Immunoselection of functional CMRF-56+ blood dendritic cells from multiple myeloma patients for immunotherapy

Dendritic cells (DCs) loaded with tumor-associated antigens are a promising treatment to prevent disease relapse in patients with multiple myeloma (MM). Early-phase clinical trials have shown safety, efficacy, and immunologic responses in MM, but a key issue now is the isolation of a functional, clinically relevant DC preparation. The authors have described a unique blood DC (BDC) isolation platform based on positive immunoselection with the CMRF-56 antibody. To validate this as a feasible source of BDCs for immunotherapy, the authors undertook a quantitative and functional analysis of BDCs in MM patients and healthy donors. These data show that MM patients have similar numbers of CD11c+CD16+ and CD11c+CD16- BDCs but about half the number of CD11c-CD123+ BDCs in whole blood compared with healthy donors. BDCs could be isolated by CMRF-56+ immunoselection from all MM patients tested, with similar yields and purity to healthy donors. These BDCs could be activated ex vivo with poly I:C or LPS. Furthermore, CMRF-56+ preparations could induce potent CD4+ and CD8+ T-lymphocyte responses in both MM patients and healthy donors. These data suggest that BDCs with in vitro functional integrity can be isolated from MM patients in sufficient numbers to justify a clinical trial.     

Home-based resistance training is not sufficient to maintain improved glycemic control following supervised training in older individuals with type 2 diabetes

OBJECTIVE: To examine whether improvements in glycemic control and body composition resulting from 6 months of supervised high-intensity progressive resistance training could be maintained after an additional 6 months of home-based resistance training. RESEARCH DESIGN AND METHODS: We performed a 12-month randomized controlled trial in 36 sedentary, overweight men and women with type 2 diabetes (aged 60-80 years) who were randomly assigned to moderate weight loss plus high-intensity progressive resistance training (RT&WL group) or moderate weight loss plus a control program (WL group). Supervised gymnasium-based training for 6 months was followed by an additional 6 months of home-based training. Glycemic control (HbA1c), body composition, muscle strength, and metabolic syndrome abnormalities were assessed at 0, 3, 6, 9, and 12 months. RESULTS: Compared with the WL group, HbA1c decreased significantly more in the RT&WL group (-0.8%) during 6 months of supervised gymnasium-based training; however, this effect was not maintained after an additional 6 months of home-based training. In contrast, the greater increase in lean body mass (LBM) observed in the RT&WL group compared with the WL group (0.9 kg, P < 0.05) after the gymnasium-based training tended to be maintained after the home-based training (0.8 kg, P = 0.08). Similarly, the gymnasium-based increases in upper body and lower body muscle strength in the RT&WL group were maintained over the 12 months (P < 0.001). There were no between-group differences for changes in body weight, fat mass, fasting glucose, or insulin at 6 or 12 months. CONCLUSIONS: In older adults with type 2 diabetes, home-based progressive resistance training was effective for maintaining the gymnasium-based improvements in muscle strength and LBM but not glycemic control. Reductions in adherence and exercise training volume and intensity seem to impede the effectiveness of home-based training for maintaining improved glycemic control.     

The use of preventive strategies for bone loss

Osteoporosis is a worldwide problem that is increasing significantly as the global population both increases and ages. While osteoporosis has been extensively studied in recent years, the utilization of traditional Chinese medicine (TCM) for the diagnosis, prevention and treatment of this condition has seldom been examined. This paper examines the theories and the literature that relate to diagnosis, prevention and treatment of bone loss at the time of menopause according to the principles of TCM. It also considers practical developments in these areas as illustrated by the authors' research findings in recent studies. TCM diagnosis attributes a number of different underlying patterns to menopausal bone loss. A very common pattern in this situation is a Kidney qi and yin deficiency pattern. TCM analysis can be used as an early determinant of those persons who are potentially at risk of bone loss. Acupuncture, herbal medicine and Tai Ji exercise can then be applied to prevent and treat osteoporosis. These treatments can be effective, if they are applied correctly. The therapies may also be used in the treatment and prevention of osteoporosis, as well as the general maintenance of women's health during menopause.     

G protein beta3 subunit C825T polymorphism in primary IgA nephropathy

BACKGROUND: The T allele of the G protein beta3 subunit (GNB3) C825T polymorphism has been associated with increased signal transduction, increased activity of the kidney Na+/H+ exchanger, and also with late-onset essential hypertension. Hypertension is a strong independent risk factor for progression in IgA nephropathy (IgAN). METHODS: We have studied this polymorphism in a regularly followed cohort of 299 biopsy-proven incident cases of IgAN, collected from 1989 to 1999 [208 males (70%)] and compared the genotypes and alleles distributions to 303 local Caucasian controls matched for the male predominance (214 males). The technique used was a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) with BseDI as restriction enzyme and specific primers, followed by gel electrophoresis. RESULTS: The TT, CT, and CC genotype frequencies were 13.7%, 45.8%, and 40.5% in IgAN, respectively, versus 7.6%, 47.2%, and 45.2% in controls, respectively (chi(2)= 6.16; P= 0.05). The excess of TT patients versus non-TT was significant in IgAN versus controls (chi(2)= 5.94; P= 0.015). The T allele frequency was 0.366 in IgAN versus 0.312 in controls (chi(2)= 3.97; P= 0.05). This data indicated that this polymorphism had a significant but mild influence on the occurrence/initiation of IgAN (RR = 1.81; 95% CI 1.07-3.07). In contrast, we could not demonstrate any significant and sustained difference in the clinical presentation and evolution of the homozygous TT patients compared to non-TT patients (CC + CT) despite a mean and median follow-up about 10 years. The progression to arterial hypertension or to chronic renal failure or to end-stage renal failure (ESRF) was not significantly different. In addition, multivariate Cox regression analysis excluded a significant independent role of C825T polymorphism on progression. CONCLUSION: The C825T GNB3 polymorphism had a mild influence on occurrence/initiation of IgAN, but played no significant role in the progression of the disease.     

Biomedical Literature Mining

It is now obvious that the rate-limiting step in high throughput experimentation is neither data acquisition nor analysis, but rather our ability to interpret data on a genome-wide scale. Indeed, the explosion of data sampling capacity combined with increasing publication rates greatly impairs our ability to find meaning in vast collections of data. In order to support data interpretation, bioinformatic tools are needed to identify critical information contained in large bodies of literature. However, extracting knowledge embedded in free text is an arduous task, compounded in the biomedical field by an inconsistent gene nomenclature, domain-specific language and restricted access to full text articles. This paper presents a selection of currently available biomedical literature mining software. These tools rely on statistic and, more recently, semantic analyses (Natural Language Processing) to automatically extract information from the literature. In addition, a literature mining strategy has been developed to explore patterns of term occurrences in abstracts. This method automatically identifies relevant keywords in collections of abstracts, and uses a pattern discovery algorithm to generate a visual interface for exploring functional associations among genes. Term occurrence heatmaps can also be combined with gene expression profiles to provide valuable functional annotations. Furthermore, as demonstrated with tumor cell line literature profiling results, this approach can be applied to a variety of themes beyond genomic data analysis. Altogether, these examples illustrate how literature analysis can be employed to support knowledge discovery in biomedical research.     

PFA-100 and flow cytometry: can they challenge aggregometry to assess antiplatelet agents,other than GPIIbIIIa blockers,in coronary angioplasty?

The objective of this current trial was to evaluate the rate of deep-vein thrombosis (DVT) in patients after low clinical risk stratification and to evaluate the value of D-dimer and different imaging techniques in the diagnostic algorithm. A total of 99 consecutive patients were included in this prospective trial. After clinical risk assessment, D-dimer was determined. Final diagnosis was based on the results of duplex sonography, in cases of indeterminate scans on those of ascending venography. Three months after admission, follow-up investigations were performed by a telephone interview to evaluate possible further venous thromboembolism. Final diagnosis was based on the results of colour Doppler ultrasound in 92.9% and on those of venography in 7.1%. DVT was diagnosed in 2%, D-dimer was positive in 48.4%, giving a sensitivity of 100%, a specificity of 52.7% and a negative predictive value of 100%. Follow-up was possible in 89.9%--no further thromboembolic event occurred. In this specific patient group, a negative D-dimer excludes DVT and can therefore reduce the number of imaging procedures by one-half, which, on the contrary, is necessary in patients with positive D-dimer.     

Incidence and nature of CD20-negative relapses following rituximab therapy in aggressive B-cell non-Hodgkin's lymphoma: a retrospective review

Re-treatment with rituximab for B-cell non-Hodgkin's lymphoma (NHL) relapsing after previous rituximab therapy has recently been shown to be clinically efficacious. Although the mechanism of resistance to rituximab re-treatment in non-responding patients is unknown, it is possible that loss of CD20 expression in the relapsed NHL could be important in some patients. We examined the incidence and nature of CD20 negative relapses following rituximab therapy in aggressive B-cell NHL treated at our institution. Of a total of 18 patients who received rituximab, 13 have relapsed, with 10 patients subsequently undergoing repeat tissue biopsy. Six of these 10 patients (60%) were shown to have lost CD20 expression by either immunohistochemistry and/or flow cytometry. Furthermore, three of the six patients who relapsed with CD20-negative NHL also suffered relapses at unusual anatomical sites. We conclude that loss of CD20 expression in aggressive B-cell NHL relapsing post-rituximab therapy is common. As such, repeat tissue biopsy should be undertaken to document CD20 expression by both flow cytometry and immunohistochemistry prior to considering repeated courses of rituximab in relapsed aggressive lymphomas.     

Transcatheter occlusion of a large aortoazygos fistula using the Amplatzer device

This report describes the percutaneous embolization of an unusual aortoazygos arteriovenous fistula in a 22-month-old child. The large fistula (8 mm) was successfully occluded using a 12- to 10-mm Amplatzer Duct Occluder device using the arterial approach. The device was incompletely deployed into the abnormal vessel to avoid tearing of the intima by the sharp distal disk.     

Thrombotic thrombocytopenic purpura: medical and biological monitoring of six pregnancies

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a rare cause of severe thrombocytopenia in pregnancy. METHODS: Six pregnancies in five patients with TTP were followed prospectively over 5 years. Ultralarge von Willebrand factor (ULvWF) multimers and cleaving protease (cp) levels were measured. RESULTS: TTP relapsed, complicating four of the six pregnancies. Of three patients who relapsed, two had complete or partial vWF-cleaving protease (vWF-cp) deficiency, and one had a normal vWF-cleaving protease level. In all three we found abnormal UL multimers. The two women who did not relapse had normal vWF-cleaving protease level and an absence or loss of UL multimers. CONCLUSIONS: Pregnant patients with a history of TTP must be followed in a tertiary obstetric unit with plasmapheresis available. Influence of vWF-cleaving protease and vWF multimeric abnormalities on TTP relapsing during pregnancy has to be evaluated in a further multicentre study.