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Inhibitory effects of glucocorticoids on collagen synthesis by mouse sponge granulomas and granuloma fibroblasts in culture.

The basis for the glucocorticoid-mediated decrease in tissue collagen was studied in mouse granulomas and in primary granuloma fibroblast cultures. Injection of mice for 12 days with dexamethasone (0.35 mg/kg body weight) resulted in a 50--70% inhibition of collagen synthesis and accumulation in polyvinyl sponge-induced granulomas whereas total protein synthesis was inhibited by only about 25%. The decreased collagen content of the granuloma was accounted for by both a reduced fibroblast number and diminished synthesis per cell. Growth rates, total protein synthesis and collagen synthesis were the same in granuloma fibroblast cultures derived from control or steroid-treated mice. However, addition of 3.10(-7) M hydrocortisone to the culture medium caused a 30--50% inhibition of both collagen and non-collagen protein synthesis in firbroblasts from either source. These inhibitory effects were dose- and time-dependent with a lag time of 12--24 h. Prolyl hydroxylase activity was reduced both in sponge granulomas from glucocorticoid-treated mice and in hydrocortisone-treated fibroblast cultures. However, protein synthesis was inhibited to the same extent as the inhibition of prolyl hydroxylase activity and there was no effect on peptidyl prolyl hydroxylation. These results indicate that the glucocorticoid-induced reduction of collagen synthesis and accumulation observed in mouse granulomas and primary granuloma fibroblast cultures is not specific for this protein. Furthermore, glucocorticoid-induced inhibition of collagen synthesis cannot be attributed to underhydroxylation of collagen prolyl residues.

Animals

Granuloma dual RNA-seq reveals composite transcriptional programs driven by neutrophils and necrosis within tuberculous granulomas.

Mycobacterial granulomas lie at the center of tuberculosis (TB) pathogenesis and represent a unique niche where infecting bacteria survive under nutrient-restricted conditions and in the face of a host immune response. The granuloma's necrotic core, where bacteria reside extracellularly in humans, is difficult to assess in many experimentally tractable models. Here, using necrotic mycobacterial granulomas in adult zebrafish, we develop dual RNA sequencing (RNA-seq) across different host genotypes to identify the transcriptional alterations that enable bacteria to survive within this key microenvironment. Using pharmacological and genetic interventions, we find that neutrophils within mature, necrotic granulomas promote bacterial growth, in part through up-regulation of the bacterial devR regulon. We identify conserved suites of bacterial transcriptional programs induced only in the context of this unique necrotic extracellular niche, including bacterial modules related to K+ transport and rpf genes. Analysis of Mycobacterium tuberculosis strains across diverse lineages and human populations suggests that granuloma-specific transcriptional modules are targets for bacterial genetic adaptation in the context of human infection.

Animals

The Churg-Strauss granuloma: cutaneous, necrotizing, palisading granuloma in vasculitis syndromes.

The cutaneous, necrotizing, palisading granuloma (Churg-Strauss granuloma) was observed on histopathologic study of skin specimens from seven patients. Two patients had Wegener's granulomatosis and one patient each had allergic granulomatosis, limited Wegener's granulomatosis, bacterial endocarditis, systemic lupus erythematosus, and rheumatoid arthritis. The microscopic picture consists of extravascular, palisading, dermal granuloma. The center of the granuloma consists of basophilic fibrillar necrosis in which linear bands of destroyed tissue are interspersed with masses of polymorphonuclear leukocytes and leukocytoclastic debris. This necrotic leukocytic mass is surrounded by histiocytes and some lymphocytes. The clinical lesions are symmetric, erythematous papules or nodules on the extremities. The histopathologic picture of the Churg-Strauss granuloma is unique and, as demonstrated in these cases, indicates the presence of systemic vasculitis.

Granulomatosis with Polyangiitis

The Schistosoma japonicum egg granuloma. II. Cellular composition, granuloma size, and immunologic concomitants.

Studies of granulomatous hypersensitivity to Schistosoma japonicum eggs were performed at various time periods up to 20 wk after the induction of light infections in mice. Cell populations which were determined in granulomas isolated from the livers revealed a maximum in the total number of cells at 6 wk with a decline of 36% by 20 wk. Large mononuclear cells were predominant at all time periods, with eosinophils being the second most common cell. Measurements of granuloma diameters around single viable eggs in the livers also revealed peak size at 6 wk with a decline of 51% between 16 and 24 wk. Immunodiffusion analysis demonstrated the presence of precipitating antibodies as early as 7 wk after infection. Investigations of lymphocyte blastogenesis revealed a profound depression in response to T-cell mitogens by 8 wk of infection. Studies of footpad swelling to soluble S. japonicum egg antigens revealed massive immediate reactions starting at 6 wk. but no delayed reactivity over a period from 3 to 20 wk. All of these results are related to differences in the biology of S. japonicum in comparison with S. mansoni with respect to the earlier onset of egg production, the much larger numbers of eggs produced, and the possibility of differences in the antigens emitted by the eggs.

Animals

[Role of antigens and adjuvant substances in the histological response in experimental granulomas (immunogenic granuloma)].

The injection in rabbits of vaccinal antigens combined with immunity adjuvants (in particular calcium phosphate) causes a local lesion in which it is possible to recognize histologically, after a transitory afflux of polymorphonuclear leukocytes, a central area of adjuvant deposit, a middle area of histiocytes and monocytes, and a peripheral immunogenic area of lymphocytes and plasmocytes. These two cellular zones are rich in highly fluorescent cells in the presence of an antiglobulin serum with an embedding technique which respects to the upmost the structures and immunoreactivity of the cells. These histological features are not completely observed on the separate injection of antigen or adjuvant. They must be interpreted, after a fleeting non-specific reaction, while taking into account the still poorly understood method of action of the inorganic adjuvant and spread of the antigen in the organism.

Adjuvants, Immunologic

Spermatic granuloma of vas deferens after vasectomy in rhesus monkeys and men: light and electron microscopic study.

Spermatic granuloma of the vas deferens is a common complication of vasectomy which has received scant morphologic study. This study investigated the light and electron microscopic structure of such granulomas detected in rhesus monkeys (Macaca mulatta) and man after various modes of vasectomy and postoperative periods. Unilateral experimental vasectomy in monkeys was performed by either silk ligation or clasp occlusion; in 4 of 13 ligated animals and 5 of 5 clasp vasectomized animals granulomas developed at the site of fasectomy. In man, portions of the vas deferens were excised adjacent to the site of vasectomy preparatory to vasovasostomy. Of 5 patients studied, unilateral spermatic granulomas developed in 3. Such granulomas in both monkey and man were characterized by (1) masses of sperm surrounded by epithelioid cells and connective tissue, and (2) multiple epithelial-lined channels which often contained sperm and spermiophages. In both species, fine structural characteristics of the epithelium lining such channels closely resembled those of the principal cells of the normal vas. Spermiophagic cells included macrophages, epithelioid cells, and, in the monkey only, neutrophils. Lymphocytic invasion was a common feature of the human granulomas but was found only occasionally in the monkey granulomas. As a greater number of granulomas are studied in humans and monkeys, it is hoped that the processes underlying granuloma formation and the role of such granulomas in the development of complications after vasectomy will be clarified.

Animals

Comparative study of proteins extracted form metal-induced allergic and foreign body granulomas in man.

In order to characterize proteins unique to organized epitheloid cells, proteins havebeen sequentially extracted form both foreign body and allergic granulomas in man at varoius times after intradermal injection of beryllium oxide suspension. Treitium-labeled l-tyrosine was injected intralesionally 2 weeks before excision of granulomas. Prolongedextraction with 8 m urea yeilded increases amounts of radioactivie protein form older (8-to 26-week) allergic granulomas but not from 4-to6-week-old or foreign body granulomas (consisting of mononuclear cells and phagocytes). Sephadex G-200 column chromatographyand sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis of the urea extractsfrom 8-week and older allergic granulomas revealed distinct readioactive protein peaks with molecular weights of approximately 172,000 to 208,000. Antisera raised to one of these proteins gave a precipitin line in agar gel diffusion with lines of identity againsturea extracts of several allergic granulomas but not against similiar extracts of foreignbody granulomas. The results suggest synthesis of distinctive high molecular weight proteins in allergic granulomas which may serve as "markers" for organized epitheloid cell granulomas as they transform from mononuclear cells.

Animals

Sperm granuloma and reversibility of vasectomy.

Ninety-two consecutive patients who had undergone bilateral vasectomy 1 month to 28 years earlier were studied at the time of vasectomy reversal for sperm output, dilatation of the vas-deferens lumen, and sperm granuloma. Thirty-nine men had unilateral or bilateral sperm granuloma. The presence of of a sperm granuloma virtually assured normal sperm in the vas fluid no matter how long ago the vasectomy was performed. In the absence of a sperm granuloma, the interval since vasectomy had an important influence on the quality of vas fluid. The presence of a sperm granuloma was associated with significantly less dilatation of vas-deferens lumen at the testicular end. The site of the vasectomy and the amount of vas deferens removed did not influence sperm quality. A sperm granuloma on only one side resulted in normal spermatozoa in the vas fluid on that side, whereas the side without the sperm granuloma had abnormal spermatozoa or no spermatozoa in the vas fluid. It is concluded that when sperm granuloma follows vasectomy it vents the high pressure otherwise created by vasectomy and prevents disruption of sperm output in the vas fluid.

Adult

Pulmonary granulomas induced by BCG.

BCG administered by the multiple-puncture technique has been used in a prospective, randomized study of the adjuvant treatment of patients with osteogenic sarcoma. Pulmonary granulomas were found in the lungs of four of five patients receiving BCG, that underwent thoracotomy for the diagnosis of pulmonary nodules within three weeks of the last BCG injection. Except for a single, foreign-body granuloma no pulmonary granulomas were seen in seven randomized patients who did not receive BCG. In addition, two patients receiving BCG had evidence of granulomas in bone marrow and in a mediastinal lymph node. BCG administered by the multiple-puncture technique is capable of causing granulomas at sites distant from that of the BCG application. BCG can cause pulmonary granulomas and these granulomas may be confused with pulmonary metastatic disease.

BCG Vaccine

Prostaglandins and granuloma formation in vivo.

The formation of granuloma tissue is one of the major characteristics of chronic inflammation. Infiltration of phagocytic cells (a major source of prostaglandins) and in many cases (including rheumatoid arthritis) lymphocytes, is one of the earliest events in granuloma formation. Prostaglandins (PGs) may modulate the infiltration of some or all of these cells, though much in-vivo data is lacking. Additionally, PGs may modulate the release of the products of these inflammatory cells, which contribute to granuloma formation. Once granulomatous tissue becomes established, PGs may also control the growth of the granuloma through actions on proliferating cells and connective tissue constituents. In-vivo data suggest that the anti-granuloma actions may be mediated by cyclic AMP. While prevention of endogenous PG production by anti-inflammatory drugs has little beneficial effect on preexisting granuloma, facilitation or mimickry of the anti-granuloma actions of PGs may be a possible line for future therapy of diseases such as rheumatoid arthritis.

Animals

Fc-receptor-bearing macrophages isolated from hypersensitivity and foreign-body granulomas. Delineation of macrophage dynamics, fc receptor density/avidity and specificity.

Foreign-body and delayed hypersensitivity granulomas were induced in mice; and the dynamics of macrophages isolated from dispersed, 1--4-week-old lesions was delineated. The size and histologic complexity of the lesions increased as shown: adjuvant greater than schistosome egg greater than methylated bovine serum albumin greater than bead. Esterase staining, spreading on glass, and the percentage of Fc-receptor--bearing macrophages present in the various granulomas reflected the same gradient. The Fc receptors were examined by rosetting with rabbit-antibody--SRBC complex (EA). Whereas more than 90% of the population of macrophages of the dermal adjuvant granuloma contained undiminished numbers of receptor-bearing macrophages throughout the 4 weeks, the percentage of macrophages that displayed receptors in pulmonary foreign-body (40%) and delayed hypersensitivity granulomas (70%) peaked at 1 week and subsequently declined. The EA rosetting of the foreign-body and delayed hypersensitivity granuloma macrophages was strongly inhibited by monomeric IgG2a-specific and weakly by aggregated IgG2b-specific mouse myeloma proteins. Also, macrophages of the delayed hypersensitivity granulomas rosetted in higher percentages with SRBCs coupled with monomeric IgC2a than with those coupled with aggregated IgG2b myeloma proteins. Macrophages of the foreign-body lesion did not react with aggregated IgG2b--SRBC. Rosetting with monomeric IgG2a--SRBC or aggregated IgG2b--SRBC could not be cross-inhibited by the myeloma proteins. Both the monomeric IgG2a--SRBC and aggregated IgG2b--SRBC complexes were readily phagocytized. Trypsin treatment of the macrophages inhibited rosetting with EA or myeloma-protein--coupled SRBCs. The display of Fc receptors on the granuloma macrophages seems to be related to the etiology of the lesion and the intensity and duration of the inflammatory reaction.

Animals

Open-ended vasectomy, sperm granuloma, and postvasectomy orchialgia.

The presence of a sperm granuloma at the vasectomy site prevents epididymal pressure build-up, perforation, and the formation of an epididymal sperm granuloma. It thus enhances reversibility of the vasectomy and lessens the likelihood of epididymal discomfort. In two prospective vasectomy series, a sperm granuloma was intentionally allowed to form by not sealing the testicular end of the vas. The sperm granuloma resulted in no instance of orchialgia, but created a greater risk of spontaneous recanalization. This latter problem could only be solved by more careful sealing of the upper end of the vas. In a separate series of nine patients vasectomized elsewhere and specifically referred to us for chronic and persistent postvasectomy orchialgia, seven had no sperm granuloma at the vasectomy site. Pain in these cases was localized in the epididymis and was relieved by vasovasotomy. Any technique of vasectomy carries a very small risk of orchialgia, whether due to the presence of a sperm granuloma at the vasectomy site or to increased epididymal pressure.

Canada

[The clinical picture of "circumscribed granuloma diseases"].

Characteristic findings, differential diagnosis and clinical course of the so-called "circumscript granulomas" (Granuloma anulare, necrobiosis lipoidica, Miescher's granulomatosis, disciformis, necrobiosis maculosa, granuloma multiforme, actinic granuloma, granuloma faciale and lethal midline granuloma etc.) are represented in a condensed clinical survey.

Diagnosis, Differential

Delayed hypersensitivity and lymphocytic transformation in patients with Hodgkin's disease and granulomas.

Noncaseating, sarcoid-like granulomas were found in the tissues of 9 out of 31 patients with Hodgkin's disease. In vivo and in vitro cell-mediated immunity was evaluated in patients with and without granulomas and compared to a group of 20 normal controls. Hodgkin's disease patients of both groups showed a significantly reduced in vivo and in vitro response when compared to the control group. However, when patients in stages IIIB and IV were eliminated and patients in stages I, II, and IIIA examined separately, a positive skin test response to one or more antigens was elicited in 85.7% of patients with granulomas, while a markedly decreased-dose dependent response was observed in patients without granulomas. In vitro lymphocyte blastic transformation by phytohemagglutinin (PHA) was severely impaired in both groups of patients as determined by dose-responses curves. These results indicate that Hodgkin's disease patients with granulomas have a significantly better skin test response than those without granulomas.

Adolescent

Maxillary giant cell reparative granuloma.

"Giant cell reparative granuloma" was introduced into medical literature by Jaffe in 1953. Prior to that time most authors considered this lesion to be a variant of the benign giant cell tumor of the long bones, or a giant cell variant of osteitis fibrosa. Bernier and Cahn established the subdivision between the rare central giant cell reparative granuloma and the common peripheral epulis. In the past, considerable emphasis has been placed on the importance of differentiating the true giant cell tumor from the giant cell reparative granuloma of the jaw bones. Most authors now believe the true giant cell tumor does not appear in the jaw bones except in rare cases associated with Paget's disease of the skull. Developing from membranous, rather than cartilaginous, ossification might account for this. Both peripheral and central intraosseous lesions, parathyroid osteopathy and the pathologic tissue of cherubism show no appreciable histologic difference. These tumefactions are histologically a proliferative fibroblastic lesion with multinucleated giant cells. The histopathology of the giant cell tumor of the long bones is probably identical to the histopathology of the giant cell reparative granuloma of the jaw bones. The diagnosis of giant cell reparative granuloma must be made by physical examination, history, laboratory, X-ray parameters and clinical follow-up. Localized maxillary swelling is the most important clinical feature. The swelling is smooth and palpation can reveal a rubbery, elastic sensation where bone has been thinned. There are no specific radiographic signs. Conservative surgical management is indicated and adequate for giant cell reparative granulomas. Radiation is not indicated because of long term risks. Steroids have not been proven useful.

Adult