Human apolipoprotein A-I Gly26Arg stimulation of inflammatory responses via NF-kB activation: Potential roles in amyloidosis?

The cascade of molecular events leading to Human apolipoprotein A–I (apoA–I) amyloidosis is not completely understood, not even the pathways that determine clinical manifestations associated to systemic protein deposition in organs such as liver, kidney and heart. About twenty natural variants of apoA–I were described as inducing amyloidosis, but the mechanisms driving their aggregation and deposition are still unclear. We previously identified that the mutant Gly26Arg but not Lys107-0 induced the release of cytokines and reactive oxygen species from cultured RAW 264.7 murine macrophages, suggesting that part of the pathogenic pathway could elicit of an inflammatory signal. In this work we gained deep insight into this mechanism and determined that Gly26Arg induced a specific pro-inflammatory cascade involving activation of NF-κB and its translocation into the nucleus. These findings suggest that some but not all apoA–I natural variants might promote a pro-oxidant microenvironment which could in turn result in oxidative processing of the variants into a misfolded conformation.     

Evaluación del seguimiento de niños con hallazgo de hipertransaminasemia

IntroductionAlthough changes in liver function tests can be non-specific in numerous clinical conditions, they can be the first sign of a potentially serious disease in an asymptomatic patient.Material and methodsRetrospective cohort study, performed by reviewing the records of children of a reference hospital central laboratory with alanine aminorransferase enzyme (ALT) elevation during a 6 month aleatory period.Results572 blood tests with serum ALT elevation corresponding to 403 patients had been assessed during the period studied. 98 patients were excluded for presenting abnormal liver test before the study period of comorbidity that could produce ALT elevation. The remaining 305 patients, 22.6% were diagnosed with a medical condition during the first blood test that explained the ALT elevation, although only 33.3% of them were followed up until verifying their normalization. Final study sample consists of 236 patients with abnormal liver test without apparent liver disease. Adequate follow-up was found only in 29% of them. From this group, 9 patients (13%) were diagnosed with liver disease. The rest of the sample were not properly monitored. In patients with higher serum ALT levels, follow-up was early and more appropiate.ConclusionsIn our area, most children without apparent liver disease are no properly monitored. Therefore, an opportunity to diagnosis and treat a potential liver disease was lost in a great number of children. All children with unexplainedhypertransaminasaemia must be studied.     

Effects of event-specific memory training on autobiographical memory retrieval and depressive symptoms in schizophrenic patients

Background and objectivesThis report describes the effects of a specific event group-based training programme on autobiographical memory, self-consciousness of memory retrieval, and depression symptoms in a sample of 24 schizophrenic patients (experimental group).MethodsTwenty-six matched schizophrenic patients who participated in social skills and occupational therapy group sessions constituted the active control group. Participants in the experimental group were trained to complete a diary with specific daily memories, followed by patients’ ratings of the associated emotional arousal of those entries. During training, significant specific events from childhood, adolescence, adulthood and the previous year were also reviewed.ResultsAfter 10 weeks of group-based sessions, the experimental group demonstrated an increase in their degree of specificity for autobiographical retrievals, had a higher level of consciousness of their memories and showed a decrease in their depression scores. Significant changes in measurements of retrieval specificity and autonoetic awareness were maintained when changes in emotional symptomatology were statistically controlled.LimitationsThe present study did not assess the impact of autobiographical memory training on the positive and negative symptoms of schizophrenia.ConclusionsThese results suggest that cognitive training strategies based on event-specific autobiographical memory training should be considered for inclusion in intervention programs for schizophrenic patients.     

Phospho-CRKL monitoring for the assessment of BCR-ABL activity in imatinib-resistant chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia patients treated with nilotinib

Actual BCR-ABL kinase inhibition in vivo as determined by phospho-CRKL (pCRKL) monitoring has been recognized as a prognostic parameter in patients with chronic myelogenous leukemia treated with imatinib. We report a biomarker sub-study of the international phase I clinical trial of nilotinib (AMN107) using the established pCRKL assay in imatinib-resistant chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia. A minimum dose (200 mg) required for effective BCR-ABL inhibition in imatinib resistant/intolerant leukemia was determined. The pre-clinical activity profile of nilotinib against mutant BCR-ABL was largely confirmed. Substantial differences between peripheral blood baseline pCRKL/CRKL ratios were observed when comparing chronic myeloid leukemia with Ph+ acute lymphoblastic leukemia. Finally, rapid BCR-ABL-reactivation shortly after starting nilotinib treatment was seen in acute lymphoblastic leukemia patients with progressive disease carrying the P-loop mutations Y253H, E255K, or mutation T315I. Monitoring the actual BCR-ABL inhibition in nilotinib treated patients using pCRKL as a surrogate is a means to establish effective dosing and to characterize resistance mechanisms against nilotinib.     

Revisiting serum thyroglobulin in the follow-up of patients with differentiated thyroid carcinoma

This study analyzed serum thyroglobulin (Tg) during hypothyroidism in 207 patients with differentiated thyroid carcinoma treated with total thyroidectomy and radioiodine ablation and undetectable anti-Tg antibodies. Disease staging was defined by clinical examination, stimulated Tg, pre- and post-ablative radioiodine scanning, and other imaging methods (X-Ray, US, CT and MIBI-scan). The average interval from initial therapy was 2.3 years. 153 patients (74%) had no evident disease, 34 (16.4%) presented neck/mediastinal disease, and 20 (9.6%) had distant metastases (Mt). The best cut-off for Tg was 1 ng/ml, showing 100% sensitivity for distant Mt and 88.2% for local recurrence or lymph node Mt, and 88.8% specificity for any Mt and 74.8% for distant Mt. In patients with Tg <1 ng/ml, 2.8% showed cervical lymph nodes Mt. Cervical or mediastinal disease were 26% of cases with Tg between 1 and 5 ng/ml. Tg from 5 to 10 ng/ml was associated to distant Mt in 14.2% of the cases and others showed lymph nodes Mt. In patients with Tg >10 ng/ml, 51.3% presented distant Mt. We suggest the need for neck US even in cases with Tg <1 ng/ml. In addition, patients with Tg levels <5 ng/ml should be investigated by neck US and mediastinal CT only, and empirical therapy should be limited to patients with a minimum Tg level >5 ng/ml.