Age-related defects in B lymphopoiesis underlie the myeloid dominance of adult leukemia

Reduced lymphopoiesis during aging contributes to declines in immunity, but little consideration has been given to its effect on the development of hematologic disease. This report demonstrates that age-related defects in lymphopoiesis underlie the myeloid dominance of adult leukemia. Using a murine model of chronic myeloid leukemia, an adult-onset malignancy that arises from transformation of hematopoietic stem cells by the BCR-ABL(P210) oncogene, we demonstrate that young bone marrow (BM) cells that were transformed with BCR-ABL(P210) initiated both a myeloproliferative disorder (MPD) and B-lymphoid leukemia, whereas BCR-ABL(P210)-transformed old BM cells recapitulated the human disease by inducing an MPD with rare lymphoid involvement. In addition, the lesser severity of MPDs initiated from old BCR-ABL(P210)-transduced BM cells revealed unappreciated defects in aged myeloid progenitors. These data demonstrate that aging affects patterns of leukemogenesis and indicate that the effects of senescence on hematopoiesis are more extensive than previously appreciated.     

Prevalence and characteristics of methicillin-resistant Staphylococcus aureus in pigs and pig workers in Tenerife, Spain

Methicillin-resistant Staphylococcus aureus (MRSA) strains belonging to sequence type (ST) 398 are being reported with increasing frequency in Europe and other countries. This MRSA type has been isolated from colonized and infected animals and humans. The aim of this study was to determine the prevalence of nasal MRSA carriage in pigs and pig workers. A total of 300 pigs from 15 different farms were sampled in the slaughterhouse of Tenerife. A total of 54 pig workers were screened for MRSA: 20 belonged to farms whose pigs had been sampled and 34 to the slaughterhouse. The percentage of positive samples of MRSA in pigs was 85.7%. The overall prevalence of nasal MRSA carriage in pig workers was 9.3%. All MRSA isolates from pigs and humans belonged to one clonal group showing multilocus sequence type (MLST) 398. Two types of Staphylococcal Chromosome Cassette (SCCmec) were found, IV and V. In conclusion, the prevalence of MRSA in nasal samples from pigs and pig workers in Tenerife was high. We therefore consider it essential to deepen epidemiological study of this strain of animal origin, as well as to increase surveillance and control measures at all stages of the food chain.     

Deficient proliferation and expansion in vitro of two bone marrow cell populations from patients with acute myeloid leukemia in response to hematopoietic cytokines

One has previously characterized two different hematopoietic cell populations (obtained by negative-selection) from normal bone marrow. Population I was enriched for CD34+ Lin- cells, whereas Population II was enriched for CD34+ CD38- Lin- cells. Both populations showed elevated proliferation and expansion potentials in serum-free liquid cultures, supplemented with a combination of eight different cytokines, with the latter displaying more immature features than the former. One has also characterized the chronic myeloid leukemia (CML) counterparts of these two populations and demonstrated functional deficiencies in terms of their growth in culture. In keeping with this line of research, the goal of the present study was to obtain the same two populations (Populations I and II) from acute myeloid leukemia (AML) bone marrow and to characterize their biological behavior under the same culture conditions. The results demonstrated that AML-derived Populations I and II were unable to proliferate in culture conditions that allowed significant proliferation of Populations I and II from normal marrow. Population I from AML also showed a deficient expansion capacity; in contrast, Population II cells were able to expand to a similar extent to the one observed for Population II from normal marrow. Both normal and AML populations were highly sensitive to the inhibitory effects of TNF-alpha; interestingly, whereas in normal fractions TNF-alpha showed a more pronounced inhibitory effect on more mature cells (Population I), this cytokine inhibited proliferation and expansion of AML Populations I and II in a similar degree. It is noteworthy that the functional deficiencies observed in AML cells were even more pronounced than those previously reported for cultures of CML cells. The results reported here may be of relevance considering the interest by several groups in developing methods for the in vitro purging of leukemic cells, as part of protocols for autologous transplantation of hematopoietic cells in leukemic patients.     

Thirty-five cases of S-carboxymethylcysteine use in paraquat poisoning

The herbicide paraquat is associated with a high mortality rate. It produces multiorgan damage through the induction of acute oxidative stress, by generation of reactive oxygen species that cause oxidative damage to biomolecules. In addition to general supportive measures, the management of paraquat poisoning includes gastric washing, forced diuresis, haemodialysis and the use of antioxidants, such as N-acetylcysteine. However, this drug is rather unavailable in Venezuela and S-carboxymethylcysteine has been used. We report 35 patients with mild to severe paraquat poisoning, which beside standard supportive treatment received 1500 mg S-carboxymethylcysteine, up to 2-3 w. The mortality rate was 22.86% (8 deaths/35 cases) and was related to the severity of paraquat poisoning (as assessed by urine dithionite tests). We conclude that S-carboxymethylcysteine is a reliable alternative in managing patients with paraquat poisoning.     

Induction chemotherapy with cisplatin and gemcitabine followed by concurrent chemoradiation with twice-weekly gemcitabine in unresectable stage III non-small cell lung cancer: final results of a phase II study

Concurrent chemoradiotherapy (CCR) followed or preceded by full-dose chemotherapy seems to be a standard treatment for unresectable non-small cell lung cancer (NSCLC). Gemcitabine is a strong radiosensitizer, and a phase I study confirmed the feasibility of CCR with low-dose gemcitabine administered twice-weekly in NSCLC patients. Consequently, we designed a prospective, multicentric, phase II trial to evaluate the efficacy and toxicity of this approach, following induction chemotherapy with cisplatin and gemcitabine. We included patients with unresectable stage III NSCLC, no pleural effusion, adequate pulmonary, renal, liver and hematological functions, Karnofsky index >70 and planned treated volume (PTV) <2200cm3. Treatment consisted of 3 cycles of cisplatin (100mg/m2, d1) and gemcitabine (1250mg/m2, d1 and 8) q3w, followed by CCR (gemcitabine 50mg/m2 on Mondays and Thursdays and radiotherapy 68.4Gy, 1.8Gyqd). After the inclusion of 22 patients (group A), an unacceptable toxicity was detected. Thus, cisplatin dose was reduced to 70mg/m2, and gemcitabine dose was adjusted to 35mg/m2 during CCR. Another 34 patients (33 eligible, group B) were included. Five patients in group A and 6 patients in group B discontinued the study treatment during induction. Thus, 17 and 27 patients, respectively initiated CCR. Hematological toxicity (grades III and IV) was particularly relevant in group A during this phase, with 35 and 23% of thrombopenia and neutropenia, respectively. Nonhematological grades III-IV toxicity of chemoradiation was significant and similar in groups A and B: esophagitis 35.2 and 33.3% and pneumonitis 23.5 and 25.9%, respectively. 40.9% of patients in group A vs. 57.5% in group B completed treatment. Overall response (intention-to-treat analysis) was 68.1% in group A and 63.5% in group B. Median survival was 17.7 months for the whole group with a mean follow-up of 41.2 months. 20% of patients were alive at 3 years. Long-term results of this schedule are encouraging. However, nonhematological toxicity of chemoradiation is substantial and different strategies should be tested to minimize it.     

Clinical value of the electrocardiogram in ambulatory care

The direct impact of the electrocardiogram (ECG) on clinical outcome in an ambulatory health care population during a six-month period was reviewed. Three hundred seventy-six ECG tracings were recorded, of which 262 (69.7 percent) were interpreted as normal. The ECG was clinically useful and had direct impact on treatment in only two instances (0.5 percent of all tracings recorded). Three patients were inappropriately referred or treated because of an incorrect ECG interpretation. No electrocardiograms done on asymptomatic persons led to useful medical interventions.