Administration of recombinant human erythropoietin alpha before autologous stem cell transplantation reduces transfusion requirement in multiple myeloma patients

Recombinant human erythropoietin administered after peripheral blood stem cell transplantation (PBSCT) has been ineffective for the treatment of anemia. We administered recombinant human erythropoietin alpha (rHuEPO) prior to high-dose therapy after peripheral blood stem cell (PBSC) collection to evaluate its efficacy on transfusion requirements and hematological parameters during the post-transplant aplastic phase. Twenty-two multiple myeloma patients (EPO-MM) were included in the trial to receive rHuEPO 10,000 IU subcutaneous daily starting 30 days before PBSCT. Forty hemoglobin (Hb)-matched patients who had not received rHuEPO before transplant were retrospectively selected (Ctr-MM) for comparative data. None of the patients received transfusions at study entry. All but one patient responded to rHuEPO. However, no significant differences in Hb levels were obtained between the two groups at the time of transplantation. At nadir, the EPO-MM cases had a significantly higher Hb level (median 10 g/dl versus 7.6 g/d; p=0.001). Consequently, less than 20% of EPO-MM patients required packed red blood cell (PRBC) transfusions compared to more than half the Ctr-MM patients (p=0.007). Furthermore, the number of PRBC transfusions performed in the EPO-MM group was significantly lower (median 0 versus 1; p=0.008). Independently of Hb levels at PBSCT, rHuEPO therapy was significantly associated with a lower risk of transfusion requirement. In conclusion, rHuEPO is shown to be effective when administered prior to high-dose therapy in MM.     

Continuous monitoring of cerebral oxygen saturation in elderly patients undergoing major abdominal surgery minimizes brain exposure to potential hypoxia

Elderly patients are more prone than younger patients to develop cerebral desaturation because of the reduced physiologic reserve that accompanies aging. To evaluate whether monitoring cerebral oxygen saturation (rSO(2)) minimizes intraoperative cerebral desaturation, we prospectively monitored rSO(2) in 122 elderly patients undergoing major abdominal surgery with general anesthesia. Patients were randomly allocated to an intervention group (the monitor was visible and rSO(2) was maintained at > or =75% of preinduction values; n = 56) or a control group (the monitor was blinded and anesthesia was managed routinely; n = 66). Cerebral desaturation (rSO(2) reduction <75% of baseline) was observed in 11 patients of the treatment group (20%) and 15 patients of the control group (23%) (P = 0.82). Mean (95% confidence intervals) values of mean rSO(2) were higher (66% [64%-68%]) and the area under the curve below 75% of baseline (AUCrSO2(2)< 75% of baseline) was lower (0.4 min% [0.1-0.8 min%]) in patients of the treatment group than in patients of the control group (61% [59%-63%] and 80 min% [2-144 min%], respectively; P = 0.002 and P = 0.017). When considering only patients developing intraoperative cerebral desaturation, a lower Mini Mental State Elimination (MMSE) score was observed at the seventh postoperative day in the control group (26 [25-30]) than in the treatment group (28 [26-30]) (P = 0.02), with a significant correlation between the AUCrSO(2) < 75% of baseline and postoperative decrease in MMSE score from preoperative values (r(2)= 0.25, P = 0.01). Patients of the control group with intraoperative cerebral desaturation also experienced a longer time to postanesthesia care unit (PACU) discharge (47 min [13-56 min]) and longer hospital stay (24 days [7-53] days) compared with patients of the treatment group (25 min [15-35 min] and 10 days [7-23 days], respectively; P = 0.01 and P = 0.007). Using rSO(2) monitoring to manage anesthesia in elderly patients undergoing major abdominal surgery reduces the potential exposure of the brain to hypoxia; this might be associated with decreased effects on cognitive function and shorter PACU and hospital stay.     

beta-Catenin regulates vascular endothelial growth factor expression in colon cancer

To evaluate whether beta-catenin signaling has a role in the regulation of angiogenesis in colon cancer, a series of angiogenesis-related gene promoters was analyzed for beta-catenin/TCF binding sites. Strikingly, the gene promoter of human vascular endothelial growth factor (VEGF, or VEGF-A) contains seven consensus binding sites for beta-catenin/TCF. Analysis of laser capture microdissected human colon cancer tissue indicated a direct correlation between up-regulation of VEGF-A expression and adenomatous polyposis coli (APC) mutational status (activation of beta-catenin signaling) in primary tumors. In metastases, this correlation was not observed. Analysis by immunohistochemistry of intestinal polyps in mice heterozygous for the multiple intestinal neoplasia gene (Min/+) at 5 months revealed an increase and redistribution of VEGF-A in proximity to those cells expressing nuclear beta-catenin with a corresponding increase in vessel density. Transfection of normal colon epithelial cells with activated beta-catenin up-regulated levels of VEGF-A mRNA and protein by 250-300%. When colon cancer cells with elevated beta-catenin levels were treated with beta-catenin antisense oligodeoxynucleotides, VEGF-A expression was reduced by more than 50%. Taken together, our observations indicate a close link between beta-catenin signaling and the regulation of VEGF-A expression in colon cancer.     

Epidemiology of type 2 diabetes in Mexico

The epidemiology of diabetes in Mexico is reviewed. In less than four decades, diabetes has become the main health problem in Mexico. It is the principal cause of death in women and the second among men since the year 2000. It is the primary cause of premature retirement, blindness, and kidney failure. By the year 2025, close to 11.7 million Mexicans are expected to be diagnosed with diabetes. In the year 2000, diabetes was the 11th most frequent cause of hospitalization but the second most common cause of hospital mortality. The number of cases reported in children has also increased since 1995. The results of population-based, nationwide surveys have detected a 25% increment over a 7-year period. Fourteen percent of people with diabetes are <40 years of age, and a large proportion of patients have other conditions that determine the appearance of macrovascular complications and kidney failure. In addition, many cases do not reach treatment goals. In conclusion, the growing number of cases and the significant health burden imposed on affected subjects makes diabetes a disease that needs to be prevented. Well-planned strategies are urgently needed to modify the lifestyle of the population and to increase their physical activity. In addition, an enormous effort will be required to educate the population and physicians to improve the diagnosis and treatment of patients with diabetes.     

Persistent B-cell lymphopenia, multiorgan disease, and erythema multiforme caused by Mycoplasma pneumoniae infection

We report a 6-year-old girl in whom Mycoplasma pneumoniae infection presenting with erythema multiforme, multiorgan, and hematologic dysfunctions induced a long-standing, marked B-cell lymphopenia. An increase of CD8+ lymphocytes was also detected. We suggest that a selective cytotoxic T lymphocyte-dependent B cell lysis and the expansion of super-antigen activated CD8+ T cells may account for the multiorgan and hematologic disturbances triggered by M. pneumoniae.     

Evaluation of serum biomarkers in nutritional disorders: glycated apolipoprotein B, fasting serum glucose, fructosamine, stable and labile glycated hemoglobin in diabetic and non-diabetic subjects

Glycated apolipoprotein B (ApoB-G), a non enzymatically glycated protein, has recently been associated with myocardial infarction. Our aim is to evaluate, in diabetic and non diabetic subjects, the relationship of ApoB-G with serum fasting glucose, fructosamine, stable and labile fractions of glycated hemoglobin ((S)HbA(1c), (L)HbA(1c), respectively) and insulin. The subjects were recruited from a previous study on ApoB-G and myocardial infarction: 141 of them were studied, 43 with and 98 without diabetes. ApoB-G was measured using a monoclonal antibody, and linear regression and correlation were used for statistical analysis of the data. ApoB-G was higher in diabetic than in non diabetic subjects. There was a statistically significant correlation of ApoB-G with triglycerides (r = 0.38, p = 0.01) in diabetic subjects, and with total proteins (r = 0.37, p = 0.0002), triglycerides (r = 0.34, p = 0.0007), and cholesterol (r = 0.23, p = 0.02) in non diabetic subjects. In the most parsimonious multiple linear regression model of ApoB-G on all the other serum variables, there was a statistically significant association of ApoB-G with triglycerides, in both diabetic and non diabetic subjects. The main results of this study suggest that serum ApoB-G is associated with serum triglycerides in both diabetic and non diabetic subjects.     

Introducing a novel human mtDNA mutation into the Paracoccus denitrificans COX I gene explains functional deficits in a patient

We identified a novel mutation (S142F) in the human mtDNA CO I gene in a patient with a clinical phenotype resembling mitochondrial cardioencephalomyopathy. To substantiate pathogenicity, we modeled the identified mutation in the homologous gene in Paracoccus denitrificans and analyzed the biochemical consequences. We observed a deleterious effect on enzyme activity, with a lack of heme a ₃ . Taking advantage of the extensive structural homology between the bacterial enzyme and the mammalian core complex, we conclude that the novel S142F mutation is disease-related. This approach can be used in other cases to support the pathogenicity of novel variants in the mitochondrial genome.     

Subcomplexes of human ATP synthase mark mitochondrial biosynthesis disorders

OBJECTIVE: Methods: We describe biochemically and clinically relevant aspects of mitochondrial ATP synthase, the enzyme that supplies most ATP for the cells energy demand. RESULTS: Analyzing human Rho zero cells we could identify three subcomplexes of ATP synthase: F1 catalytic domain, F1 domain with bound natural IF1 inhibitor protein, and F1-c subcomplex, an assembly of F1 domain and a ring of F(O)-subunits c. Large amounts of F1 subcomplexes accumulated also in mitochondria of patients with specific mitochondrial disorders. By quantifying the F1 subcomplexes and other oxidative phosphorylation complexes in parallel, we were able to discriminate three classes of defects in mitochondrial biosynthesis, namely, mitochondrial DNA depletion, mitochondrial transfer RNA (tRNA) mutations, and mutations in the mitochondrial ATP6 gene. INTERPRETATION: The relatively simple electrophoretic assay used here is a straightforward approach to differentiate between various types of genetic alterations affecting the biosynthesis of oxidative phosphorylation complexes and will be useful to guide molecular genetic diagnostics in the field of mitochondrial neuromuscular disorders.