Inadequate response to imatinib treatment in chronic myeloid leukemia due to a drug interaction with phenytoin.

Imatinib mesylate and the newer BCR-ABL tyrosine kinase inhibitors are the standard therapy for chronic myeloid leukemia. Although these are remarkably effective drugs, some mechanisms of resistance have been identified including drug-to-drug interactions. Here we present the case of a chronic myeloid leukemia patient with an inadequate response to imatinib due to concurrent phenytoin administration. Conspicuously low imatinib plasma trough levels were documented. Imatinib dose was increased from 400 to 800 mg with good response. In conclusion, drug-to-drug interactions should be ruled out in cases of resistance to tyrosine kinase inhibitor treatment. Potent inducers of cytochrome P450 isoenzyme CYP3A4, as phenytoin, could induce inadequate responses due to increased imatinib clearance and low imatinib trough plasma levels. Thus, this interaction should be avoided. When this is not possible, dose escalation of imatinib and measurement of plasma levels, if available, is recommended.

Near-optimal feedback control for postprandial glucose regulation in type 1 diabetes.

This paper is focused on feedback control of postprandial glucose levels for patients with type 1 Diabetes Mellitus. There are two important limitations that make this a challenging problem. First, the slow subcutaneous insulin pharmacokinetics that introduces a significant lag into the control loop. Second, the positivity constraint on the control action, meaning that it is not possible to remove insulin from the body. In this paper, both issues are explicitly considered in the design process using the internal model control framework, to derive a near-optimal feedback controller. Optimality is understood here as minimizing the blood glucose peak after a meal intake and, at the same time, preventing glucose values below a prescribed threshold. It is shown how the proposed controller approaches the optimal closed-loop performance as a limit case. The theoretical results are supported by a numerical example and the feasibility of the overall strategy under uncertainties is illustrated using an extended version UVa/Padova metabolic simulator.

Super-twisting-based meal detector for type 1 diabetes management: Improvement and assessment in a real-life scenario.

BACKGROUND AND OBJECTIVE: Hybrid automated insulin delivery systems rely on carbohydrate counting to improve postprandial control in type 1 diabetes. However, this is an extra burden on subjects, and it introduces a source of potential errors that could impact control performances. In fact, carbohydrates estimation is challenging, prone to errors, and it is known that subjects sometimes struggle to adhere to this requirement, forgetting to perform this task. A possible solution is the use of automated meal detection algorithms. In this work, we extended a super-twisting-based meal detector suggested in the literature and assessed it on real-life data. METHODS: To reduce the false detections in the original meal detector, we implemented an implicit discretization of the super-twisting and replaced the Euler approximation of the glucose derivative with a Kalman filter. The modified meal detector is retrospectively evaluated in a challenging real-life dataset corresponding to a 2-week trial with 30 subjects using sensor-augmented pump control. The assessment includes an analysis of the nature and riskiness of false detections. RESULTS: The proposed algorithm achieved a recall of 70 [13] % (median [interquartile range]), a precision of 73 [26] %, and had 1.4 [1.4] false positives-per-day. False positives were related to rising glucose conditions, whereas false negatives occurred after calibrations, missing samples, or hypoglycemia treatments. CONCLUSIONS: The proposed algorithm achieves encouraging performance. Although false positives and false negatives were not avoided, they are related to situations with a low risk of hypoglycemia and hyperglycemia, respectively.

Transcription and activation under environmental stress of the complex telomeric repeats of Chironomus thummi.

In contrast to their traditional role, telomeres seem to behave as transcriptionally active regions. RNAs complementary to the short DNA repeats characteristic of telomerase-maintained telomeres have recently been identified in various mammalian cell lines, representing a new and unexpected element in telomere architecture. Here, we report the existence of transcripts complementary to telomeric sequences characteristic of Chironomus thummi telomeres. As in other Diptera, the non-canonical telomeres of chironomids lack the simple telomerase repeats and have instead more complex repetitive sequences. Northern blots of total RNA hybridized with telomere probes and RT-PCR with telomere-specific tailed primers confirm the existence of small non-coding RNAs of around 200 bp, the size of the DNA repeated telomeric unit. Telomere transcripts are heterogeneous in length, and they appear as a ladder pattern that probably corresponds to multimers of the repeat. Moreover, telomeres are activated under conditions of environmental stress, such as heat shock, appearing highly decondensed and densely labelled with acetylated H4 histone, as well as with RNA polymerase II antibodies, both marks of transcriptional activity. Changes in the expression levels of telomeric RNA were detected after heat shock. These findings provide evidence that transcriptional activity of the repetitive telomere sequences is an evolutionarily conserved feature, not limited to telomerase telomeres. The functional significance of this non-coding RNA as a new additional element in the context of telomere biology remains to be explained.

Atención a la patología infecciosa en Urgencias de Pediatría: pandemia y pospandemia / Attention to infectious pathology in Pediatric Emergencies: pandemic and post-pandemic

La llegada de un nuevo virus y la declaración de pandemia han supuesto un cambio muy importante en la aproximación a la patología infecciosa en el ámbito sanitario y especialmente en las Urgencias de Pediatría. Estamos permanentemente amenazados por el aumento de la demanda desencadenada por los virus hasta ahora conocidos como estacionales, sin saber cuál será cada año la fuerza con la que impacte la infección en la población infantil en forma de incidencia; hasta que ha llegado el SARS-CoV-2 que ha cambiado completamente el paradigma infeccioso, y que en la actualidad seguimos sufriendo sus coletazos (AU)

Heat shock regulatory elements are present in telomeric repeats of Chironomus thummi.

As in other Diptera, the telomeres of Chironomus thummi lack canonical short telomerase-specified repeats and instead contain complex sequences. They react to heat shock and other stress treatments by forming giant puffs at some chromosome termini, which are visible in polytene cells. All telomeres, except the telocentric end of chromosome four (4L), consist of large blocks of repeats, 176 bp in length. Three subfamilies of telomeric sequences have been found to show different distribution patterns between chromosome ends. TsA and TsC are characteristic of telomeres 3R and 4R, respectively, whereas TsB is present in the other non-telocentric telomeres. Heat shock transcription regulatory elements have been identified in the telomeric sequences, appearing differentially represented in the three subfamilies, but otherwise rather similar in size and sequence. Interestingly, TsA and TsB repeats share the well-conserved heat shock element (HSE) and GAGA motif, while the TATA box is only present in the former. Neither a HSE nor a TATA box appear in TsC repeats. Moreover, experimental data indicate that the HSE is functionally active in binding heat shock transcription factor (HSF). These results provide, for the first time, a molecular basis for the effect of heat shock on C.thummi telomeres and might also explain the different behaviour they show. A positive correlation between the presence of HSE and telomeric puffing and transcription under heat shock was demonstrated. This was also confirmed in the sibling species Chironomus piger. The significance of heat shock activation of telomeric repeats in relation to telomeric function is unknown at present, but it might be compared to the behaviour of other non-heat shock protein coding sequences, such as SINE-like and LINE-like retroelements, which have been reported to be activated by stress.

[Results of treatment of retinal angiomatous proliferation with photodynamic therapy]. / Resultados del tratamiento de la proliferación angiomatosa retiniana mediante terapia fotodinámica.

PURPOSE: To determine the effects of phothodynamic therapy using verteporfin in the treatment of patients with retinal angiomatous proliferation (RAP) and the incidence of this retinal disease in our area. METHODS: We performed a retrospective study of 11 cases of RAP who were treated with photodynamic therapy using verteporfin (PDT). RESULTS: The incidence of RAP in the group of eyes with minimally classic or occult subfoveal choroidal neovascularization was 8%. The mean follow-up time after treatment was 15 months. The visual acuity improved in 3, remained the same in 4, and decreased in 4. In 4 patients, angiomatous lesions were observed in both eyes. CONCLUSIONS: There is no method proven to be effective for the treatment of retinal angiomatous proliferation. Our results suggest that PDT may be useful therapy in patients with RAP as it appeared to reduce the risk of visual loss.

[Submacular hemorrhage following photodynamic therapy in the treatment of choroidal neovascularization]. / Hemorragia submacular tras terapia fotodinámica en el tratamiento de la neovascularización coroidea.

PURPOSE: To describe the incidence, clinical features and evolution of submacular hemorrhage (SMH) occurring after photodynamic therapy (PDT) with verteporfin in the treatment of choroidal neovascularization (CNV). METHODS: A retrospective analysis of the patients treated with PDT in our hospital between July 2002 and May 2005 was undertaken. RESULTS: 8 out of 504 eyes treated with PDT (1.58%) developed SMH; 4 of them (0.79%) required surgical attack. The incidence of SMH for every application of PDT was 0.65% (8/1221). The underlying disorder defined was age-related macular degeneration (AMD) in 7 cases (87.5%), and high myopia in one case (12.5%). Regarding the type of lesion, 5 were occult (62.5%; p=0.01), 1 predominantly classic, 1 minimally classic, and the last one was not classified. The average final visual acuity (VA) was 0.057, with 25% of patients having a VA >or= 0.1. Patients lost 4 Snellen lines on average. CONCLUSIONS: SMH after PDT was an event of unknown etiology and low frequency. The incidence in our series (1.58%) was comparable with that described in the world literature (0.24-9.0%). The greatest incidence of AMD was in the occult group with no classic type of CNV, suggesting a possible higher risk for SMH in this type of lesion. It is mandatory to inform patients of the possibility of this complication, which can compromise the visual result of the PDT, and sometimes require surgery. The low risk of SMH related to the PDT justifies its application when it is indicated.

Relapse of chronic myeloid leukemia after allogeneic stem cell transplantation: outcome and prognostic factors: the Chronic Myeloid Leukemia Subcommittee of the GETH (Grupo Español de Trasplante Hemopoyético).

In order to analyze the outcome of patients with chronic myeloid leukemia (CML) who relapse after allogeneic stem cell transplantation (SCT), we investigated data from 107 patients reported to the Spanish Registry, GETH. In all, 93 (87%) patients were treated after relapse; 36 out of 49 that failed to achieve a response received a second relapse-treatment, and seven a third one. At the last follow-up, the number of patients in molecular or cytogenetic remission was 29 and 13, respectively. Overall survival and progression-free survival after relapse were 53.6% (95% CI: 42.9--64.2) and 52% (95% CI: 41-63) at 5 years, respectively. In multivariate analysis, survival was significantly related to CML phase at relapse (cytogenetic or chronic phase vs advanced phases) and time from transplant to relapse (<1 vs >or=1 year). Patients with no adverse factors had a better survival compared with patients with one or two adverse features (65 vs 35 vs 0%, respectively). We conclude that a significant proportion of CML patients that relapse after transplantation can regain complete and long-lasting remissions with one or more salvage therapies. Disease stage at relapse and time from transplant to relapse should be taken into account when comparing results of different salvage treatments.

Long-term outcome of allogeneic PBSC transplantation in pediatric patients with hematological malignancies: a report of the Spanish Working Party for Blood and Marrow Transplantation in Children (GETMON) and the Spanish Group for Allogeneic Peripheral Blood Transplantation (GETH).

We analyzed the clinical outcome in 90 children undergoing allogeneic PBSC transplantation from HLA-identical relative for leukemia. GvHD prophylaxis was CsA+ methotrexate in 50 and CsA+/-steroids in 40. Median CD34+ cells infused were 6 x 10(6)/kg (range, 1.4-32). Median follow-up was 60 months (range, 6-115). CI of transplant-related mortality (TRM) was 18.4+/-4%. On multivariate analysis, high Lansky score (>80) at transplantation was associated with lower TRM (HR, 0.9; P<0.0002). Relapse incidence (RI) was 33.6+/-6%. On multivariate analysis, high Lansky score at transplantation and cGvHD were associated with lower RI (HR, 0.04; P<0.0005 and HR, 0.23; P<0.03, respectively). Disease-free survival (DFS) was 57.8+/-5%. Disease status at transplantation (HR, 0.33; P<0.02), steroid treatment at day +90 (HR, 5.61; P<0.005) and cGvHD (HR, 0.23; P<0.005) had a significant impact on DFS in multivariate analysis. CI of cGvHD was 63.7+/-7%. Patients with cGvHD had better DFS (65+/-5%) because of lower RI (15.7+/-6%) and similar TRM (27.4+/-4%). These data suggest acceptable long-term outcomes after allogeneic PBSC transplantation in children despite the high incidence of cGvHD. These patients had a lower risk of relapse and a better DFS.

HLA haploidentical cord blood cell transplant in a 15-year-old, 50 kg weight patient: successful treatment for chronic myeloid leukemia after myeloid blastic transformation.

A 15-year-old, 50 kg weight patient with CML had a myeloblastic transformation which reverted to Ph negative remission with intensive chemotherapy 5 years after diagnosis. Umbilical cord blood (UCB) from an HLA-haploidentical sister had been frozen 2 years and 9 months before, as she had no HLA-identical sibling and no suitable unrelated donor had been found. UCB transplant was selected on the basis of previous general experience with this kind of transplant, lack of a better choice of donor, and likelihood of a prompt relapse of the disease without delay and the patient developed grade II aGVHD as well as severe CsA toxicity which required discontinuation of the drug, anti-IL2r being given instead. Subsequently she only had histologic evidence of cGVHD and 1.5 years after the transplant she remains in complete hematologic remission with full chimerism and without evidence of the bcr/abl fusion gene. This case illustrates further possibilities of allo-transplantation using UCB.

Risk assessment and outcome of chronic graft-versus-host disease after allogeneic peripheral blood progenitor cell transplantation in pediatric patients.

We retrospectively evaluated the incidence, risk factors for chronic graft-versus-host disease (cGvHD) and outcome in 80 pediatric patients (36 male) (median age 13 years) who underwent allogeneic peripheral blood progenitor cell transplantation. Patients were grafted from an HLA-identical sibling after myeloablative conditioning (total body irradiation (TBI) based 52; non-TBI 28). GvHD prophylaxis used were: cyclosporin A (CsA)+ short methotrexate (MTX) in 52 and CsA+/-prednisone in 28. The median number of CD34+ cells infused were 5.8 x 10(6)/kg (range: 1.4-32.8). The median follow-up was 24 months (range: 3-94). In all, 28 patients had cGvHD (confidence interval (CI): 54.2+/-10%). Factors that were significant on univariate analysis were diagnosis (P=0.03) and GvHD prophylaxis administered (P=0.04). On multivariate analysis, only GvHD prophylaxis used was associated with a significant risk of cGvHD (hazard ratio (HR): 3.94; 95% CI: 1.41-10.91, P=0.009). The CI of cGvHD for patients receiving CsA+MTX was 40.9+/-12 vs 76.5+/-18% for patients who did not (P=0.03). The probability of relapse was 36+/-6% for all patients (12.5+/-8% for patients with cGvHD vs 47.9+/-8% without cGvHD). The probability of disease-free survival was better for patients with cGvHD (69.9+/-10 vs 37.9+/-7%; HR: 3.59, 95% CI: 1.47-5.56; P=0.001). Our data suggest that the GvHD prophylaxis used is the most relevant predictor of cGvHD. Patients with cGvHD had a lower risk of relapse and a better survival.

Mandibular lesion as the first evidence of multiple myeloma. Case report.

Plasma cell dyscrasias affect the jaws relatively infrequently, and on rare occasions this is the first sign of the disease. This article describes the case of a patient aged 53 who presented with a lytic lesion in the right mandible which was initially diagnosed as an ameloblastoma. The diagnosis was made histopathologically and further investigation showed that the patient had multiple myelomatosis.

Type A behavior pattern today: relevance of the JAS-S factor to predict heart rate reactivity.

The authors used 89 undergraduate students' scores in the S-factor of the Jenkins Activity Survey, a measure of speed and impatience, to classify 45 participants as high scorers and 44 as low scorers. They then measured the students' tonic and phasic heart rates during an examination, a genuinely stressful situation. The experiment consisted of three phases: adaptation, task, and recovery. The findings confirmed the authors' hypothesis that the high-S scorers would show higher cardiac reactivity values than the low-S scorers. The authors also observed that the high-S scorers took more time than the low-S scorers to recover their initial heart rate values after being exposed to the stress situation. This finding led the authors to suggest that each group may have different response patterns. They call for further research on individuals with "fast activation-fast recovery" and "fast activation-slow recovery" profiles.

[Changes in lipoprotein(a) after heart transplantation]. / Alteraciones de la lipoproteína (a) tras el trasplante cardíaco.

AIM: The purpose of this study was to analyze the evolutionary changes of lipoprotein (a) levels occurring in heart transplant and to evaluate the possible relationship between the plasma concentration of this lipoprotein and the immunosuppressor drugs normally used in this type of transplant. METHOD: 17 patients undergoing heart transplant and with no history of dyslipemia or dysglucemia were studied. Patients with metabolic alterations after the transplant were excluded (except when these alterations occurred during the first week), as well as those who showed intercurrent processes near to the determinations. These were performed before the transplant, and 1, 2, 4 and 6 months later. RESULTS: An increase of lipoprotein (a) was observed after the transplant, with a subsequent progressive decrease. Significant differences were found between the levels prior to the transplant (9.18 +/- 8.66) and 6 months later (7.53 +/- 8.86), with no differences found between the previous concentrations and the determinations after one month (10.29 +/- 7.58), two months (8.06 +/- 7.90) and four months (8.82 +/- 7.84). Differences were also observed between the values of the first month in relation to the subsequent months, as well as between the 4th and the 6th month. No relationship was noticed between the levels of this lipoprotein and those of cyclosporin (r = 0.10), azatioprine (r = 0.17) and deflazacort (r = 0.19). CONCLUSIONS: The lipoprotein (a) levels increase after heart transplant, with a subsequent gradual decrease even below the previous figures. These levels bear no relationship with the dose of immunosupressors normally used in heart transplant.

[Obstructive and non-obstructive hypertrophic cardiomyopathy: clinical, electrocardiographic, and echocardiographic differences]. / Miocardiopatía hipertrófica obstructiva y no obstructiva: diferencias clínicas, electrocardiográficas y ecocardiográficas.

AIM: The purpose of the study was to analyse echocardiographic, electrocardiographic and clinical variables in patients with hypertrophic cardiomyopathy, as well as to compare the possible differences between the non-obstructive (NOHCM) and the obstructive form (OHCM). METHOD: 44 consecutive patients were studied and diagnosed with hypertrophic cardiomyopathy (NOHCM 26 and OHCM 18). The following variables were analysed: 1) echocardiographic: right ventricle (RV), interventricular septum (IVS), posterior wall (pW), telediastolic and telesystolic diameter of the left ventricle (TDD-LV and TSD-LV), size of the left atrium (LA), systolic anterior motion of the mitral valve (SAM), mitral insufficiency and direction of the jet (MI and MIpW), mitral anular calcium (MAC), filling pattern (A > E); 2) electrocardiographic: repolarization disorders (RD), left ventricular hypertrophy (LVH), negative "T" waves in the precordial leads (T-), pathological "q" waves, super or ventricular arrhythmias (SA or VA), short PR, right or left bundle branch block (RBBB and LBBB), and 3) clinical: presence of dyspnea, angina, syncope, palpitations and response to treatment with beta-blockers (B-b) or Calcium-antagonists (C-A). RESULTS: There were no differences in age or sex between the obstructive and non-obstructive groups: 1) echocardiographic differences: there were none in RV, pW, TDD-LV, LA nor A > E wave. Significant differences were found (p < 0.05) in the rest of the variables; IVS (16 +/- 3 mm in NOHCM vs 22 +/- 5 mm in OHCM), TSD-LV (26 +/- 5 mm in NOHCM vs 22 +/- 6 mm in OHCM), SAM (38% in NOHCM vs 89% in OHCM), MI (19% in NOHCM vs 78% in OHCM), MIpW (20% in NOHCM vs 79% in OHCM), MAC (15% in NOHCM vs 44% in OHCM); 2) electrocardiographic differences: there were none in the presence of RD, pathological "q", VA, short PR, RBBB nor LBBB. The presence of "T" negatives was on the limit of significance in the precordial leads (31% in NOHCM vs 11% in OHCM; p = 0.09). Differences were found in the rest of the variables; LVH (58% in NOHCM vs 83% in OHCM), SA (50% in NOHCM vs 17% in OHCM); 3) clinical differences: there were none in the presence of dyspnea, angina, syncope or palpitations. Differences were found in the improvement with treatment; B-b (60% in NOHCM vs 57% in OHCM), C-A (100% in NOHCM vs 100% in OHCM). CONCLUSIONS: 1) in our patients, the most frequent cardiomyopathy is the non-obstructive one, with no predominance of age or sex; 2) in OHCM, IVS is much wider, with smaller TSD-LV, there is a greater incidence of MI, generally directed towards the posterior wall of the left atrium, and a larger tendency to calcify the mitral annulus; 3) the most frequent electrocardiographic abnormality is the alteration of repolarization. NOHCM has a greater incidence of SA and a lower degree of LVH with more prevalence of negative "T" waves in the precordial leads; 4) there are no clinical parameters differentiating the two groups, although the sustained improvement obtained with treatment is more likely to be produced by the calcium-antagonists than by beta-blockers in both types of cardiomyopathy.

[The usefulness of the isovolumetric relaxation time of both ventricles in detecting acute rejection in the heart transplant patient]. / Utilidad del tiempo de relajación isovolumétrica de ambos ventrículos en la detección de rechazo agudo del paciente trasplantado cardíaco.

AIMS: The purpose of our study was to evaluate the usefulness of the isovolumetric relaxation time in both ventricles when diagnosing acute rejection in transplanted patients. METHOD: 68 endomyocardial biopsies were performed on a total of 38 patients. An echocardiographic study was carried out within the first 24 hours of each biopsy. All registrations were made by the same person. The isovolumetric relaxation time was measured in the left and right ventricles. The patients were divided according to two criteria: according to the degree of rejection (0-I, II, III) and according to whether the rejection was treatable (III) or non-treatable (0, I and II). RESULTS: In both ventricles, there was a progressive decrease of the isovolumetric relaxation time corresponding to higher degrees of rejection: in the left ventricle (0-I = 90 +/- 16; II = 74 +/- 16; III = 70 +/- 26; significant differences of II and III in relation to 0-I) as well as in right ventricle (0-I = 43 +/- 16; II = 37 +/- 14; III = 29 +/- 8; significant difference of III in relation to 0-I). The patients with treatable and non-treatable rejection were compared: no differences were found in the isovolumetric relaxation time of the left ventricle (0, I and II = 85 +/- 16 vs III = 70 +/- 26), but they were found in the right ventricle (0, I and II = 41 +/- 15 vs III = 29 +/- 8). CONCLUSIONS: Acute heart rejection induces a decrease of the isovolumetric relaxation time in both the left ventricle and the right ventricle. However, the isovolumetric relaxation time of the right ventricle seems to be a more useful parameter than isovolumetric relaxation time of the left ventricle, as it permits to detect whether an acute heart rejection is treatable or non-treatable.