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At least 163 records · Page 9Linked to original sources

PubMed2006

A novel thoracic weight-bearing long-leg orthosis that permits ambulation after massive pelvic tumor resection.

Osteosarcomas require aggressive medical and surgical treatments that frequently result in impaired musculoskeletal function. Amputation was formerly a treatment of choice for patients with sarcomas in an extremity. Although there has been controversy over the relative benefits of amputation and limb sparing, it is undeniable that limb sparing is becoming more common and that it frequently leaves a person with a limb whose function is limited. This is particularly true in the lower extremities, where pelvic and proximal femoral resections may lead to severe weight-bearing and mobility limitations. We report a novel thoracic weight-bearing long-leg orthosis that permitted a person who otherwise would not have been able to bear weight on a lower extremity after resection of a large iliac osteosarcoma to walk with a 4-point gait and forearm crutches.

Bone Neoplasms↗

PubMed2006

Virus-induced Abl and Fyn kinase signals permit coxsackievirus entry through epithelial tight junctions.

Group B coxsackieviruses (CVBs) must cross the epithelium as they initiate infection, but the mechanism by which this occurs remains uncertain. The coxsackievirus and adenovirus receptor (CAR) is a component of the tight junction and is inaccessible to virus approaching from the apical surface. Many CVBs also interact with the GPI-anchored protein decay-accelerating factor (DAF). Here, we report that virus attachment to DAF on the apical cell surface activates Abl kinase, triggering Rac-dependent actin rearrangements that permit virus movement to the tight junction. Within the junction, interaction with CAR promotes conformational changes in the virus capsid that are essential for virus entry and release of viral RNA. Interaction with DAF also activates Fyn kinase, an event that is required for the phosphorylation of caveolin and transport of virus into the cell within caveolar vesicles. CVBs thus exploit DAF-mediated signaling pathways to surmount the epithelial barrier.

Actins↗

PubMed2006

Rapamycin analogs with differential binding specificity permit orthogonal control of protein activity.

Controlling protein dimerization with small molecules has broad application to the study of protein function. Rapamycin has two binding surfaces: one that binds to FKBP12 and the other to the Frb domain of mTor/FRAP, directing their dimerization. Rapamycin is a potent cell growth inhibitor, but chemical modification of the surface contacting Frb alleviates this effect. Productive interactions with Frb-fused proteins can be restored by mutation of Frb to accommodate the rapamycin analog (a rapalog). We have quantitatively assessed the interaction between rapalogs functionalized at C16 and C20 and a panel of Frb mutants. Several drug-Frb mutant combinations have different and nonoverlapping specificities. These Frb-rapalog partners permit the selective control of different Frb fusion proteins without crossreaction. The orthogonal control of multiple target proteins broadens the capabilities of chemical induction of dimerization to regulate biologic processes.

Glycogen Synthase Kinase 3↗

PubMed2006

Dissociation of the complex between CD151 and laminin-binding integrins permits migration of epithelial cells.

Laminin-binding integrins form a complex with CD151, a member of the tetraspanin family suggested to be involved in the regulation of cell migration. In the epidermis, CD151 is localized with alpha3beta1 and alpha6beta4 integrins at cell-cell and cell-matrix contacts, respectively, characteristic structures of non-migrating cells. Taking advantage of a monoclonal antibody against CD151, TS151r, which epitope overlaps with the tetraspanin integrin-binding site, we have investigated the role of CD151 in epithelial cell migration. Under standard culture conditions, the migratory capacity of epithelial HaCaT cells on laminins is low, apparently due to endogenous laminin 5. However, challenging HaCaT cells with TS151r allows a re-arrangement of the actin cytoskeleton, dismantling of cell-cell and beta4 integrin-mediated cell-matrix contacts and cell migration. In vivo, free CD151 is absent in resting epithelial cells of interfollicular epidermis, and all CD151 is bound to integrins in intercellular and cell-matrix contacts. By contrast, free CD151 is present at intercellular contacts in the epithelial sheet lining the deeper region of anagen hair follicles, which is considered to contain migrating cells. Together, these results strongly suggest that dissociation of the CD151-integrin complex permits remodeling of epithelial cell interactions with the extracellular matrix and cell migration.

Antigens, CD↗

PubMed1994

Outcome of cataract operations performed to permit diagnosis, to determine eligibility for laser therapy, or to perform laser therapy of retinal disorders.

Cataract operations may be recommended when retinal disease is suspected but cannot be adequately diagnosed or treated because of lens opacity. We evaluated the outcome of cataract operations performed under those circumstances. We reviewed the records of 119 patients who were examined at the Wilmer Retinal Vascular Center and within three months underwent a cataract operation. We identified 17 patients (20 eyes) who underwent a cataract operation at the recommendation of a retinal specialist, to permit diagnosis, to determine eligibility for laser therapy, or to perform laser therapy. After the cataract operation, eight (40%) of the 20 eyes were found to have a retinal disease for which laser therapy was recommended, and six (30%) of the 20 eyes underwent laser therapy that, before the cataract operation, had been impossible. These results indicate that a cataract operation may be useful when lenticular opacity prevents diagnosis or treatment in a patient with a suspected retinal disorder.

Adult↗

PubMed2000

A two-step culture method starting with early growth factors permits enhanced production of functional dendritic cells from murine splenocytes.

Dendritic cells (DC) are professional antigen presenting cells (APC) able to activate naive T cells and initiate the immune response. They are present in most tissues at very low concentrations and are difficult to isolate. DC can be obtained in larger numbers by their propagation from progenitors present in blood, bone marrow and spleen. However, biochemical studies and biological analysis of DC functions require very large numbers of these cells. In this paper, we described a two-step culture system using unfractionated splenocytes from BALB/c mice as a source of DC progenitors. The proliferative capacity of the progenitors is amplified in the first step of the culture (day 0-6) using different combinations of early acting cytokines combined or not with granulocyte-macrophage CSF (GM-CSF). The second step of the culture starts at day 6 with the removal of early growth factors in order to allow the differentiation and final maturation of DC during 2-3 weeks of culture with flt-3 ligand (flt-3L) and GM-CSF. The addition of Stem Cell Factor (SCF) or IL-6 to the standard combination of flt-3L+/-GM-CSF produces a large increase in the proliferation of GM and DC progenitors (28 times and 11 times respectively) in the first step of the culture. This proliferative wave of DC progenitors is followed by the production of a high percentage of immature and mature DC in flt-3L+GM-CSF stimulated cultures. The best combination of early cytokines in terms of proliferative activity and subsequent level of DC production was flt-3L+IL-6+GM-CSF, which permitted the generation of 1 to 2x10(9) DC from one single spleen. Using this growth factor cocktail, a mixture of immature (2/3) and mature (1/3) DC was produced until day 14 of culture, and levels of MHC class II and costimulatory molecules (CD40, B7.2) increased between 2 and 4 weeks of incubation, or within 2 days when stimulated by IL-4 or LPS. The splenic DC produced after 2 weeks of culture are fully functional, exhibiting a high capacity of endocytosis when immature, a strong stimulatory reactivity in mixed leukocyte reaction and consistently producing high levels of bioactive IL-12 p70 after CD 40 ligation in the presence of LPS between 13 and 43 days of culture.

Animals↗

PubMed2002

Combination of MHC-peptide multimer-based T cell sorting with the Immunoscope permits sensitive ex vivo quantitation and follow-up of human CD8+ T cell immune responses.

Identification of MHC-restricted antigens and progress in the induction and control of adaptive cytotoxic immune responses have led to renewed interest in immunotherapy as a treatment for severe pathologies such as cancer and autoimmune diseases. Reliable procedures for detecting and monitoring T cell responses induced by the treatment throughout a clinical trial are needed in order to design rational protocols with increased efficiency. We have attempted to develop such a procedure by combining T cell sorting using HLA-peptide complexes multimerized on magnetic beads together with the quantitative Immunoscope approach. Once a recruited patient has been typed for HLA and target antigens, relevant HLA--peptide multimers can be selected and used for sorting specific peripheral T cells prior to any treatment and at the peak of the expected response to treatment. Clonotypic primers specific for the TCR rearrangements of the specific T cell clones can then be designed and used for measuring the frequency of their TCR transcripts by quantitative PCR on blood samples or T cell subsets throughout the trial. In reconstruction experiments as well as in samples from one rheumatoid arthritis patient, we were readily able to detect and follow several T cell clones with a frequency as low as 10(-5) among CD8+ T cells. The main advantages of this procedure over other currently available assays are that it does not require any assumptions on the functional status of the specific T cells and it permits the monitoring of individual T cell clones whose phenotypic shift can thus be evaluated.

Antigens, Neoplasm↗

PubMed1999

A novel high-purity isolation method for human peripheral blood neutrophils permitting polymerase chain reaction-based mRNA studies.

In the past few years, the role of polymorphonuclear neutrophils (PMN) in specific immune responses has gained significance due to their ability to express a variety of immunoregulatory molecules. However, controversial results concerning the potential of neutrophils for cytokine production have been obtained by sensitive molecular biological techniques. This problem might be related to contaminating leukocytes in conventionally isolated neutrophil suspensions as outlined by our study. We have established a novel method yielding highly purified neutrophils by combining a discontinuous Percoll gradient with fluorescence activated cell sorting of CD16bright cells. The latter step exploits the exceptionally high expression of Fc gammaRIIIB on PMN. Neutrophils could be enriched to homogeneity (> 99.9%) with a viability exceeding 90%. Contamination with NK cells or other lymphocytes, monocytes and eosinophils could be excluded as evaluated by reverse transcription-polymerase chain reaction (RT-PCR) with primers for HLA-DR, c-fms and CD52. The transcriptional potential of such purified neutrophils was confirmed by their ability to express MHC class II molecules after stimulation with granulocyte-macrophage colony-stimulating factor (GM-CSF). Our method should permit studies of PMN at the mRNA level and future investigations concerning the specificity of immunoregulatory molecule synthesis by neutrophils.

Cell Separation↗

PubMed1988

Monoclonal antibody Leu-22 (L60) permits the demonstration of some neoplastic T cells in routinely fixed and paraffin-embedded tissue sections.

Monoclonal antibody Leu-22 (L60) detects a T cell-associated antigen which is stably expressed in routinely fixed and paraffin-embedded tissue sections. We investigated the utility of monoclonal antibody Leu-22 to immunophenotype routinely processed lymphoid neoplasms by determining its reactivity in 105 archival pathologic specimens of lymphoid neoplasia that had been previously immunophenotyped by standard cell suspension and frozen tissue section techniques. Monoclonal antibody Leu-22 reacted with 69% of T cell non-Hodgkin's lymphomas (NHLs), including cases belonging to each of the major clinicopathologic categories, and with 22% of B cell NHLs, but did not react with the Reed-Sternberg (RS) cells of Hodgkin's disease (HD). We concluded that monoclonal antibody Leu-22 reacts preferentially but not exclusively with T cell NHLs. Therefore, we performed parallel analyses of the same 105 cases with monoclonal antibodies leukocyte common antigen (LCA), Leu-M1, LN1, and LN2, which detect various paraffin-resistant antigens, and of 80 of these cases with monoclonal antibody UCHL1, which detects a paraffin-resistant T cell-associated antigen. UCHL1 reacted with 61% of the T cell NHLs studied. Sixty-nine percent of T cell NHLs expressed the LCA+, Leu-22+ or Leu-M1+, LN1- phenotype and 47% of B cell NHLs expressed the LCA+, Leu-22-, Leu-M1-, LN1+ phenotype. These phenotypes had a false-positive rate of only 7%. The substitution of UCHL1 for Leu-22 or the combined use of UCHL1 and Leu-22 in this panel did not improve our ability to correctly predict the T cell phenotype of these lymphoid neoplasms. LN1 and LN2 reacted with 13% and 56% of T cell NHLs, respectively, and LN2 reacted with RS cells in 85% of cases of HD. In summary, our results demonstrate that the judicious use of monoclonal antibody Leu-22 in combination with other selected commercially available monoclonal antibodies permits the determination of the B cell or T cell origin of a high proportion of NHLs, and is helpful in the differential diagnosis between HD and NHL among cases that have been routinely fixed and paraffin-embedded.

Antibodies, Monoclonal↗

PubMed1997

Stage-specific expression of a selectable marker in Toxoplasma gondii permits selective inhibition of either tachyzoites or bradyzoites.

The establishment of culture conditions suitable for inducing differentiation of Toxoplasma gondii tachyzoites into parasites resembling the latent bradyzoite form has opened this important developmental transition to experimental analysis. In order to develop a genetic marker suitable for positive and negative selection during parasite differentiation. the T. gondii HXGPRT gene was placed under control of 5' flanking sequences derived from two bradyzoite-specific genes: BAG1 and LDH2. Random transgene integration at undefined genomic loci resulted in modest regulation (approximately 5-6-fold induction) above relatively high background levels (approximately 4% of wild-type controls). Integration of transgenes at a defined genomic position was achieved by targeting the uracil phosphoribosyl transferase (UPRT) locus using flanking homologous sequences and fluorouracil selection. This strategy was found to provide the added advantage of enhancing bradyzoite induction frequencies under conditions of pyrimidine starvation (low CO2). Constructs integrated in the direction of normal UPRT transcription exhibited moderate levels of inducibility, but transgenes integrated in the opposite direction were dramatically induced under differentiation conditions: 50-100-fold above the very low levels observed in tachyzoites (< 1% control). Positive selection (using mycophenolic acid) was shown to inhibit tachyzoites but not bradyzoites, while negative selection (using 8-azahypoxanthine) inhibited bradyzoites only. Stage-specific regulation of the HXGPRT selectable marker should permit genetic selections for the identification of mutants in the bradyzoite differentiation process.

Animals↗

PubMed2000

The binding of Na(+) to apo-enolase permits the binding of substrate.

Enolase from rabbit muscle (betabeta-enolase) is inactivated by NaClO(4). Enolase free of divalent cations is more susceptible to inactivation by NaClO(4) than is enolase in the presence of Mg(2+). We find that substrate protects apo-enolase against inactivation, indicating that substrate can bind to enolase in the absence of a divalent cation. This binding is not due to contamination by trace levels of divalent cations since (1) it occurs even in the presence of EDTA or EGTA and (2) metal analysis by ICP (inductively coupled plasma) mass spectrometry did not reveal sufficient contamination to account for the protection. The binding of PGA to apo-enolase did require Na(+). When TMAClO(4) was used instead of NaClO(4), there was no protection by PGA. Protection was restored when TMAClO(4) plus NaCl were used. The inactivation of apo-enolase by NaClO(4) is due to dissociation into inactive monomers. We conclude that Na(+) binds to apo-enolase, permitting substrate to then bind. Of the three known Me(2+) binding sites on enolase, we believe the most likely binding site for Na(+) is the carboxylate cluster of site 1, the highest affinity site of enolase.

Animals↗

PubMed2003

Can the premises of the altered homeostatic theory permit improvement in the prevention of ischemic heart disease?

In this communication, the altered homeostatic theory will be discussed and updated, and evidence will be presented that the premises of the theory might permit improvement of the prevention of ischemic heart disease (IHD). This hypothesis, first described in 1999, argues that IHD is due basically to an inappropriate shift of homeostasis, and the theory includes the position that S-RV directly induces symptoms. In contrast, the standard approach to IHD is based fundamentally on two principles: that atherosclerosis is due fundamentally to lipid abnormalities, and that symptoms in IHD are due to obstructive complications of atherosclerosis in epicardial coronary arteries. Suggestions for prevention stem from the altered homeostatic theory's different basic conceptualization of this disorder, and it seems reasonable that accepted basic pathogenetic mechanisms help shape measures to prevent IHD. Many of the theory's positions for preventing IHD parallel standard views, but the theory's basic premises have resulted in significant differences between the standard and the theory's overall approach to the prevention of IHD. Positions for the prevention of IHD include: the possibility that any preventative factor can improve any risk factor, the use of substitute preventative factors to counter unmodifiable or difficult to correct risk factors, underestimation of the risk of IHD by the standard position in individuals with normal lipid levels but multiple other risk factors, the probable relative overemphasis of the risk factor of cholesterol, the value of a national program to reduce the incidence of multiple disorders with similar risk factors, an alternate approach to the use of statins, and the value of an evolutionary approach to preventing IHD and other disorders.

Autonomic Nervous System↗

PubMed2005

[Residence permit for foreigners for healthcare in France: survey on the advice of the public health medical officers].

BACKGROUND: Public health medical officers of the different French administrative districts are called in to advise the public authorities (Préfet) on requests for a residence permit from foreigners seeking healthcare asylum in France. Using a medical report chart, the medical officer specifies whether the foreigner requires treatment, whether lack of medical care can have exceptionally serious consequences and whether the patient can obtain a suitable treatment in his/her own country. Considering the marked increase in the number of requests for healthcare asylum and the potential subjective aspect of the medical officer's advice, a survey was conducted to assess medical officers'practices. METHODS: In March 2002, a questionnaire was addressed by email to the medical officers practising in the 94 administrative districts of metropolitan France. They were to give their advice about two fictional requests for healthcare asylum; the fictional requests closely mimicked real situations which frequently raise difficult issues. The two seekers were a 57-year-old man from Comoros treated for hypertension and noninsulin-dependent diabetes mellitus (case 1) and a 33-year-old woman from the Ivory Coast followed after treatment for tuberculosis (case 2). RESULTS: Among the 94 district medical officers contacted, 42 (45%) responded. Respectively 88% (case 1) and 67% (case 2) of the medical officers considered that the patient required medical care because lack of care would have serious consequences, but for 26% (cases 1 and 2), treatment could be delivered in the country of origin. Finally, the advise proposed by the different officers varied: for 33% (case 1) and 53% (case 2) of the medical officers, asylum in France for healthcare was unjustified. CONCLUSIONS: In spite of a low response rate, this survey shows the subjectivity of the advice provided by medical officers, raising the question of its fairness. Our study suggests that this subjectivity is related to the vagueness of the questions asked to the medical officers and the lack of a frame of reference on which to base their advice.

Delivery of Health Care↗

PubMed2003

[Spectral analysis of the ECG R-R interval permits early detection of vagal responses to neurosurgical stimuli].

OBJECTIVE: To assess the efficacy of ECG spectral analysis, compared with heart rate (HR) monitoring in the detection of vagal response to surgical stimuli. METHODS: Twenty Asa II-III patients (age: 65 +/- 13 years) scheduled for surgery of cerebellopontine angle or implantation of sacral root stimulator were examined. Target controlled infusion of propofol (2-4 microg x ml(-1)) and remifentanil (4 ng x ml(-1)) was guided by the bispectral index (Bis). Arterial pressure via a radial catheter, pulse oximetry and end tidal CO2 were continuously monitored. Spectral analysis was achieved by connecting a computer to the cardiorespiratory monitor. Online power spectrum densities were calculated from the ECG R-R interval by software based on the fast Fourier transform (LabView, National Instruments, USA). Low frequency (LF: 0.04-0.15Hz) and high frequency (HF: 0.15-0.4Hz) were associated with sympathetic and parasympathetic activities respectively. We defined vagal reaction as a decrease in FC or an increase in HF >10% of the prestimuli value. HF and FC were compared according to the detection delay (by a Student t test with p < 0.05 considered significant) and a concordance test with a kappa coefficient (kappa): -1 = total discordance to 1 = total concordance. RESULTS: Twelve vagal reactions (observed in 8 patients) were detected within 5.5 +/- 1.3 s (HF) and 12.4 +/- 1.6 (FC); p < 0.001. Concordance between the 2 parameters was 95% (kappa =0.9). CONCLUSION: The ECG spectral analysis is a non-invasive technique, which permits the detection of intra-operative vagal reactions earlier than conventional monitoring of HR.

Aged↗

PubMed1998

Will angiotensin converting enzyme genotype, receptor mutation identification, and other miracles of molecular biology permit reduction of NNT?

Severe forms of hypertension demand treatment because they have a high incidence of morbidity and mortality that can be reduced by antihypertensive therapy. Stage 1-2 hypertension has a low morbidity and mortality; short-term benefits of treatment are harder to document. Managed care organizations know that members have a high turnover rate, so they are less interested in costly mass treatment to prevent a few future events. Stage 1-2 hypertension causes the vast majority of morbid events simply because a low incidence in a large population exceeds the lower absolute number of events in a small population with a high incidence. We must focus our efforts and resources on hypertensives at highest risk and thereby reduce the number needed to treat for 5 years (NNT) to avoid a morbid event. Obvious risks include hypertension severity, existing target organ damage, and concomitant diseases. Clues to the genetic etiology of primary hypertension are less obvious. DD genotype for angiotensin-converting enzyme (ACE) is associated with more left ventricular hypertrophy and greater risk for cardiovascular morbid events. Some genotypes of nitric oxide synthetase are associated with less effective production of NO and achieve less arterial vasodilation in response to stimuli. Many receptors have mutations that make them more or less functionally appropriate. Understanding these genetic factors may permit us in the future to focus appropriate drug therapy on the population most likely to benefit, thereby reducing NNT.

Genotype↗

PubMed1989

Correction of deep overbite. A modified splint permitting rapid extrusion of posterior teeth.

The use of a modified splint in the surgical-orthodontic treatment of Class II deep overbite deformities is presented. The splint permits a reduction of the preoperative orthodontic treatment-time because hardly any (time consuming) levelling of the dental arch is indicated while the time of postoperative orthodontic treatment is shortened, because of the possibility of continuing orthodontic treatment during the intermaxillary fixation period. The clockwise rotational movement which occurs with this treatment modality has, additionally, a favourable effect on the anterior facial height and in many cases on the position of the chin. Finally the intake of food during the immobilization period is facilitated.

Humans↗

PubMed1997

Simple apparatus for serial blood sampling in rodents permitting simultaneous measurement of locomotor activity as illustrated with cocaine.

A simple device has been developed for serial venous blood sampling which permits the simultaneous measurement of locomotor activity in the freely moving rat. The device can be easily constructed from routine laboratory material and it does not interfere with the light beams used to measure locomotor activity. The device, in conjunction with an activity cage, has been applied to the combined pharmacokinetic and pharmacodynamic modeling of cocaine. The relationship between the locomotor activity following a single short iv infusion of cocaine (5 mg/kg) and cocaine plasma concentrations can be adequately described by the Sigmoid-E(max) model. Further, the relationship between activity and time can be described by the same model coupled with an effect compartment. These results suggest the applicability of the device in facilitating pharmacokinetic/pharmacodynamic modeling of drugs that affect locomotor activity.

Animals↗

PubMed1990

Hydrolysis of 3'-terminal mispairs in vitro by the 3'----5' exonuclease of DNA polymerase delta permits subsequent extension by DNA polymerase alpha.

Purified DNA polymerase alpha, the major replicating enzyme found in mammalian cells, lacks an associated 3'----5' proofreading exonuclease that, in bacteria, contributes significantly to the accuracy of DNA replication. Calf thymus DNA polymerase alpha cannot remove mispaired 3'-termini, nor can it extend them efficiently. We designed a biochemical assay to search in cell extracts for a putative proofreading exonuclease that might function in concert with DNA polymerase alpha in vivo but dissociates from it during purification. Using this assay, we purified a 3'----5' exonuclease from calf thymus that preferentially hydrolyzes mispaired 3'-termini, permitting subsequent extension of the correctly paired 3'-terminus by DNA polymerase alpha. This exonuclease copurifies with a DNA polymerase activity that is biochemically distinct from DNA polymerase alpha and exhibits characteristics described for a second replicative DNA polymerase, DNA polymerase delta. In related studies, we showed that the 3'----5' exonuclease of authentic DNA polymerase delta, like the purified exonuclease, removes terminal mispairs, allowing extension by DNA polymerase alpha. These data suggest that a single proofreading exonuclease could be shared by DNA polymerases alpha and delta, functioning at the site of DNA replication in mammalian cells.

Animals↗