomas nocaseificantes en uno o más de los órganos afectos, y la exclusiónde otras enfermedades granulomatosas, infecciosas ono, para el síndrome de Löfgren se acepta el diagnóstico sinconfirmación histológica, habida cuenta de su buen pronósticoy su presentación clínica peculiar.Presentamos tres casos de síndrome de Löfgren de aparicióncoincidente en el tiempo, y con buena evolución sintratamiento específico, a pesar de que una de las pacientesmostraba una afectación leve de la función pulmonar conafectación radiológica pulmonar (AU)

Löfgren’s syndrome is characterized by the presence oferythema nodosum, bilateral hilar adenopathy, polyarthralgias,fever and, occasionally, iritis. It is usually an acute formof sarcoidosis, which is a systemic disease of unknown etiology,characterized by the presence of non-caseificant granulomatasin the affected organs. It classically appears inspring and winter. The presence of non-caseificant granulomatason one or more of the affected organs, and the exclusionof any other granulomatous diseases (infectious or not)is necessary to diagnose sarcoidosis in addition to a compatibleclinical picture and course, However, in regards toLöfgren’s syndrome, the diagnosis can be accepted withouthistological confirmation because of its good prognosis andits characteristic clinical presentation.We present three cases of Löfgren’s syndrome which hadappeared at the same time and with good progress withoutspecific treatment even though one of the patients had aslight impairment of the pulmonary function with pulmonaryradiological involvement (AU)

Current classification and status of primary immunodeficiency diseases in Taiwan.

The incidence of primary immunodeficiency diseases (PIDD) in Taiwan is estimated at 2.17 per 100,000 live births. This is much lower than in Sweden, with 8.4 per 100,000 live births. Patients with critical combined T-cell and B-cell immunodeficiency (CID) seem to be under-diagnosed because of delayed referrals to a tertiary care center which is able to organize a cooperative transplantation team encompassing, at least, a pediatric hematologist and a immunologist for severe combined immunodeficiency (SCID) classified as "pediatric emergency". Moreover, there are rare reported cases of adult-onset (over 18-years-old) common variable immunodeficiency (CVID). These cases are possibly treated as autoimmune diseases, but not PIDD. To date around the world, 206 kinds of PIDD have been found and 110 causal genetic effects were identified. Although epidemiological studies show wide geographical and racial variations in the prevalence and distribution of PIDD, we believe in Taiwan that those patients with Mendelian susceptibility to mycobacteria disease (MSMD), belonging to "congenital phagocyte defect", are often treated as isolated refractory mycobacterial infections or chronic granulomatous disease. Also, "diseases of innate immunity" and "autoimflammatory disorders" are not yet identified. To manage patients with hemophagocytic lymphohisticytosis syndromes, one of "disease of immune dysregulation, stem cell transplantation will be considered if there is poor response to chemotherapy. Patients with PIDD need better access to specialized clinical, laboratory and therapeutic resources.

Gene-scan method for the recognition of carriers and patients with p47(phox)-deficient autosomal recessive chronic granulomatous disease.

OBJECTIVE: We devised a method to recognize carriers and patients with p47(phox)-deficient chronic granulomatous disease (A47 CGD), the most common autosomal form of the disease. CGD is characterized by the inability of phagocytic leukocytes to kill microorganisms, due to a defective NADPH oxidase system. The predominant genetic defect leading to p47(phox)-deficient CGD is a GT deletion at the beginning of exon 2 in the p47(phox) gene NCF1, most likely caused by recombination events between the NCF1 and one of its pseudogenes. It is hardly possible to investigate sequences of patients, carriers, and normal individuals using standard PCR/sequencing techniques, due to greater than 99% homology between NCF1 and its pseudogenes. METHODS: In our gene-scan method, a 198-bp region of genomic DNA around exon 2 of NCF1 is amplified by nonspecific PCR with one fluorochrome-labeled primer. The mixture of NCF1 and pseudogene product, which differs by two nucleotides in length, is separated according to size. The ratio between the peak heights indicates the relative number of NCF1 genes and pseudogenes within an individual's genome. RESULTS: The method is highly reproducible (SD = 4%) and sensitive (r = 0.998). Of the 16 healthy individuals, 15 had a 2:4 ratio (2 genes, 4 pseudogenes), 10/12 A47 CGD carriers had a 1:5 ratio, and 34 patients had only pseudogenes. In addition, gene-scans including a 20-bp duplication in intron 2 of the pseudogenes revealed insight in the crossing-over events between NCF1 and pseudogenes. CONCLUSIONS: Our method distinguishes individuals with one NCF1 gene (carriers) from controls and from NCF1-deficient patients.

Long-term follow-up and outcome of 39 patients with chronic granulomatous disease.

OBJECTIVES: To evaluate the clinical long-term course in patients with chronic granulomatous disease (CGD) with respect to different CGD subtypes and currently used antimicrobial prophylactic measures. STUDY DESIGN: The records of 39 patients with CGD who were monitored during a period of 22 years were reviewed. All infections, infectious complications, and clinical outcomes were documented for a total observation period of 610 patient-years and were stratified with respect to different CGD subtypes. RESULTS: Lymphadenitis, skin abscesses, and pneumonia occurred in 87%, 72%, and 59% of the patients, respectively. In 151 microbiologic isolates Staphylococcus aureus, Aspergillus species, Candida species, Pseudomonas species, and Salmonella species were the most frequently detected microorganisms. There were 167 severe infections requiring hospitalization and intravenous antimicrobial treatment, resulting in an incidence of 3.7 severe infections per 100 patient months (SI/100 PM). Long-term antibiotic prophylaxis significantly reduced the incidence of severe bacterial infections from 4.8 SI/100 PM to 1. 6 SI/100 PM (P =.0035). In contrast, fungal infections increased under antibiotic prophylaxis from a mean incidence of 0.2 SI/100 PM to 1.9 SI/100 PM (P =.04). We found a 50% survival rate through the fourth decade of life, with a plateau after the third decade of life. Patients with a complete absence of cytochrome b(558) showed an earlier manifestation of their disease and a higher incidence of infections and had significant lower survival than patients with only diminished cytochrome b(558) or autosomal recessive CGD. CONCLUSIONS: Infections with Aspergillus species have become the major cause of infectious complications and death in patients with CGD. Prophylactic and therapeutic measures are needed to further increase life expectancy and quality for patients with CGD.

Avances en el dianóstico de la enfermedad granulomatosa crónica

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Elf-1 and PU.1 induce expression of gp91(phox) via a promoter element mutated in a subset of chronic granulomatous disease patients.

The cytochrome b heavy chain (gp91(phox)) is the redox center of the NADPH-oxidase and is highly expressed in mature myeloid cells. Point mutations at -57, -55, -53, and -52 bp of the gp91(phox) promoter have been detected in patients with chronic granulomatous disease (CGD; Newburger et al, J Clin Invest 94:1205, 1994; and Suzuki et al, Proc Natl Acad Sci USA 95:6085, 1998). We report that Elf-1 and PU. 1, ets family members highly expressed in myeloid cells, bind to this promoter element. Either factor trans-activates the -102 to +12 bp gp91(phox) promoter when overexpressed in nonhematopoietic HeLa cells or the PLB985 myeloid cell line. However, no synergy of gp91(phox) promoter activation occurs when both Elf-1 and PU.1 are overexpressed. Introduction of the -57 bp or -55 bp CGD mutations into the gp91(phox) promoter significantly reduces the binding affinity of Elf-1 and PU.1 and also reduces the ability of these factors to trans-activate the promoter. These results indicate that Elf-1 and PU.1 contribute to directing the lineage-restricted expression of the gp91(phox) gene in phagocytes and that failure of these factors to effectively interact with this promoter results in CGD.

[Gene therapy for inherited diseases using heamatopoietic stem cells--gene therapy for patients with chronic granulomatous disease].

The possibility of gene therapy for inherited diseases with a single gene mutation in Figure 1 had been verified by the successful treatment with bone marrow transplantation. As the gene therapy method and theory has been progressing rapidly, it is expected that gene therapy will overcome the complications of bone marrow transplantation. Of these inherited diseases, chronic granulomatous disease (CGD) is the one of the most expected disease for gene therapy. CGD is an inherited immune deficiency caused by mutations in any of the following four phox genes encoding subunits of the superoxide generating phagocyte NADPH oxidase. It consists of membranous cytochrom b558 composed of gp91 phox and p22 phox, and four cytosolic components, p47 phox, p67 phox, rac p21 and p40 phox, which translocate to the membrane upon activation. In our group study, more than 220 CGD patients has been enrolled. The incidence of CGD patients was estimated as 1 out of 250,000 births. The expected life span of the CGD patients is 25 to 30 years old by the Kaplan Meier analysis. Comparing with the ratio of CGD subtype in US and Europe, that with p47phox deficiency is lower (less than 10%/o vs. 23%) and that of gp91 phox deficiency is higher (more than 75% vs. 60%). Prophylactic administration of ST antibiotics and IFN-gamma and bone marrow transplantation have been successfully employed in our therapeutic strategy. However, it is necessary to develop the gene therapy technology for CGD patients as more promising treatment. In the current study we constructed two retrovirus vectors; MFGS-gp91/293 SPA which contains only the therapeutic gp91 phox gene, a bicistronic retrovirus pHa-MDR-IRES-gp91/PA317 which carries a multi drug resistant gene (MDR1) and the gp91phox gene connected with an internal ribosome entry site (IRES). We demonstrate high efficiency transduction of gp 91 phox to CGD EB virus established cell line with high levels of functional correction of the oxidase by MFGS-gp91 and by pHa-MDR-IRES-gp91, respectively. We also demonstrate sufficient transduction of gp91 phox to CD34+ hematopoietic stem cell from the patients with gp91 phox deficiency by MFGS-gp91/293 SPA. Our current studies suggest that the combination of the 293-SPA packaging system and the bicistronic retrovirus system inserted MDR1 gene make our CGD gene therapy more feasible for clinical application.

Disturbed interaction of p21-rac with mutated p67-phox causes chronic granulomatous disease.

Chronic granulomatous disease (CGD) is characterized by the failure of phagocytic leukocytes to generate superoxide, needed for the intracellular killing of microorganisms. This is caused by mutations in any one of the four subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In a rare, autosomal recessive form of CGD, a 67-kD cytosolic component of this enzyme (p67-phox) is missing. We here report on a patient with a mutation in the p67-phox gene that leads to expression of a nonfunctional p67-phox protein. The purified granulocytes of this patient failed to produce superoxide and contained about half of the normal amount of p67-phox. Analysis of the cDNA and genomic DNA of this patient showed that the patient is a compound heterozygote for a triplet nucleotide deletion in the p67-phox gene, predicting an in-frame deletion of lysine 58 in the p67-phox protein and a larger deletion of 11-13 kb in the other allele. Interestingly, the 58Lys deletion in p67-phox disrupts the interaction with p21-rac1, a ras-related protein involved in the activation of the NADPH oxidase. In contrast to normal neutrophils, in which p47-phox and p67-phox translocate to the plasma membrane upon cell activation, the cells of the patient did not show this translocation, indicating that an interaction between p67-phox and p21-rac1 is essential for translocation of these cytosolic proteins and activation of the NADPH oxidase. Moreover, this CGD patient represents the first case of disease caused by a disturbed binding of a ras-related protein to its target protein.

A bicistronic retrovirus vector containing a picornavirus internal ribosome entry site allows for correction of X-linked CGD by selection for MDR1 expression.

Chronic granulomatous disease (CGD) is an inherited hematologic disorder involving failure of phagocytic cell oxidase to produce superoxide (O2-.), resulting in recurrent infections. The success of retrovirus gene therapy for hematopoietic diseases will be limited both by the efficiency of ex vivo transduction of target cells and by the ability of corrected cells to replace uncorrected cells in vivo. Using MFG-based retrovirus vectors containing oxidase genes, we have previously demonstrated in vitro correction of CGD, but transduction rates were low. In the present study we explore a strategy for providing a selective growth advantage to transduced cells, while retaining the single promoter feature of MFG responsible for high virus titer and enhanced protein production. We constructed a bicistronic retrovirus producing a single mRNA encoding both the therapeutic gene for the X-linked form of CGD (X-CGD), gp91phox, and the selectable human multidrug resistance gene, MDR1 linked together by the encephalomyocarditis virus internal ribosome entry site (IRES). As a control we constructed a bicistronic vector with the polio virus IRES element and using the bacterial neomycin resistance gene (neor) as the selective element. In Epstein-Barr virus transformed B (EBV-B) cells from an X-CGD patient, a tissue culture model of CGD, we show correction of the CGD defect and complete normalization of the cell population using either of these vectors and appropriate selection (vincristine for MDR1 and G418 for neor). Using a chemiluminescence assay of O2-. production, populations of cells transduced with either vector demonstrated initial correction levels of from less than 0.1% up to 2.7% of normal EBV-B cell oxidase activity. With either construct, cell growth under appropriate selection enriched the population of transduced cells, resulting in correction of X-CGD EBV-B cells to a level of O2-. production equalling or exceeding that of normal EBV-B cells. These studies show that a therapeutic gene can be linked to a resistance gene by an IRES element, allowing for selective enrichment of cells expressing the therapeutic gene. Furthermore, the use of MDR1 as a selective element in our studies validates an important approach to gene therapy that could allow in vivo selection and is generalizable to a number of therapeutic settings.

Enfermedades granulomatosas de la piel: patogenia / Granulomatous diseases of the skin: pathogeny

Las enfermedades granulomatosas de la piel están asociadas a diversas condiciones (infecciones, enfermedades subyacentes, vasculitis, etc.), por lo cual se estudian separadamente. Creemos que el estudio de ellas en conjunto permite interralacionarlas y entenderlas mejor desde una visión clínica, histopatológica y patogénica

Origem da hanseníase no Brasil / Hansen's origin in Brazil

Investigando-se como e quando a hanseníase foi introduzida no Brasil, verifica-se que a moléstia jamais foi descrita pelos navegadores ou pelos padres que vieram catequizar os silvícolas. Há inúmeros argumentos a favor da ausência da hanseníase entre os índios. Tem-se considerado o elemento europeu como uma das causas do aparecimento da hanseníase no país, introduzindo a doença provavelmente por diversos pontos da costa brasileira. Aqui, a moléstia deve ter trilhado a rota da colonizaçäo e transmitida pelo contágio. A introduçäo do elemento africano, sob o regime de escravidäo, segundo a maioria dos estudiosos, deve ter representado papel importante na origem da hanseníase no Brasil. Porém, alguns autores argumentam que nenhum comprador de escravos, quando se tratava do próprio interesse, haveria de aceitar em sua casa, lavoura ou engenho, um negro em que a doença se manifestasse. Há mais concordância entre os autores em atribuir a origem da hanseníase aos portugueses. Näo falta base histórica a esta afirmaçäo: enquanto a doença se extinguira no continente no século XVI, época da primeira colonizaçäo deste país, ela existia na Ilha da Madeira, nas Indias Portuguesas, nos Açores e nas possessöes marroquinas, de onde vinham os colonos, dentre os quais, certamente, muitos doentes de hanseníase

Chronic granulomatous disease of childhood: differential diagnosis and prognosis

Of a total of 111 children with primary immunodeficiency, 20 had phagocytic disorders (18 per cent) and 10 of them (8 boys and 2 girls) were diagnosed as chronic granulomatous disease (CGD). The children presented with repeated infections already during the first months of life. The main clinical findings were: abscess (n=8), otitis (n=8), pneumonia (n=8), lymphadenitis and pyodermits (n=6) and septicemia (4), NBT reduction was almost absent in all the children, except one of them. Bactericidal activity against S. aureus and phagocytosis were impaired in CGD patients. Different patterns of laboratory tests and prognosis were observed and girls had a better evolution

Chronic granulomatous disease of childhood: differential diagnosis and prognosis.

Of a total of 111 children with primary immunodeficiency, 20 had phagocytic disorders (18%) and 10 of them (8 boys and 2 girls) were diagnosed as chronic granulomatous disease (CGD). The children presented with repeated infections already during the first months of life. The main clinical findings were: abscess (n = 8), otitis (n = 8), pneumonia (n = 8), lymphadenitis and pyodermitis (n = 6) and septicemia (4), NBT reduction was almost absent in all the children, except one of them. Bactericidal activity against S. aureus and phagocytosis were impaired in CGD patients. Different patterns of laboratory tests and prognosis were observed and girls had a better evolution.

[New findings in chronic granulomatous disease]. / Nové poznatky o chronické granulomatózní chorobe.

Chronic granulomatous disease is a rare hereditary disease characterized by repeated infections affecting in particular the skin, lymph nodes and internal organs. Histological examination in the affected tissues reveals a granulomatous inflammation. The aetiological agents of infection are most frequently staphylococci, G-bacteria, Candida and Aspergillus. From the immunological aspect it is an inborn immunodeficiency affecting professional phagocytes (monocytes and granulocytes) which are unable to kill some ingested microorganisms. The molecular basis of the defect is affection of the NADPH oxidase enzyme complex at various sites which explains the genetic heterogeneity of the disease. The condition is usually manifested in early childhood, it has a variable course; if untreated, the affected subjects frequently die in child age. By early diagnosis of the disease and suitable therapy the quality of life of the patients can be improved, serious complications can be prevented and the patients may reach adult age. The submitted paper is a review of contemporary knowledge of the disease, in particular its molecular basis and ensuing classification, as well as possible diagnosis and treatment of the disease. Several case-histories are presented.