6-Thioguanine for Crohn's disease during pregnancy: Thiopurine metabolite measurements in both mother and child

6-Thioguanine is used as an escape thiopurine for treating inflammatory bowel disease patients intolerant or refractory to azathioprine, 6-mercaptopurine or methotrexate. Case reports show conflicting data on the use of 6-thioguanine throughout pregnancy. The administration of the standard thiopurines is believed to be relatively safe. We describe two patients with Crohn's disease treated with low-dose 6-thioguanine during all trimesters of their pregnancies. The pregnancies resulted in two healthy infants: without congenital abnormalities, laboratory signs of myelosuppression or hepatocellular injury. Thiopurine metabolites were measured in mother and infant. Significantly lower levels of 6-thioguaninenucleotides were found in the erythrocytes of the infant compared to the mother (ratio 1:12). Further studies are needed to determine the clinical importance of thiopurine metabolite measurements during pregnancy in mother and child.     

Community‐acquired respiratory viruses and co‐infection among patients of Ontario sentinel practices,April 2009 to February 2010

Please cite this paper as: Peci et al. (2012) Community‐acquired respiratory viruses and co‐infection among patients of Ontario Sentinel practices, April 2009 to February 2010. Influenza and Other Respiratory Viruses 7(4), 559–566. Background Respiratory viruses are known to cocirculate but this has not been described in detail during an influenza pandemic. Objectives To describe respiratory viruses, including co‐infection and associated attributes such as age, sex or comorbidity, in patients presenting with influenza‐like illness to a community sentinel network, during the pandemic A(H1N1)pdm09 in Ontario, Canada. Methods Respiratory samples and epidemiologic details were collected from 1018 patients with influenza‐like illness as part of respiratory virus surveillance and a multiprovincial case–control study of influenza vaccine effectiveness. Results At least one virus was detected in 668 (65·6%) of 1018 samples; 512 (50·3%) had single infections and 156 (15·3%) co‐infections. Of single infections, the most common viruses were influenza A in 304 (59·4%) samples of which 275 (90·5%) were influenza A(H1N1)pdm09, and enterovirus/rhinovirus in 149 (29·1%) samples. The most common co‐infections were influenza A and respiratory syncytial virus B, and influenza A and enterovirus/rhinovirus. In multinomial logistic regression analyses adjusted for age, sex, comorbidity, and timeliness of sample collection, single infection was less often detected in the elderly and co‐infection more often in patients <30 years of age. Co‐infection, but not single infection, was more likely detected in patients who had a sample collected within 2 days of symptom onset as compared to 3–7 days. Conclusions Respiratory viral co‐infections are commonly detected when using molecular techniques. Early sample collection increases likelihood of detection of co‐infection. Further studies are needed to better understand the clinical significance of viral co‐infection.     

Viral and bacterial aetiology of community‐acquired pneumonia in adults

Please cite this paper as: Huijskens et al. (2012) Viral and bacterial aetiology of community‐acquired pneumonia in adults. Influenza and Other Respiratory Viruses 7(4), 567–573. Background Modern molecular techniques reveal new information on the role of respiratory viruses in community‐acquired pneumonia. In this study, we tried to determine the prevalence of respiratory viruses and bacteria in patients with community‐acquired pneumonia who were admitted to the hospital. Methods Between April 2008 and April 2009, 408 adult patients (aged between 20 and 94 years) with community‐acquired pneumonia were tested for the presence of respiratory pathogens using bacterial cultures, real‐time PCR for viruses and bacteria, urinary antigen testing for Legionella and Pneumococci and serology for the presence of viral and bacterial pathogens. Results Pathogens were identified in 263 (64·5%) of the 408 patients. The most common single organisms in these 263 patients were Streptococcus pneumoniae (22·8%), Coxiella burnetii (6·8%) and influenza A virus (3·8%). Of the 263 patients detected with pathogens, 117 (44·5%) patients were positive for one or more viral pathogens. Of these 117 patients, 52 (44·4%) had no bacterial pathogen. Multiple virus infections (≥2) were found in 16 patients. Conclusion In conclusion, respiratory viruses are frequently found in patients with CAP and may therefore play an important role in the aetiology of this disease.     

Brain magnetic resonance imaging findings in patients with mucopolysaccharidosis VI

Introduction

Mucopolysaccharidosis type VI (MPS VI) is a rare lysosomal storage disorder caused by the deficient activity of N-acetylgalactosamine 4-sulfatase. MPS VI is usually considered as not being associated with mental retardation.

Aims/methods

The main objective of the present study was to describe brain magnetic resonance imaging (MRI) findings and their correlation with clinical and biochemical findings in MPS VI patients. The study was conducted at Hospital de Clínicas de Porto Alegre, Brazil with 25 MPS VI patients. All patients were evaluated through clinical evaluation, IQ tests, urinary glycosaminoglycans (GAG) analysis, and brain MRI.

Results

Mean age at evaluation was 10.6?±?4.52 years. Five of 16 patients presented total IQ below the normal range. Brain MRI was abnormal in the majority of patients (n?=?19/21), and the most frequent abnormalities found were the presence of dilated perivascular spaces and white matter lesions. Correlations were found between age and normalized white matter lesion load (NLL) (r?=?0.46; p?=?0.04) and normalized cerebral volume (NCV) (r?=??0.56; p?=?0.01), between NLL and height deficit (r?=?0.48; p?=?0.04), and between NCV and weight deficit (r?=??0.58; p?=?0.01) and height deficit (r?=??0.55; p?=?0.01). A correlation between urinary GAG levels and quantitative brain MRI findings was not found, neither between qualitative and quantitative brain MRI findings and IQ scores.

Conclusions

MPS VI patients may present abnormal IQ scores without correlation with brain abnormalities on the MRI, a finding which was found to be very frequent in MPS VI. Additional studies are required to confirm our findings.     

Performance comparison between the mycobacteria growth indicator tube system and L?wenstein-Jensen medium in the routine detection of Mycobacterium tuberculosis at public health care facilities in Rio de Janeiro, Brazil: preliminary results of a pragmatic clinical trial

In view of the fact that the World Health Organization has recommended the use of themycobacteria growth indicator tube (MGIT) 960 system for the diagnosis oftuberculosis and that there is as yet no evidence regarding the clinical impact ofits use in health care systems, we conducted a pragmatic clinical trial to evaluatethe clinical performance and cost-effectiveness of the use of MGIT 960 at two healthcare facilities in the city of Rio de Janeiro, Brazil, where the incidence oftuberculosis is high. Here, we summarize the methodology and preliminary results ofthe trial. (ISRCTN.org Identifier: ISRCTN79888843 [http://isrctn.org/])     

Circulating microparticles and microRNAs as players in atherosclerosis

Microparticles (MPs) are extracellular membrane vesicles released from normal, apoptotic and pathological cells following a process of detachment from cells of origin. MPs are typically defined by their size, exposure of phosphatidylserine, the expression of surface antigens, proteins and genetic material, originating from their donor cells, and as important vehicles of intercellular communication across numerous biological processes. MPs contain the major source of systemic RNA including microRNA (miRNA) of which aberrant expression appears to be associated with stage and progression of atherosclerosis. The involvement and influence of miRNA during the onset and progression of atherosclerotic disease have generated a lot of interest in assessing the feasibility of therapeutic regulation of miRNAs to manipulate them with a special focus on cardiovascular disease. We speculate on the future developments of MPs which contain miRNA as new therapeutic targets for proliferative vascular diseases such as atherosclerosis.     

“Normoalbuminuric” diabetic nephropathy: tubular damage and NGAL

The aim of this study was to demonstrate that neutrophil gelatinase-associated lipocalin (NGAL) increased before the onset of microalbuminuria in patients with type 1 diabetes mellitus (T1DM), representing an important biochemical parameter with high sensitivity and specificity to make a precocious diagnosis of “normoalbuminuric” diabetic nephropathy (DN). Serum NGAL (sNGAL) and urinary NGAL (uNGAL) levels were evaluated in a cohort of fifty patients affected by T1DM. They had no signs of clinical nephropathy. Thirty-five healthy subjects (HS) were recruited. sNGAL levels were significantly higher compared with those measured in HS [193.7 (103.2–405.4) vs. 46.4 (39.8–56.2) ng/ml; p < 0.0001], as were uNGAL levels [25.5 (14.2–40.2) vs. 6.5 (2.9–8.5) ng/ml; p < 0.0001]. sNGAL was found to be directly correlated with glycated hemoglobin. uNGAL also positively correlated with albuminuria, whereas an inverse correlation was found with uric acid. After multivariate analysis, significance was maintained for the correlation between uNGAL and microalbuminuria. In ROC analysis, sNGAL showed a good diagnostic profile such as uNGAL. NGAL increases in patients with T1DM, even before diagnosis of microalbuminuria representing an early biomarker of “normoalbuminuric” DN with a good sensitivity and specificity. NGAL measurement could be useful for the evaluation of early renal involvement in the course of diabetes.     

Tridimensional ultrastructure and glycolipid pattern studies of Trypanosoma dionisii

Trypanosoma (Schizotrypanum) dionisii is a non-pathogenic bat trypanosome closely related to Trypanosoma cruzi, the etiological agent of Chaga's disease. Both kinetoplastids present similar morphological stages and are able to infect mammalian cells in culture. In the present study we examined 3D ultrastructure aspects of the two species by serial sectioning epimastigote and trypomastigote forms, and identified common carbohydrate epitopes expressed in T. dionisii, T. cruzi and Leishmania major. A major difference in 3D morphology was that T. dionisii epimastigote forms present larger multivesicular structures, restricted to the parasite posterior region. These structures could be related to T. cruzi reservosomes and are also rich in cruzipain, the major cysteine-proteinase of T. cruzi. We analyzed the reactivity of two monoclonal antibodies: MEST-1 directed to galactofuranose residues of glycolipids purified from Paracoccidioides brasiliensis, and BST-1 directed to glycolipids purified from T. cruzi epimastigotes. Both antibodies were reactive with T. dionisii epimastigotes by indirect immunofluorescense, but we noted differences in the location and intensity of the epitopes, when compared to T. cruzi. In summary, despite similar features in cellular structure and life cycle of T. dionisii and T. cruzi, we observed a unique morphological characteristic in T. dionisii that deserves to be explored.     

Severe adverse events during antiviral therapy in hepatitis C virus cirrhotic patients: A systematic review

AIM: To identify severe adverse events (SAEs) leading to treatment discontinuation that occur during antiviral therapy in hepatitis C virus (HCV)-infected cirrhotic patients.METHODS: We identified all the articles published prior to December 2011 in the PubMed, Medline, Lilacs, Scopus, Ovid, EMBASE, Cochrane and Medscape databases that presented these data in cirrhotic patients. These studies evaluated the rate of SAEs leading to discontinuation of standard care treatment: Pegylated interferon (PegIFN) alpha 2a (135-180 μg/wk) or PegIFN alpha 2b (1 or 1.5 μg/kg per week) and ribavirin (800-1200 mg/d). Patients with genotype 1 + 4 underwent treatment for 48 wk, whereas those with genotypes 2 + 3 were treated for 24 wk.RESULTS: We included 17 papers in this review, comprising of 1133 patients. Treatment was discontinued due to SAEs in 14.5% of the patients. The most common SAEs were: severe thrombocytopenia and/or neutropenia (23.2%), psychiatric disorders (15.5%), decompensation of liver cirrhosis (12.1%) and severe anemia (11.2%). The proportion of patients who needed to discontinue their therapy due to SAEs was significantly higher in patients with Child-Pugh class B and C vs those with Child-Pugh class A: 22% vs 11.4% (P = 0.003). A similar discontinuation rate was found in cirrhotic patients treated with PegIFN alpha 2a and those treated with PegIFN alpha 2b, in combination with ribavirin: 14.2% vs 13.7% (P = 0.96). The overall sustained virological response rate in cirrhotic patients was 37% (95%CI: 33.5-43.1) but was significantly lower in patients with genotype 1 + 4 than in those with genotype 2 + 3: 20.5% (95%CI: 17.9-24.8) vs 56.5% (95%CI: 51.5-63.2), (P < 0.0001).CONCLUSION: Fourteen point five percent of HCV cirrhotic patients treated with PegIFN and ribavirin needed early discontinuation of therapy due to SAEs, the most common cause being hematological disorders.     

Regulation of bone remodeling by vasopressin explains the bone loss in hyponatremia

Although hyponatremia is known to be associated with osteoporosis and a high fracture risk, the mechanism through which bone loss ensues has remained unclear. As hyponatremic patients have elevated circulating arginine-vasopressin (AVP) levels, we examined whether AVP can affect the skeleton directly as yet another component of the pituitary-bone axis. Here, we report that the two Avp receptors, Avpr1α and Avpr2, coupled to Erk activation, are expressed in osteoblasts and osteoclasts. AVP injected into wild-type mice enhanced and reduced, respectively, the formation of bone-resorbing osteoclasts and bone-forming osteoblasts. Conversely, the exposure of osteoblast precursors to Avpr1α or Avpr2 antagonists, namely SR49059 or ADAM, increased osteoblastogenesis, as did the genetic deletion of Avpr1α. In contrast, osteoclast formation and bone resorption were both reduced in Avpr1α^−/− cultures. This process increased bone formation and reduced resorption resulted in a profound enhancement of bone mass in Avpr1α^−/− mice and in wild-type mice injected with SR49059. Collectively, the data not only establish a primary role for Avp signaling in bone mass regulation, but also call for further studies on the skeletal actions of Avpr inhibitors used commonly in hyponatremic patients.Over the past decade, studies by others and us have documented direct effects of pituitary hormones on the skeleton. We have identified functional receptors for thyroid stimulating hormone (TSH), follicle stimulating hormone (FSH), adrenocorticotropic hormone (ACTH), and oxytocin (OT) on murine and human bone cells, namely bone-forming osteoblasts and bone-resorbing osteoclasts (1–4). The genetic deletion of either the receptor or the ligand itself, as in the case of FSH and OT, results in overt skeletal abnormalities. Specifically, deleting OT or its receptor, the Oxtr, causes profound osteopenia, which primarily arises from a dramatic reduction in bone formation by the osteoblast (4). Such studies have helped establish a pituitary-bone axis, in which pituitary hormones bypass their known targets, such as the thyroid, ovaries, adrenal, and breast, to regulate bone directly (5).This growing body of data not only informs us of novel functions of pituitary hormones, but also explains the hitherto poorly understood mechanisms of certain forms of osteoporosis, which have traditionally been attributed solely to changes in distal hormones. For example, we find that low TSH signaling contributes to the bone loss in hyperthyroidism, which was thought solely to be a result of elevated thyroid hormones (6). We have also speculated that the rapid bone loss that occurs during late perimenopause, at a time when estradiol levels are relatively normal, could—at least in part—be caused by elevated serum FSH levels. Thus, an antibody to FSH reduces bone loss in ovariectomized mice by stimulating bone formation and inhibiting bone resorption (7). Similarly, through its skeletal anabolic actions, elevated OT levels during pregnancy and lactation could play a major role in enabling fetal skeletal mineralization and allowing the mother to recover from the osteoporosis caused by the intergenerational transfer of calcium (8).Here, we report studies on arginine-vasopressin (AVP), another posterior pituitary hormone, which differs from OT only by two amino acids (9). The direct skeletal actions of AVP have never been explored, despite multiple and recurring observations that hyponatremia, which is invariably accompanied by elevated plasma AVP levels, is associated with bone loss and a high fracture risk (10–16). It has been thought that, as bone is a large reservoir for sodium ions, hyponatremia will trigger sodium release from the skeleton by increasing bone resorption (17, 18). However, the molecular basis of any such effect remains unknown. Interestingly, a recent study has described a male patient with syndrome of inappropriate secretion of antidiuretic hormone- (SIADH) induced hyponatremia, who had severe osteoporosis, despite having no identifiable risk factors (19). Plasma AVP was elevated by ∼30-fold, raising the possibility that high circulating AVP levels may cause the profound bone loss.We show that AVP is a key regulator of bone resorption and formation, the two principal components of bone remodeling. Both Avp receptors, Avpr1α and Avpr2, are expressed on osteoclasts and osteoblasts, and their stimulation triggers extracellular signal regulated kinase (Erk) activation, which in turn suppresses bone formation and stimulates bone resorption. This decoupling would favor bone loss, as noted in hyponatremic states. However, we also find that the genetic deletion of Avpr1 or the pharmacologic inhibition of Avpr1 or Avpr2 increases bone mass not only by stimulating osteoblastogenesis and new bone synthesis, but also by simultaneously inhibiting osteoclast formation and bone resorption. We speculate, therefore, that the targeted therapy of hyponatremia with aquaretics (or AVPR inhibitors) could result in overall bone gain. Purposefully designed clinical studies in populations in whom hyponatremia is a significant clinical problem (20), and whom are otherwise also at a high risk for fracture (21), should shed further light on the proposed osteoprotective action of AVPR antagonists in people.