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Biomedical subjects

J Laurence

Publications and source records attributed to J Laurence.

At least 19 recordsLinked to original sources
PubMed2003

On being a Kunkel acolyte.

Everything is interesting if you look at it deeply enough. There is no trivial question. This sentiment, attributed to Nobel laureate and physicist Richard Feynman, was Professor Henry Kunkel's message to all who began work in his laboratory. Learn as much as you can from a single informative patient. Keep looking. Play. But play, of course, in the Kunkel sense of exploration. The life of a Kunkel acolyte might be characterized as rejection, endurance and very late dinners. But then, on a few occasions, there was the thrill of a discovery he'd always help guide.

Autoimmune Diseases↗
PubMed2001

Role of transforming growth factor beta1 in microvascular endothelial cell apoptosis associated with thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome.

Primary human microvascular endothelial cells (MVEC) of restricted lineage undergo apoptosis when exposed to plasma from patients with thrombotic thrombocytopenic purpura (TTP) and sporadic hemolytic-uremic syndrome (HUS). This reflects the pathology and tissue distribution of lesions in vivo. As extracellular matrix (ECM) is critical to MVEC survival, and cytokines which regulate ECM, such as transforming growth factor (TGF)-beta1, have been reported anecdotally to be altered in TTP/HUS, we examined the role of TGF-beta1 and two ECM proteins, fibronectin and thrombospondin (TSP), in these disorders. Levels of active TGF-beta1 were elevated in acute but not convalescent phases of TTP/sporadic HUS, as well as TTP associated with human immunodeficiency virus infection and use of the anti-platelet drug ticlopidine. MVEC from tissues susceptible to TTP-mediated apoptosis showed little active TGF-beta1 production when exposed to TTP plasmas. In contrast, pulmonary MVEC and large-vessel EC, which are resistant to TTP-linked pathology, showed marked induction of TGF-beta1 following TTP plasma exposure. Exogenous TGF-beta1 suppressed TTP plasma-mediated apoptosis in susceptible MVEC in association with blockade of cell entry into S phase. Soluble TSP, devoid of detectable bound TGF-beta1, had a similar effect, which paralleled its ability to induce TGF-beta1 production in MVEC. In vivo, TSP deposition was diminished markedly in involved tissues of TTP patients. These data highlight the role of TGF-beta1 and ECM in TTP and suggest that differential production of TGF-beta1 by MVEC may play a role in their sensitivity or resistance to TTP/sporadic HUS-mediated apoptosis in vitro and in vivo.

Apoptosis↗
PubMed2001

Endothelial cell apoptotic genes associated with the pathogenesis of thrombotic microangiopathies: an application of oligonucleotide genechip technology.

Idiopathic thrombotic thrombocytopenic purpura (TTP) is a disease characterized by the apoptotic injury of all microvascular endothelial cells (MVEC) except those of pulmonary origin. It notably also spares EC of large vessel origin. It is fatal unless treated with plasma exchange. The EC lineage restriction of the apoptotic lesions in vivo is reproduced in vitro following exposure of primary human MVEC derived from various tissues to TTP plasma. Oligonucleotide genechip technology was used to identify genes that may contribute to the resistance of lung MVEC to apoptosis induced by TTP plasma and to explore the intrinsic genotypic heterogeneity between MVEC of TTP-sensitive (skin) versus resistant (lung) lineage. Exposure of cells to TTP or normal plasma yielded 157 genes that were differentially expressed in primary human lung MVEC. A global change in expression of pro- and anti-apoptotic genes was seen, including increases in caspase 1, Fas, and Bcl-xl, already shown by experimental means to be involved in TTP pathogenesis. Additional differences suggest the importance of pathways related to the death receptor ligand TRAIL, as well as a role for disruption of EC-extracellular matrix interactions in the initiation of apoptosis. Maintenance of specific prosurvival signals at baseline may be a feature of lung MVEC resistance in TTP as suggested by higher expression than skin EC of the TRAIL antagonist, osteoprotegerin, and the vascular endothelial growth factors, VEGF/VPF and VEGF-C, and their receptors, VEGFR-2 (KDR) and VEGFR-3 (Flt4).

Apoptosis↗
PubMed2001

Efficacy and tolerability of timolol maleate ophthalmic gel-forming solution versus timolol ophthalmic solution in adults with open-angle glaucoma or ocular hypertension: a six-month, double-masked, multicenter study.

BACKGROUND: Timolol has been formulated in a highly purified gellan gum to improve its duration of action. The efficacy of this formulation in short-term studies using once-daily dosing has been reported. OBJECTIVE: The purpose of this study was to evaluate the efficacy and tolerability of 0.5% timolol maleate ophthalmic gel-forming solution (timolol GS) given once daily versus 0.5% timolol solution given twice daily in a long-term trial. METHODS: This was a multicenter, double-masked, 6-month trial. After a washout of ocular hypotensive medication, 286 patients with open-angle glaucoma or ocular hypertension were randomly assigned in a 2:1 ratio to receive 0.5% timolol GS in both eyes once daily or 0.5% timolol solution in both eyes twice daily. All patients received a morning (9 AM) and evening (9 PM) dose. For patients in the timolol GS group, the evening dose consisted of a vehicle only, whereas for patients in the timolol solution group, both doses consisted of active drug. Intraocular pressure (IOP) was measured at trough (before morning instillation) and peak (2 hours after instillation) at follow-up examinations at weeks 2, 4, 8, 12, and 24. Adverse events were monitored using patient reports. RESULTS: Of the 286 patients randomized, 191 received timolol GS and 95 received timolol solution. Ninety-three percent of patients (265/286) completed the study. At the end of the treatment interval (week 24), the mean decrease in IOP at trough ranged from 5.6 to 5.9 mm Hg in the timolol GS group and from 6.3 to 6.6 mm Hg in the timolol solution group. Similar efficacy was observed at 11 AM (peak). At week 24, the difference in mean IOP between treatments was -0.61 mm Hg (95% CI -1.44 to 0.22) at trough and -0.79 mm Hg (95% CI -1.77 to 0.20) at peak, indicating no significant difference between the 2 timolol formulations. The number of reports of blurred vision and tearing was significantly higher in the timolol GS group than in the timolol solution group (P = 0.04), whereas burning/stinging was reported more frequently in the timolol solution group than in the timolol GS group (P = 0.04). At week 12, the decrease in mean heart rate at trough (hour 0) was significantly less for patients in the timolol GS group than for those in the timolol solution group (-1.1 vs -4.2 bpm; P = 0.024). At week 24 (hour 0), the decrease in mean heart rate was less for patients treated with timolol GS by 2.5 bpm (P = 0.051). The heart rate data at peak (hour 2) was similar to that observed at trough at week 12 (-2.7 vs -5.7 bpm; P = 0.006) and week 24 (-3.1 vs -4.7 bpm; P = 0.063). The mean change in blood pressure was not significantly different between treatments. There were no clinically significant differences between the groups in visual acuity, biomicroscopy and ophthalmoscopy results, or visual fields. CONCLUSIONS: Timolol 0.5% GS administered once daily was shown to be as effective in lowering IOP as the equivalent concentration of timolol 0.5% solution administered twice daily in patients with ocular hypertension or open-angle glaucoma.

Adult↗
PubMed2001

Plasma timolol concentrations of timolol maleate: timolol gel-forming solution (TIMOPTIC-XE) once daily versus timolol maleate ophthalmic solution twice daily.

PURPOSE: The objective of this study was to compare plasma concentrations of timolol following multiple dosing of the therapeutic regimens of timolol maleate ophthalmic gel-forming solution (Timolol GS; TIMOPTIC-XE) and timolol maleate ophthalmic solution. Timolol maleate ophthalmic gel-forming solution is also referred to as Timolol GS, i.e. gel-forming solution. METHODS: This was a masked observer, two-period crossover study in six normal male subjects randomized to receive either Timolol GS, 0.5% (TIMOPTIC-XE,) once daily (0530 hours) or timolol maleate ophthalmic solution (0.5% TIMOPTIC) twice daily (0530 and 1730 hours) for 8 days, in both eyes. On Day 8, a blood sample was obtained prior to treatment, as well as 1, 2, 4, 8, 10, 12, 13, 14, 16, and 24 hours following the morning instillation. After a 7-day inter-period washout interval, subjects received the opposite treatment. RESULTS: Timolol GS (TIMOPTIC-XE): Plasma concentrations of timolol rarely exceeded 0.375 ng/ml (the lower limit of assay quantification). For all subjects, peak plasma concentrations of timolol averaged <0.3 ng/ml within 4 hours after the last dose. The highest single observation was 0.49 ng/ml in one subject (at hour 2). Timolol solution: For all subjects, peak plasma concentrations of timolol averaged about 0.5 ng/ml and 0.3 ng/ml within 4 hours following the first and second dose, respectively, on Day 8. The highest single observation was 0.95 ng/ml in one subject (at hour 2). CONCLUSIONS: The data suggest that there is less systemic exposure to timolol following once-daily therapy with Timolol GS 0.5% compared with twice daily therapy with timolol maleate ophthalmic solution 0.5%.

Absorption↗
PubMed2001

'Reverse gear' cellular movement mediated by chemokines.

We sought to model the mechanism by which leucocytes may be actively repulsed by a beta-chemokine signal. This model is used to interpret an apparent paradox in chemokine biology, whereby high levels of a T-cell chemoattractant, stromal cell derived factor-1 (SDF-1), are present in bone marrow and thymic tissues despite a paucity of mature T lymphocytes in these areas. We postulate the differential involvement in cell migration of the two binding sites on SDF-1 for its sole receptor, CXCR4, depending on whether high or low concentrations of SDF-1 are encountered by the cell. Site choice would be mediated by divergent affinities of the two binding interactions. We also propose differential signalling following SDF-1/CXCR4 interactions on the plasma membrane versus ligand/receptor complexes in endocytic vesicles. Preliminary data showing divergent susceptibility to kinase inhibitors depending on whether a cell is attracted to or repulsed by SDF-1, are consistent with this model. In terms of physical movement toward or away from a chemokine gradient, we compare the cycling of surface receptors during migration to the caterpillar drive of a tractor, which can change direction simply by altering the direction of rotation of its threads. Finally, the potential clinical implications of concentration-dependent, chemokine-based cell attraction and repulsion are discussed.

Animals↗
PubMed2001

Adhering to antiretroviral therapies.

In 1999, the AIDS program conducted a survey of more than 1,000 patients in Sao Paulo [Brazil]. It found that 69 percent achieved 80 percent adherence, which means they took their medicine properly 80 percent of the time. According to Margaret Chesney, a professor of medicine at the University of California at San Francisco who studies behavioral factors in AIDS treatment, this rate is not sufficient to control the virus - which can kill even people who take their medicine faithfully - but it is no different from adherence rates in the United States. A study in San Diego showed that 72 percent of patients took their medicine 80 percent of the time.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Facial wasting.

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Facies↗