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Background Patients receiving intermittent hemodialysis have variable times of recovery to feeling better after dialysis. QT prolongation, a precursor to clinical and subclinical cardiovascular events, may contribute to delayed recovery time. We hypothesized that abnormal electrocardiographic parameters indicating perturbations in ventricular action are associated with longer recovery times thus impacting a patient-centered quality of life. Methods Among 242 incident in-center hemodialysis participants from the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease (PACE) study, corrected QT interval (QTc), QRST angle and heart rate variance were measured on non-dialysis days using a standard 5-min electrocardiograph recording. Left ventricular hypertrophy (LVH) was defined using the Cornell voltage product. Recovery time was ascertained during a phone interview with a standardized validated questionnaire. Associations between QTc, QRST angle, heart rate variance, and LVH and natural log-transformed recovery time were examined using linear regression adjusted for participant characteristics and electrolytes. Results Mean age was 55 (standard deviation 13) years, 55% were male, 72% were African American. Longer QTc interval was associated with increased recovery time (per 10 ms increase in QTc, recovery time increased by 6.2%; 95% confidence interval: 0.0–10.5). QRST angle, heart rate, heart rate variability and LVH were not significantly associated with recovery time. Conclusion Longer QTc intervals are associated with longer recovery time independent of serum electrolytes. This supports a relationship between a patient’s underlying arrhythmic status and time to recovery after hemodialysis. Future studies will determine if maneuvers to reduce QTc improves recovery time and quality of life of patients on hemodialysis.

Tyrosine kinase inhibitors play an important role in the armamentarium against cancer. Lenvatinib is a multiple kinase inhibitor approved by the Food and Drugs Administration (FDA) for the treatment of advanced and radioresistant thyroid carcinomas and, in combination with everolimus, for renal cell carcinoma and unresectable hepatocellular carcinoma. The anti-tumoral activity is largely dependent on inhibition of neo-angiogenesis, and established side effects of anti-angiogenetic therapeutics include renal thrombotic microangiopathy (TMA). Here, we describe three cases of biopsy-proven renal TMA clinically presenting with proteinuria and stable serum creatinine in patients receiving lenvatinib for thyroid cancer. Microangiopathic lesions included glomerular basement membrane reduplication with segmental cellular interposition, mesangiolysis, and focal intracapillary and arteriolar thrombi. Drug-dose reduction or withdrawal was effective in renal function preservation, but cancer progressed in all patients. The management of lenvatinib-induced renal TMA remains a challenge. The best therapy in these patients is still uncertain. Earlier and more precise measurement of urine protein levels, allowing for early dose adjustment, could be effective in preventing further damage and drug discontinuation.

Aim:To determine the carrier frequency of ABCA4 mutations in order to achieve an insight into the prevalence of autosomal recessive Stargardt disease (arSTGD) in the Spanish population.Methods:arSTGD patients (n = 133) were analysed using ABCR400 microarray and sequencing. Control subjects were analysed by two different strategies: 200 individuals were screened for the p.Arg1129Leu mutation by denaturing-HPLC and sequencing; 78 individuals were tested for variants with the microarray and sequencing.Results:For the first strategy in control subjects, the p.Arg1129Leu variant was found in two heterozygous individuals, which would mean a carrier frequency for any variant of ∼6.0% and a calculated arSTGD prevalence of 1:1000. For the second strategy, carrier frequency was 6.4% and therefore an estimated prevalence of the disease of 1:870.Conclusion:Calculated prevalence of arSTGD based on the ABCA4 carrier frequency could be considerably higher than previous estimation. This discrepancy between observed (genotypic) and estimated (phenotypic) prevalence could be due to the existence of non-pathological or low penetrance alleles, which may result in late-onset arSTGD or may be implicated in age-related macular degeneration. This situation should be regarded with especial care when genetic counselling is given and further follow-up of these patients should be recommended.

Purpose We focused on the improvements of prenatal diagnosis by the analysis of DNA from maternal plasma, using Huntington disease as a model of disease. Methods We studied plasma from a pregnancy at risk of having a fetus affected with Huntington disease by the use of two direct analysis of the mutation and polymorphic STRs. Results Direct methods were not informative. Analysis with STRs revealed the presence of the allele that does not co-segregate with the disease, thus the fetus was healthy. Conclusions This strategy is very useful to face complex cases when the direct study is not informative not only for Huntington disease but also for many other disorders.

The myelodysplastic syndromes are characterized by ineffective hematopoiesis and refractory cytopenias. In an attempt to improve hematopoiesis, we administered recombinant human granulocyte–macrophage colony-stimulating factor (GM-CSF) to eight patients with myelodysplastic syndrome, as part of a Phase I trial. The GM-CSF was given by continuous intravenous infusion daily for two weeks and then again after a two-week rest period. Over the entire dose range tested (30 to 500 μg per square meter of body-surface area), treatment was associated with marked increases in peripheral-blood leukocytes (5- to 70-fold), including granulocytes (5- to 373-fold), in all eight patients. The absolute number of monocytes, eosinophils, and lymphocytes increased in all patients. Three of eight patients also had 2- to 10-fold increases in platelet counts and improvement in erythropoiesis, with the result that two of three patients who had required red-cell and platelet transfusions no longer needed them (at 20 to 27 weeks of follow-up). Treatment was also associated with increased marrow cellularity and a decreased percentage of blasts in the bone marrow of patients with excess blasts, resulting in an increase in the ratio of differentiated myeloid cells to immature myeloid cells. We observed relatively few side effects, but bone pain was dose-limiting when it was associated with high white-cell counts. Our results showed that GM-CSF is a potent stimulator of hematopoiesis in vivo and may produce hematologic improvement in the short term (8 to 32 weeks of observation) in patients with myelodysplastic syndrome. More experience, with longer follow-up periods, will be necessary to assess the long-term safety and efficacy of this new treatment. (N Engl J Med 1987; 317:1545–52.) THE myelodysplastic syndromes are a group of stem-cell disorders characterized by maturation defects resulting in ineffective hematopoiesis, refractory cytopenias often leading to infection or hemorrhage, and an increased risk of leukemic transformation. 1 2 3 4 5 6 7 No currently available treatment has been shown to be consistently effective in producing sustained improvement in hematopoiesis or in delaying leukemic evolution. 8 9 10 11 Several agents, including retinoids, vitamin D analogues, and cytotoxic drugs such as low-dose cytarabine have been used to treat patients with myelodysplastic syndrome 9 10 11 12 13 14 15 16 17 18 ; this therapy has been based mainly on the agents' potential for inducing differentiation of established leukemic cell lines in vitro. 19 20 21 22 23 The results . . .

By means of the polymerase chain reaction (PCR) technique, DNA sequences were amplified that flank the crossover sites of a characteristic chromosomal translocation for follicular lymphomas, t(14;18)(q32;q21). This technique permitted the detection of cells carrying the t(14;18) hybrid DNA sequences at a dilution of 1:100,000. The remission marrow and blood samples of a patient with follicular lymphoma and the t(14;18) failed to show any abnormality by morphological examination and conventional Southern blot analysis. However, the t(14;18) hybrid DNA sequences were detected by the PCR technique. Thus, this technique is a highly sensitive tool to detect minimal residual cells carrying the t(14;18) and has the potential to identify a subpopulation of patients with subclinical disease.

We treated 17 patients who had Philadelphia-Chromosome-Positive chronic myelogenous leukemia (4 of whom had not received therapy and 13 of whom had been treated with hydroxyurea or busulfan for less than six months) with recombinant human interferon alpha-A (Roferon-A). The interferon was given as 5x10 6 units per square meter of body-surface area per day intramuscularly during induction therapy. Fourteen patients responded to the treatment, of whom 13 had a hematologic remission and 1 had a partial hematologic remission. The median number of white cells in those patients declined from 60.9x10 3 to 3.4x10 3 per microliter, and the median number of platelets decreased from 476 x10 3 to 231 x10 3 per microliter. Among the five responding patients who had splenomegaly before treatment, the spleen size returned to normal in four and decreased by 75 percent in one, although it remained enlarged. Bone marrow cellularity declined from a median of 92.5 percent to a median of 57.5 percent. In six of the patients with hematologic remission, complete suppression of Philadelphia cells was observed on at least one examination. Of the 14 patients who responded, 11 have received the interferon therapy for 9 to 15 months. One patient relapsed during the treatment, and the treatment has been temporarily interrupted in two patients because of toxicity. These data are preliminary and will need further confirmation, but they suggest that recombinant human interferon alpha A is effective in inducing hematologic remission in most patients with benign-phase chronic myelogenous leukemia and in suppressing the Philadelphia chromosome in some of these patients. (N Engl J Med 1986; 314:1065–9.) CHRONIC myelogenous leukemia in patients with the Philadelphia (Ph) chromosome has a typical progressive clinical course that starts with a benign phase and ends in a blastic phase. The benign phase of the disease is easily controlled by single-agent chemotherapy with such agents as busulfan and hydroxyurea. However, these agents do not alter the progressive course of the disease. 1 The introduction of aggressive combination chemotherapy has resulted in reproducible suppression of Ph cells in the bone marrow of patients with chronic myelogenous leukemia, but the effect was invariably transient. 2 3 4 Only the use of supralethal chemotherapy and allogeneic bone marrow transplantation . . .

Election studies have identified several mechanisms through which changing patterns of electoral behavior among different types of elections in multilevel government systems can be observed. One of those mechanisms is differential abstention, which quantifies deviations in turnout rates. This article analyses it from a contextual perspective. It aims to identify how structural and socioeconomic characteristics of localities may influence the electoral choice of its inhabitants. We propose an ecological and spatial analysis of the 2012 regional election and the 2011 national one in Andalusia. Our results show that both structural and socioeconomic characteristics of localities help to understand the complexity of this electoral behaviour: urbanization increases differential abstention.

Aplastic anemia is a syndrome in which pancytopenia occurs in the presence of hypocellularity of the bone marrow. To assess the biologic activities of recombinant human granulocytemacrophage colony-stimulating factor (GM-CSF) in aplastic anemia, we gave GM-CSF (60 to 500 μg per square meter of body-surface area) to 10 patients with moderate or severe disease, by continuous intravenous infusion daily for two weeks, and repeated the treatment after a two-week rest period. The treatment increased the white-cell count (1.6- to 10-fold) in all patients, primarily because of an increase in the numbers of neutrophils (1.5- to 20-fold), eosinophils (12- to >70-fold), and monocytes (2- to 32-fold). Rates of hydrogen peroxide production in purified granulocyte fractions increased during GM-CSF treatment. Increases in bone marrow cellularity, myeloid precursor cells, and myeloid:erythroid cell ratios accompanied the white-cell response. Despite the in vivo response of the white cells, the concentration of colony-forming cells remained the same. Measurable concentrations of interleukin-2 (2 to 15 units per milliliter) were found in the serum of 8 patients, and high levels of erythropoietin (81 to 1200 IU per liter) were found in 10 patients. The predominant side effects were constitutional symptoms. These results indicate that recombinant human GM-CSF is effective in stimulating myelopoiesis in patients with severe aplastic anemia and may benefit some patients in whom the disorder is refractory to standard forms of therapy. (N Engl J Med 1988; 319:1628–34.) APLASTIC anemia is a hematopoietic disorder characterized by bone marrow failure and pancytopenia. Several mechanisms have been implicated in the pathogenesis of this disease, including the loss of pluripotent stem cells, dysfunction of progenitor cells, defects in the microenvironment of the bone marrow, abnormalities of humoral regulators of hematopoiesis, and autoimmune inhibition of hematopoiesis. 1 2 3 4 5 Transplantation of bone marrow from a histocompatible donor is currently the treatment of choice for patients under the age of 40. 6 7 8 This choice is not available, however, to a majority of patients with severe aplastic anemia, because they either are older or lack a histocompatible donor. . . .

Background: In end-stage kidney disease the dialytic cycle relates to the rate of sudden cardiac death. We hypothesized that circadian, dialytic cycles, paroxysmal arrhythmias, and cardiovascular risk factors are associated with periodic changes in heart rate and heart rate variability (HRV) in incident dialysis patients. Methods: We conducted a prospective ancillary study of the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease (PACE) cohort (n=28; age 54±13 y; 57% men; 96% black; 33% with a history of structural heart disease; left ventricular ejection fraction 70±9%). Continuous ECG monitoring was performed using an ECG patch (Zio Patch, iRhythm) and short-term HRV was measured for three minutes every hour. HRV was measured by root mean square of the successive normal-to-normal intervals (rMSSD), high and low frequency power, Poincare plot, and sample and Renyi entropy. Results: Arrhythmias were detected in 46% (n=13). Non-sustained ventricular tachycardia (VT) was more frequent during dialysis or within 6 hours post-dialysis, as compared to pre- or between-dialysis (63% vs. 37%, P=0.015), whereas supraventricular tachycardia was more frequent pre-/ between-dialysis, as compared to during- / post-dialysis (84% vs. 16%, P=0.015). In adjusted for cardiovascular disease and its risk factors autoregressive conditional heteroscedasticity panel (ARCH) model, VT events were associated with increased heart rate by 11.2 (95%CI 10.1-12.3) bpm (P<0.0001). During regular dialytic cycle, rMSSD demonstrated significant circadian pattern (Mesor 10.6(0.9-11.2) ms; Amplitude 1.5(1.0-3.1) ms; Peak at 02:01(20:22-03:16) am; P<0.0001), which was abolished on a second day interdialytic extension (adjusted ARCH trend for rMSSD -1.41(-1.67 to -1.15) ms per 24h; P<0.0001). Conclusion: Cardiac arrhythmias associate with dialytic phase. Regular dialytic schedule preserves physiological circadian rhythm, but the second day without dialysis is characterized by parasympathetic withdrawal and a steady increase in sympathetic predominance. Footnotes * https://github.com/Tereshchenkolab/HRV