The secondary alcohol and aglycone metabolites of doxorubicin alter metabolism of human erythrocytes

Anthracyclines, a class of antitumor drugs widely used for the treatment of solid and hematological malignancies, cause a cumulative dose-dependent cardiac toxicity whose biochemical basis is unclear. Recent studies of the role of the metabolites of anthracyclines, i.e., the alcohol metabolite doxorubicinol and aglycone metabolites, have suggested new hypotheses about the mechanisms of anthracycline cardiotoxicity. In the present study, human red blood cells were used as a cell model. Exposure (1 h at 37ºC) of intact human red blood cells to doxorubicinol (40 µM) and to aglycone derivatives of doxorubicin (40 µM) induced, compared with untreated red cells: i) a ~2-fold stimulation of the pentose phosphate pathway (PPP) and ii) a marked inhibition of the red cell antioxidant enzymes, glutathione peroxidase (~20%) and superoxide dismutase (~60%). In contrast to doxorubicin-derived metabolites, doxorubicin itself induced a slighter PPP stimulation (~35%) and this metabolic event was not associated with any alteration in glutathione reductase, glutathione peroxidase, catalase or superoxide dismutase activity. Furthermore, the interaction of hemoglobin with doxorubicin and its metabolites induced a significant increase (~22%) in oxygen affinity compared with hemoglobin incubated without drugs. On the basis of the results obtained in the present study, a new hypothesis, involving doxorubicinol and aglycone metabolites, has been proposed to clarify the mechanisms responsible for the doxorubicin-induced red blood cell toxicity.

The role of secondary hyperparathyroidism in left ventricular hypertrophy of patients under chronic hemodialysis

End-stage renal disease (ESRD) patients frequently develop structural cardiac abnormalities, particularly left ventricular hypertrophy (LVH). The mechanisms involved in these processes are not completely understood. In the present study, we evaluated a possible association between parathyroid hormone (PTH) levels and left ventricular mass (LVM) in patients with ESRD. Stable uremic patients on intermittent hemodialysis treatment were evaluated by standard two-dimensional echocardiography and their sera were analyzed for intact PTH. Forty-one patients (mean age 45 years, range 18 to 61 years), 61% males, who had been on hemodialysis for 3 to 186 months, were evaluated. Patients were stratified into 3 groups according to serum PTH: low levels (<100 pg/ml; group I = 10 patients), intermediate levels (100 to 280 pg/ml; group II = 10 patients) and high levels (>280 pg/ml; group III = 21 patients). A positive statistically significant association between LVM index and PTH was identified (r = 0.34; P = 0.03, Pearson's correlation coefficient) in the sample as a whole. In subgroup analyses, we did not observe significant associations in the low and intermediate PTH groups; nevertheless, PTH and LVM index were correlated in patients with high PTH levels (r = 0.62; P = 0.003). LVM index was also inversely associated with hemoglobin (r = -0.34; P = 0.03). In multivariate analysis, after adjustment for age, hemoglobin, body mass index, and blood pressure, the only independent predictor of LVM index was PTH level. Therefore, PTH is an independent predictor of LVH in patients undergoing chronic hemodialysis. Secondary hyperparathyroidism may contribute to the elevated cardiovascular morbidity associated with LVH in ESRD.

Primary and secondary esophageal contractions in patients with gastroesophageal reflux disease

We studied the primary and secondary esophageal peristalsis in 36 patients with heartburn and acid regurgitation and in 14 asymptomatic volunteers. Primary peristalsis was elicited by ten swallows of a 5-mL bolus of water and secondary peristalsis was elicited by intra-esophageal infusion of 5, 10, and 15 mL water, 0.1 N hydrochloric acid and air. Esophageal contractions were measured by an 8-lumen manometric catheter assembly incorporating a 6-cm sleeve device. Contractions were registered at 3, 9, and 15 cm from the upper margin of the sleeve and the infusion was done through a side hole located at 12 cm. Twenty patients had normal endoscopic esophageal examination, 10 with normal (group I) and 10 with abnormal pH-metric examination (group II), and 16 had esophagitis (group III). The amplitude of contractions after swallows was lower (97.8 ± 10.0 mmHg) in the distal esophagus of group III patients than in controls (142.3 ± 14.0 mmHg). Patients of group III had fewer secondary contractions (water: 25% of infusion) than patients of the other groups and controls (67% of infusion). Patients of group III also had a lower amplitude of secondary peristalsis in the distal esophagus (water: 70.1 ± 9.6 mmHg) than controls (129.2 ± 18.2 mmHg). We conclude that patients with esophagitis have an impairment of primary and secondary peristalsis in the distal esophagus.

Secondary prevention of type 1 diabetes mellitus: stopping immune destruction and promoting ß-cell regeneration

Type 1 diabetes mellitus results from a cell-mediated autoimmune attack against pancreatic ß-cells. Traditional treatments involve numerous daily insulin dosages/injections and rigorous glucose control. Many efforts toward the identification of ß-cell precursors have been made not only with the aim of understanding the physiology of islet regeneration, but also as an alternative way to produce ß-cells to be used in protocols of islet transplantation. In this review, we summarize the most recent studies related to precursor cells implicated in the regeneration process. These include embryonic stem cells, pancreas-derived multipotent precursors, pancreatic ductal cells, hematopoietic stem cells, mesenchymal stem cells, hepatic oval cells, and mature ß-cells. There is controversial evidence of the potential of these cell sources to regenerate ß-cell mass in diabetic patients. However, clinical trials using embryonic stem cells, umbilical cord blood or adult bone marrow stem cells are under way. The results of various immunosuppressive regimens aiming at blocking autoimmunity against pancreatic ß-cells and promoting ß-cell preservation are also analyzed. Most of these regimens provide transient and partial effect on insulin requirements, but new regimens are beginning to be tested. Our own clinical trial combines a high dose immunosuppression with mobilized peripheral blood hematopoietic stem cell transplantation in early-onset type 1 diabetes mellitus.

Pamidronate for the treatment of osteoporosis secondary to chronic cholestatic liver disease in Wistar rats

Osteoporosis is a major complication of chronic cholestatic liver disease (CCLD). We evaluated the efficacy of using disodium pamidronate (1.0 mg/kg body weight) for the prevention (Pr) or treatment (Tr) of cholestasis-induced osteoporosis in male Wistar rats: sham-operated (Sham = 12); bile duct-ligated (Bi = 15); bile duct-ligated animals previously treated with pamidronate before and 1 month after surgery (Pr = 9); bile duct-ligated animals treated with pamidronate 1 month after surgery (Tr = 9). Rats were sacrificed 8 weeks after surgery. Immunohistochemical expression of IGF-I and GH receptor was determined in the proximal growth plate cartilage of the left tibia. Histomorphometric analysis was performed in the right tibia and the right femur was used for biomechanical analysis. Bone material volume over tissue volume (BV/TV) was significantly affected by CCLD (Sham = 18.1 ± 3.2 vs Bi = 10.6 ± 2.2%) and pamidronate successfully increased bone volume. However, pamidronate administered in a preventive regimen presented no additional benefit on bone volume compared to secondary treatment (BV/TV: Pr = 39.4 ± 12.0; Tr = 41.2 ± 12.7%). Moreover, the force on the momentum of fracture was significantly reduced in Pr rats (Sham = 116.6 ± 23.0; Bi = 94.6 ± 33.8; Pr = 82.9 ± 22.8; Tr = 92.5 ± 29.5 N; P < 0.05, Sham vs Pr). Thus, CCLD had a significant impact on bone histomorphometric parameters and pamidronate was highly effective in increasing bone mass in CCLD; however, preventive therapy with pamidronate has no advantage regarding bone fragility.

Influence of secondary packing on the freezing time of chiken meat in air blast freezing tunnels

Freezing of poultry cuts in continuous convective air blast tunnels is normally performed with the products protected by Low Density Polyethylene (LDPE) as a primary packaging and using Corrugated Cardboard Boxes (CCB) as secondary packaging. The objective of this work was to investigate the influence of these secondary packaging on the freezing of poultry cuts in continuous convective air blast tunnels. The study was performed by replacing CCB with Perforated Metal Boxes (PMB) in order to remove the packaging thermal resistance. The assays, performed in a industrial plant, demonstrated that CCB used commercially for meat freezing have a high heat transfer resistance. Their replacement with PMB can lead to shorter freezing times and spatially homogeneous freezing. Reductions of up to 45% in the freezing times were observed using PMB. The plateau of the temperature curve, related to the freezing time of free water, was significantly reduced using PMB, which is accepted to lead to better product quality after thawing. As the products were protected by the LDPE films as primary packaging, their appearance were not affected. The results presented in this work indicate that replacing CBB with PMB can be an excellent alternative to reduce freezing time and improve freezing homogeneity in industrial air blast tunnels, which could also be applied to other products.

Utilising student profiles in mathematics course arrangements

This thesis develops a method for identifying students struggling in their mathematical studies at an early stage. It helps in directing support to students needing and benefiting from it the most. Thus, frustration felt by weaker students may decrease and therefore, hopefully, also drop outs of potential engineering students. The research concentrates on a combination of personality and intelligence aspects. Personality aspects gave information on conation and motivation for learning. This part was studied from the perspective of motivation and self-regulation. Intelligence aspects gave information on declarative and procedural knowledge: what had been taught and what was actually mastered. Students answered surveys on motivation and self-regulation in 2010 and 2011. Based on their answers, background information, results in the proficiency test, and grades in the first mathematics course, profiles describing the students were formed. In the following years, the profiles were updated with new information obtained each year. The profiles used to identify struggling students combine personality (motivation, selfregulation, and self-efficacy) and intelligence (declarative and procedural knowledge) aspects at the beginning of their studies. Identifying students in need of extra support is a good start, but methods for providing support must be found. This thesis also studies how this support could be taken into account in course arrangements. The methods used include, for example, languaging and scaffolding, and continuous feedback. The analysis revealed that allocating resources based on the predicted progress does not increase costs or lower the results of better students. Instead, it will help weaker students obtain passing grades.