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Biomedical subjects

J Martin

Publications and source records attributed to J Martin.

At least 235 records · Page 13Linked to original sources
PubMed2000

Antibody-directed enzyme prodrug therapy: efficacy and mechanism of action in colorectal carcinoma.

In antibody-directed enzyme prodrug therapy, an enzyme conjugated to an antitumor antibody is given i.v. and localizes in the tumor. A prodrug is then given, which is converted to a cytotoxic drug selectively in the tumor. Ten patients with colorectal carcinoma expressing carcinoembryonic antigen received antibody-directed enzyme prodrug therapy with A5B7 F(ab')2 antibody to carcinoembryonic antigen conjugated to carboxypeptidase G2 (CPG2). A galactosylated antibody directed against the active site of CPG2 (SB43-gal) was given to clear and inactivate circulating enzyme. A benzoic acid mustard-glutamate prodrug was given when plasma enzyme levels had fallen to a predetermined safe level, and this was converted by CPG2 in the tumor into a cytotoxic form. Enzyme levels derived from quantitative gamma camera imaging and from direct measurements in plasma and tumor biopsies showed that the median tumor:plasma ratio of enzyme exceeded 10000:1 at the time of prodrug administration. Enzyme concentrations in the tumor (median, 0.47 units g(-1)) were sufficient to generate cytotoxic levels of active drug. The concentration of prodrug needed for optimal conversion (Km) of 3 microM was achieved. Prodrug conversion to drug was shown by finding detectable levels of drug in plasma. There was evidence of tumor response; one patient had a partial response, and six patients had stable disease for a median of 4 months after previous tumor progression (one of these six had a tumor marker response). Manageable neutropenia and thrombocytopenia occurred. Conditions for effective antitumor therapy were met, and there was evidence of tumor response in colorectal cancer.

Adult↗
PubMed2000

Haemostatic and lipid determinants of prothrombin fragment F1.2 and D-dimer in plasma.

The determinants of plasma levels of prothrombin fragment F1.2 (F1.2) and D-dimer in different populations are unclear and this may complicate their interpretation as predictors of thrombotic risk, particularly in the case of D-dimer. We therefore measured F1.2 and D-dimer levels together with a number of other haemostatic and lipid variables in a cross-sectional community-based study of 150 healthy adults (73 male, 77 female), age range 23-80 years, identified from the list of a general practice by stratified random sampling within sex and decade of age. Plasma F1.2 was significantly higher in females than males and was independently and positively associated with age, factor VII activity (FVIIc) and C1 inhibitor, and inversely associated with high density lipoprotein (HDL) cholesterol. Plasma D-dimer showed a quadratic association with age (p <0.0001). In those < or =55 years D-dimer was inversely associated with dilute clot lysis time (DCLT) and activated protein C (APC) ratio. In those >55 years it was significantly higher in females than males and associated positively with age, fibrinogen and, in males, activated factor XII (FXIIa). In a multiple-linear model which combined both age groups, F1.2 and D-dimer were independently associated with each other (r = 0.22, p = 0.03). Thus, thrombin generation and fibrin turnover/fibrinolysis are associated in healthy subjects. HDL cholesterol (inversely) and FVIIc are associated with basal thrombin generation (i.e. F1.2). Determinants of D-dimer differ according to age and interpretation of the biological significance of D-dimer levels in epidemiological studies may therefore not be straightforward.

Adult↗
PubMed2000

Between the modern and the postmodern. The possibility of self and progressive understanding in psychology.

Psychology assumes defensible notions of human subjectivity and understanding. Yet, some versions of postmodernism, including some of those currently influential within psychology, eschew the possibility of the kind of understanding-capable personhood on which modern psychology has depended. The authors argue for a skeptical, middle-ground position that might allow psychologists to resist a forced choice between modernism and postmodernism in their subject matter and understanding. The authors set up their argument with 2 stories of human development and change. These stories assume no fixed, essentialist foundations of the sort favored in classically modern psychologies, yet they maintain the possibility of both self and understanding within a real but contingent physical, biological, and sociocultural world. The authors then articulate a middle-ground position as one that avoids the fixed foundationalism, essentialism, and absolute certitude of modernity, without endorsing the radical arbitrariness, antisubjectivism, and anarchistic relativism of some versions of postmodernity.

Ego↗
PubMed2000

Synovial joint degeneration and the syndrome of osteoarthritis.

The adverse effects of osteoarthritis on the quality of life for tens of millions of people and on the costs of health care and economic productivity make it a major health problem that will increase in incidence and impact with the aging of the population. Although in most patients the cause of osteoarthritis remains unknown and no cure has been identified, appropriate diagnosis and treatment, including education of the patients, can minimize symptoms and help patients maintain active and productive lives. Accomplishing this aim requires that physicians have an understanding of the pathophysiology of joint degeneration and the relationships between joint degeneration and the clinical syndrome of osteoarthritis. Although much remains to be learned about the development and progression of the joint degeneration responsible for osteoarthritis, it is clear that the loss of articular cartilage results from disruption of the structural integrity of the articular cartilage coupled with or caused by an imbalance in the anabolic and catabolic activity of the tissue. The progression of joint degeneration varies considerably among patients. In some individuals the joint degenerates rapidly; in others the degenerative changes progress slowly over decades and in others the disease may remain stable. In rare patients, the joint degenerative changes spontaneously improve. Although joint degeneration is the underlying cause of the symptoms of osteoarthritis, including joint pain and loss of joint function, not all patients with joint degeneration have symptoms of osteoarthritis. Future therapeutic approaches may include disease-modifying drugs and surgical procedures that correct mechanical abnormalities, debride joints, and replace degenerated articular cartilage with implants that stimulate restoration of a cartilaginous joint surface. Development of methods to detect and monitor subtle changes in cartilage metabolism and identify the joint changes that precede loss of articular cartilage may make it possible to detect the earliest signs of osteoarthritis, when therapeutic interventions have the greatest potential for preventing progression of the disease.

Humans↗
PubMed2000

[Technique of harvesting and preparation of amniotic membranes].

Amniotic membrane transplantation is a promising surgical technique for clinical management of ocular surface diseases. According to the first published results, the ease with which this highly available tissue can be prepared and preserved makes this technique very attractive. The aim of our study is to report procurement procedures and the preparation technique for amniotic membrane in accordance with the French tissue transplantation legislation.

Amnion↗
PubMed2000

Protecting human health in a changing world: the role of social and economic development.

The biological and physical environment of the planet is changing at an unprecedented rate as a result of human activity, and these changes may have an enormous impact on human health. One of the goals of human development is to protect health in the face of rapid environmental change, but we often fail to do this. The aim in this paper is to distinguish between socioeconomic aspects of development that are likely to be protective and those that are likely to increase vulnerability (the capacity for loss resulting from environmental change). Examples include climate change in the Pacific. We conclude that protecting human health in a changing world requires us to take steps to minimize harmful change wherever possible, and at the same time to be prepared for surprises. The goals of mitigation (reducing or preventing change) and adaptation (response to change) are not mutually exclusive. In fact, steps to make populations more resilient in the face of change are often similar to those that are needed to lighten the load on the environment. We need social policies that convert economic growth into human development. Wider application of sustainable development concepts is part of the solution. In particular, there is a need to promote health as an essential asset of poor and vulnerable populations. It is their key to productivity and to surviving shocks; it is also the key to achieving broader development goals such as universal education. For these reasons it is in the interests of all sectors--economic, social and environmental--to play their particular roles in protecting and improving health.

Adult↗
PubMed2000

[Epidemiological and therapeutic aspects of plasmodial infection from Plasmodium vivax].

A major challenge for successful treatment of Plasmodium vivax malaria is prevention of recurrence due to activation of dormant intrahepatic parasitic forms called hypnozoits. As a result of strain variability, recurrences are unpredictable and can occur months or even years after initial infection. Prevention requires elimination of both erythrocytic and hepatic parasite forms by combined use of chloroquine and primaquine. Primaquine is the only commercially available drug against hypnozoits. Several factors must be taken into account in planning treatment regimens. One factor is drug resistance of vivax strains, which as observed for Plasmodium falciparum strains is variable between geographical areas. Another factor is potential co-infection by Plasmodium vivax and falciparum, which is increasingly common. For optimal efficacy, treatment regimens must be adjusted with regard to dosage of primaquine and association with halofantrine, mefloquine or other new antimalarial agents. No regimen completely rules out the risk of recurrence.

Antimalarials↗
PubMed2000

[Nancy medicines for hospices and prisons in 1805].

The chemist François Mandel, past author of Pharmcopée de Nancy, writes a list of medicines for civil hospices and a formulary for prisons. To take care of these adult, poor sick, drugs and medicines are chosen simple, at little expense, but adequate to treat everyday diseases. The prison formulary holds many novel preparations. The two manuscripts have never been published.

France↗
PubMed1999

Identification and localization of ataxin-7 in brain and retina of a patient with cerebellar ataxia type II using anti-peptide antibody.

Autosomal dominant cerebellar ataxias (ADCAs) are a complex group of neurodegenerative disorders characterized by progressive degeneration of the cerebellum, brain stem and spinal cord. The spinocerebellar ataxia type 7 (SCA7) is associated with pigmentary macular dystrophy and retinal degeneration leading to blindness caused by a CAG/polyglutamine (polyGln) expansion in the coding region of the SCA7 gene/protein. The SCA7 gene codes for ataxin-7, a protein of unknown function. To investigate its cellular and subcellular localization, we have developed a sequence-specific polyclonal antibody against the N-terminal part of the protein. Immunohistochemical analysis indicated that ataxin-7 accumulates as single nuclear inclusion (NI) in the cells of the brain and retina of a SCA7 patient but not of controls. The 1C2 antibody, directed against expanded polyGln, confirmed the aggregation of mutant ataxin-7 in these NIs. Furthermore, ubiquitin was found in these aggregates, suggesting that mutant ataxin-7 is a target for ubiquitin-dependent proteolysis, but resistant to removal. Electron microscopic studies using immunogold labeling showed that ataxin-7 immunoreactive NIs appear as dense aggregates containing a mixture of granular and filamentary structures. Together, these data confirm the presence of NIs in brain and retina of a SCA7 patient, a common characteristic of disorders caused by expanded CAG/polyGln repeats.

Adult↗
PubMed1999

Latent membrane protein 1 associated signaling pathways are important in tumor cells of Epstein-Barr virus negative Hodgkin's disease.

The latent membrane protein 1 (LMP1) oncogene of Epstein-Barr virus (EBV) is selectively expressed in the Reed-Sternberg (RS) cells of EBV-associated Hodgkin's disease (HD). However, no differences in clinical presentation and course are found between EBV positive and EBV negative forms of HD suggesting a common pathogenetic mechanism. We have studied the LMP1 associated signaling pathways and their dominant negative inhibition in the myelomonocytic HD-MyZ and the B-lymphoid L-428 HD cell lines. In both EBV negative cell lines expression of LMP1 is associated with the formation of multinuclear RS cells. Dominant negative inhibition of NF-kappa B mediated signaling at the step of I kappa B-alpha phosphorylation results in increased cell death with only a few typical RS cells resistant to overexpression of the dominant negative inhibitor I kappa B-alpha-N delta 54. However, dominant negative inhibition of NF-kappa B mediated signaling at the early step of TRAF2 interaction results in the formation of multinuclear cells in both cell lines and, in addition, in clusters of small mononuclear cells in the HD-MyZ cell line. In HD-MyZ cells overexpression of the powerful JBD-inhibitor of the JNK signal transduction pathway is restricted to small cells and never observed in RS cells. These small cells undergo apoptosis as shown by the TUNEL technique. Apoptosis of small cells is still observed after co-transfection of JBD and LMP1 but in addition a few apoptotic HD-MyZ cells with large fused nuclear masses are identified suggesting that specific inhibition of JNK leads also to apoptosis of LMP1 induced RS cells. Thus, activation of the JNK signaling pathway is also important in the formation of Reed-Sternberg cells. Our findings are consistent with a model where all three LMP1 associated functions, i.e. NF-kappa B mediated transcription, TRAF2 dependent signaling, and c-Jun activation act as a common pathogenetic denominator of both EBV negative and EBV positive HD.

Herpesvirus 4, Human↗
PubMed1999

Spinocerebellar ataxia type 7 (SCA7) - correlations between phenotype and genotype in one large Belgian family.

Spinocerebellar ataxia type 7 (SCA7), in which the degenerative process also affect the retina, belongs to the category of the autosomal dominant cerebellar ataxia type II (ADCA II). We have described the neuropathology of this condition [Martin JJ, Van Regemorter N, Krols L, Brucher JM, de Barsy T, Szliwowski H, et al. On an autosomal dominant form of retino-cerebellar degeneration: an autopsy study of five patients in one family. Acta Neuropathol (Berl) 1994;88:277-286] in a very large Belgian family (CA-1). We have observed anticipation in the age of onset with increasing severity of the symptoms in consecutive generations. The SCA7 gene was mapped to chromosome 3p12-13 [David G, Abbas N, Stevanin G, Dürr A, Yvert G, Cancel G, et al. Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat Genet 1997;17:65-70; Del-Favero J, Krols L, Michalik A, Theuns J, Löfgren A, Goossens D, et al. Molecular genetic analysis of autosomal dominant cerebellar ataxia with retinal degeneration (ADCA type II) caused by CAG triplet repeat expansion. Hum Mol Genet 1998;7:177-186], and the gene identified. SCA7 is a new gene of unknown function that contains an expansion of CAG repeats in SCA7 patients. During the procedure of positional cloning, we examined 26 patients belonging to the CA-1 family and realized, in some of them, an ophthalmologic examination and neuro-imaging of the brain. This allowed us to differentiate four groups: (1) asymptomatic young carriers with 38 to 43 CAG repeats; (2) mildly symptomatic, older patients with 38-41 CAG repeats; (3) patients with the full-blown picture of SCA7 and age of onset during adolescence, with 54-55 CAG repeats; (4) children with early onset and rapid fatal course of the disease who had over 55 CAG repeats. We were able to draw correlations between clinical phenotype, age at onset and CAG repeat number and to make predictions, to some extent, as to the clinical course of the disease in new patients.

Adult↗
PubMed1999

Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-coupled receptor SLC-1.

The underlying causes of obesity are poorly understood but probably involve complex interactions between many neurotransmitter and neuropeptide systems involved in the regulation of food intake and energy balance. Three pieces of evidence indicate that the neuropeptide melanin-concentrating hormone (MCH) is an important component of this system. First, MCH stimulates feeding when injected directly into rat brains; second, the messenger RNA for the MCH precursor is upregulated in the hypothalamus of genetically obese mice and in fasted animals; and third, mice lacking MCH eat less and are lean. MCH antagonists might, therefore, provide a treatment for obesity. However, the development of such molecules has been hampered because the identity of the MCH receptor has been unknown until now. Here we show that the 353-amino-acid human orphan G-protein-coupled receptor SLC-1 expressed in HEK293 cells binds MCH with sub-nanomolar affinity, and is stimulated by MCH to mobilize intracellular Ca2+ and reduce forskolin-elevated cyclic AMP levels. We also show that SLC-1 messenger RNA and protein is expressed in the ventromedial and dorsomedial nuclei of the hypothalamus, consistent with a role for SLC-1 in mediating the effects of MCH on feeding.

Alternative Splicing↗
PubMed1999

Self-immolative anthracycline prodrugs for suicide gene therapy.

Four novel potential prodrugs derived from daunorubicin (8, 10) and doxorubicin (12, 14) were designed and synthesized. They are self-immolative prodrugs for suicide gene therapy activation by the enzyme carboxypeptidase G2 (CPG2) subsequently releasing the corresponding anthracyclines, by a 1,6-elimination mechanism. A mammary carcinoma cell line (MDA MB 361) was engineered to express CPG2 intracellularly (CPG2) or extracellularly, tethered to the outer cell membrane (stCPG2(Q)3). The prodrugs derived from doxorubicin showed prodrug/drug cytotoxicity differentials of 21-fold (compound 12) and 23-fold (compound 14). Prodrug 12 underwent an 11-fold activation when assayed in the cell line expressing externally surface-tethered CPG2.

Antineoplastic Agents↗
PubMed1999

Sleep-disordered breathing and periodic limb movements in sleep in older patients with schizophrenia.

BACKGROUND: Since the prevalence of both sleep-disordered breathing (SDB) and periodic limb movements in sleep (PLMS) increase with age, we explored whether older schizophrenia patients would have a high incidence of SDB and PLMS. Correlations between sleep and clinical variables were also examined. METHODS: Fifty-two patients (mean age = 59.6 years, SD = 8.9) had their sleep/wake, respiration, and leg movements recorded using a modified Medilog/Respitrace portable recording system plus oximetry. A battery of clinical, psychosocial, and motor disturbance variables were collected by research center staff. RESULTS: Forty-eight percent of these patients had at least 10 respiratory events per hour of sleep. These patients reported more symptoms of daytime sleepiness than patients with fewer than 10 events per hour. The relatively high prevalence of SDB in this group may contribute to overall sleep disturbances, and does not appear to be a result of high body mass index. Only 14% of the patients had at least five limb movements per hour of sleep, suggesting the prevalence of PLMS is much lower than expected in this age group. The number of leg jerks was inversely related to symptoms of tardive dyskinesia. CONCLUSIONS: The disturbance of sleep in these patients may be due, in part, to SDB, but is unlikely due to PLMS.

Age Factors↗