Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoproliferative malignancies: a randomized multicenter study.

This randomized study assessed if intravenous iron improves hemoglobin (Hb) response and permits decreased epoetin dose in anemic (Hb 9-11 g/dl), transfusion-independent patients with stainable iron in the bone marrow and lymphoproliferative malignancies not receiving chemotherapy. Patients (n=67) were randomized to subcutaneous epoetin beta 30 000 IU once weekly for 16 weeks with or without concomitant intravenous iron supplementation. There was a significantly (P<0.05) greater increase in mean Hb from week 8 onwards in the iron group and the percentage of patients with Hb increase >or=2 g/dl was significantly higher in the iron group (93%) than in the no-iron group (53%) (per-protocol population; P=0.001). Higher serum ferritin and transferrin saturation in the iron group indicated that iron availability accounted for the Hb response difference. The mean weekly patient epoetin dose was significantly lower after 13 weeks of therapy (P=0.029) and after 15 weeks approximately 10 000 IU (>25%) lower in the iron group, as was the total epoetin dose (P=0.051). In conclusion, the Hb increase and response rate were significantly greater with the addition of intravenous iron to epoetin treatment in iron-replete patients and a lower dose of epoetin was required.     

Extending postgrafting cyclosporine decreases the risk of severe graft-versus-host disease after nonmyeloablative hematopoietic cell transplantation

BACKGROUND: It is unknown whether the duration of systemic immunosuppressive treatment after allogeneic nonmyeloablative hematopoietic cell transplantation (HCT) might influence the incidence, severity, timing, and/or corticosteroid-responsiveness of graft-versus-host disease (GVHD). METHODS: We retrospectively analyzed outcomes among 185 patients with hematologic malignancies who were given grafts from HLA-matched related donors following conditioning with 2 Gy total body irradiation alone or in combination with fludarabine between December 1998 and March 2003. Postgrafting immunosuppression consisted of mycophenolate mofetil (days 0-27) in combination with 3 different cyclosporine (CSP) regimens: taper from (A) days 35 to 56 (n=107), (B) days 56 to 77 (n=35), and (C) days 56 to 180 (n=43). RESULTS: The overall incidences of grades II-IV and III-IV acute GVHD, and extensive chronic GVHD were 52%, 13%, and 56%, respectively. The duration of CSP prophylaxis did not significantly influence the overall rate of acute GVHD (grade II-IV), extensive chronic GVHD, or non-relapse mortality. However, prolonged administration of CSP (group C) was associated with a significantly decreased hazard of grades III-IV acute GVHD (HR 0.2, 95% CI [0.04, 0.9]) and with an increased likelihood of discontinuing all systemic immunosuppression (HR 2.4, 95% CI [1.1, 5.2]) when compared to the shortest course of CSP (group A). CONCLUSION: Longer CSP duration decreased the risk of severe GVHD and increased the likelihood of discontinuing all systemic immunosuppression after nonmyeloablative HCT with HLA-matched related grafts.     

Pulmonary embolism after off-pump coronary artery bypass surgery as detected by computed tomography

BACKGROUND: The incidence of pulmonary embolism (PE) after coronary artery bypass surgery is ill defined. METHODS: Twenty-four patients undergoing off-pump coronary artery bypass surgery were enrolled in a prospective randomized study evaluating a new proximal aortic anastomotic device. Computed tomography was performed postoperatively about 1 week after surgery. RESULTS: Computed tomography showed signs of PE in 6 patients (25%), which were bilateral in 2 cases. None of these patients had symptoms or signs of PE or deep venous thrombosis. CONCLUSIONS: The present findings widen the controversial issue of thromboprophylaxis after cardiac surgery and suggest that low-dose heparin may be indicated after coronary artery bypass surgery.     

Estrogen receptor alpha genotype confers interindividual variability of response to estrogen and testosterone in mesenchymal-stem-cell-derived osteoblasts

Hormone replacement therapy is effectively used to prevent postmenopausal bone loss. Variation in response to the therapy is, however, frequently seen. In addition, the direct effects of sex steroids on isolated human bone marrow stromal cells have been reported to vary depending on the donor, but the biological mechanisms are not understood. The aim of this study was to investigate the effects of 17beta-estradiol (E2) and testosterone in human-bone-marrow-derived mesenchymal stem cell (MSC) cultures from both female and male donors of various ages. The osteoblast differentiation capacity and activity of the MSCs were quantified in vitro by measuring alkaline phosphatase activity and calcium deposition. We show here that also the osteoblast responses of MSCs to sex hormones vary widely depending on the donor. When the results from all donors were analyzed together, treatment with E2 increased calcium deposition significantly by MSCs of both sexes but ALP activity only in the male MSCs. Testosterone had no effect on ALP activity nor calcium deposition in either sex. To further characterize the individual variation, we investigated estrogen receptor alpha PvuII restriction site polymorphism with PCR. Restriction fragment-length polymorphism was assigned as P or non-P, P signifying the absence of the restriction site. Our results indicate that higher basal osteoblast differentiation capacity of MSCs is associated with the presence of the P allele in females, whereas higher response to sex steroids treatment is associated with the non-P allele. These results could help explain the contradictory effects of E2 on osteoblasts in vitro and might also provide new insights to understanding the differences in responses to hormone replacement therapy.     

Fingernail cystine of vanadium workers

Summary The fingernail cystine content of 22 vanadium workers and 22 case controls not exposed to vanadium was measured. The duration of exposure was about 14 years and the level of exposure was 0.1–0.6 mg/m³. Unlike some earlier studies, this survey indicated no difference in fingernail cystine contents of vanadium workers and their controls. It was not possible to reveal any significant difference between the duration of exposure and fingernail cystine content, either.     

Short-term memory functions of the human fetus recorded with magnetoencephalography

Studies in fetuses and in prematurely born infants show that auditory discriminative skills are present prior to birth. The magnetic fields generated by the fetal brain activity pass the maternal tissues and, despite their weakness, can be detected externally using MEG. Recent studies on the auditory evoked magnetic responses show that the fetal brain responds to sound onset. In contrast, higher-level auditory skills, such as those involving discriminative and memory functions, were not so far studied in fetuses with MEG. Here we show that fetal responses related to discriminating sounds can be recorded, implicating that the auditory change-detection system is functional. These results open new views to developmental neuroscience by enabling one to determine the sensory capabilities as well as the extent and accuracy of the short-term memory system of the fetus, and, further, to follow the development of these crucial processes.     

Childhood adversities experienced by working-aged coronary heart disease patients

OBJECTIVE: The aim of this study is to investigate associations between childhood adversities and coronary heart disease (CHD). METHODS: This was a case-control study based on a postal questionnaire addressed to randomly selected working-aged Finns, and response rate was 39% (N = 15,477). The sample comprised 319 CHD patients. Four age- and gender-matched controls were selected for every patient. The participants were asked in six questions to think about their childhood adversities. RESULTS: Fear of some family member and someone in the family being seriously or chronically ill were more common during childhood among working-aged CHD patients than among controls. Likewise, among female CHD patients, serious conflicts in the family and someone in the family having had alcohol problems and, among male CHD patients, long-lasting financial problems were more common than among controls. Odds ratios (OR) varied between 1.27 and 2.66. Adjustment for education had no influence among women, but it had an influence among men. Upon adjustment for conventional risk factors (smoking, obesity, and hypertension), the association mostly disappeared. A family member having been seriously or chronically ill was statistically significant after full adjustment among both genders. CONCLUSION: Working-aged CHD patients have experienced more dramatic events during their childhood than did the control population. This issue cannot be solved in doctors' offices. Health-promoting social policies are of vital importance.     

Association of Chlamydia trachomatis with persistence of high-risk types of human papillomavirus in a cohort of female adolescents

Human papillomavirus (HPV) infection is a necessary but not sufficient cause of cervical cancer. While chlamydia infection has been associated with cervical cancer, the meaning of this association remains unclear. The authors' objective was to investigate this association by evaluating whether concurrent genital tract infections are associated with HPV persistence, a precursor to cervical cancer. Interview data and biologic samples for HPV, Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, and bacterial vaginosis testing were collected from female adolescents in an Atlanta, Georgia, longitudinal cohort study at 6-month visits (1999-2003). Associations with persistence (detection of the same HPV type at two sequential visits (visit pair)) were assessed among subjects with 2-5 visits and > or =6 months of follow-up. Associations were evaluated by logistic regression using methods for correlated data. Type-specific persistence of high-risk HPV types was detected in 77 of 181 (43%) analyzed visit pairs. Concurrent infection with C. trachomatis was independently associated with persistence of high-risk HPV types (adjusted odds ratio = 2.1, 95% confidence interval: 1.0, 4.1). Infection with more than one HPV type at the initial visit was also associated with high-risk persistence (adjusted odds ratio = 2.8, 95% confidence interval: 1.6, 4.9). The association between chlamydia infection and cervical cancer may be due to an effect of chlamydia infection on persistence of high-risk HPV.     

Mutations in two short noncoding mononucleotide repeats in most microsatellite-unstable colorectal cancers

DNA mismatch repair (MMR)-deficient cells typically accumulate mutations in short repetitive DNA tracts. This microsatellite instability (MSI) facilitates malignant transformation when affecting genes with growth-related and caretaker functions. To date, several putative MSI target genes have been proposed mainly based on high mutation frequency within their coding regions. However, some intronic repeat mutations have also been suggested to associate with MSI tumorigenesis, indicating the need for additional analyses on noncoding repeats. Here we have analyzed an intronic T9 repeat of semenogelin I (SEMG1) and report mutation frequencies of 51% (75 of 146) and 62% (8 of 13) in MMR-deficient primary colorectal cancers and cell lines, respectively. The putative effect of the SEMG1 mutations was assessed by RNA and protein level analyses, but no differences were detected between colorectal cancer cell lines with different SEMG1 status. Subsequently, the general background mutation frequency of MSI colorectal cancers was assessed by screening for intergenic T9 repeat alterations. One of 10 examined repeats was mutated in 70% (102 of 145) of the colorectal cancers evaluated. The frequencies observed here are notably higher than previously published in noncoding repeats shorter than 10 bp in MMR-deficient primary tumors. Our results indicate that high mutation frequencies, similar or higher than those observed in proposed and approved target genes, can be detected in repeat tracts of MSI tumors without any apparent selection pressure. These data call for urgent and thorough large-scale evaluation of mutation frequencies in neutral short repetitive sequences in MMR-deficient tumors.