Urticaria unresponsive to antihistaminic treatment: An open study of therapeutic options based on histopathologic features

Background: The non- or low-sedating H1 receptor antagonists represent the basic therapy for urticaria. Objective: To test an alternative approach to patients unresponsive to conventional treatment. Materials and methods: A total of 22 patients with chronic urticaria unresponsive to conventional antihistamine treatment were enrolled for this study. They had uncontrolled urticaria even using multiple combinations of antihistamines on maximum doses and corticosteroids in short cycles (prednisone 20-40 mg, per os once a day, 3-7 days per month). Cutaneous biopsies of the urticaria lesions were taken. These findings were classified as: (I) a mixture of perivascular dermal inflammatory infiltrate composed of lymphocytes, monocytes and neutrophils and/or eosinophils; (II) inflammatory infiltrate composed chiefly of neutrophils; and (III) inflammatory infiltrate composed mainly of eosinophils. According to histology, the patients were submitted to one of the following therapeutic schemes: class A - antihistamine treatment plus dapsone; class B - colchicine or dapsone; class C montelukast. Results: Four patients in class A, 08 in class B and seven in class C displayed complete control of urticaria after 12 weeks of treatment; one patient in class B and two in class C did not respond to treatment. Two years after discontinuation, 16 patients are still free of urticaria. Conclusions: This study suggests an alternative approach for treating unresponsive chronic urticaria.

Assessment of Occupational Genotoxic Risk among Brazilian Hairdressers

Objectives: To evaluate the genotoxic risk to hairdressers exposed daily to chemical substances such as hair dyes, waving and straightening preparations and manicurists` products by the Comet assay test (single-cell gel electrophoresis). Methods: The Comet assay was performed on blood samples from 69 female hairdressers (36.4 +/- 10.7 years old) currently employed in 21 different beauty institutes in Sao Paulo, Brazil, and on 55 female control blood donors (32.6 +/- 10.0 years old) from the Sao Paulo University Clinical Hospital blood bank. All the control subjects had occupations other than hairdresser. Comet assays were performed by evaluating 100 blood lymphocytes per individual and graded by visual score according to comet tail length. Results: The hairdressers showed a higher frequency of DNA damage revealed by Comet Score (159.8 +/- 71) when compared to the control group (125.4 +/- 64.1), and the difference was statistically significant by the Student`s t-test (P = 0.005). Multiple regression analysis showed that in addition to the hairdressers` profession, tobacco use contributed to the higher frequency of cells with comets (P < 0.05). Conclusions: The observed DNA damage could be associated with the hairdressers` occupational environment, where different chemicals are chronically manipulated and inhaled. Considering that this profession in many countries, including Brazil, is not officially regulated, more attention should focus on these professionals not only by legislative bodies but also by multidisciplinary teams able to develop and implement risk prevention and control strategies for chemical, physical and biological agents to which hairdressers are exposed.

DNA damage and repair in leukocytes of melanoma patients exposed in vitro to cisplatin

Resistance to chemotherapeutic drugs can be an obstacle to a successful treatment of cancer patients in part associated with individual response and differences in the DNA repair system. The Comet assay is an informative test to investigate DNA damage and repair in cells in response to a variety of DNA-damaging agents, including chemotherapeutic drugs. The aim of this study was to assess leukocytes damage after in-vitro cisplatin treatment and DNA repair action using the Comet assay in 20 patients with melanoma and 20 cancer-free individuals. Leukocytes` DNA damage before and after cisplatin treatment, in three different concentrations, was analyzed. The DNA repair capability was investigated after 1-5 h of in-vitro cells growing without cisplatin. The Comet score of the patients` basal DNA damage was higher than that observed in controls, but the difference was not statistically significant (P=0.85). Although both groups had similar Comet scores to all cisplatin concentrations tested and the DNA repair times, the basal DNA damage (P < 0.001) and cisplatin damages (P < 0.005) were statistically lower than the different repair times investigated. Considering the progressive increase in the Comet score due to repair time, the negative results here observed could be associated with the reduced cell culture incubation that should be better evaluated. Considering the mutagenic action of cisplatin on tumor cells and the importance of individual DNA repair mechanisms in the chemotherapeutic melanoma treatment, the peripheral leukocytes could be particularly useful as a tool for DNA repair response identified by the Comet assay. Melanoma Res 21:99-105 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Identification of FAM46D as a novel cancer/testis antigen using EST data and serological analysis

Cancer/testis Antigens (CTAs) are immunogenic proteins with a restricted expression pattern in normal tissues and aberrant expression in different types of tumors being considered promising candidates for immunotherapy. We used the alignment between EST sequences and the human genome sequence to identify novel CT genes. By examining the EST tissue composition of known CT clusters we defined parameters for the selection of 1184 EST clusters corresponding to putative CT genes. The expression pattern of 70 CT gene candidates was evaluated by RT-PCR in 21 normal tissues, 17 tumor cell lines and 160 primary tumors. We were able to identify 4 CT genes expressed in different types of tumors. The presence of antibodies against the protein encoded by 1 of these 4 CT genes (FAM46D) was exclusively detected in plasma samples from cancer patients. Due to its restricted expression pattern and immunogenicity FAM46D represents a novel target for cancer immunotherapy. (c) 2009 Elsevier Inc. All rights reserved.

Transvaginal ultrasonography with bowel preparation is able to predict the number of lesions and rectosigmoid layers affected in cases of deep endometriosis, defining surgical strategy

Successful surgical treatment of deep bowel endometriosis depends on obtaining detailed information about the lesions, prior to the procedure. The objective of this study was to determine the capability of transvaginal ultrasonography with bowel preparation (TVUS-BP) to predict the presence of one or more rectosigmoid nodules and the deepest bowel layer affected by the disease. A prospective study of 194 patients with clinical and TVUS-BP suspected deep endometriosis submitted to videolaparoscopy. Image data were compared with surgical and histological results. With respect to bowel nodule detection and presence of at least two rectosigmoid lesions, TVUS-BP had a sensitivity of 97 and 81%, specificity 100 and 99%, positive predictive value (PPV) 100 and 93% and negative predictive value (NPV) 98 and 96%, respectively. Regarding diagnosis of infiltration of the submucosal/mucosal layer, TVUS-BP had a sensitivity of 83%, specificity 94%, PPV 77%, NPV 96%. These findings show that TVUS-BP is an adequate exam for evaluating the presence of one or more rectosigmoid nodules and the deepest layer affected in deep infiltrating bowel endometriosis, confirming the importance of this technique for defining the most appropriate surgical strategy to be implemented.

Endometriosis of the ureter and bladder are not associated diseases

Objective: To verify whether bladder and ureter endometriosis had the same clinical features and disease behavior. Design: Case-control study. Setting: Multidisciplinary group in Sao Paulo, Brazil. Patient(s): A total of 690 patients were submitted to laparoscopy with histologically diagnosis of endometriosis between July 1999 and December 2006. Twelve of these patients had lesions affecting the ureter and 26 had lesions affecting the bladder. A control group consisted of 652 patients in whom endometriosis was not affecting either the ureter or the bladder. Intervention(s): None. Main Outcome Measure(s): Clinical and surgical features of patients with ureteral or bladder endometriosis. Result(s): No patients with ureteral endometriosis had lesions affecting the bladder. Compared with the control group, patients with ureteral endometriosis had more advanced disease (Stages III and IV) according to the American Society of Reproductive Medicine (ASRM) staging classification (100% vs. 65.5%); they also had more retrocervical (83.3% vs. 21.6%) and rectum-sigmoid lesions (91.7% vs. 17.9%). Compared with the control group, more patients with bladder endometriosis had cyclic dysuria and/or hematuria (34.6% vs. 9.8%), more advanced stages of the disease (88.4% vs. 65.5%), and an association with endometriosis of the rectum-sigmoid (65.3% vs. 17.9%). Conclusion(s): Ureter endometriosis is not associated with the bladder disease; however, it is associated with advanced ASRM stages and with retrocervical and rectum-sigmoid lesions. (Fertil Steril (R) 2009;91:1662-7. (C)2009 by American Society for Reproductive Medicine.)

Interleukin-12 but not interieukin-18 is associated with severe endometriosis

Objective: To evaluate interleukin (IL)-12 and IL-18 levels in the serum and peritoneal fluid of women with and without endometriosis. Design: Cross-sectional survey. Setting: University hospital. Patients: Interleukin-12 and IL-18 levels were compared in 105 patients submitted to laparoscopy because of symptoms suggestive of endometriosis (pain and/or infertility). The disease was confirmed in 72 patients (study group), while in 33 patients findings were not compatible with endometriosis (control group). Intevention(s): Blood sample and peritoneal fluid were obtained from patients during videolaparoscopy. Main Outcome Measure(s): The levels of IL-12 and IL-18 in peripheral blood and peritoneal fluid were determined and compared with the stage and site of the disease and histologic classification. Result(s): IL-12 levels measured in peritoneal fluid were higher inpatients with endometriosis compared with the control group. A significant increase in IL-12 levels was found when the more advanced stages of the disease were compared with the initial stages. No statistically significant differences were found in IL-18 levels, either in serum or in peritoneal fluid samples. Conclusion(s): Patients with severe endometriosis have higher IL-12 levels irrespective of IL-18 levels, suggesting that in this disease an alternative pathway is involved in induction of the Th1 immune response. (Fertil Steril (R) 2009;91:320-4. (C)2009 by American Society for Reproductive Medicine.)

Endometriosis lesions that compromise the rectum deeper than the inner muscularis layer have more than 40% of the circumference of the rectum affected by the disease

Study Objective: To estimate the relationship between the depth of lesions of rectal endometriosis and the percentage of the circumference of the bowel segment affected by the disease. Design: A prospective pathologic analysis of 45 surgical specimens of bowel endometriosis obtained by laparoscopic segmental resection of the rectosigmoid (Canadian Task Force classification II-1). Setting: Tertiary referral hospital. Patients: forty-five patients were submitted to a segmental resection of the rectum due to endometriosis between July 2004 and September 2006. Interventions: Morphometric aspects of endometriotic lesions were analyzed, such as size and thickness of the lesion, deepest layer of bowel affected by lesion, and percentage of circumference of bowel affected by endometriosis. Measurements and Main Results: Results showed that in lesions that reached the submucous layer of the bowel, the circumference affected was 31.6% greater than in lesions that reached only the outer muscular layer, whereas in lesions that reached the mucous layer, the circumference affected was 52.5% greater than in those that reached the outer muscular layer of the bowel. In addition, 89.3% of lesions with an affected circumference greater than 40% were those affecting the submucous or mucous layers of the bowel. These results suggest that when a lesion reaches these 2 deepest layers of the rectosiamoid, risk increases that the circumference affected will be greater than 40% (relative risk = 1.5; 95% CI: 1.0-2.3; p =.03). Conclusion: In endometriotic lesions affecting the rectosigmoid beyond the inner muscular layer of the bowel wall, more than 40% of the circumference of the rectosigmoid is affected by the disease, confirming the recommendation of segmental resection of the bowel for this form of the disease.

CYP17 polymorphism and hot flushes in postmenopausal women

Objective To investigate the association between the CYP17 alpha gene polymorphism and hot flushes in postmenopausal women. Methods Ninety-three non-hysterectomized, postmenopausal women were enrolled in this study. Vasomotor symptoms were assessed at the baseline visit and based on information provided by each participant. The genotypic polymorphism of CYP17 alpha gene was analyzed by PCR-RFLP assay using genomic DNA isolated from peripheral blood lymphocytes. Results Thirty-six women reported hot flushes of mild intensity, 25 reported hot flushes of moderate intensity and 32 of severe intensity. There was no significant difference between the severity of hot flushes and the CYP17 genotype or allele frequencies, 0.58 and 0.67 respectively. No association was found between hot flush severity and the CYP17 allele (odds ratio = 1.17, p = 0.61). Conclusion The results of this study suggest that the CYP17 MspAI polymorphism was not significantly associated with an increased risk of reporting hot flushes. At the World Congress on Menopause in Madrid, May 2008, Dr Massad-Costa was awarded the Robert Greenblatt Prize for Basic Science for the study reported in this paper.

Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies

Introduction Associations between systemic lupus erythematosus (SLE) and primary immunodeficiencies (PIDs) were analyzed to gain insight into the physiopathology of SLE. Some PIDs have been consistently associated with SLE or lupus-like manifestations: (a) homozygous deficiencies of the early components of the classical complement pathway in the following decreasing order: in C1q, 93% of affected patients developed SLE; in C4, 75%; in C1r/s, 57%; and in C2, up to 25%; (b) female carriers of X-linked chronic granulomatous disease allele; and (c) IgA deficiency, present in around 5% of juvenile SLE. Discussion In the first two groups, disturbances of cellular waste-disposal have been proposed as the main mechanisms of pathogenesis. On the other hand and very interestingly, there are PIDs systematically associated with several autoimmune manifestations in which SLE has not been described, such as autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), immunedys-regulation polyendocrinopathy enteropathy X-linked (IPEX), and autoinumme lymphoproliferative syndrome (ALPS), suggesting that mechanisms considered as critical players for induction and maintenance of tolerance to autoantigens, such as (1) AME-mediated thymic negative selection of lymphocytes, (2) Foxp3+ regulatory T cell-mediated peripheral tolerance, and (3) deletion of auto-reactive lymphocytes by Fas-mediated apoptosis, could not be relevant in SLE physiopathology. The non-description of SLE and neither the most characteristic SLE clinical features among patients with agammaglobulinemia are also interesting observations, which reinforce the essential role of B lymphocytes and antibodies for SLE pathogenesis. Conclusion Therefore, monogenic PIDs represent unique and not fully explored human models for unraveling components of the conundrum represented by the physiopathology of SLE, a prototypical polygenic disease.

Submandibular and sublingual glands involvement in advanced acquired immunodeficiency syndrome (AIDS): an autopsy-based study

Objective. To assess the histopathological, immunohistochemical (IHC), and in situ hybridization (ISH) features found in the submandibular (SM) and sublingual (SL) glands of 105 acquired immunodeficiency syndrome (AIDS) patients at autopsy. Study design. Gender, age, CD4 cell level, and clinical histories were obtained from clinical charts (SM: n = 103; SL: n = 92). Histologic analysis of hematoxylin and eosin, Gomori-Grocott, and Ziehl-Neelsen stained tissues, IHC to detect infectious agents and characterize inflammatory cells in sialadenitis, and ISH for EBER-1/2 were performed. Results. The mean age of the patients and CD4 cell count were 36 years and 76 cells/mu L, respectively. Fifty-eight cases (SM: n = 51 [49%]; SL: n = 54 [59%]) were considered to be microscopically normal. The most common infectious conditions were mycobacteriosis (SM: n = 11 [10%]; SL: n = 7 [7%]), followed by cytomegalovirus (CMV) (SM: n = 14 [13%]; SL: n = 2 [2%]), and cryptococcosis (SM: n = 3 [3%]; SL: n = 4 [4%]). Human immunodeficiency virus (HIV) p24 (SM: n = 2 [2%]; SL: n = 1 [1%]) and EBER-1/2 (SM: n = 9 [39%]; SL: n = 4 [20%]) were seen only in macrophages and lymphocytes, respectively. The most prevalent cells seen in chronic nonspecific sialadenitis (SM: n = 25; SL: n = 25) were CD8+ T lymphocytes, whereas CD68+ macrophages were predominant in the mycobacteriosis-associated granulomatous and nonspecific diffuse macrophagic sialadenitis. Concomitant infections occurred in 5 cases (SM: n = 4; SL: n = 1) and non-Hodgkin lymphoma in 1 case. Conclusions. Infectious diseases and chronic nonspecific sialadenitis were the main alterations found in the SM and SL glands. These alterations were greater in the SM than in the SL glands. CD8+ T lymphocytes and CD68+ macrophages might be relevant to the pathogenesis of the sialadenitis. Clinicians should consider these diseases when assessing the major salivary glands in advanced AIDS patients and follow biosafety procedures to avoid contamination by HIV, CMV, mycobacteriosis, and cryptococcosis. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009; 108: 216-226)

Human T-cell lymphotropic virus type 1 infective dermatitis emerging in adulthood

Background Infective dermatitis (ID) is a rare dermatologic condition of childhood that has been linked to human T-cell lymphotropic virus type 1 (HTLV-1). Objective To analyze the clinical and laboratory features associated with adult-onset ID linked to HTLV-1. Methods From December 1995 to December 2007, four patients with ID were followed in the dermatology outpatient clinic of the ""Hospital das Clinicas"" of the University of Sao Paulo Medical School, Sao Paulo, Brazil. Epidemiologic data were collected and dermatologic examination was performed. Patients were submitted to histopathologic, hematologic, virologic, and immunologic investigations. Results All patients had a diagnosis of ID according to previously established criteria, despite being adults. HTLV-1 infection was demonstrated by enzyme-linked immunosorbent assay, Western blotting assays, and polymerase chain reaction. The male to female ratio was 1 : 3 and the median age at diagnosis was 42 years. The cutaneous manifestations were erythematous, scaly, and crusted lesions in all patients, and ichthyosis in three of the four cases. Histopathologic study showed lymphocytic epidermotropism in two cases. The median proviral load was 281 copies/10,000 peripheral blood mononuclear cells. Immunodeficiency was not observed in any case. The therapies used were antimicrobials, corticosteroids, and phototherapy. Conclusions Although many authors have considered ID to be a form of childhood dermatitis, we have described four cases that fulfilled the major criteria for ID, except for onset in adulthood.

Wave expansion of CD(34+) progenitor cells in the spleen in rodent malaria

Defense against malaria depends upon amplification of the spleen structure and function for the clearance of parasitized red blood cells (pRBC). We studied the distribution and amount of CD(34+) cells in the spleens of mice infected with rodent malaria. We sought to identify these cells in the spleen and determine their relationship to infection. C57BL/6J mice were infected with self-resolving, Plasmodium chabaudi CR, or one of the lethal rodent malaria strains, P. chabaudi AJ and P. berghei ANKA. We then recorded parasitemia, mortality, and the presence of CD(34+) cells in spleen, as determined by immunohistochemistry and flow cytometry. In the non-lethal strain, the spleen structure was maintained during amplification, but disrupted in lethal models. The abundance of CD(34+) cells increased in the red pulp on the 4th and 6th days p.i. in all models, and subsided on the 8th day p.i. Faint CD(34+) staining on the 8th day p.i., was probably due to differentiation of committed cell lineages. In this work, increase of spleen CD(34+) cells did not correlate with infection control. (c) 2009 Published by Elsevier Inc.

Immunophenotyping and remodeling process in small airways of idiopathic interstitial pneumonias: functional and prognostic significance

Background and Aims: To test whether different degrees of immunologic and fibrotic airway remodeling processes occur in idiopathic interstitial pneumonias (IIPs), with impact on functional tests and survival, we studied the collagen/elastic system and immune cell density in the bronchiolar interstitium of lungs with the major types of IIPs. Materials and Methods: Histochemistry, immunohistochemistry and morphometric analysis were used to evaluate collagen/elastic fibers and immune cells in the bronchiolar interstitium of open lung biopsies of patients with cryptogenic organizing pneumonia [COP/organizing pneumonia (OP) = 10], acute interstitial pneumonia [AIP/diffuse alveolar damage (DAD) = 20], nonspecific interstitial pneumonia (NSIP/NSIP = 20) and idiopathic pulmonary fibrosis/usual interstitial pneumonia (UIP) = 20. Results: OP lungs presented a significant increase in collagenous/elastic fibers and in the total density of immune cells in the bronchiolar interstitium compared to controls, DAD, NSIP and UIP. We observed a significant increase in CD4, CD8 and CD20 lymphocytes, as well as in neutrophils, macrophages and plasma cells in OP. The increased amount of elastic fibers in the bronchiolar interstitium from OP lungs has a direct association with forced vital capacity (FVC) (r(s) = 0.99, P = 0.03). The most important survival predictor was CD20+ lymphocytes in the bronchiolar interstitium. In decreasing order, patients with UIP [Odds Ratio (OR) = 35.01], high forced expiratory volume in 1 s (FEV1)/FVC FVC (OR = 7.01), increased CD20+ lymphocytes (OR = 4.44) and collagenous/elastic fiber densities (OR = 2.03 and OR = 1.49, respectively) in the bronchiolar interstitium were those who had the greatest risk of death, followed by those with AIP, NSIP and COP. Conclusion: Different degrees of immunologic and fibroelastotic airway remodeling processes occur in the major types of IIPs with impact on physiological tests and survival.

Changes in plasma free fatty acid levels in septic patients are associated with cardiac damage and reduction in heart rate variability

Free fatty acids (FFAs) have been shown to produce alteration of heart rate variability (HRV) in healthy and diabetic individuals. Changes in HRV have been described in septic patients and in those with hyperglycemia and elevated plasma FFA levels. We studied if sepsis-induced heart damage and HRV alteration are associated with plasma FFA levels in patients. Thirty-one patients with sepsis were included. The patients were divided into two groups: survivors(n = 12) and nonsurvivors (n = 19). The following associations were investigated: (a) troponin I elevation and HRV reduction and (b) clinical evolution and HRV index, plasma troponin, and plasma FFA levels. Initial measurements of C-reactive protein and gravity Acute Physiology and Chronic Health Evaluation scores were similar in both groups. Overall, an increase in plasma troponin level was related to increased mortality risk. From the first day of study, the nonsurvivor group presented a reduced left ventricular stroke work systolic index and a reduced low frequency (LF) that is one of HRV indexes. The correlation coefficient for LF values and troponin was r(2) = 0.75 (P < 0.05). All patients presented elevated plasma FFA levels on the first day of the study (5.11 +/- 0.53 mg/mL), and this elevation was even greater in the nonsurvivor group compared with the survivors (6.88 +/- 0.13 vs. 3.85 +/- 0.48 mg/mL, respectively; P < 0.05). Cardiac damage was confirmed by measurement of plasma troponin I and histological analysis. Heart dysfunction was determined by left ventricular stroke work systolic index and HRV index in nonsurvivor patients. A relationship was found between plasma FFA levels, LFnu index, troponin levels, and histological changes. Plasma FFA levels emerged as possible cause of heart damage in sepsis.