Voriconazole-induced periostitis.

Voriconazole is a fluorinated drug from the triazole group that is widely used in the prophylaxis and treatment of fungal infections in immunosuppressed patients. Chronic use of this medication can generate, as an adverse effect, a multifocal, asymmetric, diffuse and nodular periosteal reaction, associated with severe and disabling skeletal pain and elevated alkaline phosphatase and serum fluoride. Radiography is the imaging technique of choice for periostitis diagnosis. In general, clinical manifestations and radiographic findings disappear, when the drug is discontinued. We report the clinical case of a 44 year-old woman diagnosed with acute myeloid leukemia, who developed an invasive fungal infection treated with voriconazole after a stem cell transplant. Nine months after starting antifungal treatment, she manifested symptoms and radiological signs compatible with periostitis. Due to clinical suspicion, we decided to suspend voriconazole, with consequent resolution of clinical manifestations and radiological findings.

Management of non-renal non-neurologic persistent lupus activity in real world patients from Argentina.

Management of systemic lupus erythematosus patients is challenging because of disease heterogeneity. Although treatment of renal nephritis is more standardized, treating non-renal lupus activity remains controversial. Our objective was to identify non-renal, non-neurologic persistent active systemic lupus erythematosus patients in our cohort and described therapeutic behaviors in them. All systemic lupus erythematosus patients (American College of Rheumatology and/or Systemic Lupus Erythematosus International Collaborating Clinics criteria) seen at a university hospital between 2000 and 2017 were included and electronic medical records manually reviewed. Persistent lupus activity was defined as a patient with a Systemic Lupus Erythematosus Disease Activity Index score ≥ 6 (without renal and central nervous system manifestations) despite being on a stable treatment regimen for ≥ 30 days. Stable treatment could include prednisone alone (7.5-40 mg/d) or combined with antimalarial drugs and immunosuppressant therapies. A total of 257 lupus patients were included, 230 females (89.5%, 95% confidence interval 85.1-92.7), mean age at diagnosis 29.9 years (SD 16.4). After a median cohort follow-up of 5.7 years (interquartile range 2.4-10.2), 14 patients (5.4%, 95% confidence interval 3.2-9.0) showed persistent non-renal non neurologic lupus activity, with a median disease duration of 11.3 years (interquartile range 3.6-19.4). At that time, 12/14 (85.7 %, 95% confidence interval 52.6-97.0%) had low complement and 11/14 (78.6 %, 95% confidence interval 46.5-93.9%) had positive antiDNA antibodies. The main reasons for being refractory were mucocutaneous disease (50%, 95% confidence interval 23.5-76.5) and arthritis (42.9%, 95% confidence interval 18.5-71.2). Therapeutic choices after being refractory were: only increasing corticosteroid dose in one patient, starting rituximab in four, belimumab in eight, and in one mycophenolate and rituximab; with good response in all of them. In conclusion, 5.4% of systemic lupus erythematosus patients in our cohort were considered to have non-renal non neurologic persistent lupus activity, with mucocutaneous and arthritis the main manifestations. In total, 92.8% of these patients started a biologic treatment at this point (rituximab or belimumab).

Symptoms of Raynaud's phenomenon (RP) in fibromyalgia syndrome are similar to those reported in primary RP despite differences in objective assessment of digital microvascular function and morphology.

Symptoms of Raynaud's phenomenon (RP) are common in fibromyalgia syndrome (FMS). We compared symptom characteristics and objective assessment of digital microvascular function using infrared thermography (and nailfold capillaroscopy where available) in patients with FMS (reporting RP symptoms) and primary RP. We retrospectively reviewed the outcome of microvascular imaging studies and RP symptom characteristics (captured using patient-completed questionnaire at the time of assessment) for patients with FMS (reporting RP symptoms) and patients with primary RP referred for thermographic assessment of RP symptoms over a 2-year period. Of 257 patients referred for thermographic assessment of RP symptoms between 2010 and 2012, we identified 85 patients with primary RP and 43 patients with FMS. There were no differences in RP symptom characteristics between FMS and primary RP (p > 0.05 for all comparisons). In contrast, patients with FMS had higher baseline temperature of the digits (32.1 vs. 29.0 °C, p = 0.004), dorsum (31.9 vs. 30.2 °C, p = 0.005) and thermal gradient (temperature of digits minus temperature of dorsum; +0.0 vs. -0.9 °C, p = 0.03) compared with primary RP. Significant differences between groups persisted following local cold challenge. In primary RP, patient reporting "blue" digits, bi-phasic and tri-phasic RP was associated with lower digital perfusion. In contrast, no associations between skin temperature and RP digital colour changes/phases were identified in FMS. Our findings suggest that symptoms of RP in FMS may have a different aetiology to those seen in primary RP. These findings have potential implications for both the classification of RP symptoms and the management of RP symptoms in the context of FMS. Digital colour changes reported by patients might reflect the degree of digital microvascular compromise in primary RP.

Systemic sclerosis in Argentina: evaluation of a large cohort from a single centre and comparison with other international series.

OBJECTIVES: Prevalence of systemic sclerosis (SSc) and different clinical subsets varies across the world. Few data have been published on SSc patients in Latin America. Our objective was to describe a SSc cohort in Argentina and to compare clinical findings, disease subsets and antibodies with other international SSc populations. METHODS: Patients with SSc (n=234) seen at the Rheumatology section of the Hospital Italiano de Buenos Aires between 2000-2011 were retrospectively analysed. Data on clinical manifestations, disease subsets and antibodies were obtained. Patients were classified into diffuse cutaneous (dc) and limited cutaneous (lc) subsets. Comparison with other cohorts (France, United States, Germany, Italy, Mexico, EUSTAR and Brazil) was made based on published information. RESULTS: A higher female:male ratio (12:1) and a higher limited subset prevalence (76.1%) was found in this Argentine cohort comparing with others. We also found a lower prevalence of diffuse disease, anti Scl-70 (antitopoisomerase) and nucleolar pattern antinuclear antibodies. Within each subset, clinical findings were similar with other SSc populations except for a very low prevalence in renal crisis (0.02% of dc SS). CONCLUSIONS: With slight variations perhaps due to genetic, environmental or referral factors, SSc in this cohort appears to be similar to that described in other parts of the world.

Causes of fetal third-degree atrioventricular block and use of hydroxychloroquine in pregnant women with Ro/La antibodies.

INTRODUCTION/OBJECTIVES: Complete congenital atrioventricular block (AVB) may be due to cardiac malformations or the presence of maternal antibodies (autoimmune AVB). Our objective was to estimate the prevalence of autoimmune AVB among all AVB in newborns treated at our hospital. Secondly, we estimated the prevalence of AVB among mothers with anti-Ro/La antibodies and examined the relationship of those fetal AVB with mother's use of hydroxychloroquine during pregnancy. METHODS: Retrospective cohort in which we reviewed electronic medical records from years 2000 to 2014 of (a) all mothers with children born with third degree AVB and (b) all pregnant women with anti-Ro/La-positive antibodies. RESULTS: Twenty-three AVBs were diagnosed. Ten (43.5%, 95% CI 23.2-65.5) were associated with maternal rheumatologic disease. The remaining 13 were associated with cardiac malformations. Sixty-two pregnancies in 47 mothers with Ro/La antibodies were identified; eight (12.9%, 95% CI 5.7-23.8) suffered AVB. Fourteen mothers consumed hydroxychloroquine during full pregnancy (one newborn (7.1%) suffered AVB) and 48 did not (7 newborns with AVB (14.6%); p = 0.5). CONCLUSIONS: All congenital AVB diagnosed at our hospital without cardiac malformations were associated with a maternal rheumatologic disease/antibodies. Therefore, if a AVB is diagnosed in a newborn without structural heart disease, the mother should be studied for an autoimmune disease. We found a high prevalence of AVB among mothers with anti-Ro/La antibodies. Although not statistically significant, AVBs in mothers with Ro/La antibodies were numerically more frequent in those not using hydroxychloroquine.Key Points• Although structural heart malformations were the predominant cause of third-degree AVB, autoimmune AVB was still a significant cause.• The distinction between structural or non-structural cause of AVB constitutes an essential issue since it determines the prognostic of these fetuses in terms of complications.• Although not statistically significant, AVBs in mothers with Ro/La antibodies were more frequent in those not using hydroxychloroquine.• If an AVB is diagnosed in a newborn without structural heart disease, the mother should be studied for an autoimmune disease.

Biphenotypic acute leukemia with t(15;17).

Biphenotypic acute leukemias (BAL) represent 5% of all acute leukemias. The most frequent cytogenetic abnormalities described are Philadelphia chromosome and 11q23 involvement. Here we report a BAL case, with blasts showing lymphoblast morphology and positivity for myeloperoxidase (in 6% of the blast cells). Immunophenotype revealed the compromise of myeloid and B-lymphoid lineages. Cytogenetic analysis showed the t(15;17) and 8 trisomy. PML/RARa rearrangement was detected by fluorescent in situ hybridization (FISH) on interphase nuclei while PML/RARa fusion transcript was detected in the bone marrow and peripheral blood by molecular biology studies (RT-PCR). This report describes a BAL case with an unfrequent cytogenetic abnormality, and highlights the importance of correlating the results of multiple diagnostic methods in order to establish a correct diagnosis and treatment in BAL patients.

Non-malignant leukocytes delay spontaneous B-CLL cell apoptosis.

Malignant B cells from chronic lymphocytic leukemia (B-CLL) patients have a long survival in vivo, although, in culture, they spontaneously die by apoptosis. Here, we analyzed the capacity of accessory leukocytes to modulate apoptosis of B-CLL cells in vitro. To this end, we performed long-term cultures using total mononuclear cells (TMC) from B-CLL patients and TMC depleted from monocytes, NK cells and T lymphocytes (B-CLL cells). In all the patients studied (n = 25) the presence of accessory leukocytes markedly prolonged the survival of B-CLL cells. The anti-apoptotic effect was exerted by monocytes and, to a lesser degree, NK cells, partially through the release of soluble factors. Indeed, accessory leukocytes separated from leukemic cells by semipermeable membranes were still able to prolong B-CLL cell survival. By flow cytometric analysis we found that the protective effect of non-malignant cells was associated with delayed down-regulation of Bcl-2 expression on leukemic cells. By contrast, the expression of Fas and Fas ligand proteins was unchanged in most samples. Our findings suggest that monocytes and NK cells, by delaying leukemic cell apoptosis, may play a role in B-CLL cell accumulation in vivo.

Modulator activity of PSC 833 and cyclosporin-A in vincristine and doxorubicin-selected multidrug resistant murine leukemic cells.

Multidrug resistance (MDR) lines from a murine T-cell leukemia were selected in increasing vincristine (VCR) or doxorubicin (DOX) concentrations. Daunorubicin (DNR) efflux was evidenced after 25 additional passages with constant 160 ng ml(-1) of either VCR or DOX, an effect that was inhibited by verapamil, cyclosporin-A (CsA) and PSC 833. The expression of Pgp was not evidenced in the resistant cell lines using anti-human Pgp antibodies. Cell proliferation assay showed that cell lines resistant to VCR (LBR-V160) or DOX (LBR-D160) required higher doses of either drug to produce GI50 compared with control cell line obtained after culture in the absence of VCR or DOX. When resistant cell lines were maintained during 60 days in the absence of either VCR or DOX, MDR phenotype reversal was obtained in LBR-D160 while LBR-V160 remained resistant to the drug, as shown by cell proliferation assays and by drug efflux pump functionality. When VCR or DOX were used together with either CsA or PSC 833, the latter was more effective to produce reversal of resistance than the former, whereas CsA presented greater cytotoxic effect than PSC 833 for sensitive and resistant cells. Cross-resistance was found between VCR, DOX and other antineoplasic agents on murine leukemic cell line. VCR was more effective to induce MDR since the resistant cell lines were more stable to the MDR phenotype.

Trilineage phenotypic compromise in acute leukemia.

The expression of three lineage specific antigens in the leukemic blasts is extremely infrequent. We here report a case of triphenotypic acute leukemia with involvement of the myeloid and B and T lineages. The morphology of the blasts showed promyelocytic features with agranular cytoplasm, suggesting a M3-variant of AML. The blasts were positive for myeloperoxidase PAS and Sudan Black. Immunophenotype and cytogenetics did not confirm M3-AML diagnosis, showing a trilineage compromise (myeloid and T and B lymphoid markers) and the cytogenetic alterations +8 and +11, respectively. This report highlights the importance of correlating the results of multiple diagnostic methods in order to establish a correct diagnosis of mixed lineage acute leukemias, and allows evaluation of the prognostic importance of this subgroup of patients.

Promyelocytic blast crisis of chronic myelogenous leukaemia with translocations (9;22) and (15;17).

The promyelocytic blast crisis is a rare form of transformation during the evolution of chronic myeloid leukaemia (CML). We report a case of promyelocytic blast crisis with t(15;17) in addition to t(9;22). The morphology and immunophenotype of the blasts were similar to those seen in acute promyelocytic leukaemia (APL). The t(15;17) was confirmed by FISH. The patient had evidence of coagulopathy with clinical and laboratory findings of disseminated intravascular coagulation (DIC). This report highlights the importance of correlating the results of multiple diagnostic methods in order to establish a correct diagnosis of the promyelocytic blast crisis of CML.

Comparative study of experimentally induced benign and atypical hyperplasia in the ventral prostate of different rat strains.

The induction of prostatic lesions in the rat by hormonal manipulation and/or chemical carcinogens in different strains is well documented in literature. However, the selection of a strain for such studies was merely based on the laboratory husbandry facilities rather than on the animal genotype. It is well accepted that the morphology and function of the prostate exhibit a marked species-specific differences that makes extrapolation to other animals and man difficult. Our group has developed an experimental model for the study of rat prostatic hyperplasia and/or dysplasia induced by citral--a flavor constituent. Previous observations have revealed that the Wistar rat ventral prostate is reactive to citral, especially during its adolescent growth period as well as during the redifferentiation stage among postcastrated rats treated with exogenous testosterone. The present study presents data on the ventral prostate susceptibility of three additional strains selected by their interrelated endocrine morbidity. In order to facilitate an objective comparative analysis of the prostatic lesions a histopathological score chart was elaborated. The present findings showed that the Wistar and Sprague-Dawley strains were the most susceptible to developing benign and atypical prostatic hyperplasia both in intact and postcastrated rats. The F344 and ACl/Ztm rat strains remained refractory toward all of these treatments. Our data provide evidence that the strain genotype and, more precisely, their endocrine background, play a determinative role in the prostatic responsiveness towards citral. It is suggested that additional consideration be given to the selection of an adequate animal strain when studying experimental neoplastic transformation, especially when hormonal interactions might be involved.

Effects of senescence and citral on neuronal vacuolar degeneration in rat pelvic ganglia.

A significant part of the morbidity in elderly men involves pelvic organs and their autonomic neural regulation. Environmental stimuli also impair the structure and function of pelvic organs. One of these factors is citral, a widely-used cosmetic fragrance constituent, which causes severe prostatic hyperplasia in rats. In this study, we assessed the effect of topical administration of citral (30 days) on the morphology of pelvic ganglia (PG) in young adult and old Wistar rats. Neuronal vacuolar degeneration with preserved nuclei of PG neurons was observed in untreated senescent, but not young rats. Citral significantly increased the rate of vacuolated neurons in old rats (from 3 to 14%), but only slightly in young ones (from 0 to 0.5-0.3%). Similar lesions were not found in inferior cervical or celiac ganglia, in either group. This shows that environmental stimuli enhance age-related processes of vacuolar neuronal degeneration in PG, and may contribute to the dysfunction of pelvic organs in the elderly.

Spontaneous uterine granular cell tumour in a Fischer 344 rat.

The microscopic features of a spontaneous uterine granular cell tumour in a Fischer 344 rat are described. The location of the tumour is novel for the rat. The neoplasm is characterized by the presence of cells with cytoplasmic granules which were PAS positive and diastase resistant. Electron microscopy and immunohistochemistry results are presented and the origin of the tumour is discussed.

[Detection of minimal residual disease in acute leukemias by flow cytometry]. / Detección de enfermedad mínima residual en leucemias agudas por citometría de flujo.

Detection of minimal residual disease in acute leukemias by flow cytometry has become an interesting tool for the analysis of minimal residual disease in acute leukemias. Some complementary studies can be used for this purpose such as conventional cytogenetics, FISH and molecular biology (PCR and Southern Blot). Flow cytometry study can detect smoldering blast cells in patients with acute leukemias who appear to be in complete remission by conventional morphologic criteria (< 5% of blast cells in bone marrow aspirate sample). This method can recognize 1 blast in 10(-4) mononuclear bone marrow cells considering the characteristics of immunophenotype at diagnosis (aberrant, asynchronous and overexpressed phenotypes) or using the analysis cell maturation to identify normal and abnormal patterns. These differences can be distinguished when the cells occupy the 'empty spaces' where no normal cells are evident. The principal objective of detecting low levels of tumor cells is to obtain more information about the efficacy of the treatment in order to: 1) design adapted post-remission protocols for high risk patients, 2) predict relapses previous to the clinical manifestations, 3) study the quality of stem cells harvested for autologous bone marrow transplantation.

[Hairy cell leukemia. An alternative method for the detection of minimal residual disease using flow cytometry]. / Leucemia de células vellosas. Un método alternativo para la detección de enfermedad minima residual por citometría de flujo.

In patients with hairy cell leukemia (HCL) who received chemotherapeutic treatment and achieved complete remission (CR), minimal residual disease (MRD) can be detected in bone marrow biopsies using immunohistochemical (IHC) techniques. In this study, we investigated the value of flow cytometry (FCM) and IHC to detect MRD and to establish whether MRD+ could predict relapse. A total of 15 HCL patients in CR were studied. Samples of bone marrow (BM) and peripheral blood (PB) were processed by FCM with triple staining of the following monoclonal antibodies (mAbs): CD20, CD22, CD11c, CD103, CD25, anti-Kappa and anti-Lambda light chains. Reference values were obtained from normal samples of peripheral blood and bone marrow. FCM detected MRD in 64% of the patients. BM samples were more demonstrative than peripheral blood for MRD detection in HCL. IHC was performed in paraffin-embedded BM biopsies using CD20 and DBA44 mAbs. MRD+ was detected in 46% of patients. Although not statistically significant, FCM appeared more sensitive compared with IHC. Detection of MRD by either of these methods in our series did not predict hematological relapse. The results show that FCM is a useful alternative method to detect MRD in HCL and that a longer, follow-up is required to establish the predictive outcome of MRD+ patients.

Remission criteria and activity indices in psoriatic arthritis.

Remission criteria and activity indices used in rheumatoid arthritis (RA) are often applied in psoriatic arthritis (PsA). Some new indices have been specifically developed for PsA. Our objective was to evaluate the performance of different remission criteria and activity indices in PsA. This is a cross-sectional study that includes consecutive patients with PsA. Information necessary to complete the following indices was captured: Composite Psoriatic Disease Activity Index (CPDAI), Psoriatic Arthritis Screening and Evaluation (PASE), Disease Activity Index for Psoriatic Arthritis (DAPSA), Disease Activity Score in 28 Joints (DAS28), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), and American College of Rheumatology and European League Against Rheumatism (ACR/EULAR) Boolean RA remission criteria. Patients were classified according to activity categories (remission, low, medium, or high disease activity). Correlation between indices was established. Fifty-five patients were included. Mean age was 53 years (SD = 12), and 35 (63.6 %) were males. Mean PsA disease duration was 5.9 years (SD = 8.5), and mean psoriasis duration was 15.9 (SD = 12.6). We found important differences in the percentage of patients classified as in remission by applying different remission criteria: DAS28 = 33 % (95 % confidence interval (CI) 20-45) vs ACR/EULAR = 4 % (95 % CI 1-17). Particularly, DAS28 and minimal disease activity seemed to be less stringent in PsA than the other indices. Of the specific PsA indices evaluated, CPDAI showed the poorest correlation with all the other activity measurements, although differences were not statistically significant in most cases. Disease activity in PsA is measured by many different indices. In spite they all showed good correlations between them, they classified different patients in different disease status.

Incidence and prevalence of lupus in Buenos Aires, Argentina: a 11-year health management organisation-based study.

OBJECTIVES: Studies regarding the epidemiology of systemic lupus erythematosus (SLE) are lacking in Argentina. Our purpose was to estimate the incidence and prevalence of SLE in a university hospital-based health management organisation in Buenos Aires (HIMCP). METHODS: For incidence calculation, the population at risk included all adult members of the HIMCP, with continuous affiliation for at least 1 year from January 1998 to January 2009. Each person was followed until he/she voluntarily left the HIMCP, death or finalisation of the study. Multiple methods for case finding were used to ensure complete ascertainment: (a) patients with problem SLE, undifferentiated autoimmune disease or mixed connective tissue disease in the Computer-based Patient Record System, (b) patients with positive antinuclear antibody test, anti-Sm antibodies and/or anti-dsDNA antibodies in the laboratory database and (c) patients who consumed hydroxichloroquine, chloroquine, azathioprine, cyclophosphamide, mycophenolate, cyclosporine or rituximab, from the administrative HIMCP drugs database. Medical records of all patients found were reviewed, and only patients fulfilling ACR criteria for SLE were included. Global and gender incidence rate (IR) was calculated. Prevalence was estimated on 1 January 2009, and the denominator population was the number of active members >18 years at that date (n=127 959). RESULTS: In the study period, 68 patients developed SLE. The observed IR (per 100 000 person-years, (CI 95%)) was 6.3 (4.9 to 7.7) for total population; 8.9 (CI 6.6 to 11.2) for women and 2.6 (1.2 to 3.9) for men. On 1 January 2009, 75 prevalent cases were identified. Prevalence rates (cases per 100 000 habitants, (CI 95%)) were 58.6 (46.1 to 73.5) for total population; 83.2 (63.9 to 106.4) for women and 23 (CI 11.9 to 40.1) for men. CONCLUSIONS: SLE incidence and prevalence rates in Argentina are in agreement with those of other studies from different parts of the world.

Value of repeat biopsy in lupus nephritis flares.

OBJECTIVES: Renal flares are common in lupus nephritis (LN), and class switch is thought to be characteristic. There is no agreement on indications for performing a repeat renal biopsy. Our objective was to retrospectively review patients who had more than one renal biopsy performed on clinical indications, and analyse clinical, pathological and treatment changes after successive biopsies. METHODS: Forty-five patients with LN and one or more repeat renal biopsies were included, with a total of 116 biopsies. RESULTS: Of the 71 repeat biopsies, pathological transition occurred in 39 (54.9%). When having a previous biopsy with a proliferative lesion, class switch occurred in 55.6%, with 24.4% evolving into non-proliferative classes. When previous biopsy was class V, transition to other classes occurred in 58.3% and changes were all into proliferative classes. Conversion from one pure proliferative form to another (class III to class IV or vice versa) happened in 11.3% of the rebiopsies, with 62 rebiopsies (87.3%) leading to a change in the treatment regimen. CONCLUSIONS: Histological transformations were common, and they occurred when the previous biopsy had non-proliferative lesions as well as when lesions were proliferative. Treatments were modified after repeat renal biopsy in the majority of patients. In this experience, kidney repeat biopsies were useful in guiding treatment of LN flares.

The development of vascular supply of normal rat prostate during the sexual maturation: an angiographic study.

Vascular distribution of small blood vessels and capillaries using India ink angiography was studied in normal rat prostate from puberty up to full sexual maturation. The study included both macroscopic observation of the lobular vascular irrigation and the histological assessment of the periacinar capillary network. The topographical distribution of the main prostate branches was found to be different among the rat prostate lobes. The ventral lobe seems to be better irrigated than the dorsal one. The former being supplied by two parallel vascular systems, one irrigating the median two-thirds of the ventral lobe, whereas the remaining external one-third was found to be conjointly irrigated from the pericapsular branches of the fat pads. The blood vessels of the dorsal and lateral lobes emerged radially from a periurethral circle, with the dorsal branches ending blindly in the connective tissue of the pelvic cavity, whereas the lateral prostate was also conjointly irrigated by a dual vascularization from the pericapsular fat pad and the periurethral circle branch. The histological study revealed quantitative differences between the periacinar capillaries of both ventral and dorsal lobes. The capillary density was found to be age dependent and directly proportional to the acinar size. Small acini were less well irrigated by capillaries than were the larger ones. The number of capillaries per acinar area increased progressively toward the maturation (day 90); thereafter, their number remained constant. Both prostate lobes showed identical patterns. The heterogeneous vascular networks among the rat prostatic lobes might offer an additional clue for their distinctive morphophysiological characteristics, which most probably play a role in various pathogenetic processes.