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Biomedical subjects

M Feinberg

Publications and source records attributed to M Feinberg.

At least 19 recordsLinked to original sources

Multiple equilibria in complex chemical reaction networks: extensions to entrapped species models.

In two earlier papers, means were provided to decide the capacity of complex chemical reaction networks, taken with mass-action kinetics, to admit multiple equilibria in the context of the isothermal homogeneous continuous flow stirred tank reactor (CFSTR). In such a reactor, all species are deemed to be in the outflow, a fact which has an important bearing on the nature of the governing equations. In contrast, one can imagine CFSTR-like models of the cell in which certain large molecules (e.g., enzymes) remain entrapped within the cell, whereas smaller ones (e.g., metabolites) are free to diffuse through the cell boundary. Although such models bear a strong physical resemblance to the classical CFSTR picture, there are substantive differences in the corresponding mathematics. Without a presumption of mass-action kinetics, this research is intended to indicate a general way in which results about uniqueness of equilibria in the classical CFSTR context extend to entrapped species models.

Bioreactors↗

[Harmonisation of validation strategies and estimation of the associated uncertainty in the framework of assay laboratoires accreditation].

In order to achieve the harmonization of validation strategies, the interpretation of several validation criteria is proposed. Furthermore, a simple and visual decision tool to assess the validity of an analytical procedure is described: the accuracy profile based on the estimation of the total error of the measurements. This profile build with beta-expectation tolerance intervals can also compute with efficiency the uncertainty related to the results of a laboratory, which is an essential parameter for the accreditation of laboratories under ISO 17025.

Accreditation↗

The lack of a simple relation between physician's percutaneous coronary intervention volume and outcomes in the era of coronary stenting: a two-centre experience.

The 2001 ACC/AHA guidelines recommend that percutaneous coronary intervention (PCI) operators perform at least 75 procedures per year to maintain their competency. We performed a post hoc analysis of prospectively gathered PCI data, in the current era of ubiquitous stent use, at two tertiary cardiac care centres. Operators were assigned to a low (<50 cases per year), intermediate (50-74 cases per year) or high volume (>or=75 cases per year) group. Complications evaluated were death, myocardial infarction, coronary perforation, emergent coronary artery bypass surgery and pericardial tamponade. Between 2000 and 2002, 51 operators performed 6,510 PCIs. Stents were used in 79% of cases. Major complications occurred in 0.45% (7/1,572 cases) for the low-volume group, 1.1% in the intermediate-volume group (16/1,438 cases) and 0.86% (30/3,500 cases) for the high-volume group. After adjusting for baseline factors, low- and intermediate-volume operators were not significantly associated with major complications. This study questions the relationship between operator volume and PCI complications in the current era.

Aged↗

Harmonization of strategies for the validation of quantitative analytical procedures. A SFSTP proposal--Part I.

This paper is the first part of a summary report of a new commission of the Société Française des Sciences et Techniques Pharmaceutiques (SFSTP). The main objective of this commission was the harmonization of approaches for the validation of quantitative analytical procedures. Indeed, the principle of the validation of theses procedures is today widely spread in all the domains of activities where measurements are made. Nevertheless, this simple question of acceptability or not of an analytical procedure for a given application, remains incompletely determined in several cases despite the various regulations relating to the good practices (GLP, GMP, ...) and other documents of normative character (ISO, ICH, FDA, ...). There are many official documents describing the criteria of validation to be tested, but they do not propose any experimental protocol and limit themselves most often to the general concepts. For those reasons, two previous SFSTP commissions elaborated validation guides to concretely help the industrial scientists in charge of drug development to apply those regulatory recommendations. If these two first guides widely contributed to the use and progress of analytical validations, they present, nevertheless, weaknesses regarding the conclusions of the performed statistical tests and the decisions to be made with respect to the acceptance limits defined by the use of an analytical procedure. The present paper proposes to review even the bases of the analytical validation for developing harmonized approach, by distinguishing notably the diagnosis rules and the decision rules. This latter rule is based on the use of the accuracy profile, uses the notion of total error and allows to simplify the approach of the validation of an analytical procedure while checking the associated risk to its usage. Thanks to this novel validation approach, it is possible to unambiguously demonstrate the fitness for purpose of a new method as stated in all regulatory documents.

Chemistry Techniques, Analytical↗

Statistical methodology to evaluate food exposure to a contaminant and influence of sanitary limits: application to Ochratoxin A.

This paper presents some statistical methodologies to evaluate the food exposure to a contaminant and quantify the outcome of a new maximum limit on a food item. Our application deals with Ochratoxin A (OTA). We focus on the quantitative evaluation of the distribution of exposure based on both consumption data and contamination data. One specific aspect of contamination data is left censorship due to the limits of detection. Three calculation procedures are proposed: [P1] a deterministic method using means of contamination; [P2] a probabilistic method using a parametric adjustment of the distributions of contamination taking into account the left censorship; and [P3] a non-parametric method which consists in randomly selecting the consumption data and the contamination values. Our main result shows that a non-parametric probabilistic approach is well adapted for the purpose of exposure assessment, when large samples are available. In the application to OTA, the probability to exceed a safe level is high, particularly for children. Simulations show that the impact of the existing standards on cereals and the currently proposed standards on wine generally do not significantly reduce the risk to be overexposed to OTA.

Adult↗

Establishing a new research agenda for studying psychiatric emergency room treatment decisions.

With the growing complexity of treatment decisions made at presentation to a psychiatric emergency room (PER) and the increasing influence of managed care on the decision-making process, it is increasingly important to establish a new and more sophisticated research agenda for studying PER decision making. The main goal of this paper is to propose a comprehensive conceptual model of the PER decision-making process that will facilitate active pursuit of such a research agenda. The proposed model presents both traditional and emerging elements of the PER decision-making process (i.e., determinants, mediating mechanisms, and outcomes) and explicates the nature of the relationships among them at different levels of analysis. The model's theoretical and empirical implications for future research are discussed and suggestions are made as to the research designs and methods needed to pursue this agenda.

Decision Making↗

Differential parenting as a within-family variable.

Nonshared environmental influences have been found to be important for adolescent development. This study of 516 families investigated whether differential parental negativity or warmth is linked to adolescent adjustment apart from the effect of the level of parenting toward each child separately. After accounting for level of parental treatment to the adolescent, the authors found that differential parenting to the siblings contributed unique variance in adjustment. Significant interactions were found between level of parenting and differential parenting. In each case, differential parenting was more strongly linked to adjustment when the level of parenting was low in warmth or high in negativity. These results are indirect evidence that differential parenting can be considered a within-family influence on sibling adjustment and as direct evidence that nonshared environmental factors may systematically vary in strength between families.

Adaptation, Psychological↗

Lymph node architecture preceding and following 6 months of potent antiviral therapy: follicular hyperplasia persists in parallel with p24 antigen restoration after involution and CD4 cell depletion in an AIDS patient.

OBJECTIVES: To evaluate changes in architecture, viral RNA, and viral protein over 6 months in lymph nodes from retroviral-naïve HIV-infected persons before and after commencing highly active antiretroviral therapy (HAART). METHODS: Nine antiretroviral-naïve HIV-infected persons had lymph nodes excised at baseline and at 2 and 6-8 months after beginning a four-drug combination regimen containing zidovudine, lamivudine, nevirapine, and indinavir. Two patients had AIDS. Lymph nodes were examined by immunohistochemical staining for Gag p24 HIV, CD3, CD21, CD20, HAM 56, and Ki67 antigens and by in-situ hybridization (ISH) for HIV RNA and H3-histone RNA. RESULTS: Eight of nine baseline lymph nodes showed follicular hyperplasia and germinal center and paracortical mononuclear cell activation. At 2 months, the lymph nodes from seven patients, including the AIDS patients, showed more follicular hyperplasia and activation than their baseline specimens but with decreased mononuclear cell activation. By 6 months, seven lymph nodes were less hyperplastic and activated than their corresponding 2 month specimens. Combined ISH/immunohistochemical staining of baseline lymph nodes revealed productively infected T (CD3) and B (CD20) cells and macrophages (HAM56+). HIV RNA-positive mononuclear cells were infrequent at 2 months, and rare at 6 months. HIV RNA was still associated with follicular dendritic cells (FDC) at 2 months, but not at 6 months. HIV p24-positive antigen in germinal centers persisted through all 6, and the one 8 month specimens. The baseline lymph nodes from one of the AIDS patients was involuted and T cell depleted, whereas the follow-up lymph nodes were hyperplastic with normal T cell levels. CONCLUSION: Follicular hyperplasia and cell activation, possibly caused by persistent viral protein in germinal centers, may help explain why HIV viremia rebounds so rapidly after the interruption of HAART. Restoration of architecture may follow the treatment of patients with AIDS who initially had involuted and CD4 cell-depleted lymph nodes.

Acquired Immunodeficiency Syndrome↗

The significance of persistent ST elevation versus early resolution of ST segment elevation after primary PTCA.

OBJECTIVES: To determine the prevalence and clinical significance of early ST segment elevation resolution after primary percutaneous transluminal coronary angioplasty (PTCA) for acute myocardial infarction (AMI). BACKGROUND: Despite angiographically successful restoration of coronary flow early during AMI, adequate myocardial reperfusion might not occur in a substantial portion of the jeopardized myocardium due to microvascular damage. This phenomenon comprises the potentially beneficial effect of early recanalization of the infarct related artery (IRA). METHODS: Included in the study were 117 consecutive patients who underwent angiographically successful [Thrombolysis in Myocardial Infarction (TIMI III)] primary PTCA. The patients were classified based on the presence or absence of reduction > or =50% in ST segment elevation in an ECG performed immediately upon return to the intensive cardiac care unit after the PTCA in comparison with ECG before the intervention. RESULTS: Eighty-nine patients (76%) had early ST segment elevation resolution (Group A) and 28 patients (24%) did not (Group B). Group A and B had similar clinical and hemodynamic features before referring to primary PTCA, as well as similar angiographic results. Despite this, ST segment elevation resolution was associated with better predischarge left ventricular ejection fraction (LVEF) (44.7 +/- 8.0 vs. 38.2 +/- 8.5, p < 0.01). Group B patients, as compared with those of Group A, had a higher incidence of in-hospital mortality (11% vs. 2%, p = 0.088), congestive heart failure (CHF) [28% vs. 19%, odds ratio (OR) = 4, 95% confidence interval (CI) 1 to 15, p = 0.04], higher long-term mortality (OR = 7.3, 95% CI 1.9 to 28, p = 0.004 with Cox proportional hazard regression analysis) and long-term CHF rate (OR = 6.5, 95% CI 1.3 to 33, p = 0.016 with logistic regression). CONCLUSIONS: Absence of early ST segment elevation resolution after angiographically successful primary PTCA identifies patients who are less likely to benefit from the early restoration of flow in the IRA, probably because of microvascular damage and subsequently less myocardial salvage.

Angioplasty, Balloon, Coronary↗

Difficulties inherent in certifying people with gender dysphoria.

This is a first report of the aeromedical implications of an airman undergoing gender transformation. It is clear that during the period of instituting high-dose hormones to undergo sexual transformation appropriate observation periods should be implemented due to the strong effects of these drugs on the psyche.

Adult↗

Synaptogenesis via dendritic filopodia in developing hippocampal area CA1.

To determine the role of dendritic filopodia in the genesis of excitatory synaptic contacts and dendritic spines in hippocampal area CA1, serial section electron microscopy and three-dimensional analysis of 16 volumes of neuropil from nine male rat pups, aged postnatal day 1 (P1) through P12, were performed. The analysis revealed that numerous dendritic filopodia formed asymmetric synaptic contacts with axons and with filopodia extending from axons, especially during the first postnatal week. At P1, 22 +/- 5.5% of synapses occurred on dendritic filopodia, with 19 +/- 5.9% on filopodia at P4, 20 +/- 8.0% at P6, decreasing to 7.2 +/- 4.7% at P12 (p < 0.02). Synapses were found at the base and along the entire length of filopodia, with many filopodia exhibiting multiple synaptic contacts. In all, 162 completely traceable dendritic filopodia received 255 asymmetric synaptic contacts. These synapses were found at all parts of filopodia with equal frequency, usually occurring on fusiform swellings of the diameter. Most synaptic contacts (53 +/- 11%) occurred directly on dendritic shafts during the first postnatal week. A smaller but still substantial portion (32 +/- 12%) of synapses were on shafts at P12 (p < 0.036). There was a highly significant (p < 0.0002) increase in the proportion of dendritic spine synapses with age, rising from just 4.9 +/- 4.3% at P1 to 37 +/- 14% at P12. The concurrence of primarily shaft and filopodial synapses in the first postnatal week suggests that filopodia recruit shaft synapses that later give rise to spines through a process of outgrowth.

Aging↗

Recognition of two overlapping CTL epitopes in HIV-1 p17 by CTL from a long-term nonprogressing HIV-1-infected individual.

HIV-1 infection has been shown to elicit strong CTL responses in some infected persons, but few data are available regarding the relationship between targeted epitopes and in vivo viral quasispecies. In this study, we examined the CTL response in a person infected for 15 yr with a CD4 count persistently >500 cells/microl. The dominant in vivo activated CTL response was directed against two overlapping Gag CTL epitopes in an area of p17 known to be essential for viral replication. The 9-mer SLYNTVATL (amino acids 77-85) was recognized in conjunction with HLA-A2, whereas the overlapping 8-mer TLYCVHQR (amino acids 83-91) was recognized by HLA-A11-restricted CTL. Analysis of in vivo virus sequences both in PBMC and plasma revealed the existence of sequence variation in this region, which did not affect viral replication in vitro, but decreased recognition by the A11-restricted CTL response, with maintenance of the A2-restricted response. These results indicate that an essential region of the p17 protein can be simultaneously targeted by CTL through two different HLA molecules, and that immune escape from CTL recognition can occur without impairing viral replication. In addition, they demonstrate that Ag processing can allow for presentation of overlapping epitopes in the same infected cell, which can be affected quite differently by sequence variation.

Amino Acid Sequence↗

HIV infection: how effective is drug combination treatment?

The rate of decline of plasma HIV RNA in patients treated with anti-retroviral drugs has been postulated to reflect the half-lives of previously HIV-infected cells. Here, Zvi Grossman and colleagues argue that the observed decline is explained by the kinetics of ongoing infection cycles. Residual cell-to-cell infection that becomes increasingly difficult to block could stabilize cellular provirus reservoirs.

Anti-HIV Agents↗

Diverse host responses and outcomes following simian immunodeficiency virus SIVmac239 infection in sooty mangabeys and rhesus macaques.

Sooty mangabeys naturally infected with simian immunodeficiency virus (SIV) do not develop immunodeficiency despite the presence of viral loads of 10(5) to 10(7) RNA copies/ml. To investigate the basis of apathogenic SIV infection in sooty mangabeys, three sooty mangabeys and three rhesus macaques were inoculated intravenously with SIVmac239 and evaluated longitudinally for 1 year. SIVmac239 infection of sooty mangabeys resulted in 2- to 4-log-lower viral loads than in macaques and did not reproduce the high viral loads observed in natural SIVsmm infection. During acute SIV infection, polyclonal cytotoxic T-lymphocyte (CTL) activity coincident with decline in peak plasma viremia was observed in both macaques and mangabeys; 8 to 20 weeks later, CTL activity declined in the macaques but was sustained and broadly directed in the mangabeys. Neutralizing antibodies to SIVmac239 were detected in the macaques but not the mangabeys. Differences in expression of CD38 on CD8(+) T lymphocytes or in the percentage of naive phenotype T cells expressing CD45RA and CD62L-selection did not correlate with development of AIDS in rhesus macaques. In macaques, the proportion of CD4(+) T lymphocytes expressing CD25 declined during SIV infection, while in mangabeys, CD25-expressing CD4(+) T lymphocytes increased. Longitudinal evaluation of cytokine secretion by flow cytometric analysis of unstimulated lymphocytes revealed elevation of interleukin-2 and gamma interferon in a macaque and only interleukin-10 in a concurrently infected mangabey during acute SIV infection. Differences in host responses following experimental SIVmac239 infection may be associated with the divergent outcome in sooty mangabeys and rhesus macaques.

Animals↗

Recognition of the highly conserved YMDD region in the human immunodeficiency virus type 1 reverse transcriptase by HLA-A2-restricted cytotoxic T lymphocytes from an asymptomatic long-term nonprogressor.

The human immunodeficiency virus (HIV) type 1 reverse transcriptase (RT) is an important target for therapeutic intervention and for HIV-1-specific cytotoxic T lymphocytes (CTL). An HLA-A2-restricted CTL epitope containing the sequence YMDD, which is highly conserved among human and animal retroviruses and essential for function of the RNA-dependent DNA polymerase, is identified. The drug resistance mutation at RT amino acid 184 (M184V), associated with (-)-2'-deoxy-3'-thiacytidine (lamivudine), (-)-2'-deoxy-5-fluoro-3'-thiacytidine (FTC), and dideoxyinosine resistance, is located within this epitope and abolishes recognition by an established CTL response. This study demonstrates that the CTL response may target functionally relevant regions of the RT protein and suggests drug therapy may select for viral variants with altered susceptibility to established cellular immune responses.

Amino Acid Sequence↗