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At least 199 records · Page 11Linked to original sources
PubMed1987

Chromosomal subclonal evolution in paroxysmal nocturnal hemoglobinuria evolving into acute megakaryoblastic leukemia.

Four cytogenetic studies were performed in the course of a paroxysmal nocturnal hemoglobinuria evolving into acute megakaryoblastic leukemia. The clonal evolution was characterized by a unique structural change (9p) at the time of diagnosis, heralding an accelerated and complex karyotypic alteration including 5q-, 12p-, +21, -5, -7. At the terminal phase, the initial population was replaced within 1 week by a new overgrowing clone with -5, +8, +17. This suggests that the paroxysmal nocturnal hemoglobinuria-associated preleukemia and leukemic states share with acute nonlymphocytic leukemia the same nonrandom chromosomal changes.

Adult↗
PubMed1996

Collisions and encounters in simulations of receptor/GTP-binding protein interactions via simple diffusion.

In two intact cell systems in which GTP-binding protein (G) activity is initiated by the presence of agonist-bound receptors (R), it has been demonstrated that the rate of G activation is influenced by the rate of turnover of agonist occupancy among the receptor population. G activity is reduced when a low concentration of agonist-occupied receptors comprised by low fractional occupancy of a large receptor population is replaced by the presence of the same concentration of 100%-occupied receptors. This effect has been proposed to be due to a time interval of interaction between R and G (an encounter) that is long compared to the time of a single collection between R and G and long compared to the lifetime of an agonist-receptor complex. In a recent simulation study of R-G interaction via diffusion, the effect of agonist occupancy turnover was observed but it was assumed that long encounters were not operative. In this study, encounter intervals in simulations of R-G interaction by simple diffusion were measured in order to address that difference. The results demonstrate that relatively long encounters comprised of multiple, separate collisions are an inherent part of R-G interaction as modelled by diffusion. The implications for further implementation of simulation studies of R-G interaction are discussed.

Diffusion↗
PubMed2005

Regenerative medicine in Parkinson's disease: generation of mesencephalic dopaminergic cells from embryonic stem cells.

Cell replacement therapy has been proposed as a means of replacing specific populations of cells lost through trauma, disease or ageing. Parkinson's disease is a progressive neurodegenerative disorder caused by the loss of midbrain dopaminergic neurons. Intrastriatal transplants of human foetal mesencephalic tissue in Parkinson's patients have demonstrated clinical efficacy, but the limited availability of tissue precludes systematic use of this treatment. Human embryonic stem cells are capable of unlimited self-renewal and can differentiate into cells representative of all three germ layers, including cells of the central nervous system. These cells may thus provide a relatively unlimited source of cells for transplantation, if appropriate differentiation protocols to generate highly enriched and specific populations of neural cells can be developed.

Animals↗
PubMed2005

An update: spontaneous premature ovarian failure is not an early menopause.

OBJECTIVE: To update clinicians regarding the management of women with spontaneous premature ovarian failure (POF). DESIGN: Literature review and consensus building among three clinicians with experience in caring for women with spontaneous POF. CONCLUSION(S): Clearly the ovarian "failure" in this disorder is not permanent in all women. Approximately 5%-10% may conceive spontaneously and unexpectedly after the diagnosis. An integrated approach to management is best, and there is a need to first address physical and mental health issues before addressing plans for family building. Women with spontaneous POF are at increased risk of adrenal insufficiency, which should be detected and managed appropriately, especially before proceeding to ovum or embryo donation procedures. Young women with POF experience pathologically low serum E2 levels at least intermittently. Despite the absence of controlled evidence for this specific population, physiologic replacement of ovarian steroid hormones seems rational until the age of normal menopause. The disorder may be associated with other conditions that require evaluation and management, including hypothyroidism, dry eye syndrome, abnormal karyotype, or a premutation of the FMR1 gene. Finally, clinicians need to be sensitive to the emotional aspects of this disorder when delivering the diagnosis and during subsequent management.

Adrenal Insufficiency↗
PubMed2004

Pneumococcal conjugate vaccines--a European perspective.

Streptococcus pneumoniae is a leading cause of bacterial pneumonia, meningitis, and acute otitis media in children and adults worldwide. In the age group of < 2 years the incidence of invasive pneumococcal disease ranges from approximately 14 cases per 100,000 in Germany and the Netherlands and more than 90 per 100,000 children in Spain. The vulnerability of children to S. pneumoniae can also be demonstrated by the high rate of sequelae (> 20% in Germany) and the high mortality (7.5%) in pneumococcal meningitis. Furthermore, antibiotic resistance of S. pneumoniae is increasing in Europe, particularly in France, Spain, and Eastern European countries, whereas Germany and Northern Europe are only marginally affected. A 7-valent pneumococcal conjugate vaccine (7vPCV) that was shown to be highly efficacious in preventing invasive pneumococcal disease in infants in the USA was licensed in Europe in 2001. It is expected that broad usage of the vaccine would reduce the incidence of invasive pneumococcal disease and the levels of pneumococcal resistance significantly. Important questions have been raised regarding the effectiveness of this vaccine in high-risk populations, serotype replacement, the efficacy of this vaccine in otitis media, and the co-administration of the new vaccine with other standard childhood vaccines used in various European countries. France and Spain currently have the most-wide ranging guidelines recommending pneumococcal vaccination for children. Overall, the development of pneumococcal conjugate vaccines is a significant step in the control of pneumococcal disease in children in Europe. Further progress in pneumococcal vaccine development can be expected from conjugate vaccines including more than seven serotypes (9-valent, 11-valent).

Antibodies, Bacterial↗
PubMed2005

Mutagenesis of 8-oxoguanine adjacent to an abasic site in simian kidney cells: tandem mutations and enhancement of G-->T transversions.

Clustered DNA damages are well-established characteristics of ionizing radiation. As a model clustered lesion in the same strand of DNA, we have evaluated the mutagenic potential of 8-oxoguanine (8-oxoG) adjacent to a uracil in simian kidney cells using a phagemid vector. The uracil residue would be excised by the enzyme uracil DNA glycosylase in vivo generating an abasic site (AP site). A solitary uracil in either GUGTC or GTGUC sequence context provided >60% progeny containing GTGTC indicating that dAMP incorporation opposite the AP site or uracil occurred, but a >30% population showed replacement of U by A, C, or G, which suggests that dTMP, dGMP, or dCMP incorporation also occurred, respectively, opposite the AP site. While the preference for targeted base substitutions at the GUG site was T >> C > A > G, the same at the GUC site was T >> A > C > G. We conclude that base incorporation opposite an AP site is sequence-dependent. For 8-oxoG, as compared to 23-24% G-->T mutants from a single 8-oxoG in a TG(8-oxo)T sequence context, the tandem lesions UG(8-oxo)T and TG(8-oxo)U generated approximately 60 and >85% progeny, respectively, that did not contain the TGT sequence. A significant fraction of tandem mutations were detected when uracil was adjacent to 8-oxoG. What we found most interesting is that the total targeted G(8-oxo)-->T transversions that included both single and tandem mutations at the TG(8-oxo)U site was nearly 60% relative to about 30% at the UG(8-oxo)T site. A higher mutational frequency at the TG(8-oxo)U sequence may arise from a change in DNA polymerase that is more error prone. Thermal melting experiments showed that the Tm for the 8-oxoG:C pair in the TG(8-oxo)(AP*) sequence in a 12-mer was lower than the same in a (AP*)G(8-oxo)T 12-mer with deltadeltaG 0.8 kcal/mol (where AP* represents tetrahydrofuran, the model abasic site). When the 8-oxoG:C pair in each sequence was compared with a 8-oxoG:A pair, the former was found to be more stable than the latter. The preference for C over A opposite 8-oxoG for the (AP*)G(8-oxo)T 12-mer duplex with a deltadeltaG of 1.6 kcal/mol dropped to 0.4 kcal/mol in the TG(8-oxo)(AP*) 12-mer duplex. This suggests that the polymerase discrimination to incorporate dCMP over dAMP would be less efficient in the TG(8-oxo)(AP*) sequence relative to (AP*)G(8-oxo)T. Additionally, the efficiency of recognition and excision of A opposite 8-oxoG by a mismatch repair protein may be impaired in the TG(8-oxo)(AP*) sequence context.

Animals↗
PubMed2002

Increased incidence of EBV-associated lymphoproliferative disorders after allogeneic stem cell transplantation from matched unrelated donors due to a change of T cell depletion technique.

Here, the influence of T vs T and B cell depletion on the incidence of EBV-associated lymphoproliferative disorder (EBV-LPD) after bone marrow transplantation (BMT) from a matched unrelated donor (MUD) is analyzed. From 1982 to 1997 the soy bean agglutinin/sheep red blood cell (SBA/SRBC) method was used for T cell depletion. This technique is well established, but the use of SRBC has a risk of transmitting prions or viruses. Therefore, a new T cell depletion method was introduced, using CD2 and CD3 monoclonal antibodies (CD2/3 method) instead of SRBC. Unfortunately, this led to an unexpected high number of EBV-LPDs in patients receiving transplants from MUDs. SBA depletion was reintroduced and combined with the CD2/3 method (SBA/CD2/3) in this patient population, later replaced by B cell-specific (CD19 and CD22) antibodies (CD3/19/22 method). The number of T (x 10(5)/kg) and B (x 10(5)/kg) cells in the graft was 1.5 +/- 0.8 and 2 +/- 1 (T/B ratio 0.75), 2.2 +/- 2.0 and 41 +/- 21 (ratio 0.055), 5.0 +/- 0.0 and 2 +/- 1 (ratio 2.5), 2.5 +/- 1.2 and 10 +/- 6 (ratio 0.25) using the SBA/SRBC, CD2/3, SBA/CD2/3 and CD3/19/22 techniques, respectively. When B cell depletion was performed (SBA/SRBC, SBA/CD2/3, CD3/19/22) four out of 31 patients (13%) receiving a BMT from a MUD developed an EBV-LPD. Without B cell depletion (CD2/3) this occurred in five out of seven patients (71%) (P < 0.05). A T/B cell ratio in the graft of > or = 0.25 seems sufficient to significantly reduce the incidence of EBV-LPD after BMT from MUDs.

Adolescent↗
PubMed1996

Transformation of Plasmodium falciparum malaria parasites by homologous integration of plasmids that confer resistance to pyrimethamine.

Plasmodium falciparum malaria parasites were transformed with plasmids containing P. falciparum or Toxoplasma gondii dihydrofolate reductase-thymidylate synthase (dhfr-ts) coding sequences that confer resistance to pyrimethamine. Under pyrimethamine pressure, transformed parasites were obtained that maintained the transfected plasmids as unrearranged episomes for several weeks. These parasite populations were replaced after 2 to 3 months by parasites that had incorporated the transfected DNA into nuclear chromosomes. Depending upon the particular construct used for transformation, homologous integration was detected in the P. falciparum dhfr-ts locus (chromosome 4) or in hrp3 and hrp2 sequences that were used in the plasmid constructs as gene control regions (chromosomes 13 and 8, respectively). Transformation by homologous integration sets the stage for targeted gene alterations and knock-outs that will advance understanding of P. falciparum.

Animals↗
PubMed1991

Pre-procreative ages in population stability and cyclicity.

"Humans' protracted maturation before childbearing is an extreme example of a general characteristic of higher organisms: a positive lower bound on ages of procreation. The pre-procreative span, much discussed for its evolutionary and social ramifications, has consequences also for the mathematics of population renewal.... This paper proves the presence of a pre-procreative span sufficient, in and of itself, to guarantee the existence condition for bifurcation for all models in one important class. The class includes the best-studied examples of age-specific systems with and without homeostatic feedback in purely discrete and in purely continuous formulations."

Age Factors↗
PubMed2004

End-stage renal care in developing countries: the India experience.

Chronic renal failure is a devastating medical, social and economic problem for patients and their families. There is no data on the true incidence and prevalence of chronic renal failure in the developing world. Delayed diagnosis and failure of institution of measures to slow progression of renal failure result in a predominantly young ESRD population. Renal replacement therapy (RRT) is a low-priority area for healthcare planners in developing nations with two-tier healthcare delivery system. There is a severe shortage of nephrologists and hospitals offering dialysis and transplantation, more so in the poorest regions. There is a direct relationship between the number of dialysis centers and per capita gross national income of developing nations. Shortage in the number of government-funded hospitals has fanned the growth of a large number of private hospitals offering RRT. The high cost of hemodialysis (HD) puts it beyond the reach of all but the very rich and maintenance HD is the exclusively preserve of private hospitals. Government-run hospitals are busy with renal transplantation, which is the only realistic long term RRT option for a majority of patients. There are no state-funded or private health insurance schemes and patients have to raise finances for RRT on their own. Entire families are involved in such endeavors, with resulting loss of income of other family members too. A number of measures are utilized to bring down the RRT costs. For HD, these include cutting down the frequency of dialysis, use of cheaper cellulosic dialyzers, dialyzer reuse and nonutilization of expensive drugs like erythropoietin. Paradoxically, chronic peritoneal dialysis is more expensive than HD; patients use outdated connection systems and are suboptimally dialyzed on 3 exchanges/day. Most patients on dialysis are inadequately rehabilitated. Renal transplant recipients are forced to discontinue expensive drugs like cyclosporine after variable periods leading to high rates of graft loss. Financial considerations often preclude appropriate treatment of steroid-resistant rejection and cytomegalovirus infection. There is no organized cadaver donation program and an overwhelming majority of transplants are performed using living donors. This led to the practice of the sale of kidneys for transplant. To conclude, the financial burden of RRT in developing nations impacts on the lifestyle and future of entire families, and extracts a cost far higher than the actual amount of money spent on treatment.

Costs and Cost Analysis↗
PubMed1994

Structural changes in muscle crossbridges accompanying force generation.

We have investigated the structure of the crossbridges in muscles rapidly frozen while relaxed, in rigor, and at various times after activation from rigor by flash photolysis of caged ATP. We used Fourier analysis of images of cross sections to obtain an average view of the muscle structure, and correspondence analysis to extract information about individual crossbridge shapes. The crossbridge structure changes dramatically between relaxed, rigor, and with time after ATP release. In relaxed muscle, most crossbridges are detached. In rigor, all are attached and have a characteristic asymmetric shape that shows strong left-handed curvature when viewed from the M-line towards the Z-line. Immediately after ATP release, before significant force has developed (20 ms) the homogeneous rigor population is replaced by a much more diverse collection of crossbridge shapes. Over the next few hundred milliseconds, the proportion of attached crossbridges changes little, but the distribution of the crossbridges among different structural classes continues to evolve. Some forms of attached crossbridge (presumably weakly attached) increase at early times when tension is low. The proportion of several other attached non-rigor crossbridge shapes increases in parallel with the development of active tension. The results lend strong support to models of muscle contraction that have attributed force generation to structural changes in attached crossbridges.

Adenosine Triphosphate↗
PubMed1996

Case counting in epidemiology: limitations of methods based on multiple data sources.

BACKGROUND: The application of capture-recapture methods in epidemiology has been proposed as an alternative to field surveys. This methodology is important for the future of epidemiology and deserves a critical analysis. METHODS: This paper reviews conditions for applying the capture-recapture models to epidemiological data, taking into account practical considerations, in particular the problem of case definition. RESULTS: The underlying assumptions are particularly restrictive resulting in a theoretical limitation of their applicability. In spite of the statistical developments designed to overcome these difficulties, the practical conditions for using the existing lists are often not fulfilled (availability, confidentiality). The major restriction is on the quality of the data which are often far below the standards required in specific prevalence surveys and which may differ between lists. This may result in a dramatic lack of specificity. The definition of the virtual subgroup of patients missing in all lists as generated by the statistical procedure, is questionable particularly when counting living patients. Field studies would be necessary for validation. CONCLUSIONS: In some particular situations (e.g. deceased patients, rare diseases), this methodology may provide a useful approximation to the number of ill subjects events, but users should be aware of their poor specificity. It can also be useful to complement data from surveillance systems by careful cross-checking with independent sources of information. Currently, this method cannot, in any way, replace direct population prevalence or incidence surveys.

Epidemiologic Methods↗
PubMed1996

The immune response to implant materials in humans.

The etiology of aseptic loosening of prosthetic joint replacement components is unclear. Implant materials have been considered biologically inert, but recently studies indicate that inflammatory reactions directed against the implanted materials may contribute to aseptic loosening. Data suggesting a progression from a simple inflammatory reaction to complex immune responses against the biomaterials are reviewed. The cellular responses to particles of polymethylmethacrylate, ultrahigh molecular weight polyethylene, and alloys of cobalt-chromium and titanium were assayed in vitro to determine cell proliferation in patients with underlying diagnoses of osteoarthrosis, rheumatoid arthritis, and avascular necrosis who had joint replacement. Control populations were provided by patients with similar diagnoses who were preoperative surgical candidates. The underlying diagnoses did not seem to influence responses to particle stimulation. Elevated responses to both acrylic and cobalt-chromium were observed in patients with aseptically loosened prostheses. These findings suggest that the development of a cellular response to particulate debris may be significant in the pathogenesis of aseptic loosening.

Biocompatible Materials↗
PubMed2005

Pharmacodynamic evidence that ciprofloxacin failure against tuberculosis is not due to poor microbial kill but to rapid emergence of resistance.

Studies of early bactericidal activity provide a fast and economic way to evaluate the clinical efficacy of potential agents for the treatment of tuberculosis. Based on good early bactericidal activity data, ciprofloxacin entered further studies and is now recommended as part of treatment for multidrug-resistant tuberculosis. We examined the relationship between ciprofloxacin bactericidal activity and the emergence of resistance in an in vitro pharmacodynamic infection model in which we exposed Mycobacterium tuberculosis to simulated free-drug ciprofloxacin serum concentration-time profiles that mimic those encountered in humans treated with ciprofloxacin orally for 2 weeks. Mycobacterium tuberculosis cultures were sampled during the experiment in order to determine the effect of therapy on the total microbial population as well as the drug-resistant population. The ciprofloxacin regimen, which achieved a ratio of the area under the concentration time curve from 0 to 24 h to MIC of 80.4, resulted in a rapid microbial kill similar to that encountered in humans during studies of early bactericidal activity. However, despite this impressive bactericidal activity, resistance emerged quickly. By the end of the first week, most of the microbial population had been replaced by a ciprofloxacin-resistant population. Given the MICs encountered in clinical isolates of M. tuberculosis, we estimate that most clinically tolerable doses of ciprofloxacin will lead to emergence of resistance, especially when used as the only effective component of regimens given for treatment of multidrug-resistant tuberculosis. One of the explanations for why early bactericidal activity fails to predict sterilization may be the emergence of a resistant subpopulation, which only becomes >/=1% at the end of the early bactericidal activity studies.

Anti-Infective Agents↗