Quality of life during one year of postoperative prophylactic drug therapy after intestinal resection in Crohn’s patients: Results of the APPRECIA trial

Background

In APPRECIA trial, Crohn's disease (CD) patients undergoing intestinal resection were randomized to postoperative adalimumab (ADA) or azathioprine (AZA).

Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models,once tauopathy is initiated,by restoring the autophagic flux

Alterations in autophagy are increasingly being recognized in the pathogenesis of proteinopathies like Alzheimer's disease (AD). This study was conducted to evaluate whether melatonin treatment could provide beneficial effects in an Alzheimer model related to tauopathy by improving the autophagic flux and, thereby, prevent cognitive decline. The injection of AAV‐hTau^P301L viral vectors and treatment/injection with okadaic acid were used to achieve mouse and human ex vivo, and in vivo tau‐related models. Melatonin (10 μmol/L) impeded oxidative stress, tau hyperphosphorylation, and cell death by restoring autophagy flux in the ex vivo models. In the in vivo studies, intracerebroventricular injection of AAV‐hTau^P301L increased oxidative stress, neuroinflammation, and tau hyperphosphorylation in the hippocampus 7 days after the injection, without inducing cognitive impairment; however, when animals were maintained for 28 days, cognitive decline was apparent. Interestingly, late melatonin treatment (10 mg/kg), starting once the alterations mentioned above were established (from day 7 to day 28), reduced oxidative stress, neuroinflammation, tau hyperphosphorylation, and caspase‐3 activation; these observations correlated with restoration of the autophagy flux and memory improvement. This study highlights the importance of autophagic dysregulation in tauopathy and how administration of pharmacological doses of melatonin, once tauopathy is initiated, can restore the autophagy flux, reduce proteinopathy, and prevent cognitive decline. We therefore propose exogenous melatonin supplementation or the development of melatonin derivatives to improve autophagy flux for the treatment of proteinopathies like AD.     

Functional amelioration of murine galactosialidosis by genetically modified bone marrow hematopoietic progenitor cells

Protective protein/cathepsin A (PPCA), a lysosomal carboxypeptidase, is deficient in the neurodegenerative lysosomal disorder galactosialidosis (GS). PPCA(-/-) mice display a disease course similar to that of severe human GS, resulting in nephropathy, ataxia, and premature death. Bone marrow transplantation (BMT) in mutant animals using transgenic BM overexpressing the corrective enzyme in either erythroid cells or monocytes/macrophages has proven effective for the improvement of the phenotype, and encouraged the use of genetically modified BM cells for ex vivo gene therapy of GS. Here, we established stable donor hematopoiesis in PPCA(-/-) mice that received hematopoietic progenitors transduced with a murine stem cell virus (MSCV)-based, bicistronic retroviral vector overexpressing PPCA and the green fluorescent protein (GFP) marker. We observed complete correction of the disease phenotype in the systemic organs up to 10 months after transplantation. PPCA(+) BM-derived cells were detected in all tissues, with the highest expression in liver, spleen, BM, thymus, and lung. In addition, a lysosomal immunostaining was seen in nonhematopoietic cells, indicating efficient uptake of the corrective protein by these cells and cross-correction. Expression in the brain occurred throughout the parenchyma but was mainly localized on perivascular areas. However, PPCA expression in the central nervous system was apparently sufficient to delay the onset of Purkinje cell degeneration and to correct the ataxia. The long-term expression and internalization of the PPCA by cells of systemic organs and the clear improvement of the neurologic phenotype support the use of this approach for the treatment of GS in humans. (Blood. 2002;99:3169-3178)     

Growth hormone release after glucagon as a reliable test of growth hormone assessment in adults

OBJECTIVE: To investigate the GH response to glucagon in adult patients with GH deficiency and in controls compared with the GH response to the insulin tolerance test (ITT) in patients with GH deficiency and to determine whether the use of glucagon results in a diagnostic utility test. PATIENTS AND DESIGN: Seventy-three patients with adult GH deficiency and organic hypothalamic-pituitary disease were recruited, along with 46 controls. The patients were divided into five groups according to the number of associated hormone deficiencies present. MEASUREMENTS: Hypopituitary subjects underwent assessment of GH secretory status by the ITT, the glucagon test and measurement of serum IGF-I concentration. Controls underwent the glucagon test. After the ITT, glucose and GH levels were measured at baseline, 30, 60 and 90 minutes, and after glucagon at baseline, 90, 120, 150, 180, 210 and 240 minutes. RESULTS: The highest GH value after the ITT in the patient group was 3 microg/l (0.76 +/- 0.82 microg/l), and after the glucagon test the highest GH peak value was 2.9 microg/l (0.64 +/- 0.79 microg/l). A correlation was found between the GH peak and the progressive number of hormone deficiencies. After the glucagon test, the GH peak obtained in the controls at 180 minutes was 9.8 +/- 4.6 microg/l and, on an individual basis, none of the 46 controls failed to achieve peak GH levels higher than 3 microg/l. In the controls, a negative correlation was observed between the GH response to glucagon and age (r = -0.389, P = 0.0075) and body mass index (r = -0.329, P = 0.0254). The accuracy of the glucagon test for differentiating patients from controls, estimated by receiver operating characteristics (ROC) curve methodology, showed that the cut-off of 3 microg/l for the GH peak provides 100% sensitivity and 100% specificity and is a reliable decision threshold. CONCLUSIONS: The glucagon GH test is reliable and provides a clear separation between GH-deficient and normal adults. A single glucagon test with a cut-off of 3 microg/l for the GH peak is diagnostic of GH deficiency in adults and could be considered and studied as an alternative to the ITT.     

Trisomy 3 in two paediatric post-transplant lymphomas

Few cytogenetic data are available concerning the chromosomal constitution of post-transplant lymphomas. We report two paediatric cases of trisomy 3, as a primary anomaly, in post-transplant lymphoproliferative disease (PTLD) associated with B immunophenotype. Using cytogenetic analysis and fluorescence in situ hybridization on chromosome preparations, we found trisomy 3 in both patients and an extra X chromosome in one. Clinical, histological and immunophenotypical data are presented. Trisomy 3 has been observed in different types of non-Hodgkin's lymphomas but it is relatively rare in B-cell lymphomas, with the exception of marginal zone lymphoma and mantle cell lymphoma. To our knowledge, trisomy 3 is an uncommon cytogenetic finding in PTLD. Further cytogenetic studies of these lymphoproliferative disorders might contribute to evaluate the role of these chromosomal anomalies in the pathogenesis of this disease.     

Safety of a cyclooxygenase-2 inhibitor in patients with aspirin-sensitive asthma

BACKGROUND: In 5 to 10% of adult patients with asthma, aspirin (acetylsalicylic acid [ASA]) and most other nonsteroidal anti-inflammatory drugs (NSAIDs) precipitate acute asthmatic attacks. Therefore, choosing an alternative anti-inflammatory agent for patients with adverse reactions to an NSAID is a common problem in clinical practice. The discoveries that cyclooxygenase (COX)-2 is an inducible form of COX that is involved in inflammation and that COX-1 is the major isoform responsible for the production of prostaglandins have provided a reasonable basis for the development of specific COX-2 inhibitors as a new class of anti-inflammatory agents. OBJECTIVE: The purpose of this study was to demonstrate that rofecoxib, a specific inhibitor of COX-2, does not cause asthmatic attacks in patients with ASA and/or other NSAID-induced asthma. METHODS: We studied 40 patients, all of whom had experienced asthma induced by at least two different NSAIDs. The patients were challenged in a single-blind manner with different doses of rofecoxib on 3 different days, until either the therapeutic dose of 25 mg or intolerance was reached. Each patient was rechallenged with 25 mg of rofecoxib 7 days later if no evidence of intolerance had been observed previously. RESULTS: Rofecoxib, 25 mg, was proven to be well tolerated in all 40 patients with ASA-induced and NSAID-induced asthma. CONCLUSION: Our study appears to demonstrate that rofecoxib is a suitable NSAID for treatment of patients with ASA and/or other NSAID-induced asthma.     

Short report: limited and short-lasting humoral response in Taenia solium: seropositive households compared with patients with neurocysticercosis

Epidemiologic data suggest that 30-40% of Taenia solium-seropositive people become spontaneously negative without acquiring cysticercosis. To compare the responses of these individuals with those of patients with neurocysticercosis, we screened seropositive persons among family members of 16 patients. We searched for specific antibodies in patients and their 118 households by an enzyme-linked immunoelectrotransfer blot assay using specific glycoproteins of T. solium metacestodes. We found six seropositive individuals without neurocysticercosis among members of four families. The matching patients were young, harbored viable cysts, and had short evolution of disease. The baseline response of healthy seropositive individuals was scarce and showed a low frequency of antibodies against glycoproteins GP39-42 and GP24, which are immunodominant in patients with neurocysticercosis. Moreover, they became spontaneously negative in few months. The response of patients was heterogeneous as shown in other studies. The results of this work support a highly dynamic host-parasite immunologic interaction and suggest individual susceptibility or level of exposure among family members.     

Association of HTR2A-1438G/A Genetic Polymorphism With Smoking and Chronic Obstructive Pulmonary Disease

Introduction

Cigarette smoking is a major risk factor in the development of chronic obstructive pulmonary disease (COPD). Serotonin levels have been associated with COPD and smoking has been as a significant modulator. Elevated levels of serotonin are responsible for bronchoconstriction and pulmonary vasoconstriction and also nicotine dependence, thus serotonin response could be affected by genetic polymorphisms in transporters and receptors of serotonin.

Effects of treatment with GH alone or in combination with LHRH analog on bone mineral density in pubertal GH-deficient patients.

The aim of the present study was to assess the impact of treatment with GH with or without LHRH analog (LHRH-A) on bone mineralization of GH-deficient adolescents. We studied 17 pubertal, treatment-naive, GH-deficient patients (10 girls and 7 boys) in a prospective, randomized trial. Mean chronological age and mean bone age were 14.1 +/- 0.4 and 11.3 +/- 0.3 yr, respectively, at the beginning of the study. Treatment with GH + LHRH-A (n = 7) or GH alone (n = 10) started simultaneously. Nutropin was administered at a dose of 0.1 U/kg per day sc until patients reached near final height (NFH), defined as a bone age of 14 yr in girls and 16 yr in boys. Mean time of GH therapy in the patients treated with GH+LHRH-A was 4.8 +/- 0.5 yr and in the patients treated with GH alone 2.9 +/- 0.7 yr. Lupron was administered at a dose of 300 microg/kg every 28 d im for 3 yr. Bone mineral density (BMD) was assessed yearly by dual-energy x-ray absorptiometry at the lumbar spine (L2-L4) and femoral neck at the beginning of the study, after 3 yr of hormonal therapy, and at NFH. Statistical analysis was performed by t test and ANOVA. We observed a significant increase in lumbar and femoral bone mineral content, BMD, SD score, and bone mineral apparent density, compared with baseline in both groups of patients, regardless of whether they were treated with GH alone or in combination with LHRH-A. The patients treated with GH + LHRH-A had a significantly lower bone mineral content after 3 yr of therapy. This difference, however, did not persist after both groups of patients reached NFH. These results indicate that delaying puberty with LHRH-A in GH-deficient patients treated with GH diminishes transient bone mineralization but does not appear to have a permanent impact on BMD.