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Severe influenza in a paediatric patient with GATA2 deficiency and Emberger syndrome.

A 9-year-old girl was admitted to the paediatric intensive care unit with acute respiratory failure due to influenza. Nine months earlier, she presented with unexplained lymphoedema of the lower extremities and monocytopenia. She had a history of occasional finger warts and onychomycoses. During hospitalisation, the patient was diagnosed with Emberger syndrome caused by GATA2 deficiency. The admission was complicated by thromboses in the right hand, leading to amputation of multiple fingers. From then on, the patient has been in good recovery, the function of her right hand was improving and an allogeneic haematopoietic cell transplantation has now been successfully performed.

INDEXES OF CYTOKINE PROFILE OF BLOOD IN PATIENTS WITH COMPLICATED ERYSIPELAS.

The cytokine blood profile in patients with complicated erysipelas was investigated. It was found that in patients with complications of erysipelas (gangrene, phlegmon, abscess, thrombophlebitis of the subcutaneous veins of the shin) levels of pro-inflammatory cytokines IL-1ß, TNF-α, IL-2, IL-6 in serum significantly increase and level of anti-inflammatory cytokine IL-4 increases slightly, as well as was found a significant increase in coefficients reflecting the ratio of pro-inflammatory and anti-inflammatory cytokines, which indicates the prevalence in the blood of examined patients with complications of erysipelas an anti-inflammatory properties. A more significant increase in pro-inflammatory cytokines serum levels is typical for patients with destructive forms of erysipelas - phlegmonous and gangrenous, a slight increase - for patients without purulent-necrotic component of complication (thrombophlebitis of the subcutaneous veins of the shin). In the future we plan to study pharmacological correction of shifts in cytokine blood profile with drugs with immunomodulating properties in patients with complicated erysipelas.

Anti-Interferon-Inducible Protein 16 Antibodies Associate With Digital Gangrene in Patients With Scleroderma.

OBJECTIVE: To examine the association between anti-interferon-inducible protein 16 (anti-IFI-16) antibodies and clinical features of scleroderma. METHODS: Sera from a discovery sample of 94 patients with scleroderma and 47 healthy controls were assayed for anti-IFI-16 antibodies by enzyme-linked immunosorbent assay, and associations were examined using regression analyses. Since anti-IFI-16 autoantibodies were found to be strongly associated with digital gangrene in the discovery sample, a subsequent case-control study (with subjects matched 1:1 on disease duration) was designed for further exploration. Cases were patients with scleroderma and digital gangrene, while controls were patients with scleroderma and Raynaud's phenomenon alone (n = 39 matched pairs). Nonparametric, unadjusted matched pairs analysis as well as univariate and multivariable conditional logistic regression analyses were performed. RESULTS: In the discovery sample, anti-IFI-16 antibodies were more prevalent in patients with scleroderma than in healthy controls (18% versus 2%; P = 0.01). Patients with anti-IFI-16 antibodies, compared to anti-IFI-16 antibody-negative patients, were more likely to have limited scleroderma (77% versus 46%; P = 0.03), a longer disease duration (median 15.2 years [interquartile range 10.6-18.3] versus 6.0 years [interquartile range 3.4-13.8]; P < 0.01), digital gangrene (24% versus 4%; P = 0.02), and a low diffusing capacity for carbon monoxide (DLco) (P < 0.01). In the case-control study, 35 (45%) of 78 patients were anti-IFI-16 antibody positive. Anti-IFI-16 antibody levels were significantly higher in cases with digital gangrene than in matched controls (P = 0.02). In analyses adjusted for age, cutaneous scleroderma subtype, smoking, and DLco, high anti-IFI-16 antibody levels were associated with the presence of digital gangrene (adjusted odds ratio 2.3, 95% confidence interval 1.0-5.6, P = 0.05). The odds of having digital gangrene increased with higher anti-IFI-16 antibody titers, in a dose-dependent manner. CONCLUSION: Anti-IFI-16 antibodies are associated with digital gangrene in patients with scleroderma. Longitudinal prospective studies exploring anti-IFI-16 antibodies as a disease biomarker, and biologic studies investigating the pathogenicity of these antibodies, are warranted.

Mycobacterium abscessus bacteremia after receipt of intravenous infusate of cytokine-induced killer cell therapy for body beautification and health boosting.

BACKGROUND: We report the first series of Mycobacterium abscessus bacteremia after cytokine-induced killer cell therapy for body beautification and health boosting. METHODS: The clinical manifestations, laboratory and radiological investigations, cytokine/chemokine profiles, and outcomes were described and analyzed. RESULTS: Four patients were admitted, and 3 patients had septic shock. Chest radiographs showed pulmonary infiltrates in all patients. Three patients developed peripheral gangrene, and 1 patient required lower limb and finger amputations. Patient 1 also developed disseminated infection including meningitis and urinary tract infection. Postmortem examination of patient 1 showed focal areas of pulmonary hemorrhage and diffuse alveolar damage, splenic infarct, adrenal necrosis, and hemorrhage, and acid-fast bacilli (AFB) were seen in the lung, liver, kidney, and adrenal gland. Patient 2 developed inguinal granulomatous lymphadenitis about 40 days after onset of lower limb gangrene. Wedge-shaped pulmonary infarcts were found in patient 3, and retinitis and subcutaneous lesions developed in patient 4. Patients in septic shock had dysregulated cytokine/chemokine profiles. Patient 4 with relatively milder presentation had increasing levels of interleukin 17 and cytokines in the interferon-γ/interleukin 12 pathway. All survivors required prolonged intravenous antibiotics. Blood cultures grew M. abscessus for all patients, and admission peripheral blood smear revealed AFB for 3 patients. Mycobacterium abscessus was also isolated from respiratory specimens (2 patients), urine (1 patient), and cerebrospinal fluid (1 patient). Time to initial blood culture positivity (patients 1, 2, and 3: ≤52 hours; patient 4: 83 hours) appeared to correlate with disease severity. CONCLUSIONS: Empirical coverage for rapidly growing mycobacteria should be considered in patients with sepsis following cosmetic procedures.

Clinicobiochemical investigations of gangrenous mastitis in does: immunological responses and oxidative stress biomarkers.

A total of 50 does were used to determine selected hematological and biochemical parameters with special references to oxidative stress markers, acute phase protein profiles, and proinflammatory cytokines in healthy and gangrenous mastitis affected does. Animals were divided into two equal groups represented as clinically healthy (control) and diseased groups, respectively. The bacteriological examination of milk samples from diseased does revealed many types of bacterial infection. The isolated bacteria were Staphylococcus aureus (N=23/25), Escherichia coli (N=11/25), and Clostridium perfringens (N=4/25). There was a significant increase in the levels of ß-hydroxybutyrate, non-esterified free fatty acids, triglyceride, low density lipoprotein cholesterol (LDL-C), aspartate aminotransferase, and alanine aminotransferase and a significant reduction in the levels of glucose, cholesterol, and high density lipoprotein cholesterol (HDL-C) in does with gangrenous mastitis compared to healthy does. Moreover, there was a significant increase in the levels of malondialdehyde and uric acid with a significant decrease in the levels of reduced glutathione, super oxide dismutase, and catalase in does with gangrenous mastitis compared to healthy does. In addition, there was a significant increase in the haptoglobin, serum amyloid A, fibrinogen, interleukin 6 (IL-6), IL-1ß, and tumor necrosis factor-α (TNF-α) in does with gangrenous mastitis compared to healthy ones. Conclusively, oxidative stress biomarkers, acute phase proteins, and proinflammatory cytokines play an essential task as biomarkers for gangrenous mastitis in does. Mastitis may be considered as one of the ketotic stressors in does after parturition.

Ecthyma gangrenosum and neutropenia in a previously healthy child.

Ecthyma gangrenosum is the cutaneous manifestation of pseudomonas infection in patients with sepsis. A previously healthy 7-month-old girl who developed ecthyma gangrenosum without apparent inciting factors became neutropenic secondary to autoimmune neutropenia 2 months after initial presentation. She was treated with appropriate surgical and medical intervention and was discharged in stable condition only to die suddenly 2 days after discharge.

Rapid-onset heparin-induced thrombocytopenia without previous heparin exposure.

Heparin-induced thrombocytopenia (HIT) is one of the most common immune-mediated drug reactions. Immunoglobulin G-type antibodies against platelet factor 4(PF4)/heparin complexes are known to play a key role in the pathogenesis of HIT. Rapid-onset HIT is caused by the presence of circulating HIT antibodies at the time of heparin readministration. These antibodies are generally resulted from a recent immunizing exposure to heparin. Here we report a case of rapid-onset HIT developed after a septicemia without previous heparin exposure. The diagnosis of HIT as well as the presence of platelet activating and heparin-dependent antibodies was confirmed by ELISA and flow cytometric functional assays. Our case report reinforces that rapid-onset HIT cannot be excluded only based on the absence of previous heparin exposure. In addition, it may support the new theory of pre-immunization by PF4-coated bacteria in the pathomechanism of HIT. We also call the attention that venous limb gangrene can be rarely associated with HIT and thrombosis even in the absence of coumarin therapy. Furthermore, transient presence of anti-phospholipid antibodies can cause a differential diagnostic problem in the cases of HIT.

Genome-wide differential gene expression profiles in broiler chickens with gangrenous dermatitis.

Gangrenous dermatitis (GD) is a disease of poultry characterized by necrosis of the skin and severe cellulitis of the subcutaneous tissues caused by infection with Clostridium septicum (CS) and/or Clostridium perfringens (CP) type A. While GD causes significant morbidity, mortality, and economic loss to the poultry industry, the fundamental mechanisms underlying this host-pathogen interaction are relatively unknown. This study used comparative global gene expression microarray analysis of GD-affected and clinically healthy chickens from a recent GD outbreak to glean insights into the molecular and cellular changes associated with this disease process. Histopathologic and immunohistochemical analyses confirmed extensive muscle damage and prominent leukocyte infiltration in the skin of GD-affected birds but not in healthy controls. The levels of mRNAs in the skin and underlying muscle corresponding to 952 microarray elements were altered in GD-afflicted birds compared with healthy controls, with 468 being increased and 484 decreased. From these, a subset of 386 genes was identified and used for biologic function and pathway analyses. The biologic functions that were most significantly associated with the differentially expressed genes were "inflammatory response" and "cellular growth and proliferation" classified under the categories of "disease and disorders" and "molecular and cellular functions," respectively. The biologic pathway that was most significantly associated with the differentially expressed genes was the nuclear factor-erythroid 2-related factor 2 (NRF2)-mediated oxidative stress pathway. Finally, in vitro infection of chicken macrophages with CS or CP modified the levels of mRNAs encoding interferon (IFN)-alpha, IFN-gamma, interleukin (IL)-1beta, IL-6, IL-12p40, tumor necrosis factor superfamily 15 (downregulated), IL-8, and IL-10 (upregulated), thus confirming the suppressive effect of GD on the chicken immune system.

Successful treatment of Fusarium solani ecthyma gangrenosum in a patient affected by leukocyte adhesion deficiency type 1 with granulocytes transfusions.

BACKGROUND: Ecthyma gangrenosum (EG) manifests as a skin lesion affecting patients suffering extreme neutropenia and is commonly associated with Pseudomonas aeruginosa in immunocompromised patients. Leukocyte adhesion deficiency I (LAD I) which count among primary immunodeficiency syndromes of the innate immunity, is an autosomal recessive disorder characterized in its severe phenotype by a complete defect in CD18 expression on neutrophils, delayed cord separation, chronic skin ulcers mainly due to recurrent bacterial and fungal infections, leucocytosis with high numbers of circulating neutrophils and an accumulation of abnormally low number of neutrophils at sites of infection. CASE PRESENTATION: We report at our knowledge the first case of a child affected by LAD-1, who experienced during her disease course a multi-bacterial and fungal EG lesion caused by fusarium solani. Despite targeted antibiotics and anti-fungi therapy, the lesion extended for as long as 18 months and only massive granulocytes pockets transfusions in association with G-CSF had the capacity to cure this lesion. CONCLUSION: We propose that granulocytes pockets transfusions will be beneficial to heal EG especially in severely immunocompromised patients.

Immunopathology and cytokine responses in commercial broiler chickens with gangrenous dermatitis.

Gangrenous dermatitis (GD) is an emerging disease of increasing economic importance in poultry resulting from infection by Clostridium septicum and Clostridium perfringens type A. Lack of a reproducible disease model has been a major obstacle in understanding the immunopathology of GD. To gain better understanding of host-pathogen interactions in GD infection, we evaluated various immune parameters in two groups of birds from a recent commercial outbreak of GD, the first showing typical disease signs and pathological lesions (GD-like birds) and the second lacking clinical signs (GD-free birds). Our results revealed that GD-like birds showed: reduced T-cell and B-cell mitogen-stimulated lymphoproliferation; higher levels of serum nitric oxide and alpha-1-acid glycoprotein; greater numbers of K55(+), K1(+), CD8(+), and MHC class II(+) intradermal lymphocytes, and increased K55(+), K1(+), CD8(+), TCR1(+), TCR2(+), Bu1(+), and MHC class II(+) intestinal intraepithelial lymphocytes; and increased levels of mRNAs encoding proinflammatory cytokines and chemokines in skin compared with GD-free chickens. These results provide the first evidence of altered systemic and local (skin and intestine) immune responses in GD pathogenesis in chickens.

Novel detection of parvovirus B19 DNA & IgM antibodies in patients with non-occlusive gangrene of stomach & bowel.

BACKGROUND: Gangrene of stomach or intestines owing to non-occlusive bowel infarction (NOBI) is a rare event with unknown etiology. Since B19 may cause vasculitis, arteritis, angiopathy and more importantly, localized microvascular thrombi formation hence patients with bowel gangrene were investigated for B19 infection. METHODS: Twelve patients (8 male and 4 females; median age 40 yr) of ischemic unexplained gangrene of bowel underwent emergency laparotomy. Eight cases had NOBI while four had occlusive bowel infarction (OBI). Anti-B19 antibodies in sera by ELISA and Western-blot and B19 DNA by PCR in sera and resected tissues were analysed. RESULTS: All patients underwent resection of gangrenous bowel; with exteriorization followed by restoration wherever appropriate. Histopathology showed loss of bowel mucosa and crypts with inflammatory cell infiltration besides fibrin thrombus in gastric vessels. Sera of all 8 patents of NOBI had B19 genome by nested-PCR (VP1 unique) and in 6 by PCR (VP1-VP2). In three patients resected bowel tissues also had B19 DNA besides anti-B19 IgM and IgG antibodies. NOBI patients were reticulocytopenic and anaemic while one had necrotizing vasculitis of skin a year ago. No IgM antibodies to agents causing vasculitis (HTLV-I, HIV-1+2, CMV, HSV1+2, mumps virus and Mycobacterium tuberculosis) nor any abnormality in coagulation profiles were detected. In four OBI cases's sera and resected bowel tissues and in control bowel tissues (n=36) no anti-B19 IgM antibodies or B19 DNA were detected. CONCLUSIONS: Novel finding of active B19 infection in non-occlusive gangrene of the bowel may be causal rather than casual.

Systemic Th17-like cytokine pattern in gangrenous appendicitis but not in phlegmonous appendicitis.

BACKGROUND: Increasing circumstantial evidence suggests that not all patients with appendicitis will progress to perforation and that appendicitis that resolves may be a common event. Based on this theory and on indications of aberrant regulation of inflammation in gangrenous appendicitis, we hypothesized that phlegmonous and gangrenous appendicitis are different entities with divergent immunoregulation. METHODS: Blood samples were collected from patients with gangrenous appendicitis (n = 16), phlegmonous appendicitis (n = 21), and nonspecific abdominal pain (n = 42). Using multiplex bead arrays, we analyzed a range of inflammatory markers, such as interleukin (IL)-1ra, IL-1rbeta, IL-2, IL-6, IL-10, IL-12p70, IL-15, and IL-17; interferon-gamma; tumor necrosis factor; CXCL8; CCL2; CCL3; and matrix metalloproteinase (MMP)-1 MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, and MMP-13 in blood. RESULTS: Compared with patients with phlegmonous appendicitis and nonspecific abdominal pain, the patients with gangrenous appendicitis had increased levels of the proinflammatory markers IL-6, CCL2, IL-17, MMP-8, and MMP-9 (P < or = .04 each) accompanied by increased levels of the anti-inflammatory cytokines IL-1ra and IL-10 (P < or = .02). Patients with phlegmonous appendicitis had increased levels of IL-10 only. CONCLUSION: The finding of a pattern of inflammatory markers compatible with the highly inflammatory Th17 subset in sera from patients with gangrenous appendicitis, but not in phlegmonous appendicitis, supports the hypothesis that gangrenous and phlegmonous appendicitis are different entities with divergent immune regulation. Additional studies of the differential immunopathogenesis of phlegmonous and gangrenous appendicitis are warranted, as this may have important implications in the diagnosis and management of patients with suspicion of appendicitis.

Ecthyma gangrenosum: a manifestation of Pseudomonas sepsis in three paediatric patients.

Pseudomonas aeruginosa sepsis rarely occurs in healthy children. In immunocompromised children, it usually carries a high mortality rate. Ecthyma gangrenosum is a known cutaneous manifestation of Pseudomonas septicaemia. Three paediatric cases of Pseudomonas aeruginosa septicaemia with ecthyma gangrenosum were retrospectively reviewed. The three patients were aged seven years, seven months, and five months, respectively. An underlying disease of hypogammaglobulinaemia was present in the oldest patient. Blood cultures grew Pseudomonas aeruginosa in all three patients. All underwent repeated wound debridement and received intravenous ceftazidime and an aminoglycoside for a minimum of two weeks. One needed colostomy and subsequent posterior sagittal anorectoplasty as a result of complete obliteration of the anal canal from the ecthyma. There was no mortality. In conclusion, Pseudomonas aeruginosa sepsis should be treated early. Recognition of ecthyma gangrenosum as a manifestation of this problem can allow early institution of the appropriate antibiotics before culture results.

Dry gangrene of the extremities in calves associated with Salmonella dublin infection; a possible immune-mediated reaction.

Dry gangrene of the extremities in calves is a circulatory error that may occur after infection with Salmonella dublin. This report describes an examination of three affected, 12 in-contact and five control calves, a main objective being to investigate the possible role of cold agglutination in pathogenesis. The lesions included dry gangrene of the hind legs, ears and tail. A cold agglutination test gave positive results in all animals examined except the controls. The three affected calves had high titres of S. dublin antibodies, as also did four of the in-contact animals. The results suggested a relationship between cold agglutination and the occurrence of the disease.

Different cytokine profiles in patients with a history of gangrenous or phlegmonous appendicitis.

Appendicitis is one of the most common and costly acute abdominal states of illnesses. Previous studies suggest two types of appendicitis which may be different entities, one which may resolve spontaneously and another that progresses to gangrene and perforation. Gangrenous appendicitis has a positive association to states of Th1 mediated immunity whereas Th2 associated immune states are associated with lower risk of appendicitis. This study investigated the inflammatory response pattern in patients previously appendicectomized for gangrenous (n = 7), or phlegmonous appendicitis (n = 8) and those with a non-inflamed appendix (n = 5). Peripheral blood mononuclear cells were analysed with ELISPOT analysis for number of spontaneous or antigen/mitogen stimulated IFN-gamma, IL-4, IL-10 and IL-12 secreting cells or with ELISA for concentration of spontaneous or antigen/mitogen stimulated IFN-gamma, IL-5 and IL-10. Spontaneously IL-10 secreting cells/100,000 lymphocytes were increased in the gangrenous group compared to the phlegmonous group (P = 0.015). The median concentration of IL-10 secreted after Tetanus toxoid (TT)-stimulation were higher in the gangrenous group and the control group, than the phlegmonous group (P = 0.048 and P = 0.027, respectively). The median concentration of TT induced IFN-gamma secretion was higher for the gangrenous group compared to both the phlegmonous group and the control group (P = 0.037 and P = 0.003). Individuals with a history of gangrenous appendicitis demonstrated ability to increased IL-10 and IFN-gamma production. The increased IFN-gamma may support the notion of gangrenous appendicitis as an uncontrolled Th1 mediated inflammatory response and increased IL-10 may speculatively indicate the involvement of cytotoxic cells in the progression to perforation.

Heat insoluble cryoglobulin associated with gangrene in multiple myeloma.

Cryoglobulins are immunoglobulins that have tendency to precipitate in temperatures below 37 degrees C and dissolve with rewarming. Monoclonal cryoglobulins are usually associated with a distinct hematological disorder and often are asymptomatic. Heat insoluble cryoglobulin has been described with Sjogren's syndrome and glomerulonephritis but, not with multiple myeloma. Severe sensitivity to cold occurs with high thermal insolubility of the cryoprotein, with dramatic symptoms when exposed to minimal lowering of the temperature. We report a case of a 49 year old man with multiple myeloma and an unusual type I cryoglobulin that caused occlusive gangrene. The cryoglobulin appeared as a milky white precipitate that was resistant to re-suspension and did not dissolve at 37 degrees C. Immunoelectrophoresis of the cryoglobulin, which dissolved at 56 degrees C, showed it to be composed of a monoclonal IgG kappa protein (3.5 g/dl). Unlike most high thermal insoluble cryoglobulin, cold associated symptoms were not seen. In addition to steroids, plasmapheresis was initiated thrice a week with albumin fluid replacement. Plasmapheresis caused a marked decline in cryocrit levels from 21% to less than 0.5% in 9 days after 4 procedures with resolution of the gangrene of the feet and after 6 treatments, vasculitic symptoms improved dramatically. The cryoglobulin test was negative 2 weeks after initiation of treatment. The patient was treated for the myeloma and there was no recurrence of occlusive symptoms. Proper laboratory procedure and careful examination and handling of cryoglobulinemic samples facilitate detection of unusual cryoglobulins. This is a unique report of multiple myeloma with gangrene of lower extremities that has a heat insoluble cryoglobulin.